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Risks of Obesity and the Obesity EpidemicLouis J Aronne MD FACP

Professor of Clinical Medicine Weill Cornell Medical College

Adjunct Associate Professor of Clinical Medicine Columbia University College of Physicians and Surgeons

Director Comprehensive Weight Control Program

New York-Presbyterian HospitalWeill Cornell Medical Center New York NY

As faculty of Weill Cornell Medical College we are committed to providing transparency for any and all external relationships prior to giving an academic presentation

I am a consultant speaker advisor or receive research support fromBMS

Arena Aspire BariatricsMyos

GI Dynamics Novo NordiskOrexigenVivusZafgen

I may discuss off-label use of medications

Disclosure Page

Weight Management is Moving into the Workplace and Mainstream of Healthcare

bull Screening for Obesity in Adults The US Preventive Services Task Force recommends that clinicians screen all adult patients for obesity and offer intensive counseling and behavioral interventions to promote sustained weight loss for obese adults (Grade B recommendation)

bull Medicare now covers behavioral treatment of obesity

US Preventive Services Task Force Ann Intern Med 2003139930‐932

US Preventative Services Task Force

bull The USPSTF found that the most effective interventions were comprehensive and were of high intensity (12 to 26 sessions in a year)

bull Multiple behavioral management activities such as group sessions individual sessions setting weight-loss goals improving diet or nutrition physical activity sessions addressing barriers to change active use of self-monitoring and strategizing how to maintain lifestyle changes

bull A weight loss of 5 is considered clinically important by the US Food and Drug Administration (FDA)

httpwwwuspreventiveservicestaskforceorguspstf11obeseadultobesershtmAnn Intern Med 201226 June

A Proposal from CMS about Coverage for Intensive Behavioral Therapy for Obesity

bull For obese Medicare beneficiaries whose counseling is furnished by a qualified primary care physician or other primary care practitioner and in a primary care setting the CMS proposes coverage of

bull One face-to-face visit every week for the first month bull One face-to-face visit every other week for months 2 to 6 and bull One face-to-face visit every month for months 7 to 12bull At the 6-month visit a reassessment of obesity and a

determination of the amount of weight loss should be performed To be eligible for face-to-face visits occurring once a month for an additional 6 months beneficiaries must have achieved a reduction in weight of at least 3 kg during the course of the first 6 months of intensive therapy

httpscmsgov (2011)

Sturm R Pub Hlth 2007 Jul121492-496

Biggest Increases in Clinically Severe Obesity US 1987‐2005

BMI gt30

BMI gt50larr

larr

larr

BMI gt40

7

Relationship Between BMI and Risk of Type 2 Diabetes

Chan J et al Diabetes Care 199417961Colditz G et al Ann Intern Med 1995122481

Age

-Adj

uste

d R

elat

ive

Ris

k

Body Mass Index (kgm2)

Women

Men

lt22 lt23 23ndash239

24ndash249

25ndash269

27ndash289

29ndash309

31ndash329

33ndash349

35+

102910

4310

5015

8122

158

44

276

403

540

932

67 116

213

421

100

75

50

25

0

Why Should I Treat Obesity

Medical Complications of Obesity Almost every organ system is affected

Phlebitisvenous stasis

Coronary heart disease

Pulmonary diseaseasthmaobstructive sleep apneahypoventilation syndrome

Gall bladder diseaseReproductive abnormalitiesabnormal mensesinfertilitypolycystic ovarian syndrome

Gout

Stroke

Diabetes

Osteoarthritis

Cancerbreast uterus cervixcolon esophagus pancreaskidney prostate

Nonalcoholic fatty liver diseasesteatosissteatohepatitiscirrhosis Hypertension

Dyslipidemia

Cataracts

Skin

Idiopathic intracranial hypertension

Severe pancreatitis

Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and

disease

Lactate Angiotensinogen

Leptin

Adipsin (Complement D)

TNF- α

FFAFat Stores

Lipoprotein Lipase

Plasminogen Activator Inhibitor 1

(PAI-1)

Resistin

Adiponectin

DM=diabetes mellitus FFA=free fatty acid PAI-1=plasminogen activator inhibitor-1 TNFα=tumor necrosis factor alpha IL-6=interleukin 6

Slide copy2007Louis J Aronne MD after Dr G Bray

Insulin

IL - 6

Estrogen

Hypertension

Thrombosis

Inflammation

Type 2 DM

DyslipidemiaType 2 DM

Arthritis

ASCVD

Asthma

C-C L2

Waist circumference

Blood pressure

Blood glucose

Triglycerides

HDL-cholesterol

LDL-cholesterol

Insulin resistance

Thrombotic risk

Current Therapies Often Address Individual Risk Factors Cardiometabolic risk

NCEP ATP IIIdefinitionof themetabolicsyndrome

Antihypertensives

Oral antidiabetic agents

Antiplatelet agents

Lipid modifiers

Insulin sensitizers

Jupiter Trial Rosuvastatin reduced incidence of CV endpoints but increased HbA1cand reported cases of T2DM (plt01)

Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and

disease

Lactate Angiotensinogen

Leptin

Adipsin (Complement D)

TNF- α

FFAFat Stores

Lipoprotein Lipase

Plasminogen Activator Inhibitor 1

(PAI-1)

Resistin

Adiponectin

DM=diabetes mellitus FFA=free fatty acid PAI-1=plasminogen activator inhibitor-1 TNFα=tumor necrosis factor alpha IL-6=interleukin 6

Slide copy2007Louis J Aronne MD after Dr G Bray

Insulin

IL - 6

Estrogen

Hypertension

Thrombosis

Inflammation

Type 2 DM

DyslipidemiaType 2 DM

Arthritis

ASCVD

Asthma

C-C L2

Adiponectin Anti-atherogenicantidiabeticdarr darr foam cells darr vascular remodelling

uarr insulin sensitivity darr hepatic glucose output

IL-6uarr

Pro-atherogenicpro-diabeticuarr vascular inflammation darr insulin signalling

TNFαuarr

Pro-atherogenicpro-diabeticdarr insulin sensitivity in adipocytes (paracrine)

PAI-1uarr

Pro-atherogenicuarr atherothrombotic risk

IAA intra-abdominal adiposityMarette A Curr Opin Clin Nutr Metab Care 20025377-83

Are You Treating These Drivers of Cardiometabolic Risk Should You Treat The Underlying Cause

Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors

Risk FactorsPhenTPMMid

p-valuePhenTPMTop

p-value

CRP lt0001 lt0001Fibrinogen lt005 lt005Adiponectin lt00001 lt00001

p-values represent comparisons to placebo

ITT-LOCF Placebo Comparisons

Gadde KM et al Lancet 2011377(9774)1341-52

Mid = 75 mg46 mgTop = 15 mg92 mg

In My Opinion The Winds of Change are Blowing in the Treatment of Chronic

Diseasesbull ACCORD was stopped because of increased

mortality in the tight control group 28 of whom gained gt 10kg compared to 14 in control^

bull Bariatric surgery trials show gt 80 reduction in diabetes mortality with weight loss

bull I believe we are in the midst of a shift from ldquoGlucocentricrdquo to ldquoWeight-Centricrdquo Management of T 2 DM

^ NEJM 3582545-2559 Adams TD et al N Engl J Med 2007357(8)753-761

-34-48-48-88-59-29+73

Adams TD et al N Engl J Med 2007357(8)753-761

Bariatric Surgery Reduces Overall Mortality Diabetes Mortality by 88

Matched SubjectsSurgery Group (n=7925)

Co(n=

ntrol Group7925)

NoNo10000 person-yr No

No10000 person-yr

All causes of death 213 376 321 571All deaths caused by disease 150 265 285 507Cardiovascular diseases 55 97 104 185Diabetes 2 04 19 34Cancer 31 55 73 133Other diseases 62 11 89 155All non-disease causes 63 111 36 64Accident unrelated to drugs 21 37 17 30Poisoning of undetermined intent 9 16 4 07Suicide 15 26 5 09Other nondisease cause 18 32 10 18

CC-18

Health Care Costs Attributable to ObesityEstimates of what various conditions add to health-care service costs over a 12-month period

$395

$230

$225

$150

$125

$0 $100 $200 $300 $400 $500

Obesity

Smoking

20 years aging

Problem drinking

Overweight

Sturm R Health Aff (Millwood) 2002 Mar-Apr21(2)245-53 Table Wall Street Journal 3132002

Obesity increased medication costs 77inpatient and outpatient costs 36

What-if scenarios (The Lancet forthcoming)

Redrawn from Hamman RF et al Diabetes Care 2006292102‐2107

Change in Weight from Baseline (kg)0‐10 ‐5 +5In

cide

nce Ra

te per 100

Person‐Years

10

20

15

5

0

How Much Weight Loss Is Needed to Prevent T2DMndashNot Very Much The DPP Experience

In the Da Qing Study 6-year Intervention Led to Lower Incidence of Type 2 Diabetes 14 Years Later

n=530 overweight Chinese men and women with IGT mean BMI=26

17

0

20

40

60

80

100

2 4 6 8 10 12 14 16 18 20Years of follow‐up

6‐year intervention hazard ratio = 049 (95 CI 033ndash073)20‐year follow‐up hazard ratio = 057 (95 CI 041ndash081)

Cumulative Incide

nce of Type 2 Diabe

tes ()

0

Lifestyle interventionControl

Treatment Follow‐up

Li et al Lancet 20083711783ndash9

Pharmacotherapy for Weight LossLouis J Aronne MD FACP

Professor of Clinical Medicine Weill Cornell Medical College

Adjunct Associate Professor of Clinical Medicine Columbia University College of Physicians and Surgeons

Director Comprehensive Weight Control Program

New York-Presbyterian HospitalWeill Cornell Medical Center New York NY

As faculty of Weill Cornell Medical College we are committed to providing transparency for any and all external relationships prior to giving an academic presentation

I am a consultant speaker advisor or receive research support fromBMS

Arena Aspire BariatricsMyos

GI Dynamics Novo NordiskOrexigenVivusZafgen

I may discuss off-label use of medications

Disclosure Page

uarrFood intakedarr energy expenditure

darrfood intake uarrenergy expenditure

Topiramate

Naltrexone

LorcaserinPramlintideGLP-1Leptin

BupropionPhentermine

New Compounds andCombination Interventions

c Louis J Aronne MDScience Feb 7 2003 Vol 299Illustration by Katharine Sutliff

Phentermine and TopiramateExtended-Release

bull Mechanism of actionndash Phentermine Sympathomimetic amine - releaserndash Topiramate Gabaergicglutamate modulation and carbonic

anhydrase inhibitionbull February 2012 FDA advisory committee votes 20-2 for

approval bull FDA approved July 2012

ndash Schedule IVndash Pregnancy Category X = REMS

Topiramate monotherapy exposure in pregnancy associated with 2- to 5-fold increased prevalence of oral clefts

bull 4 doses Titrate upbull Available only by mail orderbull Covered through Medco Express Scripts

Phentermine and TopiramateExtended-Release

bull Dose titrationndash Once dailyndash Start treatment with phentermine 375 mgtopiramate

23 mg extended-release daily for 14 daysndash After 14 days increase to the recommended dose of

phentermine 75 mgtopiramate 46 mg extended-release once daily

ndash May titrate upwards if needed to phen 15 top 92 mg strength

EQUIP amp CONQUER Discontinuation RateDue to AEs in All Doses Studied

Placebo Low Mid Full

Number of patients 1508 241 498 1507Discontinuation due to AEs 9 12 12 18Blurred vision 05 21 08 07Headache 07 17 02 09Insomnia 04 00 04 17Depression 02 00 08 14Tingling 00 04 10 12Irritability 01 08 08 12Anxiety 03 00 02 11Dizziness 02 04 12 08

Includes adverse events (AEs) by dose for EQUIP amp CONQUER which lead to discontinuation in gt 1 of patientsPress release Sept 9 2009 Available at httpirvivuscomreleasedetailcfmReleaseID=420114Accessed April 27 2010

PhenTPMMid

-104

Phentermine and Topiramate SEQUELWeight Loss Over Time

Garvey WT Ryan DH Look M Gadde KM Am J Clin Nutr 201295(2)297-308

Placebo-25

Plt00001 v placebo

Weight Loss

Week

Total Population

0

-2

-4

-6

-8

-10

-12

-14

-16

0 12 24 36 48 60 72 84 96 108

Weight Loss ITT-LOCF

PhenTPMTop

-114

Mid = 75 mg46 mgTop = 15 mg92 mg

CONQUER Significant Improvement in Cardiovascular Risk Factors

(LS Mean Wt Loss)

QNEXAMid(78)

P valueQNEXATop

(98) P value

Waist Circumference (cm) ‐52 lt00001 ‐68 lt00001

Systolic BP (mmHg) ‐23 00008 ‐32 lt00001

Diastolic BP (mmHg) ‐07 NS ‐11 00031

Triglycerides ( ∆) ‐133 lt00001 ‐153 lt00001

Total Cholesterol ( ∆) ‐16 00345 ‐30 lt00001

LDL ( ∆) 04 NS ‐28 00069

HDL ( ∆) 40 lt00001 56 lt00001

P values represent comparisons to placebo NS= non‐significant

ITT‐LOCF Placebo ComparisonsTotal Study Population

Davidson MH et al Am J Cardiol 2013 Jan 29 pii S0002‐9149(12)02641‐0 doi 101016jamjcard201212038

Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors

Risk FactorsPhenTPMMid

p-valuePhenTPMTop

p-value

CRP lt0001 lt0001Fibrinogen lt005 lt005Adiponectin lt00001 lt00001

p-values represent comparisons to placebo

ITT-LOCF Placebo Comparisons

Gadde KM et al Lancet 2011377(9774)1341-52

Mid = 75 mg46 mgTop = 15 mg92 mg

Lorcaserin

bull Selective 5‐HT2C receptor agonist designed to promote weight loss

bull Schedule IV ndash Expected soonbull Indication weight loss and maintenance of

weight loss in patients with BMI gt30 kgm2 or BMI gt27 kgm2 + weight-related comorbidcondition(s)

bull Dose - 10 mg BIDbull Most common side effects headache nausea

dizziness dry mouth

BLOOM Study Body Weight Over Years 1 and 2

Smith SR et al N Engl J Med 2010363245-256 Study Week0 8 16 24 32 40 48 56 64 72 80 88 96 104

Bod

y W

eigh

t (kg

)

102

100

98

96

94

92

90

0

Year 1

Placebo in year 1 and 2 (n = 684)Lorcaserin in year 1 placebo in year 2 (n = 275)Lorcaserin in year 1 and 2 (n = 564)

Year 2

Endpoint Lorcaserin Placebo P valueWaist circumference (cm) minus68plusmn02 minus39plusmn02 lt001BMI (kgm2) minus209plusmn006 minus078plusmn005 lt001SBPDBP (mm Hg) minus14plusmn03minus11plusmn02 minus08plusmn03minus06plusmn02 0401Cholesterol ( ∆)Total LDLHDL

minus090plusmn033287plusmn056005plusmn033

057plusmn034403plusmn058minus021plusmn034

001

049

72Triglycerides minus615plusmn103 minus014plusmn099 lt001SafetyHR (beatsmin)PASP (mm Hg)Beck depression II score

minus20plusmn03minus092plusmn023minus11plusmn01

minus16plusmn04 minus023plusmn023 minus09plusmn01

0499014026

BLOOM StudyKey Secondary Endpoints

Smith SR et al N Engl J Med 2010363245-256

BLOOM-DMChange in Glycemic Parameters

P lt001 P lt05 LS mean change plusmn SEMOrsquoNeil PM et al Obesity 201220(7)1426-36 httpwwwnaturecomdoifinder101038oby201266

00

-05

-10

-150 12 24 36 52

Cha

nge

from

bas

elin

e (

)

A1c

Study week

0

-10

-20

-30

-400 12 24 52

Cha

nge

from

bas

elin

e m

gdl

)

Fasting plasma glucose

Study week

Lorcaserin 10 mg BID Lorcaserin 10 mg Placebo

Lorcaserin Adverse Events Reported by 5 or More in Any Group in Year 1

55

N () Lorcaserin(N = 1593)

Placebo(N = 1584)

Headache 287 (180) 175 (110)

Dizziness 130 (82) 60 (38)

Nausea 119 (75) 85 (54)

Constipation 106 (67) 64 (40)

Fatigue 95 (60) 48 (30)

Dry mouth 83 (52) 37 (23)

Smith SR et al ADA 2009 Late‐Breaking Abstract 96

LorcaserinNo Increase in Rate of Valvulopathy

Smith SR et al N Engl J Med 2010363245-256

10

8

6

4

2

024 52 76 104

1351714

9

19

3421Patie

nts

()

Week

Lorcaserin in yr 1 and 2

Lorcaserin in yr 1 Placebo in yr 2

Placebo in yr 1 and 2

Phase III Study Outcomes Compared

Buproprion SR (360 mgd) Naltrexone SR (32 mgd)

Lorcaserin(20 mgd)

Phentermine Topiramate CR

COR1 COR-I2 COR-II3 NB3043 BLOOM4 BLOSSOM5 EQUIP CONQUER

Number of patients (ITT-LOCF)

793 obese 1453 obese

1281 obese

502 type II diabetes

3182 obese 4008 obese

1230 obese BMI 44

2448 comorbidBMI 36

Mean change compared with placebo from base

93 vs5 1c

61a vs13c

64a vs12

50 a vs12c

58 vs22c

48 vs28c

11 Fullbvs 16

104 Fullb 84 Midb

vs 18

51 Lowb vs16c

Categorical change 5 compared with placebo from base

56 vs43

48a vs164

563a

vs 171445a vs189

475b

vs 203472b vs25

67 Fullb 45 Lowb vs17

70 Fullb 62 Midb

vs 21

Phenterminetopiramate doses Low 375 mg phentermine23 mg topiramate Mid 75 mg phentermine 46 mg topiramate Full 15 mg phentermine 92 mg topiramateITT-LOCF intent-to-treat last observation carried forwardData not available aP lt 001 vs placebo bP lt 0001 vs placebo

Obesity Treatments in Late Development

Kushner RF Expert Opin Pharmacother 200891339-1350

Agents ActionBupropionNaltrexone

bull Dopaminenoradrenaline reuptake inhibitorbull Opioid receptor antagonist

Liraglutide bull GLP-1 agonist

BupropionNaltrexone

bull Mechanism of Actionndash Bupropion - Dopaminenoradrenaline reuptake inhibitorndash Naltrexone- Opioid receptor antagonist

bull Was approved by FDA committee but FDA did not approve until a CV outcome study is performed 2nd concerns about BP and P in some patients

bull The Light Study is now underway and reported to be enrolling well under PI Dr Nissen

bull BupropionNaltrexone will have first completed CV outcome study

Buproprion ndash Naltrexone

Greenway FL et al Lancet 2010376(9741)595-605

0

-2

-4

-6

-8

-100 4 8 12 16 20 24 28 32 36 40 44 48 52 56

Weeks

Wei

ght c

hang

e fro

m b

asel

ine

()

Placebo

Naltrexone 16 mg plus bupropion

Naltrexone 32 mg plus bupropion

Liraglutide for Weight Loss in Patients with Type 2 Diabetes

bull GLP-1 analog approved for treatment of type 2 diabetes

bull Anorectic effect mediated both by the activation of GLP-1 receptor expressed on vagal afferents and by the GLP-1R activation in CNS

bull Affects visceral fat adiposity appetite food preference and cardiovascular biomarkers in patients with type 2 diabetes

Inoue K et al Cardiovasc Diabetol 2011 10109 doi1011861475-2840-10-109

Liraglutide Weight Loss Over 2 Years ITT Observed Means

Astrup A et al Int J Obes (Lond) 201236(6)843-54

FromScreening

-94 kg

-67 kg-88 kg

-99 kg-94 kg

-103 kg

ITT intention to treat

Phase III Study Outcomes Compared

Buproprion SR (360 mgd) Naltrexone SR (32 mgd)

Lorcaserin(20 mgd)

Phentermine Topiramate CR

COR1 COR-I2 COR-II3 NB3043 BLOOM4 BLOSSOM5 EQUIP CONQUER

Number of patients (ITT-LOCF)

793 obese 1453 obese

1281 obese

502 type II diabetes

3182 obese 4008 obese

1230 obese BMI 44

2448 comorbidBMI 36

Mean change compared with placebo from base

93 vs5 1c

61a vs13c

64a vs12

50 a vs12c

58 vs22c

48 vs28c

11 Fullbvs 16

104 Fullb 84 Midb

vs 18

51 Lowb vs16c

Categorical change 5 compared with placebo from base

56 vs43

48a vs164

563a

vs 171445a vs189

475b

vs 203472b vs25

67 Fullb 45 Lowb vs17

70 Fullb 62 Midb

vs 21

Phenterminetopiramate doses Low 375 mg phentermine23 mg topiramate Mid 75 mg phentermine 46 mg topiramate Full 15 mg phentermine 92 mg topiramateITT-LOCF intent-to-treat last observation carried forwardData not available aP lt 001 vs placebo bP lt 0001 vs placebo

Treatment Gap in theManagement of Obesity

Physicians Need Effective Pharmacotherapies That Will Reduce Weight Significantly and Reduce Weight-related Comorbidities

0 5 10 15 20 25 30 35

Diet and Lifestyle Lap Band Gastric Bypass

TreatmentGap

What will fill the gap

Too risky for many peopleNot effective enoughfor many people

Treatment Gap in theManagement of Obesity

0 5 10 15 20 25 30 35

Diet and Lifestyle Lap Band Gastric Bypass

TreatmentGap

Too risky for many peopleNot effective enoughfor many people Pharmacotherapy

Less invasive procedures

Physicians Need Effective Pharmacotherapies That Will Reduce Weight Significantly and Reduce Weight-related Comorbidities

What will fill the gap

  • Slide Number 1
  • Slide Number 2
  • Weight Management is Moving into the Workplace and Mainstream of Healthcare
  • US Preventative Services Task Force
  • A Proposal from CMS about Coverage for Intensive Behavioral Therapy for Obesity
  • Slide Number 6
  • Biggest Increases in Clinically Severe Obesity US 1987-2005
  • Relationship Between BMI and Risk of Type 2 Diabetes
  • Slide Number 9
  • Medical Complications of Obesity Almost every organ system is affected
  • Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and disease
  • Current Therapies Often Address Individual Risk Factors Cardiometabolic risk
  • Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and disease
  • Are You Treating These Drivers of Cardiometabolic Risk Should You Treat The Underlying Cause
  • Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors
  • In My Opinion The Winds of Change are Blowing in the Treatment of Chronic Diseases
  • Bariatric Surgery Reduces Overall Mortality Diabetes Mortality by 88
  • Health Care Costs Attributable to ObesityEstimates of what various conditions add to health-care service costs over a 12-month period
  • What-if scenarios (The Lancet forthcoming)
  • How Much Weight Loss Is Needed to Prevent T2DMndashNot Very Much The DPP Experience
  • In the Da Qing Study 6-year Intervention Led to Lower Incidence of Type 2 Diabetes 14 Years Later
  • Slide Number 22
  • Slide Number 23
  • New Compounds andCombination Interventions
  • Phentermine and Topiramate Extended-Release
  • Phentermine and Topiramate Extended-Release
  • EQUIP amp CONQUER Discontinuation RateDue to AEs in All Doses Studied
  • Phentermine and Topiramate SEQUELWeight Loss Over Time
  • CONQUER Significant Improvement in Cardiovascular Risk Factors
  • Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors
  • Lorcaserin
  • BLOOM Study Body Weight Over Years 1 and 2
  • BLOOM StudyKey Secondary Endpoints
  • BLOOM-DMChange in Glycemic Parameters
  • Lorcaserin Adverse Events Reported by 5 or More in Any Group in Year 1
  • LorcaserinNo Increase in Rate of Valvulopathy
  • Phase III Study Outcomes Compared
  • Obesity Treatments in Late Development
  • BupropionNaltrexone
  • Buproprion ndash Naltrexone
  • Liraglutide for Weight Loss in Patients with Type 2 Diabetes
  • Liraglutide Weight Loss Over 2 Years ITT Observed Means
  • Phase III Study Outcomes Compared
  • Treatment Gap in theManagement of Obesity
  • Treatment Gap in theManagement of Obesity

    As faculty of Weill Cornell Medical College we are committed to providing transparency for any and all external relationships prior to giving an academic presentation

    I am a consultant speaker advisor or receive research support fromBMS

    Arena Aspire BariatricsMyos

    GI Dynamics Novo NordiskOrexigenVivusZafgen

    I may discuss off-label use of medications

    Disclosure Page

    Weight Management is Moving into the Workplace and Mainstream of Healthcare

    bull Screening for Obesity in Adults The US Preventive Services Task Force recommends that clinicians screen all adult patients for obesity and offer intensive counseling and behavioral interventions to promote sustained weight loss for obese adults (Grade B recommendation)

    bull Medicare now covers behavioral treatment of obesity

    US Preventive Services Task Force Ann Intern Med 2003139930‐932

    US Preventative Services Task Force

    bull The USPSTF found that the most effective interventions were comprehensive and were of high intensity (12 to 26 sessions in a year)

    bull Multiple behavioral management activities such as group sessions individual sessions setting weight-loss goals improving diet or nutrition physical activity sessions addressing barriers to change active use of self-monitoring and strategizing how to maintain lifestyle changes

    bull A weight loss of 5 is considered clinically important by the US Food and Drug Administration (FDA)

    httpwwwuspreventiveservicestaskforceorguspstf11obeseadultobesershtmAnn Intern Med 201226 June

    A Proposal from CMS about Coverage for Intensive Behavioral Therapy for Obesity

    bull For obese Medicare beneficiaries whose counseling is furnished by a qualified primary care physician or other primary care practitioner and in a primary care setting the CMS proposes coverage of

    bull One face-to-face visit every week for the first month bull One face-to-face visit every other week for months 2 to 6 and bull One face-to-face visit every month for months 7 to 12bull At the 6-month visit a reassessment of obesity and a

    determination of the amount of weight loss should be performed To be eligible for face-to-face visits occurring once a month for an additional 6 months beneficiaries must have achieved a reduction in weight of at least 3 kg during the course of the first 6 months of intensive therapy

    httpscmsgov (2011)

    Sturm R Pub Hlth 2007 Jul121492-496

    Biggest Increases in Clinically Severe Obesity US 1987‐2005

    BMI gt30

    BMI gt50larr

    larr

    larr

    BMI gt40

    7

    Relationship Between BMI and Risk of Type 2 Diabetes

    Chan J et al Diabetes Care 199417961Colditz G et al Ann Intern Med 1995122481

    Age

    -Adj

    uste

    d R

    elat

    ive

    Ris

    k

    Body Mass Index (kgm2)

    Women

    Men

    lt22 lt23 23ndash239

    24ndash249

    25ndash269

    27ndash289

    29ndash309

    31ndash329

    33ndash349

    35+

    102910

    4310

    5015

    8122

    158

    44

    276

    403

    540

    932

    67 116

    213

    421

    100

    75

    50

    25

    0

    Why Should I Treat Obesity

    Medical Complications of Obesity Almost every organ system is affected

    Phlebitisvenous stasis

    Coronary heart disease

    Pulmonary diseaseasthmaobstructive sleep apneahypoventilation syndrome

    Gall bladder diseaseReproductive abnormalitiesabnormal mensesinfertilitypolycystic ovarian syndrome

    Gout

    Stroke

    Diabetes

    Osteoarthritis

    Cancerbreast uterus cervixcolon esophagus pancreaskidney prostate

    Nonalcoholic fatty liver diseasesteatosissteatohepatitiscirrhosis Hypertension

    Dyslipidemia

    Cataracts

    Skin

    Idiopathic intracranial hypertension

    Severe pancreatitis

    Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and

    disease

    Lactate Angiotensinogen

    Leptin

    Adipsin (Complement D)

    TNF- α

    FFAFat Stores

    Lipoprotein Lipase

    Plasminogen Activator Inhibitor 1

    (PAI-1)

    Resistin

    Adiponectin

    DM=diabetes mellitus FFA=free fatty acid PAI-1=plasminogen activator inhibitor-1 TNFα=tumor necrosis factor alpha IL-6=interleukin 6

    Slide copy2007Louis J Aronne MD after Dr G Bray

    Insulin

    IL - 6

    Estrogen

    Hypertension

    Thrombosis

    Inflammation

    Type 2 DM

    DyslipidemiaType 2 DM

    Arthritis

    ASCVD

    Asthma

    C-C L2

    Waist circumference

    Blood pressure

    Blood glucose

    Triglycerides

    HDL-cholesterol

    LDL-cholesterol

    Insulin resistance

    Thrombotic risk

    Current Therapies Often Address Individual Risk Factors Cardiometabolic risk

    NCEP ATP IIIdefinitionof themetabolicsyndrome

    Antihypertensives

    Oral antidiabetic agents

    Antiplatelet agents

    Lipid modifiers

    Insulin sensitizers

    Jupiter Trial Rosuvastatin reduced incidence of CV endpoints but increased HbA1cand reported cases of T2DM (plt01)

    Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and

    disease

    Lactate Angiotensinogen

    Leptin

    Adipsin (Complement D)

    TNF- α

    FFAFat Stores

    Lipoprotein Lipase

    Plasminogen Activator Inhibitor 1

    (PAI-1)

    Resistin

    Adiponectin

    DM=diabetes mellitus FFA=free fatty acid PAI-1=plasminogen activator inhibitor-1 TNFα=tumor necrosis factor alpha IL-6=interleukin 6

    Slide copy2007Louis J Aronne MD after Dr G Bray

    Insulin

    IL - 6

    Estrogen

    Hypertension

    Thrombosis

    Inflammation

    Type 2 DM

    DyslipidemiaType 2 DM

    Arthritis

    ASCVD

    Asthma

    C-C L2

    Adiponectin Anti-atherogenicantidiabeticdarr darr foam cells darr vascular remodelling

    uarr insulin sensitivity darr hepatic glucose output

    IL-6uarr

    Pro-atherogenicpro-diabeticuarr vascular inflammation darr insulin signalling

    TNFαuarr

    Pro-atherogenicpro-diabeticdarr insulin sensitivity in adipocytes (paracrine)

    PAI-1uarr

    Pro-atherogenicuarr atherothrombotic risk

    IAA intra-abdominal adiposityMarette A Curr Opin Clin Nutr Metab Care 20025377-83

    Are You Treating These Drivers of Cardiometabolic Risk Should You Treat The Underlying Cause

    Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors

    Risk FactorsPhenTPMMid

    p-valuePhenTPMTop

    p-value

    CRP lt0001 lt0001Fibrinogen lt005 lt005Adiponectin lt00001 lt00001

    p-values represent comparisons to placebo

    ITT-LOCF Placebo Comparisons

    Gadde KM et al Lancet 2011377(9774)1341-52

    Mid = 75 mg46 mgTop = 15 mg92 mg

    In My Opinion The Winds of Change are Blowing in the Treatment of Chronic

    Diseasesbull ACCORD was stopped because of increased

    mortality in the tight control group 28 of whom gained gt 10kg compared to 14 in control^

    bull Bariatric surgery trials show gt 80 reduction in diabetes mortality with weight loss

    bull I believe we are in the midst of a shift from ldquoGlucocentricrdquo to ldquoWeight-Centricrdquo Management of T 2 DM

    ^ NEJM 3582545-2559 Adams TD et al N Engl J Med 2007357(8)753-761

    -34-48-48-88-59-29+73

    Adams TD et al N Engl J Med 2007357(8)753-761

    Bariatric Surgery Reduces Overall Mortality Diabetes Mortality by 88

    Matched SubjectsSurgery Group (n=7925)

    Co(n=

    ntrol Group7925)

    NoNo10000 person-yr No

    No10000 person-yr

    All causes of death 213 376 321 571All deaths caused by disease 150 265 285 507Cardiovascular diseases 55 97 104 185Diabetes 2 04 19 34Cancer 31 55 73 133Other diseases 62 11 89 155All non-disease causes 63 111 36 64Accident unrelated to drugs 21 37 17 30Poisoning of undetermined intent 9 16 4 07Suicide 15 26 5 09Other nondisease cause 18 32 10 18

    CC-18

    Health Care Costs Attributable to ObesityEstimates of what various conditions add to health-care service costs over a 12-month period

    $395

    $230

    $225

    $150

    $125

    $0 $100 $200 $300 $400 $500

    Obesity

    Smoking

    20 years aging

    Problem drinking

    Overweight

    Sturm R Health Aff (Millwood) 2002 Mar-Apr21(2)245-53 Table Wall Street Journal 3132002

    Obesity increased medication costs 77inpatient and outpatient costs 36

    What-if scenarios (The Lancet forthcoming)

    Redrawn from Hamman RF et al Diabetes Care 2006292102‐2107

    Change in Weight from Baseline (kg)0‐10 ‐5 +5In

    cide

    nce Ra

    te per 100

    Person‐Years

    10

    20

    15

    5

    0

    How Much Weight Loss Is Needed to Prevent T2DMndashNot Very Much The DPP Experience

    In the Da Qing Study 6-year Intervention Led to Lower Incidence of Type 2 Diabetes 14 Years Later

    n=530 overweight Chinese men and women with IGT mean BMI=26

    17

    0

    20

    40

    60

    80

    100

    2 4 6 8 10 12 14 16 18 20Years of follow‐up

    6‐year intervention hazard ratio = 049 (95 CI 033ndash073)20‐year follow‐up hazard ratio = 057 (95 CI 041ndash081)

    Cumulative Incide

    nce of Type 2 Diabe

    tes ()

    0

    Lifestyle interventionControl

    Treatment Follow‐up

    Li et al Lancet 20083711783ndash9

    Pharmacotherapy for Weight LossLouis J Aronne MD FACP

    Professor of Clinical Medicine Weill Cornell Medical College

    Adjunct Associate Professor of Clinical Medicine Columbia University College of Physicians and Surgeons

    Director Comprehensive Weight Control Program

    New York-Presbyterian HospitalWeill Cornell Medical Center New York NY

    As faculty of Weill Cornell Medical College we are committed to providing transparency for any and all external relationships prior to giving an academic presentation

    I am a consultant speaker advisor or receive research support fromBMS

    Arena Aspire BariatricsMyos

    GI Dynamics Novo NordiskOrexigenVivusZafgen

    I may discuss off-label use of medications

    Disclosure Page

    uarrFood intakedarr energy expenditure

    darrfood intake uarrenergy expenditure

    Topiramate

    Naltrexone

    LorcaserinPramlintideGLP-1Leptin

    BupropionPhentermine

    New Compounds andCombination Interventions

    c Louis J Aronne MDScience Feb 7 2003 Vol 299Illustration by Katharine Sutliff

    Phentermine and TopiramateExtended-Release

    bull Mechanism of actionndash Phentermine Sympathomimetic amine - releaserndash Topiramate Gabaergicglutamate modulation and carbonic

    anhydrase inhibitionbull February 2012 FDA advisory committee votes 20-2 for

    approval bull FDA approved July 2012

    ndash Schedule IVndash Pregnancy Category X = REMS

    Topiramate monotherapy exposure in pregnancy associated with 2- to 5-fold increased prevalence of oral clefts

    bull 4 doses Titrate upbull Available only by mail orderbull Covered through Medco Express Scripts

    Phentermine and TopiramateExtended-Release

    bull Dose titrationndash Once dailyndash Start treatment with phentermine 375 mgtopiramate

    23 mg extended-release daily for 14 daysndash After 14 days increase to the recommended dose of

    phentermine 75 mgtopiramate 46 mg extended-release once daily

    ndash May titrate upwards if needed to phen 15 top 92 mg strength

    EQUIP amp CONQUER Discontinuation RateDue to AEs in All Doses Studied

    Placebo Low Mid Full

    Number of patients 1508 241 498 1507Discontinuation due to AEs 9 12 12 18Blurred vision 05 21 08 07Headache 07 17 02 09Insomnia 04 00 04 17Depression 02 00 08 14Tingling 00 04 10 12Irritability 01 08 08 12Anxiety 03 00 02 11Dizziness 02 04 12 08

    Includes adverse events (AEs) by dose for EQUIP amp CONQUER which lead to discontinuation in gt 1 of patientsPress release Sept 9 2009 Available at httpirvivuscomreleasedetailcfmReleaseID=420114Accessed April 27 2010

    PhenTPMMid

    -104

    Phentermine and Topiramate SEQUELWeight Loss Over Time

    Garvey WT Ryan DH Look M Gadde KM Am J Clin Nutr 201295(2)297-308

    Placebo-25

    Plt00001 v placebo

    Weight Loss

    Week

    Total Population

    0

    -2

    -4

    -6

    -8

    -10

    -12

    -14

    -16

    0 12 24 36 48 60 72 84 96 108

    Weight Loss ITT-LOCF

    PhenTPMTop

    -114

    Mid = 75 mg46 mgTop = 15 mg92 mg

    CONQUER Significant Improvement in Cardiovascular Risk Factors

    (LS Mean Wt Loss)

    QNEXAMid(78)

    P valueQNEXATop

    (98) P value

    Waist Circumference (cm) ‐52 lt00001 ‐68 lt00001

    Systolic BP (mmHg) ‐23 00008 ‐32 lt00001

    Diastolic BP (mmHg) ‐07 NS ‐11 00031

    Triglycerides ( ∆) ‐133 lt00001 ‐153 lt00001

    Total Cholesterol ( ∆) ‐16 00345 ‐30 lt00001

    LDL ( ∆) 04 NS ‐28 00069

    HDL ( ∆) 40 lt00001 56 lt00001

    P values represent comparisons to placebo NS= non‐significant

    ITT‐LOCF Placebo ComparisonsTotal Study Population

    Davidson MH et al Am J Cardiol 2013 Jan 29 pii S0002‐9149(12)02641‐0 doi 101016jamjcard201212038

    Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors

    Risk FactorsPhenTPMMid

    p-valuePhenTPMTop

    p-value

    CRP lt0001 lt0001Fibrinogen lt005 lt005Adiponectin lt00001 lt00001

    p-values represent comparisons to placebo

    ITT-LOCF Placebo Comparisons

    Gadde KM et al Lancet 2011377(9774)1341-52

    Mid = 75 mg46 mgTop = 15 mg92 mg

    Lorcaserin

    bull Selective 5‐HT2C receptor agonist designed to promote weight loss

    bull Schedule IV ndash Expected soonbull Indication weight loss and maintenance of

    weight loss in patients with BMI gt30 kgm2 or BMI gt27 kgm2 + weight-related comorbidcondition(s)

    bull Dose - 10 mg BIDbull Most common side effects headache nausea

    dizziness dry mouth

    BLOOM Study Body Weight Over Years 1 and 2

    Smith SR et al N Engl J Med 2010363245-256 Study Week0 8 16 24 32 40 48 56 64 72 80 88 96 104

    Bod

    y W

    eigh

    t (kg

    )

    102

    100

    98

    96

    94

    92

    90

    0

    Year 1

    Placebo in year 1 and 2 (n = 684)Lorcaserin in year 1 placebo in year 2 (n = 275)Lorcaserin in year 1 and 2 (n = 564)

    Year 2

    Endpoint Lorcaserin Placebo P valueWaist circumference (cm) minus68plusmn02 minus39plusmn02 lt001BMI (kgm2) minus209plusmn006 minus078plusmn005 lt001SBPDBP (mm Hg) minus14plusmn03minus11plusmn02 minus08plusmn03minus06plusmn02 0401Cholesterol ( ∆)Total LDLHDL

    minus090plusmn033287plusmn056005plusmn033

    057plusmn034403plusmn058minus021plusmn034

    001

    049

    72Triglycerides minus615plusmn103 minus014plusmn099 lt001SafetyHR (beatsmin)PASP (mm Hg)Beck depression II score

    minus20plusmn03minus092plusmn023minus11plusmn01

    minus16plusmn04 minus023plusmn023 minus09plusmn01

    0499014026

    BLOOM StudyKey Secondary Endpoints

    Smith SR et al N Engl J Med 2010363245-256

    BLOOM-DMChange in Glycemic Parameters

    P lt001 P lt05 LS mean change plusmn SEMOrsquoNeil PM et al Obesity 201220(7)1426-36 httpwwwnaturecomdoifinder101038oby201266

    00

    -05

    -10

    -150 12 24 36 52

    Cha

    nge

    from

    bas

    elin

    e (

    )

    A1c

    Study week

    0

    -10

    -20

    -30

    -400 12 24 52

    Cha

    nge

    from

    bas

    elin

    e m

    gdl

    )

    Fasting plasma glucose

    Study week

    Lorcaserin 10 mg BID Lorcaserin 10 mg Placebo

    Lorcaserin Adverse Events Reported by 5 or More in Any Group in Year 1

    55

    N () Lorcaserin(N = 1593)

    Placebo(N = 1584)

    Headache 287 (180) 175 (110)

    Dizziness 130 (82) 60 (38)

    Nausea 119 (75) 85 (54)

    Constipation 106 (67) 64 (40)

    Fatigue 95 (60) 48 (30)

    Dry mouth 83 (52) 37 (23)

    Smith SR et al ADA 2009 Late‐Breaking Abstract 96

    LorcaserinNo Increase in Rate of Valvulopathy

    Smith SR et al N Engl J Med 2010363245-256

    10

    8

    6

    4

    2

    024 52 76 104

    1351714

    9

    19

    3421Patie

    nts

    ()

    Week

    Lorcaserin in yr 1 and 2

    Lorcaserin in yr 1 Placebo in yr 2

    Placebo in yr 1 and 2

    Phase III Study Outcomes Compared

    Buproprion SR (360 mgd) Naltrexone SR (32 mgd)

    Lorcaserin(20 mgd)

    Phentermine Topiramate CR

    COR1 COR-I2 COR-II3 NB3043 BLOOM4 BLOSSOM5 EQUIP CONQUER

    Number of patients (ITT-LOCF)

    793 obese 1453 obese

    1281 obese

    502 type II diabetes

    3182 obese 4008 obese

    1230 obese BMI 44

    2448 comorbidBMI 36

    Mean change compared with placebo from base

    93 vs5 1c

    61a vs13c

    64a vs12

    50 a vs12c

    58 vs22c

    48 vs28c

    11 Fullbvs 16

    104 Fullb 84 Midb

    vs 18

    51 Lowb vs16c

    Categorical change 5 compared with placebo from base

    56 vs43

    48a vs164

    563a

    vs 171445a vs189

    475b

    vs 203472b vs25

    67 Fullb 45 Lowb vs17

    70 Fullb 62 Midb

    vs 21

    Phenterminetopiramate doses Low 375 mg phentermine23 mg topiramate Mid 75 mg phentermine 46 mg topiramate Full 15 mg phentermine 92 mg topiramateITT-LOCF intent-to-treat last observation carried forwardData not available aP lt 001 vs placebo bP lt 0001 vs placebo

    Obesity Treatments in Late Development

    Kushner RF Expert Opin Pharmacother 200891339-1350

    Agents ActionBupropionNaltrexone

    bull Dopaminenoradrenaline reuptake inhibitorbull Opioid receptor antagonist

    Liraglutide bull GLP-1 agonist

    BupropionNaltrexone

    bull Mechanism of Actionndash Bupropion - Dopaminenoradrenaline reuptake inhibitorndash Naltrexone- Opioid receptor antagonist

    bull Was approved by FDA committee but FDA did not approve until a CV outcome study is performed 2nd concerns about BP and P in some patients

    bull The Light Study is now underway and reported to be enrolling well under PI Dr Nissen

    bull BupropionNaltrexone will have first completed CV outcome study

    Buproprion ndash Naltrexone

    Greenway FL et al Lancet 2010376(9741)595-605

    0

    -2

    -4

    -6

    -8

    -100 4 8 12 16 20 24 28 32 36 40 44 48 52 56

    Weeks

    Wei

    ght c

    hang

    e fro

    m b

    asel

    ine

    ()

    Placebo

    Naltrexone 16 mg plus bupropion

    Naltrexone 32 mg plus bupropion

    Liraglutide for Weight Loss in Patients with Type 2 Diabetes

    bull GLP-1 analog approved for treatment of type 2 diabetes

    bull Anorectic effect mediated both by the activation of GLP-1 receptor expressed on vagal afferents and by the GLP-1R activation in CNS

    bull Affects visceral fat adiposity appetite food preference and cardiovascular biomarkers in patients with type 2 diabetes

    Inoue K et al Cardiovasc Diabetol 2011 10109 doi1011861475-2840-10-109

    Liraglutide Weight Loss Over 2 Years ITT Observed Means

    Astrup A et al Int J Obes (Lond) 201236(6)843-54

    FromScreening

    -94 kg

    -67 kg-88 kg

    -99 kg-94 kg

    -103 kg

    ITT intention to treat

    Phase III Study Outcomes Compared

    Buproprion SR (360 mgd) Naltrexone SR (32 mgd)

    Lorcaserin(20 mgd)

    Phentermine Topiramate CR

    COR1 COR-I2 COR-II3 NB3043 BLOOM4 BLOSSOM5 EQUIP CONQUER

    Number of patients (ITT-LOCF)

    793 obese 1453 obese

    1281 obese

    502 type II diabetes

    3182 obese 4008 obese

    1230 obese BMI 44

    2448 comorbidBMI 36

    Mean change compared with placebo from base

    93 vs5 1c

    61a vs13c

    64a vs12

    50 a vs12c

    58 vs22c

    48 vs28c

    11 Fullbvs 16

    104 Fullb 84 Midb

    vs 18

    51 Lowb vs16c

    Categorical change 5 compared with placebo from base

    56 vs43

    48a vs164

    563a

    vs 171445a vs189

    475b

    vs 203472b vs25

    67 Fullb 45 Lowb vs17

    70 Fullb 62 Midb

    vs 21

    Phenterminetopiramate doses Low 375 mg phentermine23 mg topiramate Mid 75 mg phentermine 46 mg topiramate Full 15 mg phentermine 92 mg topiramateITT-LOCF intent-to-treat last observation carried forwardData not available aP lt 001 vs placebo bP lt 0001 vs placebo

    Treatment Gap in theManagement of Obesity

    Physicians Need Effective Pharmacotherapies That Will Reduce Weight Significantly and Reduce Weight-related Comorbidities

    0 5 10 15 20 25 30 35

    Diet and Lifestyle Lap Band Gastric Bypass

    TreatmentGap

    What will fill the gap

    Too risky for many peopleNot effective enoughfor many people

    Treatment Gap in theManagement of Obesity

    0 5 10 15 20 25 30 35

    Diet and Lifestyle Lap Band Gastric Bypass

    TreatmentGap

    Too risky for many peopleNot effective enoughfor many people Pharmacotherapy

    Less invasive procedures

    Physicians Need Effective Pharmacotherapies That Will Reduce Weight Significantly and Reduce Weight-related Comorbidities

    What will fill the gap

    • Slide Number 1
    • Slide Number 2
    • Weight Management is Moving into the Workplace and Mainstream of Healthcare
    • US Preventative Services Task Force
    • A Proposal from CMS about Coverage for Intensive Behavioral Therapy for Obesity
    • Slide Number 6
    • Biggest Increases in Clinically Severe Obesity US 1987-2005
    • Relationship Between BMI and Risk of Type 2 Diabetes
    • Slide Number 9
    • Medical Complications of Obesity Almost every organ system is affected
    • Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and disease
    • Current Therapies Often Address Individual Risk Factors Cardiometabolic risk
    • Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and disease
    • Are You Treating These Drivers of Cardiometabolic Risk Should You Treat The Underlying Cause
    • Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors
    • In My Opinion The Winds of Change are Blowing in the Treatment of Chronic Diseases
    • Bariatric Surgery Reduces Overall Mortality Diabetes Mortality by 88
    • Health Care Costs Attributable to ObesityEstimates of what various conditions add to health-care service costs over a 12-month period
    • What-if scenarios (The Lancet forthcoming)
    • How Much Weight Loss Is Needed to Prevent T2DMndashNot Very Much The DPP Experience
    • In the Da Qing Study 6-year Intervention Led to Lower Incidence of Type 2 Diabetes 14 Years Later
    • Slide Number 22
    • Slide Number 23
    • New Compounds andCombination Interventions
    • Phentermine and Topiramate Extended-Release
    • Phentermine and Topiramate Extended-Release
    • EQUIP amp CONQUER Discontinuation RateDue to AEs in All Doses Studied
    • Phentermine and Topiramate SEQUELWeight Loss Over Time
    • CONQUER Significant Improvement in Cardiovascular Risk Factors
    • Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors
    • Lorcaserin
    • BLOOM Study Body Weight Over Years 1 and 2
    • BLOOM StudyKey Secondary Endpoints
    • BLOOM-DMChange in Glycemic Parameters
    • Lorcaserin Adverse Events Reported by 5 or More in Any Group in Year 1
    • LorcaserinNo Increase in Rate of Valvulopathy
    • Phase III Study Outcomes Compared
    • Obesity Treatments in Late Development
    • BupropionNaltrexone
    • Buproprion ndash Naltrexone
    • Liraglutide for Weight Loss in Patients with Type 2 Diabetes
    • Liraglutide Weight Loss Over 2 Years ITT Observed Means
    • Phase III Study Outcomes Compared
    • Treatment Gap in theManagement of Obesity
    • Treatment Gap in theManagement of Obesity

      Weight Management is Moving into the Workplace and Mainstream of Healthcare

      bull Screening for Obesity in Adults The US Preventive Services Task Force recommends that clinicians screen all adult patients for obesity and offer intensive counseling and behavioral interventions to promote sustained weight loss for obese adults (Grade B recommendation)

      bull Medicare now covers behavioral treatment of obesity

      US Preventive Services Task Force Ann Intern Med 2003139930‐932

      US Preventative Services Task Force

      bull The USPSTF found that the most effective interventions were comprehensive and were of high intensity (12 to 26 sessions in a year)

      bull Multiple behavioral management activities such as group sessions individual sessions setting weight-loss goals improving diet or nutrition physical activity sessions addressing barriers to change active use of self-monitoring and strategizing how to maintain lifestyle changes

      bull A weight loss of 5 is considered clinically important by the US Food and Drug Administration (FDA)

      httpwwwuspreventiveservicestaskforceorguspstf11obeseadultobesershtmAnn Intern Med 201226 June

      A Proposal from CMS about Coverage for Intensive Behavioral Therapy for Obesity

      bull For obese Medicare beneficiaries whose counseling is furnished by a qualified primary care physician or other primary care practitioner and in a primary care setting the CMS proposes coverage of

      bull One face-to-face visit every week for the first month bull One face-to-face visit every other week for months 2 to 6 and bull One face-to-face visit every month for months 7 to 12bull At the 6-month visit a reassessment of obesity and a

      determination of the amount of weight loss should be performed To be eligible for face-to-face visits occurring once a month for an additional 6 months beneficiaries must have achieved a reduction in weight of at least 3 kg during the course of the first 6 months of intensive therapy

      httpscmsgov (2011)

      Sturm R Pub Hlth 2007 Jul121492-496

      Biggest Increases in Clinically Severe Obesity US 1987‐2005

      BMI gt30

      BMI gt50larr

      larr

      larr

      BMI gt40

      7

      Relationship Between BMI and Risk of Type 2 Diabetes

      Chan J et al Diabetes Care 199417961Colditz G et al Ann Intern Med 1995122481

      Age

      -Adj

      uste

      d R

      elat

      ive

      Ris

      k

      Body Mass Index (kgm2)

      Women

      Men

      lt22 lt23 23ndash239

      24ndash249

      25ndash269

      27ndash289

      29ndash309

      31ndash329

      33ndash349

      35+

      102910

      4310

      5015

      8122

      158

      44

      276

      403

      540

      932

      67 116

      213

      421

      100

      75

      50

      25

      0

      Why Should I Treat Obesity

      Medical Complications of Obesity Almost every organ system is affected

      Phlebitisvenous stasis

      Coronary heart disease

      Pulmonary diseaseasthmaobstructive sleep apneahypoventilation syndrome

      Gall bladder diseaseReproductive abnormalitiesabnormal mensesinfertilitypolycystic ovarian syndrome

      Gout

      Stroke

      Diabetes

      Osteoarthritis

      Cancerbreast uterus cervixcolon esophagus pancreaskidney prostate

      Nonalcoholic fatty liver diseasesteatosissteatohepatitiscirrhosis Hypertension

      Dyslipidemia

      Cataracts

      Skin

      Idiopathic intracranial hypertension

      Severe pancreatitis

      Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and

      disease

      Lactate Angiotensinogen

      Leptin

      Adipsin (Complement D)

      TNF- α

      FFAFat Stores

      Lipoprotein Lipase

      Plasminogen Activator Inhibitor 1

      (PAI-1)

      Resistin

      Adiponectin

      DM=diabetes mellitus FFA=free fatty acid PAI-1=plasminogen activator inhibitor-1 TNFα=tumor necrosis factor alpha IL-6=interleukin 6

      Slide copy2007Louis J Aronne MD after Dr G Bray

      Insulin

      IL - 6

      Estrogen

      Hypertension

      Thrombosis

      Inflammation

      Type 2 DM

      DyslipidemiaType 2 DM

      Arthritis

      ASCVD

      Asthma

      C-C L2

      Waist circumference

      Blood pressure

      Blood glucose

      Triglycerides

      HDL-cholesterol

      LDL-cholesterol

      Insulin resistance

      Thrombotic risk

      Current Therapies Often Address Individual Risk Factors Cardiometabolic risk

      NCEP ATP IIIdefinitionof themetabolicsyndrome

      Antihypertensives

      Oral antidiabetic agents

      Antiplatelet agents

      Lipid modifiers

      Insulin sensitizers

      Jupiter Trial Rosuvastatin reduced incidence of CV endpoints but increased HbA1cand reported cases of T2DM (plt01)

      Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and

      disease

      Lactate Angiotensinogen

      Leptin

      Adipsin (Complement D)

      TNF- α

      FFAFat Stores

      Lipoprotein Lipase

      Plasminogen Activator Inhibitor 1

      (PAI-1)

      Resistin

      Adiponectin

      DM=diabetes mellitus FFA=free fatty acid PAI-1=plasminogen activator inhibitor-1 TNFα=tumor necrosis factor alpha IL-6=interleukin 6

      Slide copy2007Louis J Aronne MD after Dr G Bray

      Insulin

      IL - 6

      Estrogen

      Hypertension

      Thrombosis

      Inflammation

      Type 2 DM

      DyslipidemiaType 2 DM

      Arthritis

      ASCVD

      Asthma

      C-C L2

      Adiponectin Anti-atherogenicantidiabeticdarr darr foam cells darr vascular remodelling

      uarr insulin sensitivity darr hepatic glucose output

      IL-6uarr

      Pro-atherogenicpro-diabeticuarr vascular inflammation darr insulin signalling

      TNFαuarr

      Pro-atherogenicpro-diabeticdarr insulin sensitivity in adipocytes (paracrine)

      PAI-1uarr

      Pro-atherogenicuarr atherothrombotic risk

      IAA intra-abdominal adiposityMarette A Curr Opin Clin Nutr Metab Care 20025377-83

      Are You Treating These Drivers of Cardiometabolic Risk Should You Treat The Underlying Cause

      Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors

      Risk FactorsPhenTPMMid

      p-valuePhenTPMTop

      p-value

      CRP lt0001 lt0001Fibrinogen lt005 lt005Adiponectin lt00001 lt00001

      p-values represent comparisons to placebo

      ITT-LOCF Placebo Comparisons

      Gadde KM et al Lancet 2011377(9774)1341-52

      Mid = 75 mg46 mgTop = 15 mg92 mg

      In My Opinion The Winds of Change are Blowing in the Treatment of Chronic

      Diseasesbull ACCORD was stopped because of increased

      mortality in the tight control group 28 of whom gained gt 10kg compared to 14 in control^

      bull Bariatric surgery trials show gt 80 reduction in diabetes mortality with weight loss

      bull I believe we are in the midst of a shift from ldquoGlucocentricrdquo to ldquoWeight-Centricrdquo Management of T 2 DM

      ^ NEJM 3582545-2559 Adams TD et al N Engl J Med 2007357(8)753-761

      -34-48-48-88-59-29+73

      Adams TD et al N Engl J Med 2007357(8)753-761

      Bariatric Surgery Reduces Overall Mortality Diabetes Mortality by 88

      Matched SubjectsSurgery Group (n=7925)

      Co(n=

      ntrol Group7925)

      NoNo10000 person-yr No

      No10000 person-yr

      All causes of death 213 376 321 571All deaths caused by disease 150 265 285 507Cardiovascular diseases 55 97 104 185Diabetes 2 04 19 34Cancer 31 55 73 133Other diseases 62 11 89 155All non-disease causes 63 111 36 64Accident unrelated to drugs 21 37 17 30Poisoning of undetermined intent 9 16 4 07Suicide 15 26 5 09Other nondisease cause 18 32 10 18

      CC-18

      Health Care Costs Attributable to ObesityEstimates of what various conditions add to health-care service costs over a 12-month period

      $395

      $230

      $225

      $150

      $125

      $0 $100 $200 $300 $400 $500

      Obesity

      Smoking

      20 years aging

      Problem drinking

      Overweight

      Sturm R Health Aff (Millwood) 2002 Mar-Apr21(2)245-53 Table Wall Street Journal 3132002

      Obesity increased medication costs 77inpatient and outpatient costs 36

      What-if scenarios (The Lancet forthcoming)

      Redrawn from Hamman RF et al Diabetes Care 2006292102‐2107

      Change in Weight from Baseline (kg)0‐10 ‐5 +5In

      cide

      nce Ra

      te per 100

      Person‐Years

      10

      20

      15

      5

      0

      How Much Weight Loss Is Needed to Prevent T2DMndashNot Very Much The DPP Experience

      In the Da Qing Study 6-year Intervention Led to Lower Incidence of Type 2 Diabetes 14 Years Later

      n=530 overweight Chinese men and women with IGT mean BMI=26

      17

      0

      20

      40

      60

      80

      100

      2 4 6 8 10 12 14 16 18 20Years of follow‐up

      6‐year intervention hazard ratio = 049 (95 CI 033ndash073)20‐year follow‐up hazard ratio = 057 (95 CI 041ndash081)

      Cumulative Incide

      nce of Type 2 Diabe

      tes ()

      0

      Lifestyle interventionControl

      Treatment Follow‐up

      Li et al Lancet 20083711783ndash9

      Pharmacotherapy for Weight LossLouis J Aronne MD FACP

      Professor of Clinical Medicine Weill Cornell Medical College

      Adjunct Associate Professor of Clinical Medicine Columbia University College of Physicians and Surgeons

      Director Comprehensive Weight Control Program

      New York-Presbyterian HospitalWeill Cornell Medical Center New York NY

      As faculty of Weill Cornell Medical College we are committed to providing transparency for any and all external relationships prior to giving an academic presentation

      I am a consultant speaker advisor or receive research support fromBMS

      Arena Aspire BariatricsMyos

      GI Dynamics Novo NordiskOrexigenVivusZafgen

      I may discuss off-label use of medications

      Disclosure Page

      uarrFood intakedarr energy expenditure

      darrfood intake uarrenergy expenditure

      Topiramate

      Naltrexone

      LorcaserinPramlintideGLP-1Leptin

      BupropionPhentermine

      New Compounds andCombination Interventions

      c Louis J Aronne MDScience Feb 7 2003 Vol 299Illustration by Katharine Sutliff

      Phentermine and TopiramateExtended-Release

      bull Mechanism of actionndash Phentermine Sympathomimetic amine - releaserndash Topiramate Gabaergicglutamate modulation and carbonic

      anhydrase inhibitionbull February 2012 FDA advisory committee votes 20-2 for

      approval bull FDA approved July 2012

      ndash Schedule IVndash Pregnancy Category X = REMS

      Topiramate monotherapy exposure in pregnancy associated with 2- to 5-fold increased prevalence of oral clefts

      bull 4 doses Titrate upbull Available only by mail orderbull Covered through Medco Express Scripts

      Phentermine and TopiramateExtended-Release

      bull Dose titrationndash Once dailyndash Start treatment with phentermine 375 mgtopiramate

      23 mg extended-release daily for 14 daysndash After 14 days increase to the recommended dose of

      phentermine 75 mgtopiramate 46 mg extended-release once daily

      ndash May titrate upwards if needed to phen 15 top 92 mg strength

      EQUIP amp CONQUER Discontinuation RateDue to AEs in All Doses Studied

      Placebo Low Mid Full

      Number of patients 1508 241 498 1507Discontinuation due to AEs 9 12 12 18Blurred vision 05 21 08 07Headache 07 17 02 09Insomnia 04 00 04 17Depression 02 00 08 14Tingling 00 04 10 12Irritability 01 08 08 12Anxiety 03 00 02 11Dizziness 02 04 12 08

      Includes adverse events (AEs) by dose for EQUIP amp CONQUER which lead to discontinuation in gt 1 of patientsPress release Sept 9 2009 Available at httpirvivuscomreleasedetailcfmReleaseID=420114Accessed April 27 2010

      PhenTPMMid

      -104

      Phentermine and Topiramate SEQUELWeight Loss Over Time

      Garvey WT Ryan DH Look M Gadde KM Am J Clin Nutr 201295(2)297-308

      Placebo-25

      Plt00001 v placebo

      Weight Loss

      Week

      Total Population

      0

      -2

      -4

      -6

      -8

      -10

      -12

      -14

      -16

      0 12 24 36 48 60 72 84 96 108

      Weight Loss ITT-LOCF

      PhenTPMTop

      -114

      Mid = 75 mg46 mgTop = 15 mg92 mg

      CONQUER Significant Improvement in Cardiovascular Risk Factors

      (LS Mean Wt Loss)

      QNEXAMid(78)

      P valueQNEXATop

      (98) P value

      Waist Circumference (cm) ‐52 lt00001 ‐68 lt00001

      Systolic BP (mmHg) ‐23 00008 ‐32 lt00001

      Diastolic BP (mmHg) ‐07 NS ‐11 00031

      Triglycerides ( ∆) ‐133 lt00001 ‐153 lt00001

      Total Cholesterol ( ∆) ‐16 00345 ‐30 lt00001

      LDL ( ∆) 04 NS ‐28 00069

      HDL ( ∆) 40 lt00001 56 lt00001

      P values represent comparisons to placebo NS= non‐significant

      ITT‐LOCF Placebo ComparisonsTotal Study Population

      Davidson MH et al Am J Cardiol 2013 Jan 29 pii S0002‐9149(12)02641‐0 doi 101016jamjcard201212038

      Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors

      Risk FactorsPhenTPMMid

      p-valuePhenTPMTop

      p-value

      CRP lt0001 lt0001Fibrinogen lt005 lt005Adiponectin lt00001 lt00001

      p-values represent comparisons to placebo

      ITT-LOCF Placebo Comparisons

      Gadde KM et al Lancet 2011377(9774)1341-52

      Mid = 75 mg46 mgTop = 15 mg92 mg

      Lorcaserin

      bull Selective 5‐HT2C receptor agonist designed to promote weight loss

      bull Schedule IV ndash Expected soonbull Indication weight loss and maintenance of

      weight loss in patients with BMI gt30 kgm2 or BMI gt27 kgm2 + weight-related comorbidcondition(s)

      bull Dose - 10 mg BIDbull Most common side effects headache nausea

      dizziness dry mouth

      BLOOM Study Body Weight Over Years 1 and 2

      Smith SR et al N Engl J Med 2010363245-256 Study Week0 8 16 24 32 40 48 56 64 72 80 88 96 104

      Bod

      y W

      eigh

      t (kg

      )

      102

      100

      98

      96

      94

      92

      90

      0

      Year 1

      Placebo in year 1 and 2 (n = 684)Lorcaserin in year 1 placebo in year 2 (n = 275)Lorcaserin in year 1 and 2 (n = 564)

      Year 2

      Endpoint Lorcaserin Placebo P valueWaist circumference (cm) minus68plusmn02 minus39plusmn02 lt001BMI (kgm2) minus209plusmn006 minus078plusmn005 lt001SBPDBP (mm Hg) minus14plusmn03minus11plusmn02 minus08plusmn03minus06plusmn02 0401Cholesterol ( ∆)Total LDLHDL

      minus090plusmn033287plusmn056005plusmn033

      057plusmn034403plusmn058minus021plusmn034

      001

      049

      72Triglycerides minus615plusmn103 minus014plusmn099 lt001SafetyHR (beatsmin)PASP (mm Hg)Beck depression II score

      minus20plusmn03minus092plusmn023minus11plusmn01

      minus16plusmn04 minus023plusmn023 minus09plusmn01

      0499014026

      BLOOM StudyKey Secondary Endpoints

      Smith SR et al N Engl J Med 2010363245-256

      BLOOM-DMChange in Glycemic Parameters

      P lt001 P lt05 LS mean change plusmn SEMOrsquoNeil PM et al Obesity 201220(7)1426-36 httpwwwnaturecomdoifinder101038oby201266

      00

      -05

      -10

      -150 12 24 36 52

      Cha

      nge

      from

      bas

      elin

      e (

      )

      A1c

      Study week

      0

      -10

      -20

      -30

      -400 12 24 52

      Cha

      nge

      from

      bas

      elin

      e m

      gdl

      )

      Fasting plasma glucose

      Study week

      Lorcaserin 10 mg BID Lorcaserin 10 mg Placebo

      Lorcaserin Adverse Events Reported by 5 or More in Any Group in Year 1

      55

      N () Lorcaserin(N = 1593)

      Placebo(N = 1584)

      Headache 287 (180) 175 (110)

      Dizziness 130 (82) 60 (38)

      Nausea 119 (75) 85 (54)

      Constipation 106 (67) 64 (40)

      Fatigue 95 (60) 48 (30)

      Dry mouth 83 (52) 37 (23)

      Smith SR et al ADA 2009 Late‐Breaking Abstract 96

      LorcaserinNo Increase in Rate of Valvulopathy

      Smith SR et al N Engl J Med 2010363245-256

      10

      8

      6

      4

      2

      024 52 76 104

      1351714

      9

      19

      3421Patie

      nts

      ()

      Week

      Lorcaserin in yr 1 and 2

      Lorcaserin in yr 1 Placebo in yr 2

      Placebo in yr 1 and 2

      Phase III Study Outcomes Compared

      Buproprion SR (360 mgd) Naltrexone SR (32 mgd)

      Lorcaserin(20 mgd)

      Phentermine Topiramate CR

      COR1 COR-I2 COR-II3 NB3043 BLOOM4 BLOSSOM5 EQUIP CONQUER

      Number of patients (ITT-LOCF)

      793 obese 1453 obese

      1281 obese

      502 type II diabetes

      3182 obese 4008 obese

      1230 obese BMI 44

      2448 comorbidBMI 36

      Mean change compared with placebo from base

      93 vs5 1c

      61a vs13c

      64a vs12

      50 a vs12c

      58 vs22c

      48 vs28c

      11 Fullbvs 16

      104 Fullb 84 Midb

      vs 18

      51 Lowb vs16c

      Categorical change 5 compared with placebo from base

      56 vs43

      48a vs164

      563a

      vs 171445a vs189

      475b

      vs 203472b vs25

      67 Fullb 45 Lowb vs17

      70 Fullb 62 Midb

      vs 21

      Phenterminetopiramate doses Low 375 mg phentermine23 mg topiramate Mid 75 mg phentermine 46 mg topiramate Full 15 mg phentermine 92 mg topiramateITT-LOCF intent-to-treat last observation carried forwardData not available aP lt 001 vs placebo bP lt 0001 vs placebo

      Obesity Treatments in Late Development

      Kushner RF Expert Opin Pharmacother 200891339-1350

      Agents ActionBupropionNaltrexone

      bull Dopaminenoradrenaline reuptake inhibitorbull Opioid receptor antagonist

      Liraglutide bull GLP-1 agonist

      BupropionNaltrexone

      bull Mechanism of Actionndash Bupropion - Dopaminenoradrenaline reuptake inhibitorndash Naltrexone- Opioid receptor antagonist

      bull Was approved by FDA committee but FDA did not approve until a CV outcome study is performed 2nd concerns about BP and P in some patients

      bull The Light Study is now underway and reported to be enrolling well under PI Dr Nissen

      bull BupropionNaltrexone will have first completed CV outcome study

      Buproprion ndash Naltrexone

      Greenway FL et al Lancet 2010376(9741)595-605

      0

      -2

      -4

      -6

      -8

      -100 4 8 12 16 20 24 28 32 36 40 44 48 52 56

      Weeks

      Wei

      ght c

      hang

      e fro

      m b

      asel

      ine

      ()

      Placebo

      Naltrexone 16 mg plus bupropion

      Naltrexone 32 mg plus bupropion

      Liraglutide for Weight Loss in Patients with Type 2 Diabetes

      bull GLP-1 analog approved for treatment of type 2 diabetes

      bull Anorectic effect mediated both by the activation of GLP-1 receptor expressed on vagal afferents and by the GLP-1R activation in CNS

      bull Affects visceral fat adiposity appetite food preference and cardiovascular biomarkers in patients with type 2 diabetes

      Inoue K et al Cardiovasc Diabetol 2011 10109 doi1011861475-2840-10-109

      Liraglutide Weight Loss Over 2 Years ITT Observed Means

      Astrup A et al Int J Obes (Lond) 201236(6)843-54

      FromScreening

      -94 kg

      -67 kg-88 kg

      -99 kg-94 kg

      -103 kg

      ITT intention to treat

      Phase III Study Outcomes Compared

      Buproprion SR (360 mgd) Naltrexone SR (32 mgd)

      Lorcaserin(20 mgd)

      Phentermine Topiramate CR

      COR1 COR-I2 COR-II3 NB3043 BLOOM4 BLOSSOM5 EQUIP CONQUER

      Number of patients (ITT-LOCF)

      793 obese 1453 obese

      1281 obese

      502 type II diabetes

      3182 obese 4008 obese

      1230 obese BMI 44

      2448 comorbidBMI 36

      Mean change compared with placebo from base

      93 vs5 1c

      61a vs13c

      64a vs12

      50 a vs12c

      58 vs22c

      48 vs28c

      11 Fullbvs 16

      104 Fullb 84 Midb

      vs 18

      51 Lowb vs16c

      Categorical change 5 compared with placebo from base

      56 vs43

      48a vs164

      563a

      vs 171445a vs189

      475b

      vs 203472b vs25

      67 Fullb 45 Lowb vs17

      70 Fullb 62 Midb

      vs 21

      Phenterminetopiramate doses Low 375 mg phentermine23 mg topiramate Mid 75 mg phentermine 46 mg topiramate Full 15 mg phentermine 92 mg topiramateITT-LOCF intent-to-treat last observation carried forwardData not available aP lt 001 vs placebo bP lt 0001 vs placebo

      Treatment Gap in theManagement of Obesity

      Physicians Need Effective Pharmacotherapies That Will Reduce Weight Significantly and Reduce Weight-related Comorbidities

      0 5 10 15 20 25 30 35

      Diet and Lifestyle Lap Band Gastric Bypass

      TreatmentGap

      What will fill the gap

      Too risky for many peopleNot effective enoughfor many people

      Treatment Gap in theManagement of Obesity

      0 5 10 15 20 25 30 35

      Diet and Lifestyle Lap Band Gastric Bypass

      TreatmentGap

      Too risky for many peopleNot effective enoughfor many people Pharmacotherapy

      Less invasive procedures

      Physicians Need Effective Pharmacotherapies That Will Reduce Weight Significantly and Reduce Weight-related Comorbidities

      What will fill the gap

      • Slide Number 1
      • Slide Number 2
      • Weight Management is Moving into the Workplace and Mainstream of Healthcare
      • US Preventative Services Task Force
      • A Proposal from CMS about Coverage for Intensive Behavioral Therapy for Obesity
      • Slide Number 6
      • Biggest Increases in Clinically Severe Obesity US 1987-2005
      • Relationship Between BMI and Risk of Type 2 Diabetes
      • Slide Number 9
      • Medical Complications of Obesity Almost every organ system is affected
      • Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and disease
      • Current Therapies Often Address Individual Risk Factors Cardiometabolic risk
      • Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and disease
      • Are You Treating These Drivers of Cardiometabolic Risk Should You Treat The Underlying Cause
      • Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors
      • In My Opinion The Winds of Change are Blowing in the Treatment of Chronic Diseases
      • Bariatric Surgery Reduces Overall Mortality Diabetes Mortality by 88
      • Health Care Costs Attributable to ObesityEstimates of what various conditions add to health-care service costs over a 12-month period
      • What-if scenarios (The Lancet forthcoming)
      • How Much Weight Loss Is Needed to Prevent T2DMndashNot Very Much The DPP Experience
      • In the Da Qing Study 6-year Intervention Led to Lower Incidence of Type 2 Diabetes 14 Years Later
      • Slide Number 22
      • Slide Number 23
      • New Compounds andCombination Interventions
      • Phentermine and Topiramate Extended-Release
      • Phentermine and Topiramate Extended-Release
      • EQUIP amp CONQUER Discontinuation RateDue to AEs in All Doses Studied
      • Phentermine and Topiramate SEQUELWeight Loss Over Time
      • CONQUER Significant Improvement in Cardiovascular Risk Factors
      • Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors
      • Lorcaserin
      • BLOOM Study Body Weight Over Years 1 and 2
      • BLOOM StudyKey Secondary Endpoints
      • BLOOM-DMChange in Glycemic Parameters
      • Lorcaserin Adverse Events Reported by 5 or More in Any Group in Year 1
      • LorcaserinNo Increase in Rate of Valvulopathy
      • Phase III Study Outcomes Compared
      • Obesity Treatments in Late Development
      • BupropionNaltrexone
      • Buproprion ndash Naltrexone
      • Liraglutide for Weight Loss in Patients with Type 2 Diabetes
      • Liraglutide Weight Loss Over 2 Years ITT Observed Means
      • Phase III Study Outcomes Compared
      • Treatment Gap in theManagement of Obesity
      • Treatment Gap in theManagement of Obesity

        US Preventative Services Task Force

        bull The USPSTF found that the most effective interventions were comprehensive and were of high intensity (12 to 26 sessions in a year)

        bull Multiple behavioral management activities such as group sessions individual sessions setting weight-loss goals improving diet or nutrition physical activity sessions addressing barriers to change active use of self-monitoring and strategizing how to maintain lifestyle changes

        bull A weight loss of 5 is considered clinically important by the US Food and Drug Administration (FDA)

        httpwwwuspreventiveservicestaskforceorguspstf11obeseadultobesershtmAnn Intern Med 201226 June

        A Proposal from CMS about Coverage for Intensive Behavioral Therapy for Obesity

        bull For obese Medicare beneficiaries whose counseling is furnished by a qualified primary care physician or other primary care practitioner and in a primary care setting the CMS proposes coverage of

        bull One face-to-face visit every week for the first month bull One face-to-face visit every other week for months 2 to 6 and bull One face-to-face visit every month for months 7 to 12bull At the 6-month visit a reassessment of obesity and a

        determination of the amount of weight loss should be performed To be eligible for face-to-face visits occurring once a month for an additional 6 months beneficiaries must have achieved a reduction in weight of at least 3 kg during the course of the first 6 months of intensive therapy

        httpscmsgov (2011)

        Sturm R Pub Hlth 2007 Jul121492-496

        Biggest Increases in Clinically Severe Obesity US 1987‐2005

        BMI gt30

        BMI gt50larr

        larr

        larr

        BMI gt40

        7

        Relationship Between BMI and Risk of Type 2 Diabetes

        Chan J et al Diabetes Care 199417961Colditz G et al Ann Intern Med 1995122481

        Age

        -Adj

        uste

        d R

        elat

        ive

        Ris

        k

        Body Mass Index (kgm2)

        Women

        Men

        lt22 lt23 23ndash239

        24ndash249

        25ndash269

        27ndash289

        29ndash309

        31ndash329

        33ndash349

        35+

        102910

        4310

        5015

        8122

        158

        44

        276

        403

        540

        932

        67 116

        213

        421

        100

        75

        50

        25

        0

        Why Should I Treat Obesity

        Medical Complications of Obesity Almost every organ system is affected

        Phlebitisvenous stasis

        Coronary heart disease

        Pulmonary diseaseasthmaobstructive sleep apneahypoventilation syndrome

        Gall bladder diseaseReproductive abnormalitiesabnormal mensesinfertilitypolycystic ovarian syndrome

        Gout

        Stroke

        Diabetes

        Osteoarthritis

        Cancerbreast uterus cervixcolon esophagus pancreaskidney prostate

        Nonalcoholic fatty liver diseasesteatosissteatohepatitiscirrhosis Hypertension

        Dyslipidemia

        Cataracts

        Skin

        Idiopathic intracranial hypertension

        Severe pancreatitis

        Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and

        disease

        Lactate Angiotensinogen

        Leptin

        Adipsin (Complement D)

        TNF- α

        FFAFat Stores

        Lipoprotein Lipase

        Plasminogen Activator Inhibitor 1

        (PAI-1)

        Resistin

        Adiponectin

        DM=diabetes mellitus FFA=free fatty acid PAI-1=plasminogen activator inhibitor-1 TNFα=tumor necrosis factor alpha IL-6=interleukin 6

        Slide copy2007Louis J Aronne MD after Dr G Bray

        Insulin

        IL - 6

        Estrogen

        Hypertension

        Thrombosis

        Inflammation

        Type 2 DM

        DyslipidemiaType 2 DM

        Arthritis

        ASCVD

        Asthma

        C-C L2

        Waist circumference

        Blood pressure

        Blood glucose

        Triglycerides

        HDL-cholesterol

        LDL-cholesterol

        Insulin resistance

        Thrombotic risk

        Current Therapies Often Address Individual Risk Factors Cardiometabolic risk

        NCEP ATP IIIdefinitionof themetabolicsyndrome

        Antihypertensives

        Oral antidiabetic agents

        Antiplatelet agents

        Lipid modifiers

        Insulin sensitizers

        Jupiter Trial Rosuvastatin reduced incidence of CV endpoints but increased HbA1cand reported cases of T2DM (plt01)

        Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and

        disease

        Lactate Angiotensinogen

        Leptin

        Adipsin (Complement D)

        TNF- α

        FFAFat Stores

        Lipoprotein Lipase

        Plasminogen Activator Inhibitor 1

        (PAI-1)

        Resistin

        Adiponectin

        DM=diabetes mellitus FFA=free fatty acid PAI-1=plasminogen activator inhibitor-1 TNFα=tumor necrosis factor alpha IL-6=interleukin 6

        Slide copy2007Louis J Aronne MD after Dr G Bray

        Insulin

        IL - 6

        Estrogen

        Hypertension

        Thrombosis

        Inflammation

        Type 2 DM

        DyslipidemiaType 2 DM

        Arthritis

        ASCVD

        Asthma

        C-C L2

        Adiponectin Anti-atherogenicantidiabeticdarr darr foam cells darr vascular remodelling

        uarr insulin sensitivity darr hepatic glucose output

        IL-6uarr

        Pro-atherogenicpro-diabeticuarr vascular inflammation darr insulin signalling

        TNFαuarr

        Pro-atherogenicpro-diabeticdarr insulin sensitivity in adipocytes (paracrine)

        PAI-1uarr

        Pro-atherogenicuarr atherothrombotic risk

        IAA intra-abdominal adiposityMarette A Curr Opin Clin Nutr Metab Care 20025377-83

        Are You Treating These Drivers of Cardiometabolic Risk Should You Treat The Underlying Cause

        Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors

        Risk FactorsPhenTPMMid

        p-valuePhenTPMTop

        p-value

        CRP lt0001 lt0001Fibrinogen lt005 lt005Adiponectin lt00001 lt00001

        p-values represent comparisons to placebo

        ITT-LOCF Placebo Comparisons

        Gadde KM et al Lancet 2011377(9774)1341-52

        Mid = 75 mg46 mgTop = 15 mg92 mg

        In My Opinion The Winds of Change are Blowing in the Treatment of Chronic

        Diseasesbull ACCORD was stopped because of increased

        mortality in the tight control group 28 of whom gained gt 10kg compared to 14 in control^

        bull Bariatric surgery trials show gt 80 reduction in diabetes mortality with weight loss

        bull I believe we are in the midst of a shift from ldquoGlucocentricrdquo to ldquoWeight-Centricrdquo Management of T 2 DM

        ^ NEJM 3582545-2559 Adams TD et al N Engl J Med 2007357(8)753-761

        -34-48-48-88-59-29+73

        Adams TD et al N Engl J Med 2007357(8)753-761

        Bariatric Surgery Reduces Overall Mortality Diabetes Mortality by 88

        Matched SubjectsSurgery Group (n=7925)

        Co(n=

        ntrol Group7925)

        NoNo10000 person-yr No

        No10000 person-yr

        All causes of death 213 376 321 571All deaths caused by disease 150 265 285 507Cardiovascular diseases 55 97 104 185Diabetes 2 04 19 34Cancer 31 55 73 133Other diseases 62 11 89 155All non-disease causes 63 111 36 64Accident unrelated to drugs 21 37 17 30Poisoning of undetermined intent 9 16 4 07Suicide 15 26 5 09Other nondisease cause 18 32 10 18

        CC-18

        Health Care Costs Attributable to ObesityEstimates of what various conditions add to health-care service costs over a 12-month period

        $395

        $230

        $225

        $150

        $125

        $0 $100 $200 $300 $400 $500

        Obesity

        Smoking

        20 years aging

        Problem drinking

        Overweight

        Sturm R Health Aff (Millwood) 2002 Mar-Apr21(2)245-53 Table Wall Street Journal 3132002

        Obesity increased medication costs 77inpatient and outpatient costs 36

        What-if scenarios (The Lancet forthcoming)

        Redrawn from Hamman RF et al Diabetes Care 2006292102‐2107

        Change in Weight from Baseline (kg)0‐10 ‐5 +5In

        cide

        nce Ra

        te per 100

        Person‐Years

        10

        20

        15

        5

        0

        How Much Weight Loss Is Needed to Prevent T2DMndashNot Very Much The DPP Experience

        In the Da Qing Study 6-year Intervention Led to Lower Incidence of Type 2 Diabetes 14 Years Later

        n=530 overweight Chinese men and women with IGT mean BMI=26

        17

        0

        20

        40

        60

        80

        100

        2 4 6 8 10 12 14 16 18 20Years of follow‐up

        6‐year intervention hazard ratio = 049 (95 CI 033ndash073)20‐year follow‐up hazard ratio = 057 (95 CI 041ndash081)

        Cumulative Incide

        nce of Type 2 Diabe

        tes ()

        0

        Lifestyle interventionControl

        Treatment Follow‐up

        Li et al Lancet 20083711783ndash9

        Pharmacotherapy for Weight LossLouis J Aronne MD FACP

        Professor of Clinical Medicine Weill Cornell Medical College

        Adjunct Associate Professor of Clinical Medicine Columbia University College of Physicians and Surgeons

        Director Comprehensive Weight Control Program

        New York-Presbyterian HospitalWeill Cornell Medical Center New York NY

        As faculty of Weill Cornell Medical College we are committed to providing transparency for any and all external relationships prior to giving an academic presentation

        I am a consultant speaker advisor or receive research support fromBMS

        Arena Aspire BariatricsMyos

        GI Dynamics Novo NordiskOrexigenVivusZafgen

        I may discuss off-label use of medications

        Disclosure Page

        uarrFood intakedarr energy expenditure

        darrfood intake uarrenergy expenditure

        Topiramate

        Naltrexone

        LorcaserinPramlintideGLP-1Leptin

        BupropionPhentermine

        New Compounds andCombination Interventions

        c Louis J Aronne MDScience Feb 7 2003 Vol 299Illustration by Katharine Sutliff

        Phentermine and TopiramateExtended-Release

        bull Mechanism of actionndash Phentermine Sympathomimetic amine - releaserndash Topiramate Gabaergicglutamate modulation and carbonic

        anhydrase inhibitionbull February 2012 FDA advisory committee votes 20-2 for

        approval bull FDA approved July 2012

        ndash Schedule IVndash Pregnancy Category X = REMS

        Topiramate monotherapy exposure in pregnancy associated with 2- to 5-fold increased prevalence of oral clefts

        bull 4 doses Titrate upbull Available only by mail orderbull Covered through Medco Express Scripts

        Phentermine and TopiramateExtended-Release

        bull Dose titrationndash Once dailyndash Start treatment with phentermine 375 mgtopiramate

        23 mg extended-release daily for 14 daysndash After 14 days increase to the recommended dose of

        phentermine 75 mgtopiramate 46 mg extended-release once daily

        ndash May titrate upwards if needed to phen 15 top 92 mg strength

        EQUIP amp CONQUER Discontinuation RateDue to AEs in All Doses Studied

        Placebo Low Mid Full

        Number of patients 1508 241 498 1507Discontinuation due to AEs 9 12 12 18Blurred vision 05 21 08 07Headache 07 17 02 09Insomnia 04 00 04 17Depression 02 00 08 14Tingling 00 04 10 12Irritability 01 08 08 12Anxiety 03 00 02 11Dizziness 02 04 12 08

        Includes adverse events (AEs) by dose for EQUIP amp CONQUER which lead to discontinuation in gt 1 of patientsPress release Sept 9 2009 Available at httpirvivuscomreleasedetailcfmReleaseID=420114Accessed April 27 2010

        PhenTPMMid

        -104

        Phentermine and Topiramate SEQUELWeight Loss Over Time

        Garvey WT Ryan DH Look M Gadde KM Am J Clin Nutr 201295(2)297-308

        Placebo-25

        Plt00001 v placebo

        Weight Loss

        Week

        Total Population

        0

        -2

        -4

        -6

        -8

        -10

        -12

        -14

        -16

        0 12 24 36 48 60 72 84 96 108

        Weight Loss ITT-LOCF

        PhenTPMTop

        -114

        Mid = 75 mg46 mgTop = 15 mg92 mg

        CONQUER Significant Improvement in Cardiovascular Risk Factors

        (LS Mean Wt Loss)

        QNEXAMid(78)

        P valueQNEXATop

        (98) P value

        Waist Circumference (cm) ‐52 lt00001 ‐68 lt00001

        Systolic BP (mmHg) ‐23 00008 ‐32 lt00001

        Diastolic BP (mmHg) ‐07 NS ‐11 00031

        Triglycerides ( ∆) ‐133 lt00001 ‐153 lt00001

        Total Cholesterol ( ∆) ‐16 00345 ‐30 lt00001

        LDL ( ∆) 04 NS ‐28 00069

        HDL ( ∆) 40 lt00001 56 lt00001

        P values represent comparisons to placebo NS= non‐significant

        ITT‐LOCF Placebo ComparisonsTotal Study Population

        Davidson MH et al Am J Cardiol 2013 Jan 29 pii S0002‐9149(12)02641‐0 doi 101016jamjcard201212038

        Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors

        Risk FactorsPhenTPMMid

        p-valuePhenTPMTop

        p-value

        CRP lt0001 lt0001Fibrinogen lt005 lt005Adiponectin lt00001 lt00001

        p-values represent comparisons to placebo

        ITT-LOCF Placebo Comparisons

        Gadde KM et al Lancet 2011377(9774)1341-52

        Mid = 75 mg46 mgTop = 15 mg92 mg

        Lorcaserin

        bull Selective 5‐HT2C receptor agonist designed to promote weight loss

        bull Schedule IV ndash Expected soonbull Indication weight loss and maintenance of

        weight loss in patients with BMI gt30 kgm2 or BMI gt27 kgm2 + weight-related comorbidcondition(s)

        bull Dose - 10 mg BIDbull Most common side effects headache nausea

        dizziness dry mouth

        BLOOM Study Body Weight Over Years 1 and 2

        Smith SR et al N Engl J Med 2010363245-256 Study Week0 8 16 24 32 40 48 56 64 72 80 88 96 104

        Bod

        y W

        eigh

        t (kg

        )

        102

        100

        98

        96

        94

        92

        90

        0

        Year 1

        Placebo in year 1 and 2 (n = 684)Lorcaserin in year 1 placebo in year 2 (n = 275)Lorcaserin in year 1 and 2 (n = 564)

        Year 2

        Endpoint Lorcaserin Placebo P valueWaist circumference (cm) minus68plusmn02 minus39plusmn02 lt001BMI (kgm2) minus209plusmn006 minus078plusmn005 lt001SBPDBP (mm Hg) minus14plusmn03minus11plusmn02 minus08plusmn03minus06plusmn02 0401Cholesterol ( ∆)Total LDLHDL

        minus090plusmn033287plusmn056005plusmn033

        057plusmn034403plusmn058minus021plusmn034

        001

        049

        72Triglycerides minus615plusmn103 minus014plusmn099 lt001SafetyHR (beatsmin)PASP (mm Hg)Beck depression II score

        minus20plusmn03minus092plusmn023minus11plusmn01

        minus16plusmn04 minus023plusmn023 minus09plusmn01

        0499014026

        BLOOM StudyKey Secondary Endpoints

        Smith SR et al N Engl J Med 2010363245-256

        BLOOM-DMChange in Glycemic Parameters

        P lt001 P lt05 LS mean change plusmn SEMOrsquoNeil PM et al Obesity 201220(7)1426-36 httpwwwnaturecomdoifinder101038oby201266

        00

        -05

        -10

        -150 12 24 36 52

        Cha

        nge

        from

        bas

        elin

        e (

        )

        A1c

        Study week

        0

        -10

        -20

        -30

        -400 12 24 52

        Cha

        nge

        from

        bas

        elin

        e m

        gdl

        )

        Fasting plasma glucose

        Study week

        Lorcaserin 10 mg BID Lorcaserin 10 mg Placebo

        Lorcaserin Adverse Events Reported by 5 or More in Any Group in Year 1

        55

        N () Lorcaserin(N = 1593)

        Placebo(N = 1584)

        Headache 287 (180) 175 (110)

        Dizziness 130 (82) 60 (38)

        Nausea 119 (75) 85 (54)

        Constipation 106 (67) 64 (40)

        Fatigue 95 (60) 48 (30)

        Dry mouth 83 (52) 37 (23)

        Smith SR et al ADA 2009 Late‐Breaking Abstract 96

        LorcaserinNo Increase in Rate of Valvulopathy

        Smith SR et al N Engl J Med 2010363245-256

        10

        8

        6

        4

        2

        024 52 76 104

        1351714

        9

        19

        3421Patie

        nts

        ()

        Week

        Lorcaserin in yr 1 and 2

        Lorcaserin in yr 1 Placebo in yr 2

        Placebo in yr 1 and 2

        Phase III Study Outcomes Compared

        Buproprion SR (360 mgd) Naltrexone SR (32 mgd)

        Lorcaserin(20 mgd)

        Phentermine Topiramate CR

        COR1 COR-I2 COR-II3 NB3043 BLOOM4 BLOSSOM5 EQUIP CONQUER

        Number of patients (ITT-LOCF)

        793 obese 1453 obese

        1281 obese

        502 type II diabetes

        3182 obese 4008 obese

        1230 obese BMI 44

        2448 comorbidBMI 36

        Mean change compared with placebo from base

        93 vs5 1c

        61a vs13c

        64a vs12

        50 a vs12c

        58 vs22c

        48 vs28c

        11 Fullbvs 16

        104 Fullb 84 Midb

        vs 18

        51 Lowb vs16c

        Categorical change 5 compared with placebo from base

        56 vs43

        48a vs164

        563a

        vs 171445a vs189

        475b

        vs 203472b vs25

        67 Fullb 45 Lowb vs17

        70 Fullb 62 Midb

        vs 21

        Phenterminetopiramate doses Low 375 mg phentermine23 mg topiramate Mid 75 mg phentermine 46 mg topiramate Full 15 mg phentermine 92 mg topiramateITT-LOCF intent-to-treat last observation carried forwardData not available aP lt 001 vs placebo bP lt 0001 vs placebo

        Obesity Treatments in Late Development

        Kushner RF Expert Opin Pharmacother 200891339-1350

        Agents ActionBupropionNaltrexone

        bull Dopaminenoradrenaline reuptake inhibitorbull Opioid receptor antagonist

        Liraglutide bull GLP-1 agonist

        BupropionNaltrexone

        bull Mechanism of Actionndash Bupropion - Dopaminenoradrenaline reuptake inhibitorndash Naltrexone- Opioid receptor antagonist

        bull Was approved by FDA committee but FDA did not approve until a CV outcome study is performed 2nd concerns about BP and P in some patients

        bull The Light Study is now underway and reported to be enrolling well under PI Dr Nissen

        bull BupropionNaltrexone will have first completed CV outcome study

        Buproprion ndash Naltrexone

        Greenway FL et al Lancet 2010376(9741)595-605

        0

        -2

        -4

        -6

        -8

        -100 4 8 12 16 20 24 28 32 36 40 44 48 52 56

        Weeks

        Wei

        ght c

        hang

        e fro

        m b

        asel

        ine

        ()

        Placebo

        Naltrexone 16 mg plus bupropion

        Naltrexone 32 mg plus bupropion

        Liraglutide for Weight Loss in Patients with Type 2 Diabetes

        bull GLP-1 analog approved for treatment of type 2 diabetes

        bull Anorectic effect mediated both by the activation of GLP-1 receptor expressed on vagal afferents and by the GLP-1R activation in CNS

        bull Affects visceral fat adiposity appetite food preference and cardiovascular biomarkers in patients with type 2 diabetes

        Inoue K et al Cardiovasc Diabetol 2011 10109 doi1011861475-2840-10-109

        Liraglutide Weight Loss Over 2 Years ITT Observed Means

        Astrup A et al Int J Obes (Lond) 201236(6)843-54

        FromScreening

        -94 kg

        -67 kg-88 kg

        -99 kg-94 kg

        -103 kg

        ITT intention to treat

        Phase III Study Outcomes Compared

        Buproprion SR (360 mgd) Naltrexone SR (32 mgd)

        Lorcaserin(20 mgd)

        Phentermine Topiramate CR

        COR1 COR-I2 COR-II3 NB3043 BLOOM4 BLOSSOM5 EQUIP CONQUER

        Number of patients (ITT-LOCF)

        793 obese 1453 obese

        1281 obese

        502 type II diabetes

        3182 obese 4008 obese

        1230 obese BMI 44

        2448 comorbidBMI 36

        Mean change compared with placebo from base

        93 vs5 1c

        61a vs13c

        64a vs12

        50 a vs12c

        58 vs22c

        48 vs28c

        11 Fullbvs 16

        104 Fullb 84 Midb

        vs 18

        51 Lowb vs16c

        Categorical change 5 compared with placebo from base

        56 vs43

        48a vs164

        563a

        vs 171445a vs189

        475b

        vs 203472b vs25

        67 Fullb 45 Lowb vs17

        70 Fullb 62 Midb

        vs 21

        Phenterminetopiramate doses Low 375 mg phentermine23 mg topiramate Mid 75 mg phentermine 46 mg topiramate Full 15 mg phentermine 92 mg topiramateITT-LOCF intent-to-treat last observation carried forwardData not available aP lt 001 vs placebo bP lt 0001 vs placebo

        Treatment Gap in theManagement of Obesity

        Physicians Need Effective Pharmacotherapies That Will Reduce Weight Significantly and Reduce Weight-related Comorbidities

        0 5 10 15 20 25 30 35

        Diet and Lifestyle Lap Band Gastric Bypass

        TreatmentGap

        What will fill the gap

        Too risky for many peopleNot effective enoughfor many people

        Treatment Gap in theManagement of Obesity

        0 5 10 15 20 25 30 35

        Diet and Lifestyle Lap Band Gastric Bypass

        TreatmentGap

        Too risky for many peopleNot effective enoughfor many people Pharmacotherapy

        Less invasive procedures

        Physicians Need Effective Pharmacotherapies That Will Reduce Weight Significantly and Reduce Weight-related Comorbidities

        What will fill the gap

        • Slide Number 1
        • Slide Number 2
        • Weight Management is Moving into the Workplace and Mainstream of Healthcare
        • US Preventative Services Task Force
        • A Proposal from CMS about Coverage for Intensive Behavioral Therapy for Obesity
        • Slide Number 6
        • Biggest Increases in Clinically Severe Obesity US 1987-2005
        • Relationship Between BMI and Risk of Type 2 Diabetes
        • Slide Number 9
        • Medical Complications of Obesity Almost every organ system is affected
        • Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and disease
        • Current Therapies Often Address Individual Risk Factors Cardiometabolic risk
        • Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and disease
        • Are You Treating These Drivers of Cardiometabolic Risk Should You Treat The Underlying Cause
        • Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors
        • In My Opinion The Winds of Change are Blowing in the Treatment of Chronic Diseases
        • Bariatric Surgery Reduces Overall Mortality Diabetes Mortality by 88
        • Health Care Costs Attributable to ObesityEstimates of what various conditions add to health-care service costs over a 12-month period
        • What-if scenarios (The Lancet forthcoming)
        • How Much Weight Loss Is Needed to Prevent T2DMndashNot Very Much The DPP Experience
        • In the Da Qing Study 6-year Intervention Led to Lower Incidence of Type 2 Diabetes 14 Years Later
        • Slide Number 22
        • Slide Number 23
        • New Compounds andCombination Interventions
        • Phentermine and Topiramate Extended-Release
        • Phentermine and Topiramate Extended-Release
        • EQUIP amp CONQUER Discontinuation RateDue to AEs in All Doses Studied
        • Phentermine and Topiramate SEQUELWeight Loss Over Time
        • CONQUER Significant Improvement in Cardiovascular Risk Factors
        • Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors
        • Lorcaserin
        • BLOOM Study Body Weight Over Years 1 and 2
        • BLOOM StudyKey Secondary Endpoints
        • BLOOM-DMChange in Glycemic Parameters
        • Lorcaserin Adverse Events Reported by 5 or More in Any Group in Year 1
        • LorcaserinNo Increase in Rate of Valvulopathy
        • Phase III Study Outcomes Compared
        • Obesity Treatments in Late Development
        • BupropionNaltrexone
        • Buproprion ndash Naltrexone
        • Liraglutide for Weight Loss in Patients with Type 2 Diabetes
        • Liraglutide Weight Loss Over 2 Years ITT Observed Means
        • Phase III Study Outcomes Compared
        • Treatment Gap in theManagement of Obesity
        • Treatment Gap in theManagement of Obesity

          A Proposal from CMS about Coverage for Intensive Behavioral Therapy for Obesity

          bull For obese Medicare beneficiaries whose counseling is furnished by a qualified primary care physician or other primary care practitioner and in a primary care setting the CMS proposes coverage of

          bull One face-to-face visit every week for the first month bull One face-to-face visit every other week for months 2 to 6 and bull One face-to-face visit every month for months 7 to 12bull At the 6-month visit a reassessment of obesity and a

          determination of the amount of weight loss should be performed To be eligible for face-to-face visits occurring once a month for an additional 6 months beneficiaries must have achieved a reduction in weight of at least 3 kg during the course of the first 6 months of intensive therapy

          httpscmsgov (2011)

          Sturm R Pub Hlth 2007 Jul121492-496

          Biggest Increases in Clinically Severe Obesity US 1987‐2005

          BMI gt30

          BMI gt50larr

          larr

          larr

          BMI gt40

          7

          Relationship Between BMI and Risk of Type 2 Diabetes

          Chan J et al Diabetes Care 199417961Colditz G et al Ann Intern Med 1995122481

          Age

          -Adj

          uste

          d R

          elat

          ive

          Ris

          k

          Body Mass Index (kgm2)

          Women

          Men

          lt22 lt23 23ndash239

          24ndash249

          25ndash269

          27ndash289

          29ndash309

          31ndash329

          33ndash349

          35+

          102910

          4310

          5015

          8122

          158

          44

          276

          403

          540

          932

          67 116

          213

          421

          100

          75

          50

          25

          0

          Why Should I Treat Obesity

          Medical Complications of Obesity Almost every organ system is affected

          Phlebitisvenous stasis

          Coronary heart disease

          Pulmonary diseaseasthmaobstructive sleep apneahypoventilation syndrome

          Gall bladder diseaseReproductive abnormalitiesabnormal mensesinfertilitypolycystic ovarian syndrome

          Gout

          Stroke

          Diabetes

          Osteoarthritis

          Cancerbreast uterus cervixcolon esophagus pancreaskidney prostate

          Nonalcoholic fatty liver diseasesteatosissteatohepatitiscirrhosis Hypertension

          Dyslipidemia

          Cataracts

          Skin

          Idiopathic intracranial hypertension

          Severe pancreatitis

          Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and

          disease

          Lactate Angiotensinogen

          Leptin

          Adipsin (Complement D)

          TNF- α

          FFAFat Stores

          Lipoprotein Lipase

          Plasminogen Activator Inhibitor 1

          (PAI-1)

          Resistin

          Adiponectin

          DM=diabetes mellitus FFA=free fatty acid PAI-1=plasminogen activator inhibitor-1 TNFα=tumor necrosis factor alpha IL-6=interleukin 6

          Slide copy2007Louis J Aronne MD after Dr G Bray

          Insulin

          IL - 6

          Estrogen

          Hypertension

          Thrombosis

          Inflammation

          Type 2 DM

          DyslipidemiaType 2 DM

          Arthritis

          ASCVD

          Asthma

          C-C L2

          Waist circumference

          Blood pressure

          Blood glucose

          Triglycerides

          HDL-cholesterol

          LDL-cholesterol

          Insulin resistance

          Thrombotic risk

          Current Therapies Often Address Individual Risk Factors Cardiometabolic risk

          NCEP ATP IIIdefinitionof themetabolicsyndrome

          Antihypertensives

          Oral antidiabetic agents

          Antiplatelet agents

          Lipid modifiers

          Insulin sensitizers

          Jupiter Trial Rosuvastatin reduced incidence of CV endpoints but increased HbA1cand reported cases of T2DM (plt01)

          Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and

          disease

          Lactate Angiotensinogen

          Leptin

          Adipsin (Complement D)

          TNF- α

          FFAFat Stores

          Lipoprotein Lipase

          Plasminogen Activator Inhibitor 1

          (PAI-1)

          Resistin

          Adiponectin

          DM=diabetes mellitus FFA=free fatty acid PAI-1=plasminogen activator inhibitor-1 TNFα=tumor necrosis factor alpha IL-6=interleukin 6

          Slide copy2007Louis J Aronne MD after Dr G Bray

          Insulin

          IL - 6

          Estrogen

          Hypertension

          Thrombosis

          Inflammation

          Type 2 DM

          DyslipidemiaType 2 DM

          Arthritis

          ASCVD

          Asthma

          C-C L2

          Adiponectin Anti-atherogenicantidiabeticdarr darr foam cells darr vascular remodelling

          uarr insulin sensitivity darr hepatic glucose output

          IL-6uarr

          Pro-atherogenicpro-diabeticuarr vascular inflammation darr insulin signalling

          TNFαuarr

          Pro-atherogenicpro-diabeticdarr insulin sensitivity in adipocytes (paracrine)

          PAI-1uarr

          Pro-atherogenicuarr atherothrombotic risk

          IAA intra-abdominal adiposityMarette A Curr Opin Clin Nutr Metab Care 20025377-83

          Are You Treating These Drivers of Cardiometabolic Risk Should You Treat The Underlying Cause

          Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors

          Risk FactorsPhenTPMMid

          p-valuePhenTPMTop

          p-value

          CRP lt0001 lt0001Fibrinogen lt005 lt005Adiponectin lt00001 lt00001

          p-values represent comparisons to placebo

          ITT-LOCF Placebo Comparisons

          Gadde KM et al Lancet 2011377(9774)1341-52

          Mid = 75 mg46 mgTop = 15 mg92 mg

          In My Opinion The Winds of Change are Blowing in the Treatment of Chronic

          Diseasesbull ACCORD was stopped because of increased

          mortality in the tight control group 28 of whom gained gt 10kg compared to 14 in control^

          bull Bariatric surgery trials show gt 80 reduction in diabetes mortality with weight loss

          bull I believe we are in the midst of a shift from ldquoGlucocentricrdquo to ldquoWeight-Centricrdquo Management of T 2 DM

          ^ NEJM 3582545-2559 Adams TD et al N Engl J Med 2007357(8)753-761

          -34-48-48-88-59-29+73

          Adams TD et al N Engl J Med 2007357(8)753-761

          Bariatric Surgery Reduces Overall Mortality Diabetes Mortality by 88

          Matched SubjectsSurgery Group (n=7925)

          Co(n=

          ntrol Group7925)

          NoNo10000 person-yr No

          No10000 person-yr

          All causes of death 213 376 321 571All deaths caused by disease 150 265 285 507Cardiovascular diseases 55 97 104 185Diabetes 2 04 19 34Cancer 31 55 73 133Other diseases 62 11 89 155All non-disease causes 63 111 36 64Accident unrelated to drugs 21 37 17 30Poisoning of undetermined intent 9 16 4 07Suicide 15 26 5 09Other nondisease cause 18 32 10 18

          CC-18

          Health Care Costs Attributable to ObesityEstimates of what various conditions add to health-care service costs over a 12-month period

          $395

          $230

          $225

          $150

          $125

          $0 $100 $200 $300 $400 $500

          Obesity

          Smoking

          20 years aging

          Problem drinking

          Overweight

          Sturm R Health Aff (Millwood) 2002 Mar-Apr21(2)245-53 Table Wall Street Journal 3132002

          Obesity increased medication costs 77inpatient and outpatient costs 36

          What-if scenarios (The Lancet forthcoming)

          Redrawn from Hamman RF et al Diabetes Care 2006292102‐2107

          Change in Weight from Baseline (kg)0‐10 ‐5 +5In

          cide

          nce Ra

          te per 100

          Person‐Years

          10

          20

          15

          5

          0

          How Much Weight Loss Is Needed to Prevent T2DMndashNot Very Much The DPP Experience

          In the Da Qing Study 6-year Intervention Led to Lower Incidence of Type 2 Diabetes 14 Years Later

          n=530 overweight Chinese men and women with IGT mean BMI=26

          17

          0

          20

          40

          60

          80

          100

          2 4 6 8 10 12 14 16 18 20Years of follow‐up

          6‐year intervention hazard ratio = 049 (95 CI 033ndash073)20‐year follow‐up hazard ratio = 057 (95 CI 041ndash081)

          Cumulative Incide

          nce of Type 2 Diabe

          tes ()

          0

          Lifestyle interventionControl

          Treatment Follow‐up

          Li et al Lancet 20083711783ndash9

          Pharmacotherapy for Weight LossLouis J Aronne MD FACP

          Professor of Clinical Medicine Weill Cornell Medical College

          Adjunct Associate Professor of Clinical Medicine Columbia University College of Physicians and Surgeons

          Director Comprehensive Weight Control Program

          New York-Presbyterian HospitalWeill Cornell Medical Center New York NY

          As faculty of Weill Cornell Medical College we are committed to providing transparency for any and all external relationships prior to giving an academic presentation

          I am a consultant speaker advisor or receive research support fromBMS

          Arena Aspire BariatricsMyos

          GI Dynamics Novo NordiskOrexigenVivusZafgen

          I may discuss off-label use of medications

          Disclosure Page

          uarrFood intakedarr energy expenditure

          darrfood intake uarrenergy expenditure

          Topiramate

          Naltrexone

          LorcaserinPramlintideGLP-1Leptin

          BupropionPhentermine

          New Compounds andCombination Interventions

          c Louis J Aronne MDScience Feb 7 2003 Vol 299Illustration by Katharine Sutliff

          Phentermine and TopiramateExtended-Release

          bull Mechanism of actionndash Phentermine Sympathomimetic amine - releaserndash Topiramate Gabaergicglutamate modulation and carbonic

          anhydrase inhibitionbull February 2012 FDA advisory committee votes 20-2 for

          approval bull FDA approved July 2012

          ndash Schedule IVndash Pregnancy Category X = REMS

          Topiramate monotherapy exposure in pregnancy associated with 2- to 5-fold increased prevalence of oral clefts

          bull 4 doses Titrate upbull Available only by mail orderbull Covered through Medco Express Scripts

          Phentermine and TopiramateExtended-Release

          bull Dose titrationndash Once dailyndash Start treatment with phentermine 375 mgtopiramate

          23 mg extended-release daily for 14 daysndash After 14 days increase to the recommended dose of

          phentermine 75 mgtopiramate 46 mg extended-release once daily

          ndash May titrate upwards if needed to phen 15 top 92 mg strength

          EQUIP amp CONQUER Discontinuation RateDue to AEs in All Doses Studied

          Placebo Low Mid Full

          Number of patients 1508 241 498 1507Discontinuation due to AEs 9 12 12 18Blurred vision 05 21 08 07Headache 07 17 02 09Insomnia 04 00 04 17Depression 02 00 08 14Tingling 00 04 10 12Irritability 01 08 08 12Anxiety 03 00 02 11Dizziness 02 04 12 08

          Includes adverse events (AEs) by dose for EQUIP amp CONQUER which lead to discontinuation in gt 1 of patientsPress release Sept 9 2009 Available at httpirvivuscomreleasedetailcfmReleaseID=420114Accessed April 27 2010

          PhenTPMMid

          -104

          Phentermine and Topiramate SEQUELWeight Loss Over Time

          Garvey WT Ryan DH Look M Gadde KM Am J Clin Nutr 201295(2)297-308

          Placebo-25

          Plt00001 v placebo

          Weight Loss

          Week

          Total Population

          0

          -2

          -4

          -6

          -8

          -10

          -12

          -14

          -16

          0 12 24 36 48 60 72 84 96 108

          Weight Loss ITT-LOCF

          PhenTPMTop

          -114

          Mid = 75 mg46 mgTop = 15 mg92 mg

          CONQUER Significant Improvement in Cardiovascular Risk Factors

          (LS Mean Wt Loss)

          QNEXAMid(78)

          P valueQNEXATop

          (98) P value

          Waist Circumference (cm) ‐52 lt00001 ‐68 lt00001

          Systolic BP (mmHg) ‐23 00008 ‐32 lt00001

          Diastolic BP (mmHg) ‐07 NS ‐11 00031

          Triglycerides ( ∆) ‐133 lt00001 ‐153 lt00001

          Total Cholesterol ( ∆) ‐16 00345 ‐30 lt00001

          LDL ( ∆) 04 NS ‐28 00069

          HDL ( ∆) 40 lt00001 56 lt00001

          P values represent comparisons to placebo NS= non‐significant

          ITT‐LOCF Placebo ComparisonsTotal Study Population

          Davidson MH et al Am J Cardiol 2013 Jan 29 pii S0002‐9149(12)02641‐0 doi 101016jamjcard201212038

          Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors

          Risk FactorsPhenTPMMid

          p-valuePhenTPMTop

          p-value

          CRP lt0001 lt0001Fibrinogen lt005 lt005Adiponectin lt00001 lt00001

          p-values represent comparisons to placebo

          ITT-LOCF Placebo Comparisons

          Gadde KM et al Lancet 2011377(9774)1341-52

          Mid = 75 mg46 mgTop = 15 mg92 mg

          Lorcaserin

          bull Selective 5‐HT2C receptor agonist designed to promote weight loss

          bull Schedule IV ndash Expected soonbull Indication weight loss and maintenance of

          weight loss in patients with BMI gt30 kgm2 or BMI gt27 kgm2 + weight-related comorbidcondition(s)

          bull Dose - 10 mg BIDbull Most common side effects headache nausea

          dizziness dry mouth

          BLOOM Study Body Weight Over Years 1 and 2

          Smith SR et al N Engl J Med 2010363245-256 Study Week0 8 16 24 32 40 48 56 64 72 80 88 96 104

          Bod

          y W

          eigh

          t (kg

          )

          102

          100

          98

          96

          94

          92

          90

          0

          Year 1

          Placebo in year 1 and 2 (n = 684)Lorcaserin in year 1 placebo in year 2 (n = 275)Lorcaserin in year 1 and 2 (n = 564)

          Year 2

          Endpoint Lorcaserin Placebo P valueWaist circumference (cm) minus68plusmn02 minus39plusmn02 lt001BMI (kgm2) minus209plusmn006 minus078plusmn005 lt001SBPDBP (mm Hg) minus14plusmn03minus11plusmn02 minus08plusmn03minus06plusmn02 0401Cholesterol ( ∆)Total LDLHDL

          minus090plusmn033287plusmn056005plusmn033

          057plusmn034403plusmn058minus021plusmn034

          001

          049

          72Triglycerides minus615plusmn103 minus014plusmn099 lt001SafetyHR (beatsmin)PASP (mm Hg)Beck depression II score

          minus20plusmn03minus092plusmn023minus11plusmn01

          minus16plusmn04 minus023plusmn023 minus09plusmn01

          0499014026

          BLOOM StudyKey Secondary Endpoints

          Smith SR et al N Engl J Med 2010363245-256

          BLOOM-DMChange in Glycemic Parameters

          P lt001 P lt05 LS mean change plusmn SEMOrsquoNeil PM et al Obesity 201220(7)1426-36 httpwwwnaturecomdoifinder101038oby201266

          00

          -05

          -10

          -150 12 24 36 52

          Cha

          nge

          from

          bas

          elin

          e (

          )

          A1c

          Study week

          0

          -10

          -20

          -30

          -400 12 24 52

          Cha

          nge

          from

          bas

          elin

          e m

          gdl

          )

          Fasting plasma glucose

          Study week

          Lorcaserin 10 mg BID Lorcaserin 10 mg Placebo

          Lorcaserin Adverse Events Reported by 5 or More in Any Group in Year 1

          55

          N () Lorcaserin(N = 1593)

          Placebo(N = 1584)

          Headache 287 (180) 175 (110)

          Dizziness 130 (82) 60 (38)

          Nausea 119 (75) 85 (54)

          Constipation 106 (67) 64 (40)

          Fatigue 95 (60) 48 (30)

          Dry mouth 83 (52) 37 (23)

          Smith SR et al ADA 2009 Late‐Breaking Abstract 96

          LorcaserinNo Increase in Rate of Valvulopathy

          Smith SR et al N Engl J Med 2010363245-256

          10

          8

          6

          4

          2

          024 52 76 104

          1351714

          9

          19

          3421Patie

          nts

          ()

          Week

          Lorcaserin in yr 1 and 2

          Lorcaserin in yr 1 Placebo in yr 2

          Placebo in yr 1 and 2

          Phase III Study Outcomes Compared

          Buproprion SR (360 mgd) Naltrexone SR (32 mgd)

          Lorcaserin(20 mgd)

          Phentermine Topiramate CR

          COR1 COR-I2 COR-II3 NB3043 BLOOM4 BLOSSOM5 EQUIP CONQUER

          Number of patients (ITT-LOCF)

          793 obese 1453 obese

          1281 obese

          502 type II diabetes

          3182 obese 4008 obese

          1230 obese BMI 44

          2448 comorbidBMI 36

          Mean change compared with placebo from base

          93 vs5 1c

          61a vs13c

          64a vs12

          50 a vs12c

          58 vs22c

          48 vs28c

          11 Fullbvs 16

          104 Fullb 84 Midb

          vs 18

          51 Lowb vs16c

          Categorical change 5 compared with placebo from base

          56 vs43

          48a vs164

          563a

          vs 171445a vs189

          475b

          vs 203472b vs25

          67 Fullb 45 Lowb vs17

          70 Fullb 62 Midb

          vs 21

          Phenterminetopiramate doses Low 375 mg phentermine23 mg topiramate Mid 75 mg phentermine 46 mg topiramate Full 15 mg phentermine 92 mg topiramateITT-LOCF intent-to-treat last observation carried forwardData not available aP lt 001 vs placebo bP lt 0001 vs placebo

          Obesity Treatments in Late Development

          Kushner RF Expert Opin Pharmacother 200891339-1350

          Agents ActionBupropionNaltrexone

          bull Dopaminenoradrenaline reuptake inhibitorbull Opioid receptor antagonist

          Liraglutide bull GLP-1 agonist

          BupropionNaltrexone

          bull Mechanism of Actionndash Bupropion - Dopaminenoradrenaline reuptake inhibitorndash Naltrexone- Opioid receptor antagonist

          bull Was approved by FDA committee but FDA did not approve until a CV outcome study is performed 2nd concerns about BP and P in some patients

          bull The Light Study is now underway and reported to be enrolling well under PI Dr Nissen

          bull BupropionNaltrexone will have first completed CV outcome study

          Buproprion ndash Naltrexone

          Greenway FL et al Lancet 2010376(9741)595-605

          0

          -2

          -4

          -6

          -8

          -100 4 8 12 16 20 24 28 32 36 40 44 48 52 56

          Weeks

          Wei

          ght c

          hang

          e fro

          m b

          asel

          ine

          ()

          Placebo

          Naltrexone 16 mg plus bupropion

          Naltrexone 32 mg plus bupropion

          Liraglutide for Weight Loss in Patients with Type 2 Diabetes

          bull GLP-1 analog approved for treatment of type 2 diabetes

          bull Anorectic effect mediated both by the activation of GLP-1 receptor expressed on vagal afferents and by the GLP-1R activation in CNS

          bull Affects visceral fat adiposity appetite food preference and cardiovascular biomarkers in patients with type 2 diabetes

          Inoue K et al Cardiovasc Diabetol 2011 10109 doi1011861475-2840-10-109

          Liraglutide Weight Loss Over 2 Years ITT Observed Means

          Astrup A et al Int J Obes (Lond) 201236(6)843-54

          FromScreening

          -94 kg

          -67 kg-88 kg

          -99 kg-94 kg

          -103 kg

          ITT intention to treat

          Phase III Study Outcomes Compared

          Buproprion SR (360 mgd) Naltrexone SR (32 mgd)

          Lorcaserin(20 mgd)

          Phentermine Topiramate CR

          COR1 COR-I2 COR-II3 NB3043 BLOOM4 BLOSSOM5 EQUIP CONQUER

          Number of patients (ITT-LOCF)

          793 obese 1453 obese

          1281 obese

          502 type II diabetes

          3182 obese 4008 obese

          1230 obese BMI 44

          2448 comorbidBMI 36

          Mean change compared with placebo from base

          93 vs5 1c

          61a vs13c

          64a vs12

          50 a vs12c

          58 vs22c

          48 vs28c

          11 Fullbvs 16

          104 Fullb 84 Midb

          vs 18

          51 Lowb vs16c

          Categorical change 5 compared with placebo from base

          56 vs43

          48a vs164

          563a

          vs 171445a vs189

          475b

          vs 203472b vs25

          67 Fullb 45 Lowb vs17

          70 Fullb 62 Midb

          vs 21

          Phenterminetopiramate doses Low 375 mg phentermine23 mg topiramate Mid 75 mg phentermine 46 mg topiramate Full 15 mg phentermine 92 mg topiramateITT-LOCF intent-to-treat last observation carried forwardData not available aP lt 001 vs placebo bP lt 0001 vs placebo

          Treatment Gap in theManagement of Obesity

          Physicians Need Effective Pharmacotherapies That Will Reduce Weight Significantly and Reduce Weight-related Comorbidities

          0 5 10 15 20 25 30 35

          Diet and Lifestyle Lap Band Gastric Bypass

          TreatmentGap

          What will fill the gap

          Too risky for many peopleNot effective enoughfor many people

          Treatment Gap in theManagement of Obesity

          0 5 10 15 20 25 30 35

          Diet and Lifestyle Lap Band Gastric Bypass

          TreatmentGap

          Too risky for many peopleNot effective enoughfor many people Pharmacotherapy

          Less invasive procedures

          Physicians Need Effective Pharmacotherapies That Will Reduce Weight Significantly and Reduce Weight-related Comorbidities

          What will fill the gap

          • Slide Number 1
          • Slide Number 2
          • Weight Management is Moving into the Workplace and Mainstream of Healthcare
          • US Preventative Services Task Force
          • A Proposal from CMS about Coverage for Intensive Behavioral Therapy for Obesity
          • Slide Number 6
          • Biggest Increases in Clinically Severe Obesity US 1987-2005
          • Relationship Between BMI and Risk of Type 2 Diabetes
          • Slide Number 9
          • Medical Complications of Obesity Almost every organ system is affected
          • Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and disease
          • Current Therapies Often Address Individual Risk Factors Cardiometabolic risk
          • Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and disease
          • Are You Treating These Drivers of Cardiometabolic Risk Should You Treat The Underlying Cause
          • Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors
          • In My Opinion The Winds of Change are Blowing in the Treatment of Chronic Diseases
          • Bariatric Surgery Reduces Overall Mortality Diabetes Mortality by 88
          • Health Care Costs Attributable to ObesityEstimates of what various conditions add to health-care service costs over a 12-month period
          • What-if scenarios (The Lancet forthcoming)
          • How Much Weight Loss Is Needed to Prevent T2DMndashNot Very Much The DPP Experience
          • In the Da Qing Study 6-year Intervention Led to Lower Incidence of Type 2 Diabetes 14 Years Later
          • Slide Number 22
          • Slide Number 23
          • New Compounds andCombination Interventions
          • Phentermine and Topiramate Extended-Release
          • Phentermine and Topiramate Extended-Release
          • EQUIP amp CONQUER Discontinuation RateDue to AEs in All Doses Studied
          • Phentermine and Topiramate SEQUELWeight Loss Over Time
          • CONQUER Significant Improvement in Cardiovascular Risk Factors
          • Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors
          • Lorcaserin
          • BLOOM Study Body Weight Over Years 1 and 2
          • BLOOM StudyKey Secondary Endpoints
          • BLOOM-DMChange in Glycemic Parameters
          • Lorcaserin Adverse Events Reported by 5 or More in Any Group in Year 1
          • LorcaserinNo Increase in Rate of Valvulopathy
          • Phase III Study Outcomes Compared
          • Obesity Treatments in Late Development
          • BupropionNaltrexone
          • Buproprion ndash Naltrexone
          • Liraglutide for Weight Loss in Patients with Type 2 Diabetes
          • Liraglutide Weight Loss Over 2 Years ITT Observed Means
          • Phase III Study Outcomes Compared
          • Treatment Gap in theManagement of Obesity
          • Treatment Gap in theManagement of Obesity

            Sturm R Pub Hlth 2007 Jul121492-496

            Biggest Increases in Clinically Severe Obesity US 1987‐2005

            BMI gt30

            BMI gt50larr

            larr

            larr

            BMI gt40

            7

            Relationship Between BMI and Risk of Type 2 Diabetes

            Chan J et al Diabetes Care 199417961Colditz G et al Ann Intern Med 1995122481

            Age

            -Adj

            uste

            d R

            elat

            ive

            Ris

            k

            Body Mass Index (kgm2)

            Women

            Men

            lt22 lt23 23ndash239

            24ndash249

            25ndash269

            27ndash289

            29ndash309

            31ndash329

            33ndash349

            35+

            102910

            4310

            5015

            8122

            158

            44

            276

            403

            540

            932

            67 116

            213

            421

            100

            75

            50

            25

            0

            Why Should I Treat Obesity

            Medical Complications of Obesity Almost every organ system is affected

            Phlebitisvenous stasis

            Coronary heart disease

            Pulmonary diseaseasthmaobstructive sleep apneahypoventilation syndrome

            Gall bladder diseaseReproductive abnormalitiesabnormal mensesinfertilitypolycystic ovarian syndrome

            Gout

            Stroke

            Diabetes

            Osteoarthritis

            Cancerbreast uterus cervixcolon esophagus pancreaskidney prostate

            Nonalcoholic fatty liver diseasesteatosissteatohepatitiscirrhosis Hypertension

            Dyslipidemia

            Cataracts

            Skin

            Idiopathic intracranial hypertension

            Severe pancreatitis

            Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and

            disease

            Lactate Angiotensinogen

            Leptin

            Adipsin (Complement D)

            TNF- α

            FFAFat Stores

            Lipoprotein Lipase

            Plasminogen Activator Inhibitor 1

            (PAI-1)

            Resistin

            Adiponectin

            DM=diabetes mellitus FFA=free fatty acid PAI-1=plasminogen activator inhibitor-1 TNFα=tumor necrosis factor alpha IL-6=interleukin 6

            Slide copy2007Louis J Aronne MD after Dr G Bray

            Insulin

            IL - 6

            Estrogen

            Hypertension

            Thrombosis

            Inflammation

            Type 2 DM

            DyslipidemiaType 2 DM

            Arthritis

            ASCVD

            Asthma

            C-C L2

            Waist circumference

            Blood pressure

            Blood glucose

            Triglycerides

            HDL-cholesterol

            LDL-cholesterol

            Insulin resistance

            Thrombotic risk

            Current Therapies Often Address Individual Risk Factors Cardiometabolic risk

            NCEP ATP IIIdefinitionof themetabolicsyndrome

            Antihypertensives

            Oral antidiabetic agents

            Antiplatelet agents

            Lipid modifiers

            Insulin sensitizers

            Jupiter Trial Rosuvastatin reduced incidence of CV endpoints but increased HbA1cand reported cases of T2DM (plt01)

            Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and

            disease

            Lactate Angiotensinogen

            Leptin

            Adipsin (Complement D)

            TNF- α

            FFAFat Stores

            Lipoprotein Lipase

            Plasminogen Activator Inhibitor 1

            (PAI-1)

            Resistin

            Adiponectin

            DM=diabetes mellitus FFA=free fatty acid PAI-1=plasminogen activator inhibitor-1 TNFα=tumor necrosis factor alpha IL-6=interleukin 6

            Slide copy2007Louis J Aronne MD after Dr G Bray

            Insulin

            IL - 6

            Estrogen

            Hypertension

            Thrombosis

            Inflammation

            Type 2 DM

            DyslipidemiaType 2 DM

            Arthritis

            ASCVD

            Asthma

            C-C L2

            Adiponectin Anti-atherogenicantidiabeticdarr darr foam cells darr vascular remodelling

            uarr insulin sensitivity darr hepatic glucose output

            IL-6uarr

            Pro-atherogenicpro-diabeticuarr vascular inflammation darr insulin signalling

            TNFαuarr

            Pro-atherogenicpro-diabeticdarr insulin sensitivity in adipocytes (paracrine)

            PAI-1uarr

            Pro-atherogenicuarr atherothrombotic risk

            IAA intra-abdominal adiposityMarette A Curr Opin Clin Nutr Metab Care 20025377-83

            Are You Treating These Drivers of Cardiometabolic Risk Should You Treat The Underlying Cause

            Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors

            Risk FactorsPhenTPMMid

            p-valuePhenTPMTop

            p-value

            CRP lt0001 lt0001Fibrinogen lt005 lt005Adiponectin lt00001 lt00001

            p-values represent comparisons to placebo

            ITT-LOCF Placebo Comparisons

            Gadde KM et al Lancet 2011377(9774)1341-52

            Mid = 75 mg46 mgTop = 15 mg92 mg

            In My Opinion The Winds of Change are Blowing in the Treatment of Chronic

            Diseasesbull ACCORD was stopped because of increased

            mortality in the tight control group 28 of whom gained gt 10kg compared to 14 in control^

            bull Bariatric surgery trials show gt 80 reduction in diabetes mortality with weight loss

            bull I believe we are in the midst of a shift from ldquoGlucocentricrdquo to ldquoWeight-Centricrdquo Management of T 2 DM

            ^ NEJM 3582545-2559 Adams TD et al N Engl J Med 2007357(8)753-761

            -34-48-48-88-59-29+73

            Adams TD et al N Engl J Med 2007357(8)753-761

            Bariatric Surgery Reduces Overall Mortality Diabetes Mortality by 88

            Matched SubjectsSurgery Group (n=7925)

            Co(n=

            ntrol Group7925)

            NoNo10000 person-yr No

            No10000 person-yr

            All causes of death 213 376 321 571All deaths caused by disease 150 265 285 507Cardiovascular diseases 55 97 104 185Diabetes 2 04 19 34Cancer 31 55 73 133Other diseases 62 11 89 155All non-disease causes 63 111 36 64Accident unrelated to drugs 21 37 17 30Poisoning of undetermined intent 9 16 4 07Suicide 15 26 5 09Other nondisease cause 18 32 10 18

            CC-18

            Health Care Costs Attributable to ObesityEstimates of what various conditions add to health-care service costs over a 12-month period

            $395

            $230

            $225

            $150

            $125

            $0 $100 $200 $300 $400 $500

            Obesity

            Smoking

            20 years aging

            Problem drinking

            Overweight

            Sturm R Health Aff (Millwood) 2002 Mar-Apr21(2)245-53 Table Wall Street Journal 3132002

            Obesity increased medication costs 77inpatient and outpatient costs 36

            What-if scenarios (The Lancet forthcoming)

            Redrawn from Hamman RF et al Diabetes Care 2006292102‐2107

            Change in Weight from Baseline (kg)0‐10 ‐5 +5In

            cide

            nce Ra

            te per 100

            Person‐Years

            10

            20

            15

            5

            0

            How Much Weight Loss Is Needed to Prevent T2DMndashNot Very Much The DPP Experience

            In the Da Qing Study 6-year Intervention Led to Lower Incidence of Type 2 Diabetes 14 Years Later

            n=530 overweight Chinese men and women with IGT mean BMI=26

            17

            0

            20

            40

            60

            80

            100

            2 4 6 8 10 12 14 16 18 20Years of follow‐up

            6‐year intervention hazard ratio = 049 (95 CI 033ndash073)20‐year follow‐up hazard ratio = 057 (95 CI 041ndash081)

            Cumulative Incide

            nce of Type 2 Diabe

            tes ()

            0

            Lifestyle interventionControl

            Treatment Follow‐up

            Li et al Lancet 20083711783ndash9

            Pharmacotherapy for Weight LossLouis J Aronne MD FACP

            Professor of Clinical Medicine Weill Cornell Medical College

            Adjunct Associate Professor of Clinical Medicine Columbia University College of Physicians and Surgeons

            Director Comprehensive Weight Control Program

            New York-Presbyterian HospitalWeill Cornell Medical Center New York NY

            As faculty of Weill Cornell Medical College we are committed to providing transparency for any and all external relationships prior to giving an academic presentation

            I am a consultant speaker advisor or receive research support fromBMS

            Arena Aspire BariatricsMyos

            GI Dynamics Novo NordiskOrexigenVivusZafgen

            I may discuss off-label use of medications

            Disclosure Page

            uarrFood intakedarr energy expenditure

            darrfood intake uarrenergy expenditure

            Topiramate

            Naltrexone

            LorcaserinPramlintideGLP-1Leptin

            BupropionPhentermine

            New Compounds andCombination Interventions

            c Louis J Aronne MDScience Feb 7 2003 Vol 299Illustration by Katharine Sutliff

            Phentermine and TopiramateExtended-Release

            bull Mechanism of actionndash Phentermine Sympathomimetic amine - releaserndash Topiramate Gabaergicglutamate modulation and carbonic

            anhydrase inhibitionbull February 2012 FDA advisory committee votes 20-2 for

            approval bull FDA approved July 2012

            ndash Schedule IVndash Pregnancy Category X = REMS

            Topiramate monotherapy exposure in pregnancy associated with 2- to 5-fold increased prevalence of oral clefts

            bull 4 doses Titrate upbull Available only by mail orderbull Covered through Medco Express Scripts

            Phentermine and TopiramateExtended-Release

            bull Dose titrationndash Once dailyndash Start treatment with phentermine 375 mgtopiramate

            23 mg extended-release daily for 14 daysndash After 14 days increase to the recommended dose of

            phentermine 75 mgtopiramate 46 mg extended-release once daily

            ndash May titrate upwards if needed to phen 15 top 92 mg strength

            EQUIP amp CONQUER Discontinuation RateDue to AEs in All Doses Studied

            Placebo Low Mid Full

            Number of patients 1508 241 498 1507Discontinuation due to AEs 9 12 12 18Blurred vision 05 21 08 07Headache 07 17 02 09Insomnia 04 00 04 17Depression 02 00 08 14Tingling 00 04 10 12Irritability 01 08 08 12Anxiety 03 00 02 11Dizziness 02 04 12 08

            Includes adverse events (AEs) by dose for EQUIP amp CONQUER which lead to discontinuation in gt 1 of patientsPress release Sept 9 2009 Available at httpirvivuscomreleasedetailcfmReleaseID=420114Accessed April 27 2010

            PhenTPMMid

            -104

            Phentermine and Topiramate SEQUELWeight Loss Over Time

            Garvey WT Ryan DH Look M Gadde KM Am J Clin Nutr 201295(2)297-308

            Placebo-25

            Plt00001 v placebo

            Weight Loss

            Week

            Total Population

            0

            -2

            -4

            -6

            -8

            -10

            -12

            -14

            -16

            0 12 24 36 48 60 72 84 96 108

            Weight Loss ITT-LOCF

            PhenTPMTop

            -114

            Mid = 75 mg46 mgTop = 15 mg92 mg

            CONQUER Significant Improvement in Cardiovascular Risk Factors

            (LS Mean Wt Loss)

            QNEXAMid(78)

            P valueQNEXATop

            (98) P value

            Waist Circumference (cm) ‐52 lt00001 ‐68 lt00001

            Systolic BP (mmHg) ‐23 00008 ‐32 lt00001

            Diastolic BP (mmHg) ‐07 NS ‐11 00031

            Triglycerides ( ∆) ‐133 lt00001 ‐153 lt00001

            Total Cholesterol ( ∆) ‐16 00345 ‐30 lt00001

            LDL ( ∆) 04 NS ‐28 00069

            HDL ( ∆) 40 lt00001 56 lt00001

            P values represent comparisons to placebo NS= non‐significant

            ITT‐LOCF Placebo ComparisonsTotal Study Population

            Davidson MH et al Am J Cardiol 2013 Jan 29 pii S0002‐9149(12)02641‐0 doi 101016jamjcard201212038

            Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors

            Risk FactorsPhenTPMMid

            p-valuePhenTPMTop

            p-value

            CRP lt0001 lt0001Fibrinogen lt005 lt005Adiponectin lt00001 lt00001

            p-values represent comparisons to placebo

            ITT-LOCF Placebo Comparisons

            Gadde KM et al Lancet 2011377(9774)1341-52

            Mid = 75 mg46 mgTop = 15 mg92 mg

            Lorcaserin

            bull Selective 5‐HT2C receptor agonist designed to promote weight loss

            bull Schedule IV ndash Expected soonbull Indication weight loss and maintenance of

            weight loss in patients with BMI gt30 kgm2 or BMI gt27 kgm2 + weight-related comorbidcondition(s)

            bull Dose - 10 mg BIDbull Most common side effects headache nausea

            dizziness dry mouth

            BLOOM Study Body Weight Over Years 1 and 2

            Smith SR et al N Engl J Med 2010363245-256 Study Week0 8 16 24 32 40 48 56 64 72 80 88 96 104

            Bod

            y W

            eigh

            t (kg

            )

            102

            100

            98

            96

            94

            92

            90

            0

            Year 1

            Placebo in year 1 and 2 (n = 684)Lorcaserin in year 1 placebo in year 2 (n = 275)Lorcaserin in year 1 and 2 (n = 564)

            Year 2

            Endpoint Lorcaserin Placebo P valueWaist circumference (cm) minus68plusmn02 minus39plusmn02 lt001BMI (kgm2) minus209plusmn006 minus078plusmn005 lt001SBPDBP (mm Hg) minus14plusmn03minus11plusmn02 minus08plusmn03minus06plusmn02 0401Cholesterol ( ∆)Total LDLHDL

            minus090plusmn033287plusmn056005plusmn033

            057plusmn034403plusmn058minus021plusmn034

            001

            049

            72Triglycerides minus615plusmn103 minus014plusmn099 lt001SafetyHR (beatsmin)PASP (mm Hg)Beck depression II score

            minus20plusmn03minus092plusmn023minus11plusmn01

            minus16plusmn04 minus023plusmn023 minus09plusmn01

            0499014026

            BLOOM StudyKey Secondary Endpoints

            Smith SR et al N Engl J Med 2010363245-256

            BLOOM-DMChange in Glycemic Parameters

            P lt001 P lt05 LS mean change plusmn SEMOrsquoNeil PM et al Obesity 201220(7)1426-36 httpwwwnaturecomdoifinder101038oby201266

            00

            -05

            -10

            -150 12 24 36 52

            Cha

            nge

            from

            bas

            elin

            e (

            )

            A1c

            Study week

            0

            -10

            -20

            -30

            -400 12 24 52

            Cha

            nge

            from

            bas

            elin

            e m

            gdl

            )

            Fasting plasma glucose

            Study week

            Lorcaserin 10 mg BID Lorcaserin 10 mg Placebo

            Lorcaserin Adverse Events Reported by 5 or More in Any Group in Year 1

            55

            N () Lorcaserin(N = 1593)

            Placebo(N = 1584)

            Headache 287 (180) 175 (110)

            Dizziness 130 (82) 60 (38)

            Nausea 119 (75) 85 (54)

            Constipation 106 (67) 64 (40)

            Fatigue 95 (60) 48 (30)

            Dry mouth 83 (52) 37 (23)

            Smith SR et al ADA 2009 Late‐Breaking Abstract 96

            LorcaserinNo Increase in Rate of Valvulopathy

            Smith SR et al N Engl J Med 2010363245-256

            10

            8

            6

            4

            2

            024 52 76 104

            1351714

            9

            19

            3421Patie

            nts

            ()

            Week

            Lorcaserin in yr 1 and 2

            Lorcaserin in yr 1 Placebo in yr 2

            Placebo in yr 1 and 2

            Phase III Study Outcomes Compared

            Buproprion SR (360 mgd) Naltrexone SR (32 mgd)

            Lorcaserin(20 mgd)

            Phentermine Topiramate CR

            COR1 COR-I2 COR-II3 NB3043 BLOOM4 BLOSSOM5 EQUIP CONQUER

            Number of patients (ITT-LOCF)

            793 obese 1453 obese

            1281 obese

            502 type II diabetes

            3182 obese 4008 obese

            1230 obese BMI 44

            2448 comorbidBMI 36

            Mean change compared with placebo from base

            93 vs5 1c

            61a vs13c

            64a vs12

            50 a vs12c

            58 vs22c

            48 vs28c

            11 Fullbvs 16

            104 Fullb 84 Midb

            vs 18

            51 Lowb vs16c

            Categorical change 5 compared with placebo from base

            56 vs43

            48a vs164

            563a

            vs 171445a vs189

            475b

            vs 203472b vs25

            67 Fullb 45 Lowb vs17

            70 Fullb 62 Midb

            vs 21

            Phenterminetopiramate doses Low 375 mg phentermine23 mg topiramate Mid 75 mg phentermine 46 mg topiramate Full 15 mg phentermine 92 mg topiramateITT-LOCF intent-to-treat last observation carried forwardData not available aP lt 001 vs placebo bP lt 0001 vs placebo

            Obesity Treatments in Late Development

            Kushner RF Expert Opin Pharmacother 200891339-1350

            Agents ActionBupropionNaltrexone

            bull Dopaminenoradrenaline reuptake inhibitorbull Opioid receptor antagonist

            Liraglutide bull GLP-1 agonist

            BupropionNaltrexone

            bull Mechanism of Actionndash Bupropion - Dopaminenoradrenaline reuptake inhibitorndash Naltrexone- Opioid receptor antagonist

            bull Was approved by FDA committee but FDA did not approve until a CV outcome study is performed 2nd concerns about BP and P in some patients

            bull The Light Study is now underway and reported to be enrolling well under PI Dr Nissen

            bull BupropionNaltrexone will have first completed CV outcome study

            Buproprion ndash Naltrexone

            Greenway FL et al Lancet 2010376(9741)595-605

            0

            -2

            -4

            -6

            -8

            -100 4 8 12 16 20 24 28 32 36 40 44 48 52 56

            Weeks

            Wei

            ght c

            hang

            e fro

            m b

            asel

            ine

            ()

            Placebo

            Naltrexone 16 mg plus bupropion

            Naltrexone 32 mg plus bupropion

            Liraglutide for Weight Loss in Patients with Type 2 Diabetes

            bull GLP-1 analog approved for treatment of type 2 diabetes

            bull Anorectic effect mediated both by the activation of GLP-1 receptor expressed on vagal afferents and by the GLP-1R activation in CNS

            bull Affects visceral fat adiposity appetite food preference and cardiovascular biomarkers in patients with type 2 diabetes

            Inoue K et al Cardiovasc Diabetol 2011 10109 doi1011861475-2840-10-109

            Liraglutide Weight Loss Over 2 Years ITT Observed Means

            Astrup A et al Int J Obes (Lond) 201236(6)843-54

            FromScreening

            -94 kg

            -67 kg-88 kg

            -99 kg-94 kg

            -103 kg

            ITT intention to treat

            Phase III Study Outcomes Compared

            Buproprion SR (360 mgd) Naltrexone SR (32 mgd)

            Lorcaserin(20 mgd)

            Phentermine Topiramate CR

            COR1 COR-I2 COR-II3 NB3043 BLOOM4 BLOSSOM5 EQUIP CONQUER

            Number of patients (ITT-LOCF)

            793 obese 1453 obese

            1281 obese

            502 type II diabetes

            3182 obese 4008 obese

            1230 obese BMI 44

            2448 comorbidBMI 36

            Mean change compared with placebo from base

            93 vs5 1c

            61a vs13c

            64a vs12

            50 a vs12c

            58 vs22c

            48 vs28c

            11 Fullbvs 16

            104 Fullb 84 Midb

            vs 18

            51 Lowb vs16c

            Categorical change 5 compared with placebo from base

            56 vs43

            48a vs164

            563a

            vs 171445a vs189

            475b

            vs 203472b vs25

            67 Fullb 45 Lowb vs17

            70 Fullb 62 Midb

            vs 21

            Phenterminetopiramate doses Low 375 mg phentermine23 mg topiramate Mid 75 mg phentermine 46 mg topiramate Full 15 mg phentermine 92 mg topiramateITT-LOCF intent-to-treat last observation carried forwardData not available aP lt 001 vs placebo bP lt 0001 vs placebo

            Treatment Gap in theManagement of Obesity

            Physicians Need Effective Pharmacotherapies That Will Reduce Weight Significantly and Reduce Weight-related Comorbidities

            0 5 10 15 20 25 30 35

            Diet and Lifestyle Lap Band Gastric Bypass

            TreatmentGap

            What will fill the gap

            Too risky for many peopleNot effective enoughfor many people

            Treatment Gap in theManagement of Obesity

            0 5 10 15 20 25 30 35

            Diet and Lifestyle Lap Band Gastric Bypass

            TreatmentGap

            Too risky for many peopleNot effective enoughfor many people Pharmacotherapy

            Less invasive procedures

            Physicians Need Effective Pharmacotherapies That Will Reduce Weight Significantly and Reduce Weight-related Comorbidities

            What will fill the gap

            • Slide Number 1
            • Slide Number 2
            • Weight Management is Moving into the Workplace and Mainstream of Healthcare
            • US Preventative Services Task Force
            • A Proposal from CMS about Coverage for Intensive Behavioral Therapy for Obesity
            • Slide Number 6
            • Biggest Increases in Clinically Severe Obesity US 1987-2005
            • Relationship Between BMI and Risk of Type 2 Diabetes
            • Slide Number 9
            • Medical Complications of Obesity Almost every organ system is affected
            • Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and disease
            • Current Therapies Often Address Individual Risk Factors Cardiometabolic risk
            • Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and disease
            • Are You Treating These Drivers of Cardiometabolic Risk Should You Treat The Underlying Cause
            • Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors
            • In My Opinion The Winds of Change are Blowing in the Treatment of Chronic Diseases
            • Bariatric Surgery Reduces Overall Mortality Diabetes Mortality by 88
            • Health Care Costs Attributable to ObesityEstimates of what various conditions add to health-care service costs over a 12-month period
            • What-if scenarios (The Lancet forthcoming)
            • How Much Weight Loss Is Needed to Prevent T2DMndashNot Very Much The DPP Experience
            • In the Da Qing Study 6-year Intervention Led to Lower Incidence of Type 2 Diabetes 14 Years Later
            • Slide Number 22
            • Slide Number 23
            • New Compounds andCombination Interventions
            • Phentermine and Topiramate Extended-Release
            • Phentermine and Topiramate Extended-Release
            • EQUIP amp CONQUER Discontinuation RateDue to AEs in All Doses Studied
            • Phentermine and Topiramate SEQUELWeight Loss Over Time
            • CONQUER Significant Improvement in Cardiovascular Risk Factors
            • Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors
            • Lorcaserin
            • BLOOM Study Body Weight Over Years 1 and 2
            • BLOOM StudyKey Secondary Endpoints
            • BLOOM-DMChange in Glycemic Parameters
            • Lorcaserin Adverse Events Reported by 5 or More in Any Group in Year 1
            • LorcaserinNo Increase in Rate of Valvulopathy
            • Phase III Study Outcomes Compared
            • Obesity Treatments in Late Development
            • BupropionNaltrexone
            • Buproprion ndash Naltrexone
            • Liraglutide for Weight Loss in Patients with Type 2 Diabetes
            • Liraglutide Weight Loss Over 2 Years ITT Observed Means
            • Phase III Study Outcomes Compared
            • Treatment Gap in theManagement of Obesity
            • Treatment Gap in theManagement of Obesity

              Relationship Between BMI and Risk of Type 2 Diabetes

              Chan J et al Diabetes Care 199417961Colditz G et al Ann Intern Med 1995122481

              Age

              -Adj

              uste

              d R

              elat

              ive

              Ris

              k

              Body Mass Index (kgm2)

              Women

              Men

              lt22 lt23 23ndash239

              24ndash249

              25ndash269

              27ndash289

              29ndash309

              31ndash329

              33ndash349

              35+

              102910

              4310

              5015

              8122

              158

              44

              276

              403

              540

              932

              67 116

              213

              421

              100

              75

              50

              25

              0

              Why Should I Treat Obesity

              Medical Complications of Obesity Almost every organ system is affected

              Phlebitisvenous stasis

              Coronary heart disease

              Pulmonary diseaseasthmaobstructive sleep apneahypoventilation syndrome

              Gall bladder diseaseReproductive abnormalitiesabnormal mensesinfertilitypolycystic ovarian syndrome

              Gout

              Stroke

              Diabetes

              Osteoarthritis

              Cancerbreast uterus cervixcolon esophagus pancreaskidney prostate

              Nonalcoholic fatty liver diseasesteatosissteatohepatitiscirrhosis Hypertension

              Dyslipidemia

              Cataracts

              Skin

              Idiopathic intracranial hypertension

              Severe pancreatitis

              Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and

              disease

              Lactate Angiotensinogen

              Leptin

              Adipsin (Complement D)

              TNF- α

              FFAFat Stores

              Lipoprotein Lipase

              Plasminogen Activator Inhibitor 1

              (PAI-1)

              Resistin

              Adiponectin

              DM=diabetes mellitus FFA=free fatty acid PAI-1=plasminogen activator inhibitor-1 TNFα=tumor necrosis factor alpha IL-6=interleukin 6

              Slide copy2007Louis J Aronne MD after Dr G Bray

              Insulin

              IL - 6

              Estrogen

              Hypertension

              Thrombosis

              Inflammation

              Type 2 DM

              DyslipidemiaType 2 DM

              Arthritis

              ASCVD

              Asthma

              C-C L2

              Waist circumference

              Blood pressure

              Blood glucose

              Triglycerides

              HDL-cholesterol

              LDL-cholesterol

              Insulin resistance

              Thrombotic risk

              Current Therapies Often Address Individual Risk Factors Cardiometabolic risk

              NCEP ATP IIIdefinitionof themetabolicsyndrome

              Antihypertensives

              Oral antidiabetic agents

              Antiplatelet agents

              Lipid modifiers

              Insulin sensitizers

              Jupiter Trial Rosuvastatin reduced incidence of CV endpoints but increased HbA1cand reported cases of T2DM (plt01)

              Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and

              disease

              Lactate Angiotensinogen

              Leptin

              Adipsin (Complement D)

              TNF- α

              FFAFat Stores

              Lipoprotein Lipase

              Plasminogen Activator Inhibitor 1

              (PAI-1)

              Resistin

              Adiponectin

              DM=diabetes mellitus FFA=free fatty acid PAI-1=plasminogen activator inhibitor-1 TNFα=tumor necrosis factor alpha IL-6=interleukin 6

              Slide copy2007Louis J Aronne MD after Dr G Bray

              Insulin

              IL - 6

              Estrogen

              Hypertension

              Thrombosis

              Inflammation

              Type 2 DM

              DyslipidemiaType 2 DM

              Arthritis

              ASCVD

              Asthma

              C-C L2

              Adiponectin Anti-atherogenicantidiabeticdarr darr foam cells darr vascular remodelling

              uarr insulin sensitivity darr hepatic glucose output

              IL-6uarr

              Pro-atherogenicpro-diabeticuarr vascular inflammation darr insulin signalling

              TNFαuarr

              Pro-atherogenicpro-diabeticdarr insulin sensitivity in adipocytes (paracrine)

              PAI-1uarr

              Pro-atherogenicuarr atherothrombotic risk

              IAA intra-abdominal adiposityMarette A Curr Opin Clin Nutr Metab Care 20025377-83

              Are You Treating These Drivers of Cardiometabolic Risk Should You Treat The Underlying Cause

              Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors

              Risk FactorsPhenTPMMid

              p-valuePhenTPMTop

              p-value

              CRP lt0001 lt0001Fibrinogen lt005 lt005Adiponectin lt00001 lt00001

              p-values represent comparisons to placebo

              ITT-LOCF Placebo Comparisons

              Gadde KM et al Lancet 2011377(9774)1341-52

              Mid = 75 mg46 mgTop = 15 mg92 mg

              In My Opinion The Winds of Change are Blowing in the Treatment of Chronic

              Diseasesbull ACCORD was stopped because of increased

              mortality in the tight control group 28 of whom gained gt 10kg compared to 14 in control^

              bull Bariatric surgery trials show gt 80 reduction in diabetes mortality with weight loss

              bull I believe we are in the midst of a shift from ldquoGlucocentricrdquo to ldquoWeight-Centricrdquo Management of T 2 DM

              ^ NEJM 3582545-2559 Adams TD et al N Engl J Med 2007357(8)753-761

              -34-48-48-88-59-29+73

              Adams TD et al N Engl J Med 2007357(8)753-761

              Bariatric Surgery Reduces Overall Mortality Diabetes Mortality by 88

              Matched SubjectsSurgery Group (n=7925)

              Co(n=

              ntrol Group7925)

              NoNo10000 person-yr No

              No10000 person-yr

              All causes of death 213 376 321 571All deaths caused by disease 150 265 285 507Cardiovascular diseases 55 97 104 185Diabetes 2 04 19 34Cancer 31 55 73 133Other diseases 62 11 89 155All non-disease causes 63 111 36 64Accident unrelated to drugs 21 37 17 30Poisoning of undetermined intent 9 16 4 07Suicide 15 26 5 09Other nondisease cause 18 32 10 18

              CC-18

              Health Care Costs Attributable to ObesityEstimates of what various conditions add to health-care service costs over a 12-month period

              $395

              $230

              $225

              $150

              $125

              $0 $100 $200 $300 $400 $500

              Obesity

              Smoking

              20 years aging

              Problem drinking

              Overweight

              Sturm R Health Aff (Millwood) 2002 Mar-Apr21(2)245-53 Table Wall Street Journal 3132002

              Obesity increased medication costs 77inpatient and outpatient costs 36

              What-if scenarios (The Lancet forthcoming)

              Redrawn from Hamman RF et al Diabetes Care 2006292102‐2107

              Change in Weight from Baseline (kg)0‐10 ‐5 +5In

              cide

              nce Ra

              te per 100

              Person‐Years

              10

              20

              15

              5

              0

              How Much Weight Loss Is Needed to Prevent T2DMndashNot Very Much The DPP Experience

              In the Da Qing Study 6-year Intervention Led to Lower Incidence of Type 2 Diabetes 14 Years Later

              n=530 overweight Chinese men and women with IGT mean BMI=26

              17

              0

              20

              40

              60

              80

              100

              2 4 6 8 10 12 14 16 18 20Years of follow‐up

              6‐year intervention hazard ratio = 049 (95 CI 033ndash073)20‐year follow‐up hazard ratio = 057 (95 CI 041ndash081)

              Cumulative Incide

              nce of Type 2 Diabe

              tes ()

              0

              Lifestyle interventionControl

              Treatment Follow‐up

              Li et al Lancet 20083711783ndash9

              Pharmacotherapy for Weight LossLouis J Aronne MD FACP

              Professor of Clinical Medicine Weill Cornell Medical College

              Adjunct Associate Professor of Clinical Medicine Columbia University College of Physicians and Surgeons

              Director Comprehensive Weight Control Program

              New York-Presbyterian HospitalWeill Cornell Medical Center New York NY

              As faculty of Weill Cornell Medical College we are committed to providing transparency for any and all external relationships prior to giving an academic presentation

              I am a consultant speaker advisor or receive research support fromBMS

              Arena Aspire BariatricsMyos

              GI Dynamics Novo NordiskOrexigenVivusZafgen

              I may discuss off-label use of medications

              Disclosure Page

              uarrFood intakedarr energy expenditure

              darrfood intake uarrenergy expenditure

              Topiramate

              Naltrexone

              LorcaserinPramlintideGLP-1Leptin

              BupropionPhentermine

              New Compounds andCombination Interventions

              c Louis J Aronne MDScience Feb 7 2003 Vol 299Illustration by Katharine Sutliff

              Phentermine and TopiramateExtended-Release

              bull Mechanism of actionndash Phentermine Sympathomimetic amine - releaserndash Topiramate Gabaergicglutamate modulation and carbonic

              anhydrase inhibitionbull February 2012 FDA advisory committee votes 20-2 for

              approval bull FDA approved July 2012

              ndash Schedule IVndash Pregnancy Category X = REMS

              Topiramate monotherapy exposure in pregnancy associated with 2- to 5-fold increased prevalence of oral clefts

              bull 4 doses Titrate upbull Available only by mail orderbull Covered through Medco Express Scripts

              Phentermine and TopiramateExtended-Release

              bull Dose titrationndash Once dailyndash Start treatment with phentermine 375 mgtopiramate

              23 mg extended-release daily for 14 daysndash After 14 days increase to the recommended dose of

              phentermine 75 mgtopiramate 46 mg extended-release once daily

              ndash May titrate upwards if needed to phen 15 top 92 mg strength

              EQUIP amp CONQUER Discontinuation RateDue to AEs in All Doses Studied

              Placebo Low Mid Full

              Number of patients 1508 241 498 1507Discontinuation due to AEs 9 12 12 18Blurred vision 05 21 08 07Headache 07 17 02 09Insomnia 04 00 04 17Depression 02 00 08 14Tingling 00 04 10 12Irritability 01 08 08 12Anxiety 03 00 02 11Dizziness 02 04 12 08

              Includes adverse events (AEs) by dose for EQUIP amp CONQUER which lead to discontinuation in gt 1 of patientsPress release Sept 9 2009 Available at httpirvivuscomreleasedetailcfmReleaseID=420114Accessed April 27 2010

              PhenTPMMid

              -104

              Phentermine and Topiramate SEQUELWeight Loss Over Time

              Garvey WT Ryan DH Look M Gadde KM Am J Clin Nutr 201295(2)297-308

              Placebo-25

              Plt00001 v placebo

              Weight Loss

              Week

              Total Population

              0

              -2

              -4

              -6

              -8

              -10

              -12

              -14

              -16

              0 12 24 36 48 60 72 84 96 108

              Weight Loss ITT-LOCF

              PhenTPMTop

              -114

              Mid = 75 mg46 mgTop = 15 mg92 mg

              CONQUER Significant Improvement in Cardiovascular Risk Factors

              (LS Mean Wt Loss)

              QNEXAMid(78)

              P valueQNEXATop

              (98) P value

              Waist Circumference (cm) ‐52 lt00001 ‐68 lt00001

              Systolic BP (mmHg) ‐23 00008 ‐32 lt00001

              Diastolic BP (mmHg) ‐07 NS ‐11 00031

              Triglycerides ( ∆) ‐133 lt00001 ‐153 lt00001

              Total Cholesterol ( ∆) ‐16 00345 ‐30 lt00001

              LDL ( ∆) 04 NS ‐28 00069

              HDL ( ∆) 40 lt00001 56 lt00001

              P values represent comparisons to placebo NS= non‐significant

              ITT‐LOCF Placebo ComparisonsTotal Study Population

              Davidson MH et al Am J Cardiol 2013 Jan 29 pii S0002‐9149(12)02641‐0 doi 101016jamjcard201212038

              Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors

              Risk FactorsPhenTPMMid

              p-valuePhenTPMTop

              p-value

              CRP lt0001 lt0001Fibrinogen lt005 lt005Adiponectin lt00001 lt00001

              p-values represent comparisons to placebo

              ITT-LOCF Placebo Comparisons

              Gadde KM et al Lancet 2011377(9774)1341-52

              Mid = 75 mg46 mgTop = 15 mg92 mg

              Lorcaserin

              bull Selective 5‐HT2C receptor agonist designed to promote weight loss

              bull Schedule IV ndash Expected soonbull Indication weight loss and maintenance of

              weight loss in patients with BMI gt30 kgm2 or BMI gt27 kgm2 + weight-related comorbidcondition(s)

              bull Dose - 10 mg BIDbull Most common side effects headache nausea

              dizziness dry mouth

              BLOOM Study Body Weight Over Years 1 and 2

              Smith SR et al N Engl J Med 2010363245-256 Study Week0 8 16 24 32 40 48 56 64 72 80 88 96 104

              Bod

              y W

              eigh

              t (kg

              )

              102

              100

              98

              96

              94

              92

              90

              0

              Year 1

              Placebo in year 1 and 2 (n = 684)Lorcaserin in year 1 placebo in year 2 (n = 275)Lorcaserin in year 1 and 2 (n = 564)

              Year 2

              Endpoint Lorcaserin Placebo P valueWaist circumference (cm) minus68plusmn02 minus39plusmn02 lt001BMI (kgm2) minus209plusmn006 minus078plusmn005 lt001SBPDBP (mm Hg) minus14plusmn03minus11plusmn02 minus08plusmn03minus06plusmn02 0401Cholesterol ( ∆)Total LDLHDL

              minus090plusmn033287plusmn056005plusmn033

              057plusmn034403plusmn058minus021plusmn034

              001

              049

              72Triglycerides minus615plusmn103 minus014plusmn099 lt001SafetyHR (beatsmin)PASP (mm Hg)Beck depression II score

              minus20plusmn03minus092plusmn023minus11plusmn01

              minus16plusmn04 minus023plusmn023 minus09plusmn01

              0499014026

              BLOOM StudyKey Secondary Endpoints

              Smith SR et al N Engl J Med 2010363245-256

              BLOOM-DMChange in Glycemic Parameters

              P lt001 P lt05 LS mean change plusmn SEMOrsquoNeil PM et al Obesity 201220(7)1426-36 httpwwwnaturecomdoifinder101038oby201266

              00

              -05

              -10

              -150 12 24 36 52

              Cha

              nge

              from

              bas

              elin

              e (

              )

              A1c

              Study week

              0

              -10

              -20

              -30

              -400 12 24 52

              Cha

              nge

              from

              bas

              elin

              e m

              gdl

              )

              Fasting plasma glucose

              Study week

              Lorcaserin 10 mg BID Lorcaserin 10 mg Placebo

              Lorcaserin Adverse Events Reported by 5 or More in Any Group in Year 1

              55

              N () Lorcaserin(N = 1593)

              Placebo(N = 1584)

              Headache 287 (180) 175 (110)

              Dizziness 130 (82) 60 (38)

              Nausea 119 (75) 85 (54)

              Constipation 106 (67) 64 (40)

              Fatigue 95 (60) 48 (30)

              Dry mouth 83 (52) 37 (23)

              Smith SR et al ADA 2009 Late‐Breaking Abstract 96

              LorcaserinNo Increase in Rate of Valvulopathy

              Smith SR et al N Engl J Med 2010363245-256

              10

              8

              6

              4

              2

              024 52 76 104

              1351714

              9

              19

              3421Patie

              nts

              ()

              Week

              Lorcaserin in yr 1 and 2

              Lorcaserin in yr 1 Placebo in yr 2

              Placebo in yr 1 and 2

              Phase III Study Outcomes Compared

              Buproprion SR (360 mgd) Naltrexone SR (32 mgd)

              Lorcaserin(20 mgd)

              Phentermine Topiramate CR

              COR1 COR-I2 COR-II3 NB3043 BLOOM4 BLOSSOM5 EQUIP CONQUER

              Number of patients (ITT-LOCF)

              793 obese 1453 obese

              1281 obese

              502 type II diabetes

              3182 obese 4008 obese

              1230 obese BMI 44

              2448 comorbidBMI 36

              Mean change compared with placebo from base

              93 vs5 1c

              61a vs13c

              64a vs12

              50 a vs12c

              58 vs22c

              48 vs28c

              11 Fullbvs 16

              104 Fullb 84 Midb

              vs 18

              51 Lowb vs16c

              Categorical change 5 compared with placebo from base

              56 vs43

              48a vs164

              563a

              vs 171445a vs189

              475b

              vs 203472b vs25

              67 Fullb 45 Lowb vs17

              70 Fullb 62 Midb

              vs 21

              Phenterminetopiramate doses Low 375 mg phentermine23 mg topiramate Mid 75 mg phentermine 46 mg topiramate Full 15 mg phentermine 92 mg topiramateITT-LOCF intent-to-treat last observation carried forwardData not available aP lt 001 vs placebo bP lt 0001 vs placebo

              Obesity Treatments in Late Development

              Kushner RF Expert Opin Pharmacother 200891339-1350

              Agents ActionBupropionNaltrexone

              bull Dopaminenoradrenaline reuptake inhibitorbull Opioid receptor antagonist

              Liraglutide bull GLP-1 agonist

              BupropionNaltrexone

              bull Mechanism of Actionndash Bupropion - Dopaminenoradrenaline reuptake inhibitorndash Naltrexone- Opioid receptor antagonist

              bull Was approved by FDA committee but FDA did not approve until a CV outcome study is performed 2nd concerns about BP and P in some patients

              bull The Light Study is now underway and reported to be enrolling well under PI Dr Nissen

              bull BupropionNaltrexone will have first completed CV outcome study

              Buproprion ndash Naltrexone

              Greenway FL et al Lancet 2010376(9741)595-605

              0

              -2

              -4

              -6

              -8

              -100 4 8 12 16 20 24 28 32 36 40 44 48 52 56

              Weeks

              Wei

              ght c

              hang

              e fro

              m b

              asel

              ine

              ()

              Placebo

              Naltrexone 16 mg plus bupropion

              Naltrexone 32 mg plus bupropion

              Liraglutide for Weight Loss in Patients with Type 2 Diabetes

              bull GLP-1 analog approved for treatment of type 2 diabetes

              bull Anorectic effect mediated both by the activation of GLP-1 receptor expressed on vagal afferents and by the GLP-1R activation in CNS

              bull Affects visceral fat adiposity appetite food preference and cardiovascular biomarkers in patients with type 2 diabetes

              Inoue K et al Cardiovasc Diabetol 2011 10109 doi1011861475-2840-10-109

              Liraglutide Weight Loss Over 2 Years ITT Observed Means

              Astrup A et al Int J Obes (Lond) 201236(6)843-54

              FromScreening

              -94 kg

              -67 kg-88 kg

              -99 kg-94 kg

              -103 kg

              ITT intention to treat

              Phase III Study Outcomes Compared

              Buproprion SR (360 mgd) Naltrexone SR (32 mgd)

              Lorcaserin(20 mgd)

              Phentermine Topiramate CR

              COR1 COR-I2 COR-II3 NB3043 BLOOM4 BLOSSOM5 EQUIP CONQUER

              Number of patients (ITT-LOCF)

              793 obese 1453 obese

              1281 obese

              502 type II diabetes

              3182 obese 4008 obese

              1230 obese BMI 44

              2448 comorbidBMI 36

              Mean change compared with placebo from base

              93 vs5 1c

              61a vs13c

              64a vs12

              50 a vs12c

              58 vs22c

              48 vs28c

              11 Fullbvs 16

              104 Fullb 84 Midb

              vs 18

              51 Lowb vs16c

              Categorical change 5 compared with placebo from base

              56 vs43

              48a vs164

              563a

              vs 171445a vs189

              475b

              vs 203472b vs25

              67 Fullb 45 Lowb vs17

              70 Fullb 62 Midb

              vs 21

              Phenterminetopiramate doses Low 375 mg phentermine23 mg topiramate Mid 75 mg phentermine 46 mg topiramate Full 15 mg phentermine 92 mg topiramateITT-LOCF intent-to-treat last observation carried forwardData not available aP lt 001 vs placebo bP lt 0001 vs placebo

              Treatment Gap in theManagement of Obesity

              Physicians Need Effective Pharmacotherapies That Will Reduce Weight Significantly and Reduce Weight-related Comorbidities

              0 5 10 15 20 25 30 35

              Diet and Lifestyle Lap Band Gastric Bypass

              TreatmentGap

              What will fill the gap

              Too risky for many peopleNot effective enoughfor many people

              Treatment Gap in theManagement of Obesity

              0 5 10 15 20 25 30 35

              Diet and Lifestyle Lap Band Gastric Bypass

              TreatmentGap

              Too risky for many peopleNot effective enoughfor many people Pharmacotherapy

              Less invasive procedures

              Physicians Need Effective Pharmacotherapies That Will Reduce Weight Significantly and Reduce Weight-related Comorbidities

              What will fill the gap

              • Slide Number 1
              • Slide Number 2
              • Weight Management is Moving into the Workplace and Mainstream of Healthcare
              • US Preventative Services Task Force
              • A Proposal from CMS about Coverage for Intensive Behavioral Therapy for Obesity
              • Slide Number 6
              • Biggest Increases in Clinically Severe Obesity US 1987-2005
              • Relationship Between BMI and Risk of Type 2 Diabetes
              • Slide Number 9
              • Medical Complications of Obesity Almost every organ system is affected
              • Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and disease
              • Current Therapies Often Address Individual Risk Factors Cardiometabolic risk
              • Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and disease
              • Are You Treating These Drivers of Cardiometabolic Risk Should You Treat The Underlying Cause
              • Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors
              • In My Opinion The Winds of Change are Blowing in the Treatment of Chronic Diseases
              • Bariatric Surgery Reduces Overall Mortality Diabetes Mortality by 88
              • Health Care Costs Attributable to ObesityEstimates of what various conditions add to health-care service costs over a 12-month period
              • What-if scenarios (The Lancet forthcoming)
              • How Much Weight Loss Is Needed to Prevent T2DMndashNot Very Much The DPP Experience
              • In the Da Qing Study 6-year Intervention Led to Lower Incidence of Type 2 Diabetes 14 Years Later
              • Slide Number 22
              • Slide Number 23
              • New Compounds andCombination Interventions
              • Phentermine and Topiramate Extended-Release
              • Phentermine and Topiramate Extended-Release
              • EQUIP amp CONQUER Discontinuation RateDue to AEs in All Doses Studied
              • Phentermine and Topiramate SEQUELWeight Loss Over Time
              • CONQUER Significant Improvement in Cardiovascular Risk Factors
              • Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors
              • Lorcaserin
              • BLOOM Study Body Weight Over Years 1 and 2
              • BLOOM StudyKey Secondary Endpoints
              • BLOOM-DMChange in Glycemic Parameters
              • Lorcaserin Adverse Events Reported by 5 or More in Any Group in Year 1
              • LorcaserinNo Increase in Rate of Valvulopathy
              • Phase III Study Outcomes Compared
              • Obesity Treatments in Late Development
              • BupropionNaltrexone
              • Buproprion ndash Naltrexone
              • Liraglutide for Weight Loss in Patients with Type 2 Diabetes
              • Liraglutide Weight Loss Over 2 Years ITT Observed Means
              • Phase III Study Outcomes Compared
              • Treatment Gap in theManagement of Obesity
              • Treatment Gap in theManagement of Obesity

                Why Should I Treat Obesity

                Medical Complications of Obesity Almost every organ system is affected

                Phlebitisvenous stasis

                Coronary heart disease

                Pulmonary diseaseasthmaobstructive sleep apneahypoventilation syndrome

                Gall bladder diseaseReproductive abnormalitiesabnormal mensesinfertilitypolycystic ovarian syndrome

                Gout

                Stroke

                Diabetes

                Osteoarthritis

                Cancerbreast uterus cervixcolon esophagus pancreaskidney prostate

                Nonalcoholic fatty liver diseasesteatosissteatohepatitiscirrhosis Hypertension

                Dyslipidemia

                Cataracts

                Skin

                Idiopathic intracranial hypertension

                Severe pancreatitis

                Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and

                disease

                Lactate Angiotensinogen

                Leptin

                Adipsin (Complement D)

                TNF- α

                FFAFat Stores

                Lipoprotein Lipase

                Plasminogen Activator Inhibitor 1

                (PAI-1)

                Resistin

                Adiponectin

                DM=diabetes mellitus FFA=free fatty acid PAI-1=plasminogen activator inhibitor-1 TNFα=tumor necrosis factor alpha IL-6=interleukin 6

                Slide copy2007Louis J Aronne MD after Dr G Bray

                Insulin

                IL - 6

                Estrogen

                Hypertension

                Thrombosis

                Inflammation

                Type 2 DM

                DyslipidemiaType 2 DM

                Arthritis

                ASCVD

                Asthma

                C-C L2

                Waist circumference

                Blood pressure

                Blood glucose

                Triglycerides

                HDL-cholesterol

                LDL-cholesterol

                Insulin resistance

                Thrombotic risk

                Current Therapies Often Address Individual Risk Factors Cardiometabolic risk

                NCEP ATP IIIdefinitionof themetabolicsyndrome

                Antihypertensives

                Oral antidiabetic agents

                Antiplatelet agents

                Lipid modifiers

                Insulin sensitizers

                Jupiter Trial Rosuvastatin reduced incidence of CV endpoints but increased HbA1cand reported cases of T2DM (plt01)

                Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and

                disease

                Lactate Angiotensinogen

                Leptin

                Adipsin (Complement D)

                TNF- α

                FFAFat Stores

                Lipoprotein Lipase

                Plasminogen Activator Inhibitor 1

                (PAI-1)

                Resistin

                Adiponectin

                DM=diabetes mellitus FFA=free fatty acid PAI-1=plasminogen activator inhibitor-1 TNFα=tumor necrosis factor alpha IL-6=interleukin 6

                Slide copy2007Louis J Aronne MD after Dr G Bray

                Insulin

                IL - 6

                Estrogen

                Hypertension

                Thrombosis

                Inflammation

                Type 2 DM

                DyslipidemiaType 2 DM

                Arthritis

                ASCVD

                Asthma

                C-C L2

                Adiponectin Anti-atherogenicantidiabeticdarr darr foam cells darr vascular remodelling

                uarr insulin sensitivity darr hepatic glucose output

                IL-6uarr

                Pro-atherogenicpro-diabeticuarr vascular inflammation darr insulin signalling

                TNFαuarr

                Pro-atherogenicpro-diabeticdarr insulin sensitivity in adipocytes (paracrine)

                PAI-1uarr

                Pro-atherogenicuarr atherothrombotic risk

                IAA intra-abdominal adiposityMarette A Curr Opin Clin Nutr Metab Care 20025377-83

                Are You Treating These Drivers of Cardiometabolic Risk Should You Treat The Underlying Cause

                Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors

                Risk FactorsPhenTPMMid

                p-valuePhenTPMTop

                p-value

                CRP lt0001 lt0001Fibrinogen lt005 lt005Adiponectin lt00001 lt00001

                p-values represent comparisons to placebo

                ITT-LOCF Placebo Comparisons

                Gadde KM et al Lancet 2011377(9774)1341-52

                Mid = 75 mg46 mgTop = 15 mg92 mg

                In My Opinion The Winds of Change are Blowing in the Treatment of Chronic

                Diseasesbull ACCORD was stopped because of increased

                mortality in the tight control group 28 of whom gained gt 10kg compared to 14 in control^

                bull Bariatric surgery trials show gt 80 reduction in diabetes mortality with weight loss

                bull I believe we are in the midst of a shift from ldquoGlucocentricrdquo to ldquoWeight-Centricrdquo Management of T 2 DM

                ^ NEJM 3582545-2559 Adams TD et al N Engl J Med 2007357(8)753-761

                -34-48-48-88-59-29+73

                Adams TD et al N Engl J Med 2007357(8)753-761

                Bariatric Surgery Reduces Overall Mortality Diabetes Mortality by 88

                Matched SubjectsSurgery Group (n=7925)

                Co(n=

                ntrol Group7925)

                NoNo10000 person-yr No

                No10000 person-yr

                All causes of death 213 376 321 571All deaths caused by disease 150 265 285 507Cardiovascular diseases 55 97 104 185Diabetes 2 04 19 34Cancer 31 55 73 133Other diseases 62 11 89 155All non-disease causes 63 111 36 64Accident unrelated to drugs 21 37 17 30Poisoning of undetermined intent 9 16 4 07Suicide 15 26 5 09Other nondisease cause 18 32 10 18

                CC-18

                Health Care Costs Attributable to ObesityEstimates of what various conditions add to health-care service costs over a 12-month period

                $395

                $230

                $225

                $150

                $125

                $0 $100 $200 $300 $400 $500

                Obesity

                Smoking

                20 years aging

                Problem drinking

                Overweight

                Sturm R Health Aff (Millwood) 2002 Mar-Apr21(2)245-53 Table Wall Street Journal 3132002

                Obesity increased medication costs 77inpatient and outpatient costs 36

                What-if scenarios (The Lancet forthcoming)

                Redrawn from Hamman RF et al Diabetes Care 2006292102‐2107

                Change in Weight from Baseline (kg)0‐10 ‐5 +5In

                cide

                nce Ra

                te per 100

                Person‐Years

                10

                20

                15

                5

                0

                How Much Weight Loss Is Needed to Prevent T2DMndashNot Very Much The DPP Experience

                In the Da Qing Study 6-year Intervention Led to Lower Incidence of Type 2 Diabetes 14 Years Later

                n=530 overweight Chinese men and women with IGT mean BMI=26

                17

                0

                20

                40

                60

                80

                100

                2 4 6 8 10 12 14 16 18 20Years of follow‐up

                6‐year intervention hazard ratio = 049 (95 CI 033ndash073)20‐year follow‐up hazard ratio = 057 (95 CI 041ndash081)

                Cumulative Incide

                nce of Type 2 Diabe

                tes ()

                0

                Lifestyle interventionControl

                Treatment Follow‐up

                Li et al Lancet 20083711783ndash9

                Pharmacotherapy for Weight LossLouis J Aronne MD FACP

                Professor of Clinical Medicine Weill Cornell Medical College

                Adjunct Associate Professor of Clinical Medicine Columbia University College of Physicians and Surgeons

                Director Comprehensive Weight Control Program

                New York-Presbyterian HospitalWeill Cornell Medical Center New York NY

                As faculty of Weill Cornell Medical College we are committed to providing transparency for any and all external relationships prior to giving an academic presentation

                I am a consultant speaker advisor or receive research support fromBMS

                Arena Aspire BariatricsMyos

                GI Dynamics Novo NordiskOrexigenVivusZafgen

                I may discuss off-label use of medications

                Disclosure Page

                uarrFood intakedarr energy expenditure

                darrfood intake uarrenergy expenditure

                Topiramate

                Naltrexone

                LorcaserinPramlintideGLP-1Leptin

                BupropionPhentermine

                New Compounds andCombination Interventions

                c Louis J Aronne MDScience Feb 7 2003 Vol 299Illustration by Katharine Sutliff

                Phentermine and TopiramateExtended-Release

                bull Mechanism of actionndash Phentermine Sympathomimetic amine - releaserndash Topiramate Gabaergicglutamate modulation and carbonic

                anhydrase inhibitionbull February 2012 FDA advisory committee votes 20-2 for

                approval bull FDA approved July 2012

                ndash Schedule IVndash Pregnancy Category X = REMS

                Topiramate monotherapy exposure in pregnancy associated with 2- to 5-fold increased prevalence of oral clefts

                bull 4 doses Titrate upbull Available only by mail orderbull Covered through Medco Express Scripts

                Phentermine and TopiramateExtended-Release

                bull Dose titrationndash Once dailyndash Start treatment with phentermine 375 mgtopiramate

                23 mg extended-release daily for 14 daysndash After 14 days increase to the recommended dose of

                phentermine 75 mgtopiramate 46 mg extended-release once daily

                ndash May titrate upwards if needed to phen 15 top 92 mg strength

                EQUIP amp CONQUER Discontinuation RateDue to AEs in All Doses Studied

                Placebo Low Mid Full

                Number of patients 1508 241 498 1507Discontinuation due to AEs 9 12 12 18Blurred vision 05 21 08 07Headache 07 17 02 09Insomnia 04 00 04 17Depression 02 00 08 14Tingling 00 04 10 12Irritability 01 08 08 12Anxiety 03 00 02 11Dizziness 02 04 12 08

                Includes adverse events (AEs) by dose for EQUIP amp CONQUER which lead to discontinuation in gt 1 of patientsPress release Sept 9 2009 Available at httpirvivuscomreleasedetailcfmReleaseID=420114Accessed April 27 2010

                PhenTPMMid

                -104

                Phentermine and Topiramate SEQUELWeight Loss Over Time

                Garvey WT Ryan DH Look M Gadde KM Am J Clin Nutr 201295(2)297-308

                Placebo-25

                Plt00001 v placebo

                Weight Loss

                Week

                Total Population

                0

                -2

                -4

                -6

                -8

                -10

                -12

                -14

                -16

                0 12 24 36 48 60 72 84 96 108

                Weight Loss ITT-LOCF

                PhenTPMTop

                -114

                Mid = 75 mg46 mgTop = 15 mg92 mg

                CONQUER Significant Improvement in Cardiovascular Risk Factors

                (LS Mean Wt Loss)

                QNEXAMid(78)

                P valueQNEXATop

                (98) P value

                Waist Circumference (cm) ‐52 lt00001 ‐68 lt00001

                Systolic BP (mmHg) ‐23 00008 ‐32 lt00001

                Diastolic BP (mmHg) ‐07 NS ‐11 00031

                Triglycerides ( ∆) ‐133 lt00001 ‐153 lt00001

                Total Cholesterol ( ∆) ‐16 00345 ‐30 lt00001

                LDL ( ∆) 04 NS ‐28 00069

                HDL ( ∆) 40 lt00001 56 lt00001

                P values represent comparisons to placebo NS= non‐significant

                ITT‐LOCF Placebo ComparisonsTotal Study Population

                Davidson MH et al Am J Cardiol 2013 Jan 29 pii S0002‐9149(12)02641‐0 doi 101016jamjcard201212038

                Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors

                Risk FactorsPhenTPMMid

                p-valuePhenTPMTop

                p-value

                CRP lt0001 lt0001Fibrinogen lt005 lt005Adiponectin lt00001 lt00001

                p-values represent comparisons to placebo

                ITT-LOCF Placebo Comparisons

                Gadde KM et al Lancet 2011377(9774)1341-52

                Mid = 75 mg46 mgTop = 15 mg92 mg

                Lorcaserin

                bull Selective 5‐HT2C receptor agonist designed to promote weight loss

                bull Schedule IV ndash Expected soonbull Indication weight loss and maintenance of

                weight loss in patients with BMI gt30 kgm2 or BMI gt27 kgm2 + weight-related comorbidcondition(s)

                bull Dose - 10 mg BIDbull Most common side effects headache nausea

                dizziness dry mouth

                BLOOM Study Body Weight Over Years 1 and 2

                Smith SR et al N Engl J Med 2010363245-256 Study Week0 8 16 24 32 40 48 56 64 72 80 88 96 104

                Bod

                y W

                eigh

                t (kg

                )

                102

                100

                98

                96

                94

                92

                90

                0

                Year 1

                Placebo in year 1 and 2 (n = 684)Lorcaserin in year 1 placebo in year 2 (n = 275)Lorcaserin in year 1 and 2 (n = 564)

                Year 2

                Endpoint Lorcaserin Placebo P valueWaist circumference (cm) minus68plusmn02 minus39plusmn02 lt001BMI (kgm2) minus209plusmn006 minus078plusmn005 lt001SBPDBP (mm Hg) minus14plusmn03minus11plusmn02 minus08plusmn03minus06plusmn02 0401Cholesterol ( ∆)Total LDLHDL

                minus090plusmn033287plusmn056005plusmn033

                057plusmn034403plusmn058minus021plusmn034

                001

                049

                72Triglycerides minus615plusmn103 minus014plusmn099 lt001SafetyHR (beatsmin)PASP (mm Hg)Beck depression II score

                minus20plusmn03minus092plusmn023minus11plusmn01

                minus16plusmn04 minus023plusmn023 minus09plusmn01

                0499014026

                BLOOM StudyKey Secondary Endpoints

                Smith SR et al N Engl J Med 2010363245-256

                BLOOM-DMChange in Glycemic Parameters

                P lt001 P lt05 LS mean change plusmn SEMOrsquoNeil PM et al Obesity 201220(7)1426-36 httpwwwnaturecomdoifinder101038oby201266

                00

                -05

                -10

                -150 12 24 36 52

                Cha

                nge

                from

                bas

                elin

                e (

                )

                A1c

                Study week

                0

                -10

                -20

                -30

                -400 12 24 52

                Cha

                nge

                from

                bas

                elin

                e m

                gdl

                )

                Fasting plasma glucose

                Study week

                Lorcaserin 10 mg BID Lorcaserin 10 mg Placebo

                Lorcaserin Adverse Events Reported by 5 or More in Any Group in Year 1

                55

                N () Lorcaserin(N = 1593)

                Placebo(N = 1584)

                Headache 287 (180) 175 (110)

                Dizziness 130 (82) 60 (38)

                Nausea 119 (75) 85 (54)

                Constipation 106 (67) 64 (40)

                Fatigue 95 (60) 48 (30)

                Dry mouth 83 (52) 37 (23)

                Smith SR et al ADA 2009 Late‐Breaking Abstract 96

                LorcaserinNo Increase in Rate of Valvulopathy

                Smith SR et al N Engl J Med 2010363245-256

                10

                8

                6

                4

                2

                024 52 76 104

                1351714

                9

                19

                3421Patie

                nts

                ()

                Week

                Lorcaserin in yr 1 and 2

                Lorcaserin in yr 1 Placebo in yr 2

                Placebo in yr 1 and 2

                Phase III Study Outcomes Compared

                Buproprion SR (360 mgd) Naltrexone SR (32 mgd)

                Lorcaserin(20 mgd)

                Phentermine Topiramate CR

                COR1 COR-I2 COR-II3 NB3043 BLOOM4 BLOSSOM5 EQUIP CONQUER

                Number of patients (ITT-LOCF)

                793 obese 1453 obese

                1281 obese

                502 type II diabetes

                3182 obese 4008 obese

                1230 obese BMI 44

                2448 comorbidBMI 36

                Mean change compared with placebo from base

                93 vs5 1c

                61a vs13c

                64a vs12

                50 a vs12c

                58 vs22c

                48 vs28c

                11 Fullbvs 16

                104 Fullb 84 Midb

                vs 18

                51 Lowb vs16c

                Categorical change 5 compared with placebo from base

                56 vs43

                48a vs164

                563a

                vs 171445a vs189

                475b

                vs 203472b vs25

                67 Fullb 45 Lowb vs17

                70 Fullb 62 Midb

                vs 21

                Phenterminetopiramate doses Low 375 mg phentermine23 mg topiramate Mid 75 mg phentermine 46 mg topiramate Full 15 mg phentermine 92 mg topiramateITT-LOCF intent-to-treat last observation carried forwardData not available aP lt 001 vs placebo bP lt 0001 vs placebo

                Obesity Treatments in Late Development

                Kushner RF Expert Opin Pharmacother 200891339-1350

                Agents ActionBupropionNaltrexone

                bull Dopaminenoradrenaline reuptake inhibitorbull Opioid receptor antagonist

                Liraglutide bull GLP-1 agonist

                BupropionNaltrexone

                bull Mechanism of Actionndash Bupropion - Dopaminenoradrenaline reuptake inhibitorndash Naltrexone- Opioid receptor antagonist

                bull Was approved by FDA committee but FDA did not approve until a CV outcome study is performed 2nd concerns about BP and P in some patients

                bull The Light Study is now underway and reported to be enrolling well under PI Dr Nissen

                bull BupropionNaltrexone will have first completed CV outcome study

                Buproprion ndash Naltrexone

                Greenway FL et al Lancet 2010376(9741)595-605

                0

                -2

                -4

                -6

                -8

                -100 4 8 12 16 20 24 28 32 36 40 44 48 52 56

                Weeks

                Wei

                ght c

                hang

                e fro

                m b

                asel

                ine

                ()

                Placebo

                Naltrexone 16 mg plus bupropion

                Naltrexone 32 mg plus bupropion

                Liraglutide for Weight Loss in Patients with Type 2 Diabetes

                bull GLP-1 analog approved for treatment of type 2 diabetes

                bull Anorectic effect mediated both by the activation of GLP-1 receptor expressed on vagal afferents and by the GLP-1R activation in CNS

                bull Affects visceral fat adiposity appetite food preference and cardiovascular biomarkers in patients with type 2 diabetes

                Inoue K et al Cardiovasc Diabetol 2011 10109 doi1011861475-2840-10-109

                Liraglutide Weight Loss Over 2 Years ITT Observed Means

                Astrup A et al Int J Obes (Lond) 201236(6)843-54

                FromScreening

                -94 kg

                -67 kg-88 kg

                -99 kg-94 kg

                -103 kg

                ITT intention to treat

                Phase III Study Outcomes Compared

                Buproprion SR (360 mgd) Naltrexone SR (32 mgd)

                Lorcaserin(20 mgd)

                Phentermine Topiramate CR

                COR1 COR-I2 COR-II3 NB3043 BLOOM4 BLOSSOM5 EQUIP CONQUER

                Number of patients (ITT-LOCF)

                793 obese 1453 obese

                1281 obese

                502 type II diabetes

                3182 obese 4008 obese

                1230 obese BMI 44

                2448 comorbidBMI 36

                Mean change compared with placebo from base

                93 vs5 1c

                61a vs13c

                64a vs12

                50 a vs12c

                58 vs22c

                48 vs28c

                11 Fullbvs 16

                104 Fullb 84 Midb

                vs 18

                51 Lowb vs16c

                Categorical change 5 compared with placebo from base

                56 vs43

                48a vs164

                563a

                vs 171445a vs189

                475b

                vs 203472b vs25

                67 Fullb 45 Lowb vs17

                70 Fullb 62 Midb

                vs 21

                Phenterminetopiramate doses Low 375 mg phentermine23 mg topiramate Mid 75 mg phentermine 46 mg topiramate Full 15 mg phentermine 92 mg topiramateITT-LOCF intent-to-treat last observation carried forwardData not available aP lt 001 vs placebo bP lt 0001 vs placebo

                Treatment Gap in theManagement of Obesity

                Physicians Need Effective Pharmacotherapies That Will Reduce Weight Significantly and Reduce Weight-related Comorbidities

                0 5 10 15 20 25 30 35

                Diet and Lifestyle Lap Band Gastric Bypass

                TreatmentGap

                What will fill the gap

                Too risky for many peopleNot effective enoughfor many people

                Treatment Gap in theManagement of Obesity

                0 5 10 15 20 25 30 35

                Diet and Lifestyle Lap Band Gastric Bypass

                TreatmentGap

                Too risky for many peopleNot effective enoughfor many people Pharmacotherapy

                Less invasive procedures

                Physicians Need Effective Pharmacotherapies That Will Reduce Weight Significantly and Reduce Weight-related Comorbidities

                What will fill the gap

                • Slide Number 1
                • Slide Number 2
                • Weight Management is Moving into the Workplace and Mainstream of Healthcare
                • US Preventative Services Task Force
                • A Proposal from CMS about Coverage for Intensive Behavioral Therapy for Obesity
                • Slide Number 6
                • Biggest Increases in Clinically Severe Obesity US 1987-2005
                • Relationship Between BMI and Risk of Type 2 Diabetes
                • Slide Number 9
                • Medical Complications of Obesity Almost every organ system is affected
                • Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and disease
                • Current Therapies Often Address Individual Risk Factors Cardiometabolic risk
                • Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and disease
                • Are You Treating These Drivers of Cardiometabolic Risk Should You Treat The Underlying Cause
                • Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors
                • In My Opinion The Winds of Change are Blowing in the Treatment of Chronic Diseases
                • Bariatric Surgery Reduces Overall Mortality Diabetes Mortality by 88
                • Health Care Costs Attributable to ObesityEstimates of what various conditions add to health-care service costs over a 12-month period
                • What-if scenarios (The Lancet forthcoming)
                • How Much Weight Loss Is Needed to Prevent T2DMndashNot Very Much The DPP Experience
                • In the Da Qing Study 6-year Intervention Led to Lower Incidence of Type 2 Diabetes 14 Years Later
                • Slide Number 22
                • Slide Number 23
                • New Compounds andCombination Interventions
                • Phentermine and Topiramate Extended-Release
                • Phentermine and Topiramate Extended-Release
                • EQUIP amp CONQUER Discontinuation RateDue to AEs in All Doses Studied
                • Phentermine and Topiramate SEQUELWeight Loss Over Time
                • CONQUER Significant Improvement in Cardiovascular Risk Factors
                • Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors
                • Lorcaserin
                • BLOOM Study Body Weight Over Years 1 and 2
                • BLOOM StudyKey Secondary Endpoints
                • BLOOM-DMChange in Glycemic Parameters
                • Lorcaserin Adverse Events Reported by 5 or More in Any Group in Year 1
                • LorcaserinNo Increase in Rate of Valvulopathy
                • Phase III Study Outcomes Compared
                • Obesity Treatments in Late Development
                • BupropionNaltrexone
                • Buproprion ndash Naltrexone
                • Liraglutide for Weight Loss in Patients with Type 2 Diabetes
                • Liraglutide Weight Loss Over 2 Years ITT Observed Means
                • Phase III Study Outcomes Compared
                • Treatment Gap in theManagement of Obesity
                • Treatment Gap in theManagement of Obesity

                  Medical Complications of Obesity Almost every organ system is affected

                  Phlebitisvenous stasis

                  Coronary heart disease

                  Pulmonary diseaseasthmaobstructive sleep apneahypoventilation syndrome

                  Gall bladder diseaseReproductive abnormalitiesabnormal mensesinfertilitypolycystic ovarian syndrome

                  Gout

                  Stroke

                  Diabetes

                  Osteoarthritis

                  Cancerbreast uterus cervixcolon esophagus pancreaskidney prostate

                  Nonalcoholic fatty liver diseasesteatosissteatohepatitiscirrhosis Hypertension

                  Dyslipidemia

                  Cataracts

                  Skin

                  Idiopathic intracranial hypertension

                  Severe pancreatitis

                  Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and

                  disease

                  Lactate Angiotensinogen

                  Leptin

                  Adipsin (Complement D)

                  TNF- α

                  FFAFat Stores

                  Lipoprotein Lipase

                  Plasminogen Activator Inhibitor 1

                  (PAI-1)

                  Resistin

                  Adiponectin

                  DM=diabetes mellitus FFA=free fatty acid PAI-1=plasminogen activator inhibitor-1 TNFα=tumor necrosis factor alpha IL-6=interleukin 6

                  Slide copy2007Louis J Aronne MD after Dr G Bray

                  Insulin

                  IL - 6

                  Estrogen

                  Hypertension

                  Thrombosis

                  Inflammation

                  Type 2 DM

                  DyslipidemiaType 2 DM

                  Arthritis

                  ASCVD

                  Asthma

                  C-C L2

                  Waist circumference

                  Blood pressure

                  Blood glucose

                  Triglycerides

                  HDL-cholesterol

                  LDL-cholesterol

                  Insulin resistance

                  Thrombotic risk

                  Current Therapies Often Address Individual Risk Factors Cardiometabolic risk

                  NCEP ATP IIIdefinitionof themetabolicsyndrome

                  Antihypertensives

                  Oral antidiabetic agents

                  Antiplatelet agents

                  Lipid modifiers

                  Insulin sensitizers

                  Jupiter Trial Rosuvastatin reduced incidence of CV endpoints but increased HbA1cand reported cases of T2DM (plt01)

                  Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and

                  disease

                  Lactate Angiotensinogen

                  Leptin

                  Adipsin (Complement D)

                  TNF- α

                  FFAFat Stores

                  Lipoprotein Lipase

                  Plasminogen Activator Inhibitor 1

                  (PAI-1)

                  Resistin

                  Adiponectin

                  DM=diabetes mellitus FFA=free fatty acid PAI-1=plasminogen activator inhibitor-1 TNFα=tumor necrosis factor alpha IL-6=interleukin 6

                  Slide copy2007Louis J Aronne MD after Dr G Bray

                  Insulin

                  IL - 6

                  Estrogen

                  Hypertension

                  Thrombosis

                  Inflammation

                  Type 2 DM

                  DyslipidemiaType 2 DM

                  Arthritis

                  ASCVD

                  Asthma

                  C-C L2

                  Adiponectin Anti-atherogenicantidiabeticdarr darr foam cells darr vascular remodelling

                  uarr insulin sensitivity darr hepatic glucose output

                  IL-6uarr

                  Pro-atherogenicpro-diabeticuarr vascular inflammation darr insulin signalling

                  TNFαuarr

                  Pro-atherogenicpro-diabeticdarr insulin sensitivity in adipocytes (paracrine)

                  PAI-1uarr

                  Pro-atherogenicuarr atherothrombotic risk

                  IAA intra-abdominal adiposityMarette A Curr Opin Clin Nutr Metab Care 20025377-83

                  Are You Treating These Drivers of Cardiometabolic Risk Should You Treat The Underlying Cause

                  Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors

                  Risk FactorsPhenTPMMid

                  p-valuePhenTPMTop

                  p-value

                  CRP lt0001 lt0001Fibrinogen lt005 lt005Adiponectin lt00001 lt00001

                  p-values represent comparisons to placebo

                  ITT-LOCF Placebo Comparisons

                  Gadde KM et al Lancet 2011377(9774)1341-52

                  Mid = 75 mg46 mgTop = 15 mg92 mg

                  In My Opinion The Winds of Change are Blowing in the Treatment of Chronic

                  Diseasesbull ACCORD was stopped because of increased

                  mortality in the tight control group 28 of whom gained gt 10kg compared to 14 in control^

                  bull Bariatric surgery trials show gt 80 reduction in diabetes mortality with weight loss

                  bull I believe we are in the midst of a shift from ldquoGlucocentricrdquo to ldquoWeight-Centricrdquo Management of T 2 DM

                  ^ NEJM 3582545-2559 Adams TD et al N Engl J Med 2007357(8)753-761

                  -34-48-48-88-59-29+73

                  Adams TD et al N Engl J Med 2007357(8)753-761

                  Bariatric Surgery Reduces Overall Mortality Diabetes Mortality by 88

                  Matched SubjectsSurgery Group (n=7925)

                  Co(n=

                  ntrol Group7925)

                  NoNo10000 person-yr No

                  No10000 person-yr

                  All causes of death 213 376 321 571All deaths caused by disease 150 265 285 507Cardiovascular diseases 55 97 104 185Diabetes 2 04 19 34Cancer 31 55 73 133Other diseases 62 11 89 155All non-disease causes 63 111 36 64Accident unrelated to drugs 21 37 17 30Poisoning of undetermined intent 9 16 4 07Suicide 15 26 5 09Other nondisease cause 18 32 10 18

                  CC-18

                  Health Care Costs Attributable to ObesityEstimates of what various conditions add to health-care service costs over a 12-month period

                  $395

                  $230

                  $225

                  $150

                  $125

                  $0 $100 $200 $300 $400 $500

                  Obesity

                  Smoking

                  20 years aging

                  Problem drinking

                  Overweight

                  Sturm R Health Aff (Millwood) 2002 Mar-Apr21(2)245-53 Table Wall Street Journal 3132002

                  Obesity increased medication costs 77inpatient and outpatient costs 36

                  What-if scenarios (The Lancet forthcoming)

                  Redrawn from Hamman RF et al Diabetes Care 2006292102‐2107

                  Change in Weight from Baseline (kg)0‐10 ‐5 +5In

                  cide

                  nce Ra

                  te per 100

                  Person‐Years

                  10

                  20

                  15

                  5

                  0

                  How Much Weight Loss Is Needed to Prevent T2DMndashNot Very Much The DPP Experience

                  In the Da Qing Study 6-year Intervention Led to Lower Incidence of Type 2 Diabetes 14 Years Later

                  n=530 overweight Chinese men and women with IGT mean BMI=26

                  17

                  0

                  20

                  40

                  60

                  80

                  100

                  2 4 6 8 10 12 14 16 18 20Years of follow‐up

                  6‐year intervention hazard ratio = 049 (95 CI 033ndash073)20‐year follow‐up hazard ratio = 057 (95 CI 041ndash081)

                  Cumulative Incide

                  nce of Type 2 Diabe

                  tes ()

                  0

                  Lifestyle interventionControl

                  Treatment Follow‐up

                  Li et al Lancet 20083711783ndash9

                  Pharmacotherapy for Weight LossLouis J Aronne MD FACP

                  Professor of Clinical Medicine Weill Cornell Medical College

                  Adjunct Associate Professor of Clinical Medicine Columbia University College of Physicians and Surgeons

                  Director Comprehensive Weight Control Program

                  New York-Presbyterian HospitalWeill Cornell Medical Center New York NY

                  As faculty of Weill Cornell Medical College we are committed to providing transparency for any and all external relationships prior to giving an academic presentation

                  I am a consultant speaker advisor or receive research support fromBMS

                  Arena Aspire BariatricsMyos

                  GI Dynamics Novo NordiskOrexigenVivusZafgen

                  I may discuss off-label use of medications

                  Disclosure Page

                  uarrFood intakedarr energy expenditure

                  darrfood intake uarrenergy expenditure

                  Topiramate

                  Naltrexone

                  LorcaserinPramlintideGLP-1Leptin

                  BupropionPhentermine

                  New Compounds andCombination Interventions

                  c Louis J Aronne MDScience Feb 7 2003 Vol 299Illustration by Katharine Sutliff

                  Phentermine and TopiramateExtended-Release

                  bull Mechanism of actionndash Phentermine Sympathomimetic amine - releaserndash Topiramate Gabaergicglutamate modulation and carbonic

                  anhydrase inhibitionbull February 2012 FDA advisory committee votes 20-2 for

                  approval bull FDA approved July 2012

                  ndash Schedule IVndash Pregnancy Category X = REMS

                  Topiramate monotherapy exposure in pregnancy associated with 2- to 5-fold increased prevalence of oral clefts

                  bull 4 doses Titrate upbull Available only by mail orderbull Covered through Medco Express Scripts

                  Phentermine and TopiramateExtended-Release

                  bull Dose titrationndash Once dailyndash Start treatment with phentermine 375 mgtopiramate

                  23 mg extended-release daily for 14 daysndash After 14 days increase to the recommended dose of

                  phentermine 75 mgtopiramate 46 mg extended-release once daily

                  ndash May titrate upwards if needed to phen 15 top 92 mg strength

                  EQUIP amp CONQUER Discontinuation RateDue to AEs in All Doses Studied

                  Placebo Low Mid Full

                  Number of patients 1508 241 498 1507Discontinuation due to AEs 9 12 12 18Blurred vision 05 21 08 07Headache 07 17 02 09Insomnia 04 00 04 17Depression 02 00 08 14Tingling 00 04 10 12Irritability 01 08 08 12Anxiety 03 00 02 11Dizziness 02 04 12 08

                  Includes adverse events (AEs) by dose for EQUIP amp CONQUER which lead to discontinuation in gt 1 of patientsPress release Sept 9 2009 Available at httpirvivuscomreleasedetailcfmReleaseID=420114Accessed April 27 2010

                  PhenTPMMid

                  -104

                  Phentermine and Topiramate SEQUELWeight Loss Over Time

                  Garvey WT Ryan DH Look M Gadde KM Am J Clin Nutr 201295(2)297-308

                  Placebo-25

                  Plt00001 v placebo

                  Weight Loss

                  Week

                  Total Population

                  0

                  -2

                  -4

                  -6

                  -8

                  -10

                  -12

                  -14

                  -16

                  0 12 24 36 48 60 72 84 96 108

                  Weight Loss ITT-LOCF

                  PhenTPMTop

                  -114

                  Mid = 75 mg46 mgTop = 15 mg92 mg

                  CONQUER Significant Improvement in Cardiovascular Risk Factors

                  (LS Mean Wt Loss)

                  QNEXAMid(78)

                  P valueQNEXATop

                  (98) P value

                  Waist Circumference (cm) ‐52 lt00001 ‐68 lt00001

                  Systolic BP (mmHg) ‐23 00008 ‐32 lt00001

                  Diastolic BP (mmHg) ‐07 NS ‐11 00031

                  Triglycerides ( ∆) ‐133 lt00001 ‐153 lt00001

                  Total Cholesterol ( ∆) ‐16 00345 ‐30 lt00001

                  LDL ( ∆) 04 NS ‐28 00069

                  HDL ( ∆) 40 lt00001 56 lt00001

                  P values represent comparisons to placebo NS= non‐significant

                  ITT‐LOCF Placebo ComparisonsTotal Study Population

                  Davidson MH et al Am J Cardiol 2013 Jan 29 pii S0002‐9149(12)02641‐0 doi 101016jamjcard201212038

                  Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors

                  Risk FactorsPhenTPMMid

                  p-valuePhenTPMTop

                  p-value

                  CRP lt0001 lt0001Fibrinogen lt005 lt005Adiponectin lt00001 lt00001

                  p-values represent comparisons to placebo

                  ITT-LOCF Placebo Comparisons

                  Gadde KM et al Lancet 2011377(9774)1341-52

                  Mid = 75 mg46 mgTop = 15 mg92 mg

                  Lorcaserin

                  bull Selective 5‐HT2C receptor agonist designed to promote weight loss

                  bull Schedule IV ndash Expected soonbull Indication weight loss and maintenance of

                  weight loss in patients with BMI gt30 kgm2 or BMI gt27 kgm2 + weight-related comorbidcondition(s)

                  bull Dose - 10 mg BIDbull Most common side effects headache nausea

                  dizziness dry mouth

                  BLOOM Study Body Weight Over Years 1 and 2

                  Smith SR et al N Engl J Med 2010363245-256 Study Week0 8 16 24 32 40 48 56 64 72 80 88 96 104

                  Bod

                  y W

                  eigh

                  t (kg

                  )

                  102

                  100

                  98

                  96

                  94

                  92

                  90

                  0

                  Year 1

                  Placebo in year 1 and 2 (n = 684)Lorcaserin in year 1 placebo in year 2 (n = 275)Lorcaserin in year 1 and 2 (n = 564)

                  Year 2

                  Endpoint Lorcaserin Placebo P valueWaist circumference (cm) minus68plusmn02 minus39plusmn02 lt001BMI (kgm2) minus209plusmn006 minus078plusmn005 lt001SBPDBP (mm Hg) minus14plusmn03minus11plusmn02 minus08plusmn03minus06plusmn02 0401Cholesterol ( ∆)Total LDLHDL

                  minus090plusmn033287plusmn056005plusmn033

                  057plusmn034403plusmn058minus021plusmn034

                  001

                  049

                  72Triglycerides minus615plusmn103 minus014plusmn099 lt001SafetyHR (beatsmin)PASP (mm Hg)Beck depression II score

                  minus20plusmn03minus092plusmn023minus11plusmn01

                  minus16plusmn04 minus023plusmn023 minus09plusmn01

                  0499014026

                  BLOOM StudyKey Secondary Endpoints

                  Smith SR et al N Engl J Med 2010363245-256

                  BLOOM-DMChange in Glycemic Parameters

                  P lt001 P lt05 LS mean change plusmn SEMOrsquoNeil PM et al Obesity 201220(7)1426-36 httpwwwnaturecomdoifinder101038oby201266

                  00

                  -05

                  -10

                  -150 12 24 36 52

                  Cha

                  nge

                  from

                  bas

                  elin

                  e (

                  )

                  A1c

                  Study week

                  0

                  -10

                  -20

                  -30

                  -400 12 24 52

                  Cha

                  nge

                  from

                  bas

                  elin

                  e m

                  gdl

                  )

                  Fasting plasma glucose

                  Study week

                  Lorcaserin 10 mg BID Lorcaserin 10 mg Placebo

                  Lorcaserin Adverse Events Reported by 5 or More in Any Group in Year 1

                  55

                  N () Lorcaserin(N = 1593)

                  Placebo(N = 1584)

                  Headache 287 (180) 175 (110)

                  Dizziness 130 (82) 60 (38)

                  Nausea 119 (75) 85 (54)

                  Constipation 106 (67) 64 (40)

                  Fatigue 95 (60) 48 (30)

                  Dry mouth 83 (52) 37 (23)

                  Smith SR et al ADA 2009 Late‐Breaking Abstract 96

                  LorcaserinNo Increase in Rate of Valvulopathy

                  Smith SR et al N Engl J Med 2010363245-256

                  10

                  8

                  6

                  4

                  2

                  024 52 76 104

                  1351714

                  9

                  19

                  3421Patie

                  nts

                  ()

                  Week

                  Lorcaserin in yr 1 and 2

                  Lorcaserin in yr 1 Placebo in yr 2

                  Placebo in yr 1 and 2

                  Phase III Study Outcomes Compared

                  Buproprion SR (360 mgd) Naltrexone SR (32 mgd)

                  Lorcaserin(20 mgd)

                  Phentermine Topiramate CR

                  COR1 COR-I2 COR-II3 NB3043 BLOOM4 BLOSSOM5 EQUIP CONQUER

                  Number of patients (ITT-LOCF)

                  793 obese 1453 obese

                  1281 obese

                  502 type II diabetes

                  3182 obese 4008 obese

                  1230 obese BMI 44

                  2448 comorbidBMI 36

                  Mean change compared with placebo from base

                  93 vs5 1c

                  61a vs13c

                  64a vs12

                  50 a vs12c

                  58 vs22c

                  48 vs28c

                  11 Fullbvs 16

                  104 Fullb 84 Midb

                  vs 18

                  51 Lowb vs16c

                  Categorical change 5 compared with placebo from base

                  56 vs43

                  48a vs164

                  563a

                  vs 171445a vs189

                  475b

                  vs 203472b vs25

                  67 Fullb 45 Lowb vs17

                  70 Fullb 62 Midb

                  vs 21

                  Phenterminetopiramate doses Low 375 mg phentermine23 mg topiramate Mid 75 mg phentermine 46 mg topiramate Full 15 mg phentermine 92 mg topiramateITT-LOCF intent-to-treat last observation carried forwardData not available aP lt 001 vs placebo bP lt 0001 vs placebo

                  Obesity Treatments in Late Development

                  Kushner RF Expert Opin Pharmacother 200891339-1350

                  Agents ActionBupropionNaltrexone

                  bull Dopaminenoradrenaline reuptake inhibitorbull Opioid receptor antagonist

                  Liraglutide bull GLP-1 agonist

                  BupropionNaltrexone

                  bull Mechanism of Actionndash Bupropion - Dopaminenoradrenaline reuptake inhibitorndash Naltrexone- Opioid receptor antagonist

                  bull Was approved by FDA committee but FDA did not approve until a CV outcome study is performed 2nd concerns about BP and P in some patients

                  bull The Light Study is now underway and reported to be enrolling well under PI Dr Nissen

                  bull BupropionNaltrexone will have first completed CV outcome study

                  Buproprion ndash Naltrexone

                  Greenway FL et al Lancet 2010376(9741)595-605

                  0

                  -2

                  -4

                  -6

                  -8

                  -100 4 8 12 16 20 24 28 32 36 40 44 48 52 56

                  Weeks

                  Wei

                  ght c

                  hang

                  e fro

                  m b

                  asel

                  ine

                  ()

                  Placebo

                  Naltrexone 16 mg plus bupropion

                  Naltrexone 32 mg plus bupropion

                  Liraglutide for Weight Loss in Patients with Type 2 Diabetes

                  bull GLP-1 analog approved for treatment of type 2 diabetes

                  bull Anorectic effect mediated both by the activation of GLP-1 receptor expressed on vagal afferents and by the GLP-1R activation in CNS

                  bull Affects visceral fat adiposity appetite food preference and cardiovascular biomarkers in patients with type 2 diabetes

                  Inoue K et al Cardiovasc Diabetol 2011 10109 doi1011861475-2840-10-109

                  Liraglutide Weight Loss Over 2 Years ITT Observed Means

                  Astrup A et al Int J Obes (Lond) 201236(6)843-54

                  FromScreening

                  -94 kg

                  -67 kg-88 kg

                  -99 kg-94 kg

                  -103 kg

                  ITT intention to treat

                  Phase III Study Outcomes Compared

                  Buproprion SR (360 mgd) Naltrexone SR (32 mgd)

                  Lorcaserin(20 mgd)

                  Phentermine Topiramate CR

                  COR1 COR-I2 COR-II3 NB3043 BLOOM4 BLOSSOM5 EQUIP CONQUER

                  Number of patients (ITT-LOCF)

                  793 obese 1453 obese

                  1281 obese

                  502 type II diabetes

                  3182 obese 4008 obese

                  1230 obese BMI 44

                  2448 comorbidBMI 36

                  Mean change compared with placebo from base

                  93 vs5 1c

                  61a vs13c

                  64a vs12

                  50 a vs12c

                  58 vs22c

                  48 vs28c

                  11 Fullbvs 16

                  104 Fullb 84 Midb

                  vs 18

                  51 Lowb vs16c

                  Categorical change 5 compared with placebo from base

                  56 vs43

                  48a vs164

                  563a

                  vs 171445a vs189

                  475b

                  vs 203472b vs25

                  67 Fullb 45 Lowb vs17

                  70 Fullb 62 Midb

                  vs 21

                  Phenterminetopiramate doses Low 375 mg phentermine23 mg topiramate Mid 75 mg phentermine 46 mg topiramate Full 15 mg phentermine 92 mg topiramateITT-LOCF intent-to-treat last observation carried forwardData not available aP lt 001 vs placebo bP lt 0001 vs placebo

                  Treatment Gap in theManagement of Obesity

                  Physicians Need Effective Pharmacotherapies That Will Reduce Weight Significantly and Reduce Weight-related Comorbidities

                  0 5 10 15 20 25 30 35

                  Diet and Lifestyle Lap Band Gastric Bypass

                  TreatmentGap

                  What will fill the gap

                  Too risky for many peopleNot effective enoughfor many people

                  Treatment Gap in theManagement of Obesity

                  0 5 10 15 20 25 30 35

                  Diet and Lifestyle Lap Band Gastric Bypass

                  TreatmentGap

                  Too risky for many peopleNot effective enoughfor many people Pharmacotherapy

                  Less invasive procedures

                  Physicians Need Effective Pharmacotherapies That Will Reduce Weight Significantly and Reduce Weight-related Comorbidities

                  What will fill the gap

                  • Slide Number 1
                  • Slide Number 2
                  • Weight Management is Moving into the Workplace and Mainstream of Healthcare
                  • US Preventative Services Task Force
                  • A Proposal from CMS about Coverage for Intensive Behavioral Therapy for Obesity
                  • Slide Number 6
                  • Biggest Increases in Clinically Severe Obesity US 1987-2005
                  • Relationship Between BMI and Risk of Type 2 Diabetes
                  • Slide Number 9
                  • Medical Complications of Obesity Almost every organ system is affected
                  • Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and disease
                  • Current Therapies Often Address Individual Risk Factors Cardiometabolic risk
                  • Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and disease
                  • Are You Treating These Drivers of Cardiometabolic Risk Should You Treat The Underlying Cause
                  • Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors
                  • In My Opinion The Winds of Change are Blowing in the Treatment of Chronic Diseases
                  • Bariatric Surgery Reduces Overall Mortality Diabetes Mortality by 88
                  • Health Care Costs Attributable to ObesityEstimates of what various conditions add to health-care service costs over a 12-month period
                  • What-if scenarios (The Lancet forthcoming)
                  • How Much Weight Loss Is Needed to Prevent T2DMndashNot Very Much The DPP Experience
                  • In the Da Qing Study 6-year Intervention Led to Lower Incidence of Type 2 Diabetes 14 Years Later
                  • Slide Number 22
                  • Slide Number 23
                  • New Compounds andCombination Interventions
                  • Phentermine and Topiramate Extended-Release
                  • Phentermine and Topiramate Extended-Release
                  • EQUIP amp CONQUER Discontinuation RateDue to AEs in All Doses Studied
                  • Phentermine and Topiramate SEQUELWeight Loss Over Time
                  • CONQUER Significant Improvement in Cardiovascular Risk Factors
                  • Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors
                  • Lorcaserin
                  • BLOOM Study Body Weight Over Years 1 and 2
                  • BLOOM StudyKey Secondary Endpoints
                  • BLOOM-DMChange in Glycemic Parameters
                  • Lorcaserin Adverse Events Reported by 5 or More in Any Group in Year 1
                  • LorcaserinNo Increase in Rate of Valvulopathy
                  • Phase III Study Outcomes Compared
                  • Obesity Treatments in Late Development
                  • BupropionNaltrexone
                  • Buproprion ndash Naltrexone
                  • Liraglutide for Weight Loss in Patients with Type 2 Diabetes
                  • Liraglutide Weight Loss Over 2 Years ITT Observed Means
                  • Phase III Study Outcomes Compared
                  • Treatment Gap in theManagement of Obesity
                  • Treatment Gap in theManagement of Obesity

                    Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and

                    disease

                    Lactate Angiotensinogen

                    Leptin

                    Adipsin (Complement D)

                    TNF- α

                    FFAFat Stores

                    Lipoprotein Lipase

                    Plasminogen Activator Inhibitor 1

                    (PAI-1)

                    Resistin

                    Adiponectin

                    DM=diabetes mellitus FFA=free fatty acid PAI-1=plasminogen activator inhibitor-1 TNFα=tumor necrosis factor alpha IL-6=interleukin 6

                    Slide copy2007Louis J Aronne MD after Dr G Bray

                    Insulin

                    IL - 6

                    Estrogen

                    Hypertension

                    Thrombosis

                    Inflammation

                    Type 2 DM

                    DyslipidemiaType 2 DM

                    Arthritis

                    ASCVD

                    Asthma

                    C-C L2

                    Waist circumference

                    Blood pressure

                    Blood glucose

                    Triglycerides

                    HDL-cholesterol

                    LDL-cholesterol

                    Insulin resistance

                    Thrombotic risk

                    Current Therapies Often Address Individual Risk Factors Cardiometabolic risk

                    NCEP ATP IIIdefinitionof themetabolicsyndrome

                    Antihypertensives

                    Oral antidiabetic agents

                    Antiplatelet agents

                    Lipid modifiers

                    Insulin sensitizers

                    Jupiter Trial Rosuvastatin reduced incidence of CV endpoints but increased HbA1cand reported cases of T2DM (plt01)

                    Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and

                    disease

                    Lactate Angiotensinogen

                    Leptin

                    Adipsin (Complement D)

                    TNF- α

                    FFAFat Stores

                    Lipoprotein Lipase

                    Plasminogen Activator Inhibitor 1

                    (PAI-1)

                    Resistin

                    Adiponectin

                    DM=diabetes mellitus FFA=free fatty acid PAI-1=plasminogen activator inhibitor-1 TNFα=tumor necrosis factor alpha IL-6=interleukin 6

                    Slide copy2007Louis J Aronne MD after Dr G Bray

                    Insulin

                    IL - 6

                    Estrogen

                    Hypertension

                    Thrombosis

                    Inflammation

                    Type 2 DM

                    DyslipidemiaType 2 DM

                    Arthritis

                    ASCVD

                    Asthma

                    C-C L2

                    Adiponectin Anti-atherogenicantidiabeticdarr darr foam cells darr vascular remodelling

                    uarr insulin sensitivity darr hepatic glucose output

                    IL-6uarr

                    Pro-atherogenicpro-diabeticuarr vascular inflammation darr insulin signalling

                    TNFαuarr

                    Pro-atherogenicpro-diabeticdarr insulin sensitivity in adipocytes (paracrine)

                    PAI-1uarr

                    Pro-atherogenicuarr atherothrombotic risk

                    IAA intra-abdominal adiposityMarette A Curr Opin Clin Nutr Metab Care 20025377-83

                    Are You Treating These Drivers of Cardiometabolic Risk Should You Treat The Underlying Cause

                    Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors

                    Risk FactorsPhenTPMMid

                    p-valuePhenTPMTop

                    p-value

                    CRP lt0001 lt0001Fibrinogen lt005 lt005Adiponectin lt00001 lt00001

                    p-values represent comparisons to placebo

                    ITT-LOCF Placebo Comparisons

                    Gadde KM et al Lancet 2011377(9774)1341-52

                    Mid = 75 mg46 mgTop = 15 mg92 mg

                    In My Opinion The Winds of Change are Blowing in the Treatment of Chronic

                    Diseasesbull ACCORD was stopped because of increased

                    mortality in the tight control group 28 of whom gained gt 10kg compared to 14 in control^

                    bull Bariatric surgery trials show gt 80 reduction in diabetes mortality with weight loss

                    bull I believe we are in the midst of a shift from ldquoGlucocentricrdquo to ldquoWeight-Centricrdquo Management of T 2 DM

                    ^ NEJM 3582545-2559 Adams TD et al N Engl J Med 2007357(8)753-761

                    -34-48-48-88-59-29+73

                    Adams TD et al N Engl J Med 2007357(8)753-761

                    Bariatric Surgery Reduces Overall Mortality Diabetes Mortality by 88

                    Matched SubjectsSurgery Group (n=7925)

                    Co(n=

                    ntrol Group7925)

                    NoNo10000 person-yr No

                    No10000 person-yr

                    All causes of death 213 376 321 571All deaths caused by disease 150 265 285 507Cardiovascular diseases 55 97 104 185Diabetes 2 04 19 34Cancer 31 55 73 133Other diseases 62 11 89 155All non-disease causes 63 111 36 64Accident unrelated to drugs 21 37 17 30Poisoning of undetermined intent 9 16 4 07Suicide 15 26 5 09Other nondisease cause 18 32 10 18

                    CC-18

                    Health Care Costs Attributable to ObesityEstimates of what various conditions add to health-care service costs over a 12-month period

                    $395

                    $230

                    $225

                    $150

                    $125

                    $0 $100 $200 $300 $400 $500

                    Obesity

                    Smoking

                    20 years aging

                    Problem drinking

                    Overweight

                    Sturm R Health Aff (Millwood) 2002 Mar-Apr21(2)245-53 Table Wall Street Journal 3132002

                    Obesity increased medication costs 77inpatient and outpatient costs 36

                    What-if scenarios (The Lancet forthcoming)

                    Redrawn from Hamman RF et al Diabetes Care 2006292102‐2107

                    Change in Weight from Baseline (kg)0‐10 ‐5 +5In

                    cide

                    nce Ra

                    te per 100

                    Person‐Years

                    10

                    20

                    15

                    5

                    0

                    How Much Weight Loss Is Needed to Prevent T2DMndashNot Very Much The DPP Experience

                    In the Da Qing Study 6-year Intervention Led to Lower Incidence of Type 2 Diabetes 14 Years Later

                    n=530 overweight Chinese men and women with IGT mean BMI=26

                    17

                    0

                    20

                    40

                    60

                    80

                    100

                    2 4 6 8 10 12 14 16 18 20Years of follow‐up

                    6‐year intervention hazard ratio = 049 (95 CI 033ndash073)20‐year follow‐up hazard ratio = 057 (95 CI 041ndash081)

                    Cumulative Incide

                    nce of Type 2 Diabe

                    tes ()

                    0

                    Lifestyle interventionControl

                    Treatment Follow‐up

                    Li et al Lancet 20083711783ndash9

                    Pharmacotherapy for Weight LossLouis J Aronne MD FACP

                    Professor of Clinical Medicine Weill Cornell Medical College

                    Adjunct Associate Professor of Clinical Medicine Columbia University College of Physicians and Surgeons

                    Director Comprehensive Weight Control Program

                    New York-Presbyterian HospitalWeill Cornell Medical Center New York NY

                    As faculty of Weill Cornell Medical College we are committed to providing transparency for any and all external relationships prior to giving an academic presentation

                    I am a consultant speaker advisor or receive research support fromBMS

                    Arena Aspire BariatricsMyos

                    GI Dynamics Novo NordiskOrexigenVivusZafgen

                    I may discuss off-label use of medications

                    Disclosure Page

                    uarrFood intakedarr energy expenditure

                    darrfood intake uarrenergy expenditure

                    Topiramate

                    Naltrexone

                    LorcaserinPramlintideGLP-1Leptin

                    BupropionPhentermine

                    New Compounds andCombination Interventions

                    c Louis J Aronne MDScience Feb 7 2003 Vol 299Illustration by Katharine Sutliff

                    Phentermine and TopiramateExtended-Release

                    bull Mechanism of actionndash Phentermine Sympathomimetic amine - releaserndash Topiramate Gabaergicglutamate modulation and carbonic

                    anhydrase inhibitionbull February 2012 FDA advisory committee votes 20-2 for

                    approval bull FDA approved July 2012

                    ndash Schedule IVndash Pregnancy Category X = REMS

                    Topiramate monotherapy exposure in pregnancy associated with 2- to 5-fold increased prevalence of oral clefts

                    bull 4 doses Titrate upbull Available only by mail orderbull Covered through Medco Express Scripts

                    Phentermine and TopiramateExtended-Release

                    bull Dose titrationndash Once dailyndash Start treatment with phentermine 375 mgtopiramate

                    23 mg extended-release daily for 14 daysndash After 14 days increase to the recommended dose of

                    phentermine 75 mgtopiramate 46 mg extended-release once daily

                    ndash May titrate upwards if needed to phen 15 top 92 mg strength

                    EQUIP amp CONQUER Discontinuation RateDue to AEs in All Doses Studied

                    Placebo Low Mid Full

                    Number of patients 1508 241 498 1507Discontinuation due to AEs 9 12 12 18Blurred vision 05 21 08 07Headache 07 17 02 09Insomnia 04 00 04 17Depression 02 00 08 14Tingling 00 04 10 12Irritability 01 08 08 12Anxiety 03 00 02 11Dizziness 02 04 12 08

                    Includes adverse events (AEs) by dose for EQUIP amp CONQUER which lead to discontinuation in gt 1 of patientsPress release Sept 9 2009 Available at httpirvivuscomreleasedetailcfmReleaseID=420114Accessed April 27 2010

                    PhenTPMMid

                    -104

                    Phentermine and Topiramate SEQUELWeight Loss Over Time

                    Garvey WT Ryan DH Look M Gadde KM Am J Clin Nutr 201295(2)297-308

                    Placebo-25

                    Plt00001 v placebo

                    Weight Loss

                    Week

                    Total Population

                    0

                    -2

                    -4

                    -6

                    -8

                    -10

                    -12

                    -14

                    -16

                    0 12 24 36 48 60 72 84 96 108

                    Weight Loss ITT-LOCF

                    PhenTPMTop

                    -114

                    Mid = 75 mg46 mgTop = 15 mg92 mg

                    CONQUER Significant Improvement in Cardiovascular Risk Factors

                    (LS Mean Wt Loss)

                    QNEXAMid(78)

                    P valueQNEXATop

                    (98) P value

                    Waist Circumference (cm) ‐52 lt00001 ‐68 lt00001

                    Systolic BP (mmHg) ‐23 00008 ‐32 lt00001

                    Diastolic BP (mmHg) ‐07 NS ‐11 00031

                    Triglycerides ( ∆) ‐133 lt00001 ‐153 lt00001

                    Total Cholesterol ( ∆) ‐16 00345 ‐30 lt00001

                    LDL ( ∆) 04 NS ‐28 00069

                    HDL ( ∆) 40 lt00001 56 lt00001

                    P values represent comparisons to placebo NS= non‐significant

                    ITT‐LOCF Placebo ComparisonsTotal Study Population

                    Davidson MH et al Am J Cardiol 2013 Jan 29 pii S0002‐9149(12)02641‐0 doi 101016jamjcard201212038

                    Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors

                    Risk FactorsPhenTPMMid

                    p-valuePhenTPMTop

                    p-value

                    CRP lt0001 lt0001Fibrinogen lt005 lt005Adiponectin lt00001 lt00001

                    p-values represent comparisons to placebo

                    ITT-LOCF Placebo Comparisons

                    Gadde KM et al Lancet 2011377(9774)1341-52

                    Mid = 75 mg46 mgTop = 15 mg92 mg

                    Lorcaserin

                    bull Selective 5‐HT2C receptor agonist designed to promote weight loss

                    bull Schedule IV ndash Expected soonbull Indication weight loss and maintenance of

                    weight loss in patients with BMI gt30 kgm2 or BMI gt27 kgm2 + weight-related comorbidcondition(s)

                    bull Dose - 10 mg BIDbull Most common side effects headache nausea

                    dizziness dry mouth

                    BLOOM Study Body Weight Over Years 1 and 2

                    Smith SR et al N Engl J Med 2010363245-256 Study Week0 8 16 24 32 40 48 56 64 72 80 88 96 104

                    Bod

                    y W

                    eigh

                    t (kg

                    )

                    102

                    100

                    98

                    96

                    94

                    92

                    90

                    0

                    Year 1

                    Placebo in year 1 and 2 (n = 684)Lorcaserin in year 1 placebo in year 2 (n = 275)Lorcaserin in year 1 and 2 (n = 564)

                    Year 2

                    Endpoint Lorcaserin Placebo P valueWaist circumference (cm) minus68plusmn02 minus39plusmn02 lt001BMI (kgm2) minus209plusmn006 minus078plusmn005 lt001SBPDBP (mm Hg) minus14plusmn03minus11plusmn02 minus08plusmn03minus06plusmn02 0401Cholesterol ( ∆)Total LDLHDL

                    minus090plusmn033287plusmn056005plusmn033

                    057plusmn034403plusmn058minus021plusmn034

                    001

                    049

                    72Triglycerides minus615plusmn103 minus014plusmn099 lt001SafetyHR (beatsmin)PASP (mm Hg)Beck depression II score

                    minus20plusmn03minus092plusmn023minus11plusmn01

                    minus16plusmn04 minus023plusmn023 minus09plusmn01

                    0499014026

                    BLOOM StudyKey Secondary Endpoints

                    Smith SR et al N Engl J Med 2010363245-256

                    BLOOM-DMChange in Glycemic Parameters

                    P lt001 P lt05 LS mean change plusmn SEMOrsquoNeil PM et al Obesity 201220(7)1426-36 httpwwwnaturecomdoifinder101038oby201266

                    00

                    -05

                    -10

                    -150 12 24 36 52

                    Cha

                    nge

                    from

                    bas

                    elin

                    e (

                    )

                    A1c

                    Study week

                    0

                    -10

                    -20

                    -30

                    -400 12 24 52

                    Cha

                    nge

                    from

                    bas

                    elin

                    e m

                    gdl

                    )

                    Fasting plasma glucose

                    Study week

                    Lorcaserin 10 mg BID Lorcaserin 10 mg Placebo

                    Lorcaserin Adverse Events Reported by 5 or More in Any Group in Year 1

                    55

                    N () Lorcaserin(N = 1593)

                    Placebo(N = 1584)

                    Headache 287 (180) 175 (110)

                    Dizziness 130 (82) 60 (38)

                    Nausea 119 (75) 85 (54)

                    Constipation 106 (67) 64 (40)

                    Fatigue 95 (60) 48 (30)

                    Dry mouth 83 (52) 37 (23)

                    Smith SR et al ADA 2009 Late‐Breaking Abstract 96

                    LorcaserinNo Increase in Rate of Valvulopathy

                    Smith SR et al N Engl J Med 2010363245-256

                    10

                    8

                    6

                    4

                    2

                    024 52 76 104

                    1351714

                    9

                    19

                    3421Patie

                    nts

                    ()

                    Week

                    Lorcaserin in yr 1 and 2

                    Lorcaserin in yr 1 Placebo in yr 2

                    Placebo in yr 1 and 2

                    Phase III Study Outcomes Compared

                    Buproprion SR (360 mgd) Naltrexone SR (32 mgd)

                    Lorcaserin(20 mgd)

                    Phentermine Topiramate CR

                    COR1 COR-I2 COR-II3 NB3043 BLOOM4 BLOSSOM5 EQUIP CONQUER

                    Number of patients (ITT-LOCF)

                    793 obese 1453 obese

                    1281 obese

                    502 type II diabetes

                    3182 obese 4008 obese

                    1230 obese BMI 44

                    2448 comorbidBMI 36

                    Mean change compared with placebo from base

                    93 vs5 1c

                    61a vs13c

                    64a vs12

                    50 a vs12c

                    58 vs22c

                    48 vs28c

                    11 Fullbvs 16

                    104 Fullb 84 Midb

                    vs 18

                    51 Lowb vs16c

                    Categorical change 5 compared with placebo from base

                    56 vs43

                    48a vs164

                    563a

                    vs 171445a vs189

                    475b

                    vs 203472b vs25

                    67 Fullb 45 Lowb vs17

                    70 Fullb 62 Midb

                    vs 21

                    Phenterminetopiramate doses Low 375 mg phentermine23 mg topiramate Mid 75 mg phentermine 46 mg topiramate Full 15 mg phentermine 92 mg topiramateITT-LOCF intent-to-treat last observation carried forwardData not available aP lt 001 vs placebo bP lt 0001 vs placebo

                    Obesity Treatments in Late Development

                    Kushner RF Expert Opin Pharmacother 200891339-1350

                    Agents ActionBupropionNaltrexone

                    bull Dopaminenoradrenaline reuptake inhibitorbull Opioid receptor antagonist

                    Liraglutide bull GLP-1 agonist

                    BupropionNaltrexone

                    bull Mechanism of Actionndash Bupropion - Dopaminenoradrenaline reuptake inhibitorndash Naltrexone- Opioid receptor antagonist

                    bull Was approved by FDA committee but FDA did not approve until a CV outcome study is performed 2nd concerns about BP and P in some patients

                    bull The Light Study is now underway and reported to be enrolling well under PI Dr Nissen

                    bull BupropionNaltrexone will have first completed CV outcome study

                    Buproprion ndash Naltrexone

                    Greenway FL et al Lancet 2010376(9741)595-605

                    0

                    -2

                    -4

                    -6

                    -8

                    -100 4 8 12 16 20 24 28 32 36 40 44 48 52 56

                    Weeks

                    Wei

                    ght c

                    hang

                    e fro

                    m b

                    asel

                    ine

                    ()

                    Placebo

                    Naltrexone 16 mg plus bupropion

                    Naltrexone 32 mg plus bupropion

                    Liraglutide for Weight Loss in Patients with Type 2 Diabetes

                    bull GLP-1 analog approved for treatment of type 2 diabetes

                    bull Anorectic effect mediated both by the activation of GLP-1 receptor expressed on vagal afferents and by the GLP-1R activation in CNS

                    bull Affects visceral fat adiposity appetite food preference and cardiovascular biomarkers in patients with type 2 diabetes

                    Inoue K et al Cardiovasc Diabetol 2011 10109 doi1011861475-2840-10-109

                    Liraglutide Weight Loss Over 2 Years ITT Observed Means

                    Astrup A et al Int J Obes (Lond) 201236(6)843-54

                    FromScreening

                    -94 kg

                    -67 kg-88 kg

                    -99 kg-94 kg

                    -103 kg

                    ITT intention to treat

                    Phase III Study Outcomes Compared

                    Buproprion SR (360 mgd) Naltrexone SR (32 mgd)

                    Lorcaserin(20 mgd)

                    Phentermine Topiramate CR

                    COR1 COR-I2 COR-II3 NB3043 BLOOM4 BLOSSOM5 EQUIP CONQUER

                    Number of patients (ITT-LOCF)

                    793 obese 1453 obese

                    1281 obese

                    502 type II diabetes

                    3182 obese 4008 obese

                    1230 obese BMI 44

                    2448 comorbidBMI 36

                    Mean change compared with placebo from base

                    93 vs5 1c

                    61a vs13c

                    64a vs12

                    50 a vs12c

                    58 vs22c

                    48 vs28c

                    11 Fullbvs 16

                    104 Fullb 84 Midb

                    vs 18

                    51 Lowb vs16c

                    Categorical change 5 compared with placebo from base

                    56 vs43

                    48a vs164

                    563a

                    vs 171445a vs189

                    475b

                    vs 203472b vs25

                    67 Fullb 45 Lowb vs17

                    70 Fullb 62 Midb

                    vs 21

                    Phenterminetopiramate doses Low 375 mg phentermine23 mg topiramate Mid 75 mg phentermine 46 mg topiramate Full 15 mg phentermine 92 mg topiramateITT-LOCF intent-to-treat last observation carried forwardData not available aP lt 001 vs placebo bP lt 0001 vs placebo

                    Treatment Gap in theManagement of Obesity

                    Physicians Need Effective Pharmacotherapies That Will Reduce Weight Significantly and Reduce Weight-related Comorbidities

                    0 5 10 15 20 25 30 35

                    Diet and Lifestyle Lap Band Gastric Bypass

                    TreatmentGap

                    What will fill the gap

                    Too risky for many peopleNot effective enoughfor many people

                    Treatment Gap in theManagement of Obesity

                    0 5 10 15 20 25 30 35

                    Diet and Lifestyle Lap Band Gastric Bypass

                    TreatmentGap

                    Too risky for many peopleNot effective enoughfor many people Pharmacotherapy

                    Less invasive procedures

                    Physicians Need Effective Pharmacotherapies That Will Reduce Weight Significantly and Reduce Weight-related Comorbidities

                    What will fill the gap

                    • Slide Number 1
                    • Slide Number 2
                    • Weight Management is Moving into the Workplace and Mainstream of Healthcare
                    • US Preventative Services Task Force
                    • A Proposal from CMS about Coverage for Intensive Behavioral Therapy for Obesity
                    • Slide Number 6
                    • Biggest Increases in Clinically Severe Obesity US 1987-2005
                    • Relationship Between BMI and Risk of Type 2 Diabetes
                    • Slide Number 9
                    • Medical Complications of Obesity Almost every organ system is affected
                    • Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and disease
                    • Current Therapies Often Address Individual Risk Factors Cardiometabolic risk
                    • Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and disease
                    • Are You Treating These Drivers of Cardiometabolic Risk Should You Treat The Underlying Cause
                    • Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors
                    • In My Opinion The Winds of Change are Blowing in the Treatment of Chronic Diseases
                    • Bariatric Surgery Reduces Overall Mortality Diabetes Mortality by 88
                    • Health Care Costs Attributable to ObesityEstimates of what various conditions add to health-care service costs over a 12-month period
                    • What-if scenarios (The Lancet forthcoming)
                    • How Much Weight Loss Is Needed to Prevent T2DMndashNot Very Much The DPP Experience
                    • In the Da Qing Study 6-year Intervention Led to Lower Incidence of Type 2 Diabetes 14 Years Later
                    • Slide Number 22
                    • Slide Number 23
                    • New Compounds andCombination Interventions
                    • Phentermine and Topiramate Extended-Release
                    • Phentermine and Topiramate Extended-Release
                    • EQUIP amp CONQUER Discontinuation RateDue to AEs in All Doses Studied
                    • Phentermine and Topiramate SEQUELWeight Loss Over Time
                    • CONQUER Significant Improvement in Cardiovascular Risk Factors
                    • Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors
                    • Lorcaserin
                    • BLOOM Study Body Weight Over Years 1 and 2
                    • BLOOM StudyKey Secondary Endpoints
                    • BLOOM-DMChange in Glycemic Parameters
                    • Lorcaserin Adverse Events Reported by 5 or More in Any Group in Year 1
                    • LorcaserinNo Increase in Rate of Valvulopathy
                    • Phase III Study Outcomes Compared
                    • Obesity Treatments in Late Development
                    • BupropionNaltrexone
                    • Buproprion ndash Naltrexone
                    • Liraglutide for Weight Loss in Patients with Type 2 Diabetes
                    • Liraglutide Weight Loss Over 2 Years ITT Observed Means
                    • Phase III Study Outcomes Compared
                    • Treatment Gap in theManagement of Obesity
                    • Treatment Gap in theManagement of Obesity

                      Waist circumference

                      Blood pressure

                      Blood glucose

                      Triglycerides

                      HDL-cholesterol

                      LDL-cholesterol

                      Insulin resistance

                      Thrombotic risk

                      Current Therapies Often Address Individual Risk Factors Cardiometabolic risk

                      NCEP ATP IIIdefinitionof themetabolicsyndrome

                      Antihypertensives

                      Oral antidiabetic agents

                      Antiplatelet agents

                      Lipid modifiers

                      Insulin sensitizers

                      Jupiter Trial Rosuvastatin reduced incidence of CV endpoints but increased HbA1cand reported cases of T2DM (plt01)

                      Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and

                      disease

                      Lactate Angiotensinogen

                      Leptin

                      Adipsin (Complement D)

                      TNF- α

                      FFAFat Stores

                      Lipoprotein Lipase

                      Plasminogen Activator Inhibitor 1

                      (PAI-1)

                      Resistin

                      Adiponectin

                      DM=diabetes mellitus FFA=free fatty acid PAI-1=plasminogen activator inhibitor-1 TNFα=tumor necrosis factor alpha IL-6=interleukin 6

                      Slide copy2007Louis J Aronne MD after Dr G Bray

                      Insulin

                      IL - 6

                      Estrogen

                      Hypertension

                      Thrombosis

                      Inflammation

                      Type 2 DM

                      DyslipidemiaType 2 DM

                      Arthritis

                      ASCVD

                      Asthma

                      C-C L2

                      Adiponectin Anti-atherogenicantidiabeticdarr darr foam cells darr vascular remodelling

                      uarr insulin sensitivity darr hepatic glucose output

                      IL-6uarr

                      Pro-atherogenicpro-diabeticuarr vascular inflammation darr insulin signalling

                      TNFαuarr

                      Pro-atherogenicpro-diabeticdarr insulin sensitivity in adipocytes (paracrine)

                      PAI-1uarr

                      Pro-atherogenicuarr atherothrombotic risk

                      IAA intra-abdominal adiposityMarette A Curr Opin Clin Nutr Metab Care 20025377-83

                      Are You Treating These Drivers of Cardiometabolic Risk Should You Treat The Underlying Cause

                      Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors

                      Risk FactorsPhenTPMMid

                      p-valuePhenTPMTop

                      p-value

                      CRP lt0001 lt0001Fibrinogen lt005 lt005Adiponectin lt00001 lt00001

                      p-values represent comparisons to placebo

                      ITT-LOCF Placebo Comparisons

                      Gadde KM et al Lancet 2011377(9774)1341-52

                      Mid = 75 mg46 mgTop = 15 mg92 mg

                      In My Opinion The Winds of Change are Blowing in the Treatment of Chronic

                      Diseasesbull ACCORD was stopped because of increased

                      mortality in the tight control group 28 of whom gained gt 10kg compared to 14 in control^

                      bull Bariatric surgery trials show gt 80 reduction in diabetes mortality with weight loss

                      bull I believe we are in the midst of a shift from ldquoGlucocentricrdquo to ldquoWeight-Centricrdquo Management of T 2 DM

                      ^ NEJM 3582545-2559 Adams TD et al N Engl J Med 2007357(8)753-761

                      -34-48-48-88-59-29+73

                      Adams TD et al N Engl J Med 2007357(8)753-761

                      Bariatric Surgery Reduces Overall Mortality Diabetes Mortality by 88

                      Matched SubjectsSurgery Group (n=7925)

                      Co(n=

                      ntrol Group7925)

                      NoNo10000 person-yr No

                      No10000 person-yr

                      All causes of death 213 376 321 571All deaths caused by disease 150 265 285 507Cardiovascular diseases 55 97 104 185Diabetes 2 04 19 34Cancer 31 55 73 133Other diseases 62 11 89 155All non-disease causes 63 111 36 64Accident unrelated to drugs 21 37 17 30Poisoning of undetermined intent 9 16 4 07Suicide 15 26 5 09Other nondisease cause 18 32 10 18

                      CC-18

                      Health Care Costs Attributable to ObesityEstimates of what various conditions add to health-care service costs over a 12-month period

                      $395

                      $230

                      $225

                      $150

                      $125

                      $0 $100 $200 $300 $400 $500

                      Obesity

                      Smoking

                      20 years aging

                      Problem drinking

                      Overweight

                      Sturm R Health Aff (Millwood) 2002 Mar-Apr21(2)245-53 Table Wall Street Journal 3132002

                      Obesity increased medication costs 77inpatient and outpatient costs 36

                      What-if scenarios (The Lancet forthcoming)

                      Redrawn from Hamman RF et al Diabetes Care 2006292102‐2107

                      Change in Weight from Baseline (kg)0‐10 ‐5 +5In

                      cide

                      nce Ra

                      te per 100

                      Person‐Years

                      10

                      20

                      15

                      5

                      0

                      How Much Weight Loss Is Needed to Prevent T2DMndashNot Very Much The DPP Experience

                      In the Da Qing Study 6-year Intervention Led to Lower Incidence of Type 2 Diabetes 14 Years Later

                      n=530 overweight Chinese men and women with IGT mean BMI=26

                      17

                      0

                      20

                      40

                      60

                      80

                      100

                      2 4 6 8 10 12 14 16 18 20Years of follow‐up

                      6‐year intervention hazard ratio = 049 (95 CI 033ndash073)20‐year follow‐up hazard ratio = 057 (95 CI 041ndash081)

                      Cumulative Incide

                      nce of Type 2 Diabe

                      tes ()

                      0

                      Lifestyle interventionControl

                      Treatment Follow‐up

                      Li et al Lancet 20083711783ndash9

                      Pharmacotherapy for Weight LossLouis J Aronne MD FACP

                      Professor of Clinical Medicine Weill Cornell Medical College

                      Adjunct Associate Professor of Clinical Medicine Columbia University College of Physicians and Surgeons

                      Director Comprehensive Weight Control Program

                      New York-Presbyterian HospitalWeill Cornell Medical Center New York NY

                      As faculty of Weill Cornell Medical College we are committed to providing transparency for any and all external relationships prior to giving an academic presentation

                      I am a consultant speaker advisor or receive research support fromBMS

                      Arena Aspire BariatricsMyos

                      GI Dynamics Novo NordiskOrexigenVivusZafgen

                      I may discuss off-label use of medications

                      Disclosure Page

                      uarrFood intakedarr energy expenditure

                      darrfood intake uarrenergy expenditure

                      Topiramate

                      Naltrexone

                      LorcaserinPramlintideGLP-1Leptin

                      BupropionPhentermine

                      New Compounds andCombination Interventions

                      c Louis J Aronne MDScience Feb 7 2003 Vol 299Illustration by Katharine Sutliff

                      Phentermine and TopiramateExtended-Release

                      bull Mechanism of actionndash Phentermine Sympathomimetic amine - releaserndash Topiramate Gabaergicglutamate modulation and carbonic

                      anhydrase inhibitionbull February 2012 FDA advisory committee votes 20-2 for

                      approval bull FDA approved July 2012

                      ndash Schedule IVndash Pregnancy Category X = REMS

                      Topiramate monotherapy exposure in pregnancy associated with 2- to 5-fold increased prevalence of oral clefts

                      bull 4 doses Titrate upbull Available only by mail orderbull Covered through Medco Express Scripts

                      Phentermine and TopiramateExtended-Release

                      bull Dose titrationndash Once dailyndash Start treatment with phentermine 375 mgtopiramate

                      23 mg extended-release daily for 14 daysndash After 14 days increase to the recommended dose of

                      phentermine 75 mgtopiramate 46 mg extended-release once daily

                      ndash May titrate upwards if needed to phen 15 top 92 mg strength

                      EQUIP amp CONQUER Discontinuation RateDue to AEs in All Doses Studied

                      Placebo Low Mid Full

                      Number of patients 1508 241 498 1507Discontinuation due to AEs 9 12 12 18Blurred vision 05 21 08 07Headache 07 17 02 09Insomnia 04 00 04 17Depression 02 00 08 14Tingling 00 04 10 12Irritability 01 08 08 12Anxiety 03 00 02 11Dizziness 02 04 12 08

                      Includes adverse events (AEs) by dose for EQUIP amp CONQUER which lead to discontinuation in gt 1 of patientsPress release Sept 9 2009 Available at httpirvivuscomreleasedetailcfmReleaseID=420114Accessed April 27 2010

                      PhenTPMMid

                      -104

                      Phentermine and Topiramate SEQUELWeight Loss Over Time

                      Garvey WT Ryan DH Look M Gadde KM Am J Clin Nutr 201295(2)297-308

                      Placebo-25

                      Plt00001 v placebo

                      Weight Loss

                      Week

                      Total Population

                      0

                      -2

                      -4

                      -6

                      -8

                      -10

                      -12

                      -14

                      -16

                      0 12 24 36 48 60 72 84 96 108

                      Weight Loss ITT-LOCF

                      PhenTPMTop

                      -114

                      Mid = 75 mg46 mgTop = 15 mg92 mg

                      CONQUER Significant Improvement in Cardiovascular Risk Factors

                      (LS Mean Wt Loss)

                      QNEXAMid(78)

                      P valueQNEXATop

                      (98) P value

                      Waist Circumference (cm) ‐52 lt00001 ‐68 lt00001

                      Systolic BP (mmHg) ‐23 00008 ‐32 lt00001

                      Diastolic BP (mmHg) ‐07 NS ‐11 00031

                      Triglycerides ( ∆) ‐133 lt00001 ‐153 lt00001

                      Total Cholesterol ( ∆) ‐16 00345 ‐30 lt00001

                      LDL ( ∆) 04 NS ‐28 00069

                      HDL ( ∆) 40 lt00001 56 lt00001

                      P values represent comparisons to placebo NS= non‐significant

                      ITT‐LOCF Placebo ComparisonsTotal Study Population

                      Davidson MH et al Am J Cardiol 2013 Jan 29 pii S0002‐9149(12)02641‐0 doi 101016jamjcard201212038

                      Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors

                      Risk FactorsPhenTPMMid

                      p-valuePhenTPMTop

                      p-value

                      CRP lt0001 lt0001Fibrinogen lt005 lt005Adiponectin lt00001 lt00001

                      p-values represent comparisons to placebo

                      ITT-LOCF Placebo Comparisons

                      Gadde KM et al Lancet 2011377(9774)1341-52

                      Mid = 75 mg46 mgTop = 15 mg92 mg

                      Lorcaserin

                      bull Selective 5‐HT2C receptor agonist designed to promote weight loss

                      bull Schedule IV ndash Expected soonbull Indication weight loss and maintenance of

                      weight loss in patients with BMI gt30 kgm2 or BMI gt27 kgm2 + weight-related comorbidcondition(s)

                      bull Dose - 10 mg BIDbull Most common side effects headache nausea

                      dizziness dry mouth

                      BLOOM Study Body Weight Over Years 1 and 2

                      Smith SR et al N Engl J Med 2010363245-256 Study Week0 8 16 24 32 40 48 56 64 72 80 88 96 104

                      Bod

                      y W

                      eigh

                      t (kg

                      )

                      102

                      100

                      98

                      96

                      94

                      92

                      90

                      0

                      Year 1

                      Placebo in year 1 and 2 (n = 684)Lorcaserin in year 1 placebo in year 2 (n = 275)Lorcaserin in year 1 and 2 (n = 564)

                      Year 2

                      Endpoint Lorcaserin Placebo P valueWaist circumference (cm) minus68plusmn02 minus39plusmn02 lt001BMI (kgm2) minus209plusmn006 minus078plusmn005 lt001SBPDBP (mm Hg) minus14plusmn03minus11plusmn02 minus08plusmn03minus06plusmn02 0401Cholesterol ( ∆)Total LDLHDL

                      minus090plusmn033287plusmn056005plusmn033

                      057plusmn034403plusmn058minus021plusmn034

                      001

                      049

                      72Triglycerides minus615plusmn103 minus014plusmn099 lt001SafetyHR (beatsmin)PASP (mm Hg)Beck depression II score

                      minus20plusmn03minus092plusmn023minus11plusmn01

                      minus16plusmn04 minus023plusmn023 minus09plusmn01

                      0499014026

                      BLOOM StudyKey Secondary Endpoints

                      Smith SR et al N Engl J Med 2010363245-256

                      BLOOM-DMChange in Glycemic Parameters

                      P lt001 P lt05 LS mean change plusmn SEMOrsquoNeil PM et al Obesity 201220(7)1426-36 httpwwwnaturecomdoifinder101038oby201266

                      00

                      -05

                      -10

                      -150 12 24 36 52

                      Cha

                      nge

                      from

                      bas

                      elin

                      e (

                      )

                      A1c

                      Study week

                      0

                      -10

                      -20

                      -30

                      -400 12 24 52

                      Cha

                      nge

                      from

                      bas

                      elin

                      e m

                      gdl

                      )

                      Fasting plasma glucose

                      Study week

                      Lorcaserin 10 mg BID Lorcaserin 10 mg Placebo

                      Lorcaserin Adverse Events Reported by 5 or More in Any Group in Year 1

                      55

                      N () Lorcaserin(N = 1593)

                      Placebo(N = 1584)

                      Headache 287 (180) 175 (110)

                      Dizziness 130 (82) 60 (38)

                      Nausea 119 (75) 85 (54)

                      Constipation 106 (67) 64 (40)

                      Fatigue 95 (60) 48 (30)

                      Dry mouth 83 (52) 37 (23)

                      Smith SR et al ADA 2009 Late‐Breaking Abstract 96

                      LorcaserinNo Increase in Rate of Valvulopathy

                      Smith SR et al N Engl J Med 2010363245-256

                      10

                      8

                      6

                      4

                      2

                      024 52 76 104

                      1351714

                      9

                      19

                      3421Patie

                      nts

                      ()

                      Week

                      Lorcaserin in yr 1 and 2

                      Lorcaserin in yr 1 Placebo in yr 2

                      Placebo in yr 1 and 2

                      Phase III Study Outcomes Compared

                      Buproprion SR (360 mgd) Naltrexone SR (32 mgd)

                      Lorcaserin(20 mgd)

                      Phentermine Topiramate CR

                      COR1 COR-I2 COR-II3 NB3043 BLOOM4 BLOSSOM5 EQUIP CONQUER

                      Number of patients (ITT-LOCF)

                      793 obese 1453 obese

                      1281 obese

                      502 type II diabetes

                      3182 obese 4008 obese

                      1230 obese BMI 44

                      2448 comorbidBMI 36

                      Mean change compared with placebo from base

                      93 vs5 1c

                      61a vs13c

                      64a vs12

                      50 a vs12c

                      58 vs22c

                      48 vs28c

                      11 Fullbvs 16

                      104 Fullb 84 Midb

                      vs 18

                      51 Lowb vs16c

                      Categorical change 5 compared with placebo from base

                      56 vs43

                      48a vs164

                      563a

                      vs 171445a vs189

                      475b

                      vs 203472b vs25

                      67 Fullb 45 Lowb vs17

                      70 Fullb 62 Midb

                      vs 21

                      Phenterminetopiramate doses Low 375 mg phentermine23 mg topiramate Mid 75 mg phentermine 46 mg topiramate Full 15 mg phentermine 92 mg topiramateITT-LOCF intent-to-treat last observation carried forwardData not available aP lt 001 vs placebo bP lt 0001 vs placebo

                      Obesity Treatments in Late Development

                      Kushner RF Expert Opin Pharmacother 200891339-1350

                      Agents ActionBupropionNaltrexone

                      bull Dopaminenoradrenaline reuptake inhibitorbull Opioid receptor antagonist

                      Liraglutide bull GLP-1 agonist

                      BupropionNaltrexone

                      bull Mechanism of Actionndash Bupropion - Dopaminenoradrenaline reuptake inhibitorndash Naltrexone- Opioid receptor antagonist

                      bull Was approved by FDA committee but FDA did not approve until a CV outcome study is performed 2nd concerns about BP and P in some patients

                      bull The Light Study is now underway and reported to be enrolling well under PI Dr Nissen

                      bull BupropionNaltrexone will have first completed CV outcome study

                      Buproprion ndash Naltrexone

                      Greenway FL et al Lancet 2010376(9741)595-605

                      0

                      -2

                      -4

                      -6

                      -8

                      -100 4 8 12 16 20 24 28 32 36 40 44 48 52 56

                      Weeks

                      Wei

                      ght c

                      hang

                      e fro

                      m b

                      asel

                      ine

                      ()

                      Placebo

                      Naltrexone 16 mg plus bupropion

                      Naltrexone 32 mg plus bupropion

                      Liraglutide for Weight Loss in Patients with Type 2 Diabetes

                      bull GLP-1 analog approved for treatment of type 2 diabetes

                      bull Anorectic effect mediated both by the activation of GLP-1 receptor expressed on vagal afferents and by the GLP-1R activation in CNS

                      bull Affects visceral fat adiposity appetite food preference and cardiovascular biomarkers in patients with type 2 diabetes

                      Inoue K et al Cardiovasc Diabetol 2011 10109 doi1011861475-2840-10-109

                      Liraglutide Weight Loss Over 2 Years ITT Observed Means

                      Astrup A et al Int J Obes (Lond) 201236(6)843-54

                      FromScreening

                      -94 kg

                      -67 kg-88 kg

                      -99 kg-94 kg

                      -103 kg

                      ITT intention to treat

                      Phase III Study Outcomes Compared

                      Buproprion SR (360 mgd) Naltrexone SR (32 mgd)

                      Lorcaserin(20 mgd)

                      Phentermine Topiramate CR

                      COR1 COR-I2 COR-II3 NB3043 BLOOM4 BLOSSOM5 EQUIP CONQUER

                      Number of patients (ITT-LOCF)

                      793 obese 1453 obese

                      1281 obese

                      502 type II diabetes

                      3182 obese 4008 obese

                      1230 obese BMI 44

                      2448 comorbidBMI 36

                      Mean change compared with placebo from base

                      93 vs5 1c

                      61a vs13c

                      64a vs12

                      50 a vs12c

                      58 vs22c

                      48 vs28c

                      11 Fullbvs 16

                      104 Fullb 84 Midb

                      vs 18

                      51 Lowb vs16c

                      Categorical change 5 compared with placebo from base

                      56 vs43

                      48a vs164

                      563a

                      vs 171445a vs189

                      475b

                      vs 203472b vs25

                      67 Fullb 45 Lowb vs17

                      70 Fullb 62 Midb

                      vs 21

                      Phenterminetopiramate doses Low 375 mg phentermine23 mg topiramate Mid 75 mg phentermine 46 mg topiramate Full 15 mg phentermine 92 mg topiramateITT-LOCF intent-to-treat last observation carried forwardData not available aP lt 001 vs placebo bP lt 0001 vs placebo

                      Treatment Gap in theManagement of Obesity

                      Physicians Need Effective Pharmacotherapies That Will Reduce Weight Significantly and Reduce Weight-related Comorbidities

                      0 5 10 15 20 25 30 35

                      Diet and Lifestyle Lap Band Gastric Bypass

                      TreatmentGap

                      What will fill the gap

                      Too risky for many peopleNot effective enoughfor many people

                      Treatment Gap in theManagement of Obesity

                      0 5 10 15 20 25 30 35

                      Diet and Lifestyle Lap Band Gastric Bypass

                      TreatmentGap

                      Too risky for many peopleNot effective enoughfor many people Pharmacotherapy

                      Less invasive procedures

                      Physicians Need Effective Pharmacotherapies That Will Reduce Weight Significantly and Reduce Weight-related Comorbidities

                      What will fill the gap

                      • Slide Number 1
                      • Slide Number 2
                      • Weight Management is Moving into the Workplace and Mainstream of Healthcare
                      • US Preventative Services Task Force
                      • A Proposal from CMS about Coverage for Intensive Behavioral Therapy for Obesity
                      • Slide Number 6
                      • Biggest Increases in Clinically Severe Obesity US 1987-2005
                      • Relationship Between BMI and Risk of Type 2 Diabetes
                      • Slide Number 9
                      • Medical Complications of Obesity Almost every organ system is affected
                      • Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and disease
                      • Current Therapies Often Address Individual Risk Factors Cardiometabolic risk
                      • Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and disease
                      • Are You Treating These Drivers of Cardiometabolic Risk Should You Treat The Underlying Cause
                      • Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors
                      • In My Opinion The Winds of Change are Blowing in the Treatment of Chronic Diseases
                      • Bariatric Surgery Reduces Overall Mortality Diabetes Mortality by 88
                      • Health Care Costs Attributable to ObesityEstimates of what various conditions add to health-care service costs over a 12-month period
                      • What-if scenarios (The Lancet forthcoming)
                      • How Much Weight Loss Is Needed to Prevent T2DMndashNot Very Much The DPP Experience
                      • In the Da Qing Study 6-year Intervention Led to Lower Incidence of Type 2 Diabetes 14 Years Later
                      • Slide Number 22
                      • Slide Number 23
                      • New Compounds andCombination Interventions
                      • Phentermine and Topiramate Extended-Release
                      • Phentermine and Topiramate Extended-Release
                      • EQUIP amp CONQUER Discontinuation RateDue to AEs in All Doses Studied
                      • Phentermine and Topiramate SEQUELWeight Loss Over Time
                      • CONQUER Significant Improvement in Cardiovascular Risk Factors
                      • Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors
                      • Lorcaserin
                      • BLOOM Study Body Weight Over Years 1 and 2
                      • BLOOM StudyKey Secondary Endpoints
                      • BLOOM-DMChange in Glycemic Parameters
                      • Lorcaserin Adverse Events Reported by 5 or More in Any Group in Year 1
                      • LorcaserinNo Increase in Rate of Valvulopathy
                      • Phase III Study Outcomes Compared
                      • Obesity Treatments in Late Development
                      • BupropionNaltrexone
                      • Buproprion ndash Naltrexone
                      • Liraglutide for Weight Loss in Patients with Type 2 Diabetes
                      • Liraglutide Weight Loss Over 2 Years ITT Observed Means
                      • Phase III Study Outcomes Compared
                      • Treatment Gap in theManagement of Obesity
                      • Treatment Gap in theManagement of Obesity

                        Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and

                        disease

                        Lactate Angiotensinogen

                        Leptin

                        Adipsin (Complement D)

                        TNF- α

                        FFAFat Stores

                        Lipoprotein Lipase

                        Plasminogen Activator Inhibitor 1

                        (PAI-1)

                        Resistin

                        Adiponectin

                        DM=diabetes mellitus FFA=free fatty acid PAI-1=plasminogen activator inhibitor-1 TNFα=tumor necrosis factor alpha IL-6=interleukin 6

                        Slide copy2007Louis J Aronne MD after Dr G Bray

                        Insulin

                        IL - 6

                        Estrogen

                        Hypertension

                        Thrombosis

                        Inflammation

                        Type 2 DM

                        DyslipidemiaType 2 DM

                        Arthritis

                        ASCVD

                        Asthma

                        C-C L2

                        Adiponectin Anti-atherogenicantidiabeticdarr darr foam cells darr vascular remodelling

                        uarr insulin sensitivity darr hepatic glucose output

                        IL-6uarr

                        Pro-atherogenicpro-diabeticuarr vascular inflammation darr insulin signalling

                        TNFαuarr

                        Pro-atherogenicpro-diabeticdarr insulin sensitivity in adipocytes (paracrine)

                        PAI-1uarr

                        Pro-atherogenicuarr atherothrombotic risk

                        IAA intra-abdominal adiposityMarette A Curr Opin Clin Nutr Metab Care 20025377-83

                        Are You Treating These Drivers of Cardiometabolic Risk Should You Treat The Underlying Cause

                        Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors

                        Risk FactorsPhenTPMMid

                        p-valuePhenTPMTop

                        p-value

                        CRP lt0001 lt0001Fibrinogen lt005 lt005Adiponectin lt00001 lt00001

                        p-values represent comparisons to placebo

                        ITT-LOCF Placebo Comparisons

                        Gadde KM et al Lancet 2011377(9774)1341-52

                        Mid = 75 mg46 mgTop = 15 mg92 mg

                        In My Opinion The Winds of Change are Blowing in the Treatment of Chronic

                        Diseasesbull ACCORD was stopped because of increased

                        mortality in the tight control group 28 of whom gained gt 10kg compared to 14 in control^

                        bull Bariatric surgery trials show gt 80 reduction in diabetes mortality with weight loss

                        bull I believe we are in the midst of a shift from ldquoGlucocentricrdquo to ldquoWeight-Centricrdquo Management of T 2 DM

                        ^ NEJM 3582545-2559 Adams TD et al N Engl J Med 2007357(8)753-761

                        -34-48-48-88-59-29+73

                        Adams TD et al N Engl J Med 2007357(8)753-761

                        Bariatric Surgery Reduces Overall Mortality Diabetes Mortality by 88

                        Matched SubjectsSurgery Group (n=7925)

                        Co(n=

                        ntrol Group7925)

                        NoNo10000 person-yr No

                        No10000 person-yr

                        All causes of death 213 376 321 571All deaths caused by disease 150 265 285 507Cardiovascular diseases 55 97 104 185Diabetes 2 04 19 34Cancer 31 55 73 133Other diseases 62 11 89 155All non-disease causes 63 111 36 64Accident unrelated to drugs 21 37 17 30Poisoning of undetermined intent 9 16 4 07Suicide 15 26 5 09Other nondisease cause 18 32 10 18

                        CC-18

                        Health Care Costs Attributable to ObesityEstimates of what various conditions add to health-care service costs over a 12-month period

                        $395

                        $230

                        $225

                        $150

                        $125

                        $0 $100 $200 $300 $400 $500

                        Obesity

                        Smoking

                        20 years aging

                        Problem drinking

                        Overweight

                        Sturm R Health Aff (Millwood) 2002 Mar-Apr21(2)245-53 Table Wall Street Journal 3132002

                        Obesity increased medication costs 77inpatient and outpatient costs 36

                        What-if scenarios (The Lancet forthcoming)

                        Redrawn from Hamman RF et al Diabetes Care 2006292102‐2107

                        Change in Weight from Baseline (kg)0‐10 ‐5 +5In

                        cide

                        nce Ra

                        te per 100

                        Person‐Years

                        10

                        20

                        15

                        5

                        0

                        How Much Weight Loss Is Needed to Prevent T2DMndashNot Very Much The DPP Experience

                        In the Da Qing Study 6-year Intervention Led to Lower Incidence of Type 2 Diabetes 14 Years Later

                        n=530 overweight Chinese men and women with IGT mean BMI=26

                        17

                        0

                        20

                        40

                        60

                        80

                        100

                        2 4 6 8 10 12 14 16 18 20Years of follow‐up

                        6‐year intervention hazard ratio = 049 (95 CI 033ndash073)20‐year follow‐up hazard ratio = 057 (95 CI 041ndash081)

                        Cumulative Incide

                        nce of Type 2 Diabe

                        tes ()

                        0

                        Lifestyle interventionControl

                        Treatment Follow‐up

                        Li et al Lancet 20083711783ndash9

                        Pharmacotherapy for Weight LossLouis J Aronne MD FACP

                        Professor of Clinical Medicine Weill Cornell Medical College

                        Adjunct Associate Professor of Clinical Medicine Columbia University College of Physicians and Surgeons

                        Director Comprehensive Weight Control Program

                        New York-Presbyterian HospitalWeill Cornell Medical Center New York NY

                        As faculty of Weill Cornell Medical College we are committed to providing transparency for any and all external relationships prior to giving an academic presentation

                        I am a consultant speaker advisor or receive research support fromBMS

                        Arena Aspire BariatricsMyos

                        GI Dynamics Novo NordiskOrexigenVivusZafgen

                        I may discuss off-label use of medications

                        Disclosure Page

                        uarrFood intakedarr energy expenditure

                        darrfood intake uarrenergy expenditure

                        Topiramate

                        Naltrexone

                        LorcaserinPramlintideGLP-1Leptin

                        BupropionPhentermine

                        New Compounds andCombination Interventions

                        c Louis J Aronne MDScience Feb 7 2003 Vol 299Illustration by Katharine Sutliff

                        Phentermine and TopiramateExtended-Release

                        bull Mechanism of actionndash Phentermine Sympathomimetic amine - releaserndash Topiramate Gabaergicglutamate modulation and carbonic

                        anhydrase inhibitionbull February 2012 FDA advisory committee votes 20-2 for

                        approval bull FDA approved July 2012

                        ndash Schedule IVndash Pregnancy Category X = REMS

                        Topiramate monotherapy exposure in pregnancy associated with 2- to 5-fold increased prevalence of oral clefts

                        bull 4 doses Titrate upbull Available only by mail orderbull Covered through Medco Express Scripts

                        Phentermine and TopiramateExtended-Release

                        bull Dose titrationndash Once dailyndash Start treatment with phentermine 375 mgtopiramate

                        23 mg extended-release daily for 14 daysndash After 14 days increase to the recommended dose of

                        phentermine 75 mgtopiramate 46 mg extended-release once daily

                        ndash May titrate upwards if needed to phen 15 top 92 mg strength

                        EQUIP amp CONQUER Discontinuation RateDue to AEs in All Doses Studied

                        Placebo Low Mid Full

                        Number of patients 1508 241 498 1507Discontinuation due to AEs 9 12 12 18Blurred vision 05 21 08 07Headache 07 17 02 09Insomnia 04 00 04 17Depression 02 00 08 14Tingling 00 04 10 12Irritability 01 08 08 12Anxiety 03 00 02 11Dizziness 02 04 12 08

                        Includes adverse events (AEs) by dose for EQUIP amp CONQUER which lead to discontinuation in gt 1 of patientsPress release Sept 9 2009 Available at httpirvivuscomreleasedetailcfmReleaseID=420114Accessed April 27 2010

                        PhenTPMMid

                        -104

                        Phentermine and Topiramate SEQUELWeight Loss Over Time

                        Garvey WT Ryan DH Look M Gadde KM Am J Clin Nutr 201295(2)297-308

                        Placebo-25

                        Plt00001 v placebo

                        Weight Loss

                        Week

                        Total Population

                        0

                        -2

                        -4

                        -6

                        -8

                        -10

                        -12

                        -14

                        -16

                        0 12 24 36 48 60 72 84 96 108

                        Weight Loss ITT-LOCF

                        PhenTPMTop

                        -114

                        Mid = 75 mg46 mgTop = 15 mg92 mg

                        CONQUER Significant Improvement in Cardiovascular Risk Factors

                        (LS Mean Wt Loss)

                        QNEXAMid(78)

                        P valueQNEXATop

                        (98) P value

                        Waist Circumference (cm) ‐52 lt00001 ‐68 lt00001

                        Systolic BP (mmHg) ‐23 00008 ‐32 lt00001

                        Diastolic BP (mmHg) ‐07 NS ‐11 00031

                        Triglycerides ( ∆) ‐133 lt00001 ‐153 lt00001

                        Total Cholesterol ( ∆) ‐16 00345 ‐30 lt00001

                        LDL ( ∆) 04 NS ‐28 00069

                        HDL ( ∆) 40 lt00001 56 lt00001

                        P values represent comparisons to placebo NS= non‐significant

                        ITT‐LOCF Placebo ComparisonsTotal Study Population

                        Davidson MH et al Am J Cardiol 2013 Jan 29 pii S0002‐9149(12)02641‐0 doi 101016jamjcard201212038

                        Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors

                        Risk FactorsPhenTPMMid

                        p-valuePhenTPMTop

                        p-value

                        CRP lt0001 lt0001Fibrinogen lt005 lt005Adiponectin lt00001 lt00001

                        p-values represent comparisons to placebo

                        ITT-LOCF Placebo Comparisons

                        Gadde KM et al Lancet 2011377(9774)1341-52

                        Mid = 75 mg46 mgTop = 15 mg92 mg

                        Lorcaserin

                        bull Selective 5‐HT2C receptor agonist designed to promote weight loss

                        bull Schedule IV ndash Expected soonbull Indication weight loss and maintenance of

                        weight loss in patients with BMI gt30 kgm2 or BMI gt27 kgm2 + weight-related comorbidcondition(s)

                        bull Dose - 10 mg BIDbull Most common side effects headache nausea

                        dizziness dry mouth

                        BLOOM Study Body Weight Over Years 1 and 2

                        Smith SR et al N Engl J Med 2010363245-256 Study Week0 8 16 24 32 40 48 56 64 72 80 88 96 104

                        Bod

                        y W

                        eigh

                        t (kg

                        )

                        102

                        100

                        98

                        96

                        94

                        92

                        90

                        0

                        Year 1

                        Placebo in year 1 and 2 (n = 684)Lorcaserin in year 1 placebo in year 2 (n = 275)Lorcaserin in year 1 and 2 (n = 564)

                        Year 2

                        Endpoint Lorcaserin Placebo P valueWaist circumference (cm) minus68plusmn02 minus39plusmn02 lt001BMI (kgm2) minus209plusmn006 minus078plusmn005 lt001SBPDBP (mm Hg) minus14plusmn03minus11plusmn02 minus08plusmn03minus06plusmn02 0401Cholesterol ( ∆)Total LDLHDL

                        minus090plusmn033287plusmn056005plusmn033

                        057plusmn034403plusmn058minus021plusmn034

                        001

                        049

                        72Triglycerides minus615plusmn103 minus014plusmn099 lt001SafetyHR (beatsmin)PASP (mm Hg)Beck depression II score

                        minus20plusmn03minus092plusmn023minus11plusmn01

                        minus16plusmn04 minus023plusmn023 minus09plusmn01

                        0499014026

                        BLOOM StudyKey Secondary Endpoints

                        Smith SR et al N Engl J Med 2010363245-256

                        BLOOM-DMChange in Glycemic Parameters

                        P lt001 P lt05 LS mean change plusmn SEMOrsquoNeil PM et al Obesity 201220(7)1426-36 httpwwwnaturecomdoifinder101038oby201266

                        00

                        -05

                        -10

                        -150 12 24 36 52

                        Cha

                        nge

                        from

                        bas

                        elin

                        e (

                        )

                        A1c

                        Study week

                        0

                        -10

                        -20

                        -30

                        -400 12 24 52

                        Cha

                        nge

                        from

                        bas

                        elin

                        e m

                        gdl

                        )

                        Fasting plasma glucose

                        Study week

                        Lorcaserin 10 mg BID Lorcaserin 10 mg Placebo

                        Lorcaserin Adverse Events Reported by 5 or More in Any Group in Year 1

                        55

                        N () Lorcaserin(N = 1593)

                        Placebo(N = 1584)

                        Headache 287 (180) 175 (110)

                        Dizziness 130 (82) 60 (38)

                        Nausea 119 (75) 85 (54)

                        Constipation 106 (67) 64 (40)

                        Fatigue 95 (60) 48 (30)

                        Dry mouth 83 (52) 37 (23)

                        Smith SR et al ADA 2009 Late‐Breaking Abstract 96

                        LorcaserinNo Increase in Rate of Valvulopathy

                        Smith SR et al N Engl J Med 2010363245-256

                        10

                        8

                        6

                        4

                        2

                        024 52 76 104

                        1351714

                        9

                        19

                        3421Patie

                        nts

                        ()

                        Week

                        Lorcaserin in yr 1 and 2

                        Lorcaserin in yr 1 Placebo in yr 2

                        Placebo in yr 1 and 2

                        Phase III Study Outcomes Compared

                        Buproprion SR (360 mgd) Naltrexone SR (32 mgd)

                        Lorcaserin(20 mgd)

                        Phentermine Topiramate CR

                        COR1 COR-I2 COR-II3 NB3043 BLOOM4 BLOSSOM5 EQUIP CONQUER

                        Number of patients (ITT-LOCF)

                        793 obese 1453 obese

                        1281 obese

                        502 type II diabetes

                        3182 obese 4008 obese

                        1230 obese BMI 44

                        2448 comorbidBMI 36

                        Mean change compared with placebo from base

                        93 vs5 1c

                        61a vs13c

                        64a vs12

                        50 a vs12c

                        58 vs22c

                        48 vs28c

                        11 Fullbvs 16

                        104 Fullb 84 Midb

                        vs 18

                        51 Lowb vs16c

                        Categorical change 5 compared with placebo from base

                        56 vs43

                        48a vs164

                        563a

                        vs 171445a vs189

                        475b

                        vs 203472b vs25

                        67 Fullb 45 Lowb vs17

                        70 Fullb 62 Midb

                        vs 21

                        Phenterminetopiramate doses Low 375 mg phentermine23 mg topiramate Mid 75 mg phentermine 46 mg topiramate Full 15 mg phentermine 92 mg topiramateITT-LOCF intent-to-treat last observation carried forwardData not available aP lt 001 vs placebo bP lt 0001 vs placebo

                        Obesity Treatments in Late Development

                        Kushner RF Expert Opin Pharmacother 200891339-1350

                        Agents ActionBupropionNaltrexone

                        bull Dopaminenoradrenaline reuptake inhibitorbull Opioid receptor antagonist

                        Liraglutide bull GLP-1 agonist

                        BupropionNaltrexone

                        bull Mechanism of Actionndash Bupropion - Dopaminenoradrenaline reuptake inhibitorndash Naltrexone- Opioid receptor antagonist

                        bull Was approved by FDA committee but FDA did not approve until a CV outcome study is performed 2nd concerns about BP and P in some patients

                        bull The Light Study is now underway and reported to be enrolling well under PI Dr Nissen

                        bull BupropionNaltrexone will have first completed CV outcome study

                        Buproprion ndash Naltrexone

                        Greenway FL et al Lancet 2010376(9741)595-605

                        0

                        -2

                        -4

                        -6

                        -8

                        -100 4 8 12 16 20 24 28 32 36 40 44 48 52 56

                        Weeks

                        Wei

                        ght c

                        hang

                        e fro

                        m b

                        asel

                        ine

                        ()

                        Placebo

                        Naltrexone 16 mg plus bupropion

                        Naltrexone 32 mg plus bupropion

                        Liraglutide for Weight Loss in Patients with Type 2 Diabetes

                        bull GLP-1 analog approved for treatment of type 2 diabetes

                        bull Anorectic effect mediated both by the activation of GLP-1 receptor expressed on vagal afferents and by the GLP-1R activation in CNS

                        bull Affects visceral fat adiposity appetite food preference and cardiovascular biomarkers in patients with type 2 diabetes

                        Inoue K et al Cardiovasc Diabetol 2011 10109 doi1011861475-2840-10-109

                        Liraglutide Weight Loss Over 2 Years ITT Observed Means

                        Astrup A et al Int J Obes (Lond) 201236(6)843-54

                        FromScreening

                        -94 kg

                        -67 kg-88 kg

                        -99 kg-94 kg

                        -103 kg

                        ITT intention to treat

                        Phase III Study Outcomes Compared

                        Buproprion SR (360 mgd) Naltrexone SR (32 mgd)

                        Lorcaserin(20 mgd)

                        Phentermine Topiramate CR

                        COR1 COR-I2 COR-II3 NB3043 BLOOM4 BLOSSOM5 EQUIP CONQUER

                        Number of patients (ITT-LOCF)

                        793 obese 1453 obese

                        1281 obese

                        502 type II diabetes

                        3182 obese 4008 obese

                        1230 obese BMI 44

                        2448 comorbidBMI 36

                        Mean change compared with placebo from base

                        93 vs5 1c

                        61a vs13c

                        64a vs12

                        50 a vs12c

                        58 vs22c

                        48 vs28c

                        11 Fullbvs 16

                        104 Fullb 84 Midb

                        vs 18

                        51 Lowb vs16c

                        Categorical change 5 compared with placebo from base

                        56 vs43

                        48a vs164

                        563a

                        vs 171445a vs189

                        475b

                        vs 203472b vs25

                        67 Fullb 45 Lowb vs17

                        70 Fullb 62 Midb

                        vs 21

                        Phenterminetopiramate doses Low 375 mg phentermine23 mg topiramate Mid 75 mg phentermine 46 mg topiramate Full 15 mg phentermine 92 mg topiramateITT-LOCF intent-to-treat last observation carried forwardData not available aP lt 001 vs placebo bP lt 0001 vs placebo

                        Treatment Gap in theManagement of Obesity

                        Physicians Need Effective Pharmacotherapies That Will Reduce Weight Significantly and Reduce Weight-related Comorbidities

                        0 5 10 15 20 25 30 35

                        Diet and Lifestyle Lap Band Gastric Bypass

                        TreatmentGap

                        What will fill the gap

                        Too risky for many peopleNot effective enoughfor many people

                        Treatment Gap in theManagement of Obesity

                        0 5 10 15 20 25 30 35

                        Diet and Lifestyle Lap Band Gastric Bypass

                        TreatmentGap

                        Too risky for many peopleNot effective enoughfor many people Pharmacotherapy

                        Less invasive procedures

                        Physicians Need Effective Pharmacotherapies That Will Reduce Weight Significantly and Reduce Weight-related Comorbidities

                        What will fill the gap

                        • Slide Number 1
                        • Slide Number 2
                        • Weight Management is Moving into the Workplace and Mainstream of Healthcare
                        • US Preventative Services Task Force
                        • A Proposal from CMS about Coverage for Intensive Behavioral Therapy for Obesity
                        • Slide Number 6
                        • Biggest Increases in Clinically Severe Obesity US 1987-2005
                        • Relationship Between BMI and Risk of Type 2 Diabetes
                        • Slide Number 9
                        • Medical Complications of Obesity Almost every organ system is affected
                        • Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and disease
                        • Current Therapies Often Address Individual Risk Factors Cardiometabolic risk
                        • Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and disease
                        • Are You Treating These Drivers of Cardiometabolic Risk Should You Treat The Underlying Cause
                        • Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors
                        • In My Opinion The Winds of Change are Blowing in the Treatment of Chronic Diseases
                        • Bariatric Surgery Reduces Overall Mortality Diabetes Mortality by 88
                        • Health Care Costs Attributable to ObesityEstimates of what various conditions add to health-care service costs over a 12-month period
                        • What-if scenarios (The Lancet forthcoming)
                        • How Much Weight Loss Is Needed to Prevent T2DMndashNot Very Much The DPP Experience
                        • In the Da Qing Study 6-year Intervention Led to Lower Incidence of Type 2 Diabetes 14 Years Later
                        • Slide Number 22
                        • Slide Number 23
                        • New Compounds andCombination Interventions
                        • Phentermine and Topiramate Extended-Release
                        • Phentermine and Topiramate Extended-Release
                        • EQUIP amp CONQUER Discontinuation RateDue to AEs in All Doses Studied
                        • Phentermine and Topiramate SEQUELWeight Loss Over Time
                        • CONQUER Significant Improvement in Cardiovascular Risk Factors
                        • Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors
                        • Lorcaserin
                        • BLOOM Study Body Weight Over Years 1 and 2
                        • BLOOM StudyKey Secondary Endpoints
                        • BLOOM-DMChange in Glycemic Parameters
                        • Lorcaserin Adverse Events Reported by 5 or More in Any Group in Year 1
                        • LorcaserinNo Increase in Rate of Valvulopathy
                        • Phase III Study Outcomes Compared
                        • Obesity Treatments in Late Development
                        • BupropionNaltrexone
                        • Buproprion ndash Naltrexone
                        • Liraglutide for Weight Loss in Patients with Type 2 Diabetes
                        • Liraglutide Weight Loss Over 2 Years ITT Observed Means
                        • Phase III Study Outcomes Compared
                        • Treatment Gap in theManagement of Obesity
                        • Treatment Gap in theManagement of Obesity

                          Adiponectin Anti-atherogenicantidiabeticdarr darr foam cells darr vascular remodelling

                          uarr insulin sensitivity darr hepatic glucose output

                          IL-6uarr

                          Pro-atherogenicpro-diabeticuarr vascular inflammation darr insulin signalling

                          TNFαuarr

                          Pro-atherogenicpro-diabeticdarr insulin sensitivity in adipocytes (paracrine)

                          PAI-1uarr

                          Pro-atherogenicuarr atherothrombotic risk

                          IAA intra-abdominal adiposityMarette A Curr Opin Clin Nutr Metab Care 20025377-83

                          Are You Treating These Drivers of Cardiometabolic Risk Should You Treat The Underlying Cause

                          Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors

                          Risk FactorsPhenTPMMid

                          p-valuePhenTPMTop

                          p-value

                          CRP lt0001 lt0001Fibrinogen lt005 lt005Adiponectin lt00001 lt00001

                          p-values represent comparisons to placebo

                          ITT-LOCF Placebo Comparisons

                          Gadde KM et al Lancet 2011377(9774)1341-52

                          Mid = 75 mg46 mgTop = 15 mg92 mg

                          In My Opinion The Winds of Change are Blowing in the Treatment of Chronic

                          Diseasesbull ACCORD was stopped because of increased

                          mortality in the tight control group 28 of whom gained gt 10kg compared to 14 in control^

                          bull Bariatric surgery trials show gt 80 reduction in diabetes mortality with weight loss

                          bull I believe we are in the midst of a shift from ldquoGlucocentricrdquo to ldquoWeight-Centricrdquo Management of T 2 DM

                          ^ NEJM 3582545-2559 Adams TD et al N Engl J Med 2007357(8)753-761

                          -34-48-48-88-59-29+73

                          Adams TD et al N Engl J Med 2007357(8)753-761

                          Bariatric Surgery Reduces Overall Mortality Diabetes Mortality by 88

                          Matched SubjectsSurgery Group (n=7925)

                          Co(n=

                          ntrol Group7925)

                          NoNo10000 person-yr No

                          No10000 person-yr

                          All causes of death 213 376 321 571All deaths caused by disease 150 265 285 507Cardiovascular diseases 55 97 104 185Diabetes 2 04 19 34Cancer 31 55 73 133Other diseases 62 11 89 155All non-disease causes 63 111 36 64Accident unrelated to drugs 21 37 17 30Poisoning of undetermined intent 9 16 4 07Suicide 15 26 5 09Other nondisease cause 18 32 10 18

                          CC-18

                          Health Care Costs Attributable to ObesityEstimates of what various conditions add to health-care service costs over a 12-month period

                          $395

                          $230

                          $225

                          $150

                          $125

                          $0 $100 $200 $300 $400 $500

                          Obesity

                          Smoking

                          20 years aging

                          Problem drinking

                          Overweight

                          Sturm R Health Aff (Millwood) 2002 Mar-Apr21(2)245-53 Table Wall Street Journal 3132002

                          Obesity increased medication costs 77inpatient and outpatient costs 36

                          What-if scenarios (The Lancet forthcoming)

                          Redrawn from Hamman RF et al Diabetes Care 2006292102‐2107

                          Change in Weight from Baseline (kg)0‐10 ‐5 +5In

                          cide

                          nce Ra

                          te per 100

                          Person‐Years

                          10

                          20

                          15

                          5

                          0

                          How Much Weight Loss Is Needed to Prevent T2DMndashNot Very Much The DPP Experience

                          In the Da Qing Study 6-year Intervention Led to Lower Incidence of Type 2 Diabetes 14 Years Later

                          n=530 overweight Chinese men and women with IGT mean BMI=26

                          17

                          0

                          20

                          40

                          60

                          80

                          100

                          2 4 6 8 10 12 14 16 18 20Years of follow‐up

                          6‐year intervention hazard ratio = 049 (95 CI 033ndash073)20‐year follow‐up hazard ratio = 057 (95 CI 041ndash081)

                          Cumulative Incide

                          nce of Type 2 Diabe

                          tes ()

                          0

                          Lifestyle interventionControl

                          Treatment Follow‐up

                          Li et al Lancet 20083711783ndash9

                          Pharmacotherapy for Weight LossLouis J Aronne MD FACP

                          Professor of Clinical Medicine Weill Cornell Medical College

                          Adjunct Associate Professor of Clinical Medicine Columbia University College of Physicians and Surgeons

                          Director Comprehensive Weight Control Program

                          New York-Presbyterian HospitalWeill Cornell Medical Center New York NY

                          As faculty of Weill Cornell Medical College we are committed to providing transparency for any and all external relationships prior to giving an academic presentation

                          I am a consultant speaker advisor or receive research support fromBMS

                          Arena Aspire BariatricsMyos

                          GI Dynamics Novo NordiskOrexigenVivusZafgen

                          I may discuss off-label use of medications

                          Disclosure Page

                          uarrFood intakedarr energy expenditure

                          darrfood intake uarrenergy expenditure

                          Topiramate

                          Naltrexone

                          LorcaserinPramlintideGLP-1Leptin

                          BupropionPhentermine

                          New Compounds andCombination Interventions

                          c Louis J Aronne MDScience Feb 7 2003 Vol 299Illustration by Katharine Sutliff

                          Phentermine and TopiramateExtended-Release

                          bull Mechanism of actionndash Phentermine Sympathomimetic amine - releaserndash Topiramate Gabaergicglutamate modulation and carbonic

                          anhydrase inhibitionbull February 2012 FDA advisory committee votes 20-2 for

                          approval bull FDA approved July 2012

                          ndash Schedule IVndash Pregnancy Category X = REMS

                          Topiramate monotherapy exposure in pregnancy associated with 2- to 5-fold increased prevalence of oral clefts

                          bull 4 doses Titrate upbull Available only by mail orderbull Covered through Medco Express Scripts

                          Phentermine and TopiramateExtended-Release

                          bull Dose titrationndash Once dailyndash Start treatment with phentermine 375 mgtopiramate

                          23 mg extended-release daily for 14 daysndash After 14 days increase to the recommended dose of

                          phentermine 75 mgtopiramate 46 mg extended-release once daily

                          ndash May titrate upwards if needed to phen 15 top 92 mg strength

                          EQUIP amp CONQUER Discontinuation RateDue to AEs in All Doses Studied

                          Placebo Low Mid Full

                          Number of patients 1508 241 498 1507Discontinuation due to AEs 9 12 12 18Blurred vision 05 21 08 07Headache 07 17 02 09Insomnia 04 00 04 17Depression 02 00 08 14Tingling 00 04 10 12Irritability 01 08 08 12Anxiety 03 00 02 11Dizziness 02 04 12 08

                          Includes adverse events (AEs) by dose for EQUIP amp CONQUER which lead to discontinuation in gt 1 of patientsPress release Sept 9 2009 Available at httpirvivuscomreleasedetailcfmReleaseID=420114Accessed April 27 2010

                          PhenTPMMid

                          -104

                          Phentermine and Topiramate SEQUELWeight Loss Over Time

                          Garvey WT Ryan DH Look M Gadde KM Am J Clin Nutr 201295(2)297-308

                          Placebo-25

                          Plt00001 v placebo

                          Weight Loss

                          Week

                          Total Population

                          0

                          -2

                          -4

                          -6

                          -8

                          -10

                          -12

                          -14

                          -16

                          0 12 24 36 48 60 72 84 96 108

                          Weight Loss ITT-LOCF

                          PhenTPMTop

                          -114

                          Mid = 75 mg46 mgTop = 15 mg92 mg

                          CONQUER Significant Improvement in Cardiovascular Risk Factors

                          (LS Mean Wt Loss)

                          QNEXAMid(78)

                          P valueQNEXATop

                          (98) P value

                          Waist Circumference (cm) ‐52 lt00001 ‐68 lt00001

                          Systolic BP (mmHg) ‐23 00008 ‐32 lt00001

                          Diastolic BP (mmHg) ‐07 NS ‐11 00031

                          Triglycerides ( ∆) ‐133 lt00001 ‐153 lt00001

                          Total Cholesterol ( ∆) ‐16 00345 ‐30 lt00001

                          LDL ( ∆) 04 NS ‐28 00069

                          HDL ( ∆) 40 lt00001 56 lt00001

                          P values represent comparisons to placebo NS= non‐significant

                          ITT‐LOCF Placebo ComparisonsTotal Study Population

                          Davidson MH et al Am J Cardiol 2013 Jan 29 pii S0002‐9149(12)02641‐0 doi 101016jamjcard201212038

                          Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors

                          Risk FactorsPhenTPMMid

                          p-valuePhenTPMTop

                          p-value

                          CRP lt0001 lt0001Fibrinogen lt005 lt005Adiponectin lt00001 lt00001

                          p-values represent comparisons to placebo

                          ITT-LOCF Placebo Comparisons

                          Gadde KM et al Lancet 2011377(9774)1341-52

                          Mid = 75 mg46 mgTop = 15 mg92 mg

                          Lorcaserin

                          bull Selective 5‐HT2C receptor agonist designed to promote weight loss

                          bull Schedule IV ndash Expected soonbull Indication weight loss and maintenance of

                          weight loss in patients with BMI gt30 kgm2 or BMI gt27 kgm2 + weight-related comorbidcondition(s)

                          bull Dose - 10 mg BIDbull Most common side effects headache nausea

                          dizziness dry mouth

                          BLOOM Study Body Weight Over Years 1 and 2

                          Smith SR et al N Engl J Med 2010363245-256 Study Week0 8 16 24 32 40 48 56 64 72 80 88 96 104

                          Bod

                          y W

                          eigh

                          t (kg

                          )

                          102

                          100

                          98

                          96

                          94

                          92

                          90

                          0

                          Year 1

                          Placebo in year 1 and 2 (n = 684)Lorcaserin in year 1 placebo in year 2 (n = 275)Lorcaserin in year 1 and 2 (n = 564)

                          Year 2

                          Endpoint Lorcaserin Placebo P valueWaist circumference (cm) minus68plusmn02 minus39plusmn02 lt001BMI (kgm2) minus209plusmn006 minus078plusmn005 lt001SBPDBP (mm Hg) minus14plusmn03minus11plusmn02 minus08plusmn03minus06plusmn02 0401Cholesterol ( ∆)Total LDLHDL

                          minus090plusmn033287plusmn056005plusmn033

                          057plusmn034403plusmn058minus021plusmn034

                          001

                          049

                          72Triglycerides minus615plusmn103 minus014plusmn099 lt001SafetyHR (beatsmin)PASP (mm Hg)Beck depression II score

                          minus20plusmn03minus092plusmn023minus11plusmn01

                          minus16plusmn04 minus023plusmn023 minus09plusmn01

                          0499014026

                          BLOOM StudyKey Secondary Endpoints

                          Smith SR et al N Engl J Med 2010363245-256

                          BLOOM-DMChange in Glycemic Parameters

                          P lt001 P lt05 LS mean change plusmn SEMOrsquoNeil PM et al Obesity 201220(7)1426-36 httpwwwnaturecomdoifinder101038oby201266

                          00

                          -05

                          -10

                          -150 12 24 36 52

                          Cha

                          nge

                          from

                          bas

                          elin

                          e (

                          )

                          A1c

                          Study week

                          0

                          -10

                          -20

                          -30

                          -400 12 24 52

                          Cha

                          nge

                          from

                          bas

                          elin

                          e m

                          gdl

                          )

                          Fasting plasma glucose

                          Study week

                          Lorcaserin 10 mg BID Lorcaserin 10 mg Placebo

                          Lorcaserin Adverse Events Reported by 5 or More in Any Group in Year 1

                          55

                          N () Lorcaserin(N = 1593)

                          Placebo(N = 1584)

                          Headache 287 (180) 175 (110)

                          Dizziness 130 (82) 60 (38)

                          Nausea 119 (75) 85 (54)

                          Constipation 106 (67) 64 (40)

                          Fatigue 95 (60) 48 (30)

                          Dry mouth 83 (52) 37 (23)

                          Smith SR et al ADA 2009 Late‐Breaking Abstract 96

                          LorcaserinNo Increase in Rate of Valvulopathy

                          Smith SR et al N Engl J Med 2010363245-256

                          10

                          8

                          6

                          4

                          2

                          024 52 76 104

                          1351714

                          9

                          19

                          3421Patie

                          nts

                          ()

                          Week

                          Lorcaserin in yr 1 and 2

                          Lorcaserin in yr 1 Placebo in yr 2

                          Placebo in yr 1 and 2

                          Phase III Study Outcomes Compared

                          Buproprion SR (360 mgd) Naltrexone SR (32 mgd)

                          Lorcaserin(20 mgd)

                          Phentermine Topiramate CR

                          COR1 COR-I2 COR-II3 NB3043 BLOOM4 BLOSSOM5 EQUIP CONQUER

                          Number of patients (ITT-LOCF)

                          793 obese 1453 obese

                          1281 obese

                          502 type II diabetes

                          3182 obese 4008 obese

                          1230 obese BMI 44

                          2448 comorbidBMI 36

                          Mean change compared with placebo from base

                          93 vs5 1c

                          61a vs13c

                          64a vs12

                          50 a vs12c

                          58 vs22c

                          48 vs28c

                          11 Fullbvs 16

                          104 Fullb 84 Midb

                          vs 18

                          51 Lowb vs16c

                          Categorical change 5 compared with placebo from base

                          56 vs43

                          48a vs164

                          563a

                          vs 171445a vs189

                          475b

                          vs 203472b vs25

                          67 Fullb 45 Lowb vs17

                          70 Fullb 62 Midb

                          vs 21

                          Phenterminetopiramate doses Low 375 mg phentermine23 mg topiramate Mid 75 mg phentermine 46 mg topiramate Full 15 mg phentermine 92 mg topiramateITT-LOCF intent-to-treat last observation carried forwardData not available aP lt 001 vs placebo bP lt 0001 vs placebo

                          Obesity Treatments in Late Development

                          Kushner RF Expert Opin Pharmacother 200891339-1350

                          Agents ActionBupropionNaltrexone

                          bull Dopaminenoradrenaline reuptake inhibitorbull Opioid receptor antagonist

                          Liraglutide bull GLP-1 agonist

                          BupropionNaltrexone

                          bull Mechanism of Actionndash Bupropion - Dopaminenoradrenaline reuptake inhibitorndash Naltrexone- Opioid receptor antagonist

                          bull Was approved by FDA committee but FDA did not approve until a CV outcome study is performed 2nd concerns about BP and P in some patients

                          bull The Light Study is now underway and reported to be enrolling well under PI Dr Nissen

                          bull BupropionNaltrexone will have first completed CV outcome study

                          Buproprion ndash Naltrexone

                          Greenway FL et al Lancet 2010376(9741)595-605

                          0

                          -2

                          -4

                          -6

                          -8

                          -100 4 8 12 16 20 24 28 32 36 40 44 48 52 56

                          Weeks

                          Wei

                          ght c

                          hang

                          e fro

                          m b

                          asel

                          ine

                          ()

                          Placebo

                          Naltrexone 16 mg plus bupropion

                          Naltrexone 32 mg plus bupropion

                          Liraglutide for Weight Loss in Patients with Type 2 Diabetes

                          bull GLP-1 analog approved for treatment of type 2 diabetes

                          bull Anorectic effect mediated both by the activation of GLP-1 receptor expressed on vagal afferents and by the GLP-1R activation in CNS

                          bull Affects visceral fat adiposity appetite food preference and cardiovascular biomarkers in patients with type 2 diabetes

                          Inoue K et al Cardiovasc Diabetol 2011 10109 doi1011861475-2840-10-109

                          Liraglutide Weight Loss Over 2 Years ITT Observed Means

                          Astrup A et al Int J Obes (Lond) 201236(6)843-54

                          FromScreening

                          -94 kg

                          -67 kg-88 kg

                          -99 kg-94 kg

                          -103 kg

                          ITT intention to treat

                          Phase III Study Outcomes Compared

                          Buproprion SR (360 mgd) Naltrexone SR (32 mgd)

                          Lorcaserin(20 mgd)

                          Phentermine Topiramate CR

                          COR1 COR-I2 COR-II3 NB3043 BLOOM4 BLOSSOM5 EQUIP CONQUER

                          Number of patients (ITT-LOCF)

                          793 obese 1453 obese

                          1281 obese

                          502 type II diabetes

                          3182 obese 4008 obese

                          1230 obese BMI 44

                          2448 comorbidBMI 36

                          Mean change compared with placebo from base

                          93 vs5 1c

                          61a vs13c

                          64a vs12

                          50 a vs12c

                          58 vs22c

                          48 vs28c

                          11 Fullbvs 16

                          104 Fullb 84 Midb

                          vs 18

                          51 Lowb vs16c

                          Categorical change 5 compared with placebo from base

                          56 vs43

                          48a vs164

                          563a

                          vs 171445a vs189

                          475b

                          vs 203472b vs25

                          67 Fullb 45 Lowb vs17

                          70 Fullb 62 Midb

                          vs 21

                          Phenterminetopiramate doses Low 375 mg phentermine23 mg topiramate Mid 75 mg phentermine 46 mg topiramate Full 15 mg phentermine 92 mg topiramateITT-LOCF intent-to-treat last observation carried forwardData not available aP lt 001 vs placebo bP lt 0001 vs placebo

                          Treatment Gap in theManagement of Obesity

                          Physicians Need Effective Pharmacotherapies That Will Reduce Weight Significantly and Reduce Weight-related Comorbidities

                          0 5 10 15 20 25 30 35

                          Diet and Lifestyle Lap Band Gastric Bypass

                          TreatmentGap

                          What will fill the gap

                          Too risky for many peopleNot effective enoughfor many people

                          Treatment Gap in theManagement of Obesity

                          0 5 10 15 20 25 30 35

                          Diet and Lifestyle Lap Band Gastric Bypass

                          TreatmentGap

                          Too risky for many peopleNot effective enoughfor many people Pharmacotherapy

                          Less invasive procedures

                          Physicians Need Effective Pharmacotherapies That Will Reduce Weight Significantly and Reduce Weight-related Comorbidities

                          What will fill the gap

                          • Slide Number 1
                          • Slide Number 2
                          • Weight Management is Moving into the Workplace and Mainstream of Healthcare
                          • US Preventative Services Task Force
                          • A Proposal from CMS about Coverage for Intensive Behavioral Therapy for Obesity
                          • Slide Number 6
                          • Biggest Increases in Clinically Severe Obesity US 1987-2005
                          • Relationship Between BMI and Risk of Type 2 Diabetes
                          • Slide Number 9
                          • Medical Complications of Obesity Almost every organ system is affected
                          • Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and disease
                          • Current Therapies Often Address Individual Risk Factors Cardiometabolic risk
                          • Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and disease
                          • Are You Treating These Drivers of Cardiometabolic Risk Should You Treat The Underlying Cause
                          • Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors
                          • In My Opinion The Winds of Change are Blowing in the Treatment of Chronic Diseases
                          • Bariatric Surgery Reduces Overall Mortality Diabetes Mortality by 88
                          • Health Care Costs Attributable to ObesityEstimates of what various conditions add to health-care service costs over a 12-month period
                          • What-if scenarios (The Lancet forthcoming)
                          • How Much Weight Loss Is Needed to Prevent T2DMndashNot Very Much The DPP Experience
                          • In the Da Qing Study 6-year Intervention Led to Lower Incidence of Type 2 Diabetes 14 Years Later
                          • Slide Number 22
                          • Slide Number 23
                          • New Compounds andCombination Interventions
                          • Phentermine and Topiramate Extended-Release
                          • Phentermine and Topiramate Extended-Release
                          • EQUIP amp CONQUER Discontinuation RateDue to AEs in All Doses Studied
                          • Phentermine and Topiramate SEQUELWeight Loss Over Time
                          • CONQUER Significant Improvement in Cardiovascular Risk Factors
                          • Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors
                          • Lorcaserin
                          • BLOOM Study Body Weight Over Years 1 and 2
                          • BLOOM StudyKey Secondary Endpoints
                          • BLOOM-DMChange in Glycemic Parameters
                          • Lorcaserin Adverse Events Reported by 5 or More in Any Group in Year 1
                          • LorcaserinNo Increase in Rate of Valvulopathy
                          • Phase III Study Outcomes Compared
                          • Obesity Treatments in Late Development
                          • BupropionNaltrexone
                          • Buproprion ndash Naltrexone
                          • Liraglutide for Weight Loss in Patients with Type 2 Diabetes
                          • Liraglutide Weight Loss Over 2 Years ITT Observed Means
                          • Phase III Study Outcomes Compared
                          • Treatment Gap in theManagement of Obesity
                          • Treatment Gap in theManagement of Obesity

                            Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors

                            Risk FactorsPhenTPMMid

                            p-valuePhenTPMTop

                            p-value

                            CRP lt0001 lt0001Fibrinogen lt005 lt005Adiponectin lt00001 lt00001

                            p-values represent comparisons to placebo

                            ITT-LOCF Placebo Comparisons

                            Gadde KM et al Lancet 2011377(9774)1341-52

                            Mid = 75 mg46 mgTop = 15 mg92 mg

                            In My Opinion The Winds of Change are Blowing in the Treatment of Chronic

                            Diseasesbull ACCORD was stopped because of increased

                            mortality in the tight control group 28 of whom gained gt 10kg compared to 14 in control^

                            bull Bariatric surgery trials show gt 80 reduction in diabetes mortality with weight loss

                            bull I believe we are in the midst of a shift from ldquoGlucocentricrdquo to ldquoWeight-Centricrdquo Management of T 2 DM

                            ^ NEJM 3582545-2559 Adams TD et al N Engl J Med 2007357(8)753-761

                            -34-48-48-88-59-29+73

                            Adams TD et al N Engl J Med 2007357(8)753-761

                            Bariatric Surgery Reduces Overall Mortality Diabetes Mortality by 88

                            Matched SubjectsSurgery Group (n=7925)

                            Co(n=

                            ntrol Group7925)

                            NoNo10000 person-yr No

                            No10000 person-yr

                            All causes of death 213 376 321 571All deaths caused by disease 150 265 285 507Cardiovascular diseases 55 97 104 185Diabetes 2 04 19 34Cancer 31 55 73 133Other diseases 62 11 89 155All non-disease causes 63 111 36 64Accident unrelated to drugs 21 37 17 30Poisoning of undetermined intent 9 16 4 07Suicide 15 26 5 09Other nondisease cause 18 32 10 18

                            CC-18

                            Health Care Costs Attributable to ObesityEstimates of what various conditions add to health-care service costs over a 12-month period

                            $395

                            $230

                            $225

                            $150

                            $125

                            $0 $100 $200 $300 $400 $500

                            Obesity

                            Smoking

                            20 years aging

                            Problem drinking

                            Overweight

                            Sturm R Health Aff (Millwood) 2002 Mar-Apr21(2)245-53 Table Wall Street Journal 3132002

                            Obesity increased medication costs 77inpatient and outpatient costs 36

                            What-if scenarios (The Lancet forthcoming)

                            Redrawn from Hamman RF et al Diabetes Care 2006292102‐2107

                            Change in Weight from Baseline (kg)0‐10 ‐5 +5In

                            cide

                            nce Ra

                            te per 100

                            Person‐Years

                            10

                            20

                            15

                            5

                            0

                            How Much Weight Loss Is Needed to Prevent T2DMndashNot Very Much The DPP Experience

                            In the Da Qing Study 6-year Intervention Led to Lower Incidence of Type 2 Diabetes 14 Years Later

                            n=530 overweight Chinese men and women with IGT mean BMI=26

                            17

                            0

                            20

                            40

                            60

                            80

                            100

                            2 4 6 8 10 12 14 16 18 20Years of follow‐up

                            6‐year intervention hazard ratio = 049 (95 CI 033ndash073)20‐year follow‐up hazard ratio = 057 (95 CI 041ndash081)

                            Cumulative Incide

                            nce of Type 2 Diabe

                            tes ()

                            0

                            Lifestyle interventionControl

                            Treatment Follow‐up

                            Li et al Lancet 20083711783ndash9

                            Pharmacotherapy for Weight LossLouis J Aronne MD FACP

                            Professor of Clinical Medicine Weill Cornell Medical College

                            Adjunct Associate Professor of Clinical Medicine Columbia University College of Physicians and Surgeons

                            Director Comprehensive Weight Control Program

                            New York-Presbyterian HospitalWeill Cornell Medical Center New York NY

                            As faculty of Weill Cornell Medical College we are committed to providing transparency for any and all external relationships prior to giving an academic presentation

                            I am a consultant speaker advisor or receive research support fromBMS

                            Arena Aspire BariatricsMyos

                            GI Dynamics Novo NordiskOrexigenVivusZafgen

                            I may discuss off-label use of medications

                            Disclosure Page

                            uarrFood intakedarr energy expenditure

                            darrfood intake uarrenergy expenditure

                            Topiramate

                            Naltrexone

                            LorcaserinPramlintideGLP-1Leptin

                            BupropionPhentermine

                            New Compounds andCombination Interventions

                            c Louis J Aronne MDScience Feb 7 2003 Vol 299Illustration by Katharine Sutliff

                            Phentermine and TopiramateExtended-Release

                            bull Mechanism of actionndash Phentermine Sympathomimetic amine - releaserndash Topiramate Gabaergicglutamate modulation and carbonic

                            anhydrase inhibitionbull February 2012 FDA advisory committee votes 20-2 for

                            approval bull FDA approved July 2012

                            ndash Schedule IVndash Pregnancy Category X = REMS

                            Topiramate monotherapy exposure in pregnancy associated with 2- to 5-fold increased prevalence of oral clefts

                            bull 4 doses Titrate upbull Available only by mail orderbull Covered through Medco Express Scripts

                            Phentermine and TopiramateExtended-Release

                            bull Dose titrationndash Once dailyndash Start treatment with phentermine 375 mgtopiramate

                            23 mg extended-release daily for 14 daysndash After 14 days increase to the recommended dose of

                            phentermine 75 mgtopiramate 46 mg extended-release once daily

                            ndash May titrate upwards if needed to phen 15 top 92 mg strength

                            EQUIP amp CONQUER Discontinuation RateDue to AEs in All Doses Studied

                            Placebo Low Mid Full

                            Number of patients 1508 241 498 1507Discontinuation due to AEs 9 12 12 18Blurred vision 05 21 08 07Headache 07 17 02 09Insomnia 04 00 04 17Depression 02 00 08 14Tingling 00 04 10 12Irritability 01 08 08 12Anxiety 03 00 02 11Dizziness 02 04 12 08

                            Includes adverse events (AEs) by dose for EQUIP amp CONQUER which lead to discontinuation in gt 1 of patientsPress release Sept 9 2009 Available at httpirvivuscomreleasedetailcfmReleaseID=420114Accessed April 27 2010

                            PhenTPMMid

                            -104

                            Phentermine and Topiramate SEQUELWeight Loss Over Time

                            Garvey WT Ryan DH Look M Gadde KM Am J Clin Nutr 201295(2)297-308

                            Placebo-25

                            Plt00001 v placebo

                            Weight Loss

                            Week

                            Total Population

                            0

                            -2

                            -4

                            -6

                            -8

                            -10

                            -12

                            -14

                            -16

                            0 12 24 36 48 60 72 84 96 108

                            Weight Loss ITT-LOCF

                            PhenTPMTop

                            -114

                            Mid = 75 mg46 mgTop = 15 mg92 mg

                            CONQUER Significant Improvement in Cardiovascular Risk Factors

                            (LS Mean Wt Loss)

                            QNEXAMid(78)

                            P valueQNEXATop

                            (98) P value

                            Waist Circumference (cm) ‐52 lt00001 ‐68 lt00001

                            Systolic BP (mmHg) ‐23 00008 ‐32 lt00001

                            Diastolic BP (mmHg) ‐07 NS ‐11 00031

                            Triglycerides ( ∆) ‐133 lt00001 ‐153 lt00001

                            Total Cholesterol ( ∆) ‐16 00345 ‐30 lt00001

                            LDL ( ∆) 04 NS ‐28 00069

                            HDL ( ∆) 40 lt00001 56 lt00001

                            P values represent comparisons to placebo NS= non‐significant

                            ITT‐LOCF Placebo ComparisonsTotal Study Population

                            Davidson MH et al Am J Cardiol 2013 Jan 29 pii S0002‐9149(12)02641‐0 doi 101016jamjcard201212038

                            Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors

                            Risk FactorsPhenTPMMid

                            p-valuePhenTPMTop

                            p-value

                            CRP lt0001 lt0001Fibrinogen lt005 lt005Adiponectin lt00001 lt00001

                            p-values represent comparisons to placebo

                            ITT-LOCF Placebo Comparisons

                            Gadde KM et al Lancet 2011377(9774)1341-52

                            Mid = 75 mg46 mgTop = 15 mg92 mg

                            Lorcaserin

                            bull Selective 5‐HT2C receptor agonist designed to promote weight loss

                            bull Schedule IV ndash Expected soonbull Indication weight loss and maintenance of

                            weight loss in patients with BMI gt30 kgm2 or BMI gt27 kgm2 + weight-related comorbidcondition(s)

                            bull Dose - 10 mg BIDbull Most common side effects headache nausea

                            dizziness dry mouth

                            BLOOM Study Body Weight Over Years 1 and 2

                            Smith SR et al N Engl J Med 2010363245-256 Study Week0 8 16 24 32 40 48 56 64 72 80 88 96 104

                            Bod

                            y W

                            eigh

                            t (kg

                            )

                            102

                            100

                            98

                            96

                            94

                            92

                            90

                            0

                            Year 1

                            Placebo in year 1 and 2 (n = 684)Lorcaserin in year 1 placebo in year 2 (n = 275)Lorcaserin in year 1 and 2 (n = 564)

                            Year 2

                            Endpoint Lorcaserin Placebo P valueWaist circumference (cm) minus68plusmn02 minus39plusmn02 lt001BMI (kgm2) minus209plusmn006 minus078plusmn005 lt001SBPDBP (mm Hg) minus14plusmn03minus11plusmn02 minus08plusmn03minus06plusmn02 0401Cholesterol ( ∆)Total LDLHDL

                            minus090plusmn033287plusmn056005plusmn033

                            057plusmn034403plusmn058minus021plusmn034

                            001

                            049

                            72Triglycerides minus615plusmn103 minus014plusmn099 lt001SafetyHR (beatsmin)PASP (mm Hg)Beck depression II score

                            minus20plusmn03minus092plusmn023minus11plusmn01

                            minus16plusmn04 minus023plusmn023 minus09plusmn01

                            0499014026

                            BLOOM StudyKey Secondary Endpoints

                            Smith SR et al N Engl J Med 2010363245-256

                            BLOOM-DMChange in Glycemic Parameters

                            P lt001 P lt05 LS mean change plusmn SEMOrsquoNeil PM et al Obesity 201220(7)1426-36 httpwwwnaturecomdoifinder101038oby201266

                            00

                            -05

                            -10

                            -150 12 24 36 52

                            Cha

                            nge

                            from

                            bas

                            elin

                            e (

                            )

                            A1c

                            Study week

                            0

                            -10

                            -20

                            -30

                            -400 12 24 52

                            Cha

                            nge

                            from

                            bas

                            elin

                            e m

                            gdl

                            )

                            Fasting plasma glucose

                            Study week

                            Lorcaserin 10 mg BID Lorcaserin 10 mg Placebo

                            Lorcaserin Adverse Events Reported by 5 or More in Any Group in Year 1

                            55

                            N () Lorcaserin(N = 1593)

                            Placebo(N = 1584)

                            Headache 287 (180) 175 (110)

                            Dizziness 130 (82) 60 (38)

                            Nausea 119 (75) 85 (54)

                            Constipation 106 (67) 64 (40)

                            Fatigue 95 (60) 48 (30)

                            Dry mouth 83 (52) 37 (23)

                            Smith SR et al ADA 2009 Late‐Breaking Abstract 96

                            LorcaserinNo Increase in Rate of Valvulopathy

                            Smith SR et al N Engl J Med 2010363245-256

                            10

                            8

                            6

                            4

                            2

                            024 52 76 104

                            1351714

                            9

                            19

                            3421Patie

                            nts

                            ()

                            Week

                            Lorcaserin in yr 1 and 2

                            Lorcaserin in yr 1 Placebo in yr 2

                            Placebo in yr 1 and 2

                            Phase III Study Outcomes Compared

                            Buproprion SR (360 mgd) Naltrexone SR (32 mgd)

                            Lorcaserin(20 mgd)

                            Phentermine Topiramate CR

                            COR1 COR-I2 COR-II3 NB3043 BLOOM4 BLOSSOM5 EQUIP CONQUER

                            Number of patients (ITT-LOCF)

                            793 obese 1453 obese

                            1281 obese

                            502 type II diabetes

                            3182 obese 4008 obese

                            1230 obese BMI 44

                            2448 comorbidBMI 36

                            Mean change compared with placebo from base

                            93 vs5 1c

                            61a vs13c

                            64a vs12

                            50 a vs12c

                            58 vs22c

                            48 vs28c

                            11 Fullbvs 16

                            104 Fullb 84 Midb

                            vs 18

                            51 Lowb vs16c

                            Categorical change 5 compared with placebo from base

                            56 vs43

                            48a vs164

                            563a

                            vs 171445a vs189

                            475b

                            vs 203472b vs25

                            67 Fullb 45 Lowb vs17

                            70 Fullb 62 Midb

                            vs 21

                            Phenterminetopiramate doses Low 375 mg phentermine23 mg topiramate Mid 75 mg phentermine 46 mg topiramate Full 15 mg phentermine 92 mg topiramateITT-LOCF intent-to-treat last observation carried forwardData not available aP lt 001 vs placebo bP lt 0001 vs placebo

                            Obesity Treatments in Late Development

                            Kushner RF Expert Opin Pharmacother 200891339-1350

                            Agents ActionBupropionNaltrexone

                            bull Dopaminenoradrenaline reuptake inhibitorbull Opioid receptor antagonist

                            Liraglutide bull GLP-1 agonist

                            BupropionNaltrexone

                            bull Mechanism of Actionndash Bupropion - Dopaminenoradrenaline reuptake inhibitorndash Naltrexone- Opioid receptor antagonist

                            bull Was approved by FDA committee but FDA did not approve until a CV outcome study is performed 2nd concerns about BP and P in some patients

                            bull The Light Study is now underway and reported to be enrolling well under PI Dr Nissen

                            bull BupropionNaltrexone will have first completed CV outcome study

                            Buproprion ndash Naltrexone

                            Greenway FL et al Lancet 2010376(9741)595-605

                            0

                            -2

                            -4

                            -6

                            -8

                            -100 4 8 12 16 20 24 28 32 36 40 44 48 52 56

                            Weeks

                            Wei

                            ght c

                            hang

                            e fro

                            m b

                            asel

                            ine

                            ()

                            Placebo

                            Naltrexone 16 mg plus bupropion

                            Naltrexone 32 mg plus bupropion

                            Liraglutide for Weight Loss in Patients with Type 2 Diabetes

                            bull GLP-1 analog approved for treatment of type 2 diabetes

                            bull Anorectic effect mediated both by the activation of GLP-1 receptor expressed on vagal afferents and by the GLP-1R activation in CNS

                            bull Affects visceral fat adiposity appetite food preference and cardiovascular biomarkers in patients with type 2 diabetes

                            Inoue K et al Cardiovasc Diabetol 2011 10109 doi1011861475-2840-10-109

                            Liraglutide Weight Loss Over 2 Years ITT Observed Means

                            Astrup A et al Int J Obes (Lond) 201236(6)843-54

                            FromScreening

                            -94 kg

                            -67 kg-88 kg

                            -99 kg-94 kg

                            -103 kg

                            ITT intention to treat

                            Phase III Study Outcomes Compared

                            Buproprion SR (360 mgd) Naltrexone SR (32 mgd)

                            Lorcaserin(20 mgd)

                            Phentermine Topiramate CR

                            COR1 COR-I2 COR-II3 NB3043 BLOOM4 BLOSSOM5 EQUIP CONQUER

                            Number of patients (ITT-LOCF)

                            793 obese 1453 obese

                            1281 obese

                            502 type II diabetes

                            3182 obese 4008 obese

                            1230 obese BMI 44

                            2448 comorbidBMI 36

                            Mean change compared with placebo from base

                            93 vs5 1c

                            61a vs13c

                            64a vs12

                            50 a vs12c

                            58 vs22c

                            48 vs28c

                            11 Fullbvs 16

                            104 Fullb 84 Midb

                            vs 18

                            51 Lowb vs16c

                            Categorical change 5 compared with placebo from base

                            56 vs43

                            48a vs164

                            563a

                            vs 171445a vs189

                            475b

                            vs 203472b vs25

                            67 Fullb 45 Lowb vs17

                            70 Fullb 62 Midb

                            vs 21

                            Phenterminetopiramate doses Low 375 mg phentermine23 mg topiramate Mid 75 mg phentermine 46 mg topiramate Full 15 mg phentermine 92 mg topiramateITT-LOCF intent-to-treat last observation carried forwardData not available aP lt 001 vs placebo bP lt 0001 vs placebo

                            Treatment Gap in theManagement of Obesity

                            Physicians Need Effective Pharmacotherapies That Will Reduce Weight Significantly and Reduce Weight-related Comorbidities

                            0 5 10 15 20 25 30 35

                            Diet and Lifestyle Lap Band Gastric Bypass

                            TreatmentGap

                            What will fill the gap

                            Too risky for many peopleNot effective enoughfor many people

                            Treatment Gap in theManagement of Obesity

                            0 5 10 15 20 25 30 35

                            Diet and Lifestyle Lap Band Gastric Bypass

                            TreatmentGap

                            Too risky for many peopleNot effective enoughfor many people Pharmacotherapy

                            Less invasive procedures

                            Physicians Need Effective Pharmacotherapies That Will Reduce Weight Significantly and Reduce Weight-related Comorbidities

                            What will fill the gap

                            • Slide Number 1
                            • Slide Number 2
                            • Weight Management is Moving into the Workplace and Mainstream of Healthcare
                            • US Preventative Services Task Force
                            • A Proposal from CMS about Coverage for Intensive Behavioral Therapy for Obesity
                            • Slide Number 6
                            • Biggest Increases in Clinically Severe Obesity US 1987-2005
                            • Relationship Between BMI and Risk of Type 2 Diabetes
                            • Slide Number 9
                            • Medical Complications of Obesity Almost every organ system is affected
                            • Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and disease
                            • Current Therapies Often Address Individual Risk Factors Cardiometabolic risk
                            • Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and disease
                            • Are You Treating These Drivers of Cardiometabolic Risk Should You Treat The Underlying Cause
                            • Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors
                            • In My Opinion The Winds of Change are Blowing in the Treatment of Chronic Diseases
                            • Bariatric Surgery Reduces Overall Mortality Diabetes Mortality by 88
                            • Health Care Costs Attributable to ObesityEstimates of what various conditions add to health-care service costs over a 12-month period
                            • What-if scenarios (The Lancet forthcoming)
                            • How Much Weight Loss Is Needed to Prevent T2DMndashNot Very Much The DPP Experience
                            • In the Da Qing Study 6-year Intervention Led to Lower Incidence of Type 2 Diabetes 14 Years Later
                            • Slide Number 22
                            • Slide Number 23
                            • New Compounds andCombination Interventions
                            • Phentermine and Topiramate Extended-Release
                            • Phentermine and Topiramate Extended-Release
                            • EQUIP amp CONQUER Discontinuation RateDue to AEs in All Doses Studied
                            • Phentermine and Topiramate SEQUELWeight Loss Over Time
                            • CONQUER Significant Improvement in Cardiovascular Risk Factors
                            • Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors
                            • Lorcaserin
                            • BLOOM Study Body Weight Over Years 1 and 2
                            • BLOOM StudyKey Secondary Endpoints
                            • BLOOM-DMChange in Glycemic Parameters
                            • Lorcaserin Adverse Events Reported by 5 or More in Any Group in Year 1
                            • LorcaserinNo Increase in Rate of Valvulopathy
                            • Phase III Study Outcomes Compared
                            • Obesity Treatments in Late Development
                            • BupropionNaltrexone
                            • Buproprion ndash Naltrexone
                            • Liraglutide for Weight Loss in Patients with Type 2 Diabetes
                            • Liraglutide Weight Loss Over 2 Years ITT Observed Means
                            • Phase III Study Outcomes Compared
                            • Treatment Gap in theManagement of Obesity
                            • Treatment Gap in theManagement of Obesity

                              In My Opinion The Winds of Change are Blowing in the Treatment of Chronic

                              Diseasesbull ACCORD was stopped because of increased

                              mortality in the tight control group 28 of whom gained gt 10kg compared to 14 in control^

                              bull Bariatric surgery trials show gt 80 reduction in diabetes mortality with weight loss

                              bull I believe we are in the midst of a shift from ldquoGlucocentricrdquo to ldquoWeight-Centricrdquo Management of T 2 DM

                              ^ NEJM 3582545-2559 Adams TD et al N Engl J Med 2007357(8)753-761

                              -34-48-48-88-59-29+73

                              Adams TD et al N Engl J Med 2007357(8)753-761

                              Bariatric Surgery Reduces Overall Mortality Diabetes Mortality by 88

                              Matched SubjectsSurgery Group (n=7925)

                              Co(n=

                              ntrol Group7925)

                              NoNo10000 person-yr No

                              No10000 person-yr

                              All causes of death 213 376 321 571All deaths caused by disease 150 265 285 507Cardiovascular diseases 55 97 104 185Diabetes 2 04 19 34Cancer 31 55 73 133Other diseases 62 11 89 155All non-disease causes 63 111 36 64Accident unrelated to drugs 21 37 17 30Poisoning of undetermined intent 9 16 4 07Suicide 15 26 5 09Other nondisease cause 18 32 10 18

                              CC-18

                              Health Care Costs Attributable to ObesityEstimates of what various conditions add to health-care service costs over a 12-month period

                              $395

                              $230

                              $225

                              $150

                              $125

                              $0 $100 $200 $300 $400 $500

                              Obesity

                              Smoking

                              20 years aging

                              Problem drinking

                              Overweight

                              Sturm R Health Aff (Millwood) 2002 Mar-Apr21(2)245-53 Table Wall Street Journal 3132002

                              Obesity increased medication costs 77inpatient and outpatient costs 36

                              What-if scenarios (The Lancet forthcoming)

                              Redrawn from Hamman RF et al Diabetes Care 2006292102‐2107

                              Change in Weight from Baseline (kg)0‐10 ‐5 +5In

                              cide

                              nce Ra

                              te per 100

                              Person‐Years

                              10

                              20

                              15

                              5

                              0

                              How Much Weight Loss Is Needed to Prevent T2DMndashNot Very Much The DPP Experience

                              In the Da Qing Study 6-year Intervention Led to Lower Incidence of Type 2 Diabetes 14 Years Later

                              n=530 overweight Chinese men and women with IGT mean BMI=26

                              17

                              0

                              20

                              40

                              60

                              80

                              100

                              2 4 6 8 10 12 14 16 18 20Years of follow‐up

                              6‐year intervention hazard ratio = 049 (95 CI 033ndash073)20‐year follow‐up hazard ratio = 057 (95 CI 041ndash081)

                              Cumulative Incide

                              nce of Type 2 Diabe

                              tes ()

                              0

                              Lifestyle interventionControl

                              Treatment Follow‐up

                              Li et al Lancet 20083711783ndash9

                              Pharmacotherapy for Weight LossLouis J Aronne MD FACP

                              Professor of Clinical Medicine Weill Cornell Medical College

                              Adjunct Associate Professor of Clinical Medicine Columbia University College of Physicians and Surgeons

                              Director Comprehensive Weight Control Program

                              New York-Presbyterian HospitalWeill Cornell Medical Center New York NY

                              As faculty of Weill Cornell Medical College we are committed to providing transparency for any and all external relationships prior to giving an academic presentation

                              I am a consultant speaker advisor or receive research support fromBMS

                              Arena Aspire BariatricsMyos

                              GI Dynamics Novo NordiskOrexigenVivusZafgen

                              I may discuss off-label use of medications

                              Disclosure Page

                              uarrFood intakedarr energy expenditure

                              darrfood intake uarrenergy expenditure

                              Topiramate

                              Naltrexone

                              LorcaserinPramlintideGLP-1Leptin

                              BupropionPhentermine

                              New Compounds andCombination Interventions

                              c Louis J Aronne MDScience Feb 7 2003 Vol 299Illustration by Katharine Sutliff

                              Phentermine and TopiramateExtended-Release

                              bull Mechanism of actionndash Phentermine Sympathomimetic amine - releaserndash Topiramate Gabaergicglutamate modulation and carbonic

                              anhydrase inhibitionbull February 2012 FDA advisory committee votes 20-2 for

                              approval bull FDA approved July 2012

                              ndash Schedule IVndash Pregnancy Category X = REMS

                              Topiramate monotherapy exposure in pregnancy associated with 2- to 5-fold increased prevalence of oral clefts

                              bull 4 doses Titrate upbull Available only by mail orderbull Covered through Medco Express Scripts

                              Phentermine and TopiramateExtended-Release

                              bull Dose titrationndash Once dailyndash Start treatment with phentermine 375 mgtopiramate

                              23 mg extended-release daily for 14 daysndash After 14 days increase to the recommended dose of

                              phentermine 75 mgtopiramate 46 mg extended-release once daily

                              ndash May titrate upwards if needed to phen 15 top 92 mg strength

                              EQUIP amp CONQUER Discontinuation RateDue to AEs in All Doses Studied

                              Placebo Low Mid Full

                              Number of patients 1508 241 498 1507Discontinuation due to AEs 9 12 12 18Blurred vision 05 21 08 07Headache 07 17 02 09Insomnia 04 00 04 17Depression 02 00 08 14Tingling 00 04 10 12Irritability 01 08 08 12Anxiety 03 00 02 11Dizziness 02 04 12 08

                              Includes adverse events (AEs) by dose for EQUIP amp CONQUER which lead to discontinuation in gt 1 of patientsPress release Sept 9 2009 Available at httpirvivuscomreleasedetailcfmReleaseID=420114Accessed April 27 2010

                              PhenTPMMid

                              -104

                              Phentermine and Topiramate SEQUELWeight Loss Over Time

                              Garvey WT Ryan DH Look M Gadde KM Am J Clin Nutr 201295(2)297-308

                              Placebo-25

                              Plt00001 v placebo

                              Weight Loss

                              Week

                              Total Population

                              0

                              -2

                              -4

                              -6

                              -8

                              -10

                              -12

                              -14

                              -16

                              0 12 24 36 48 60 72 84 96 108

                              Weight Loss ITT-LOCF

                              PhenTPMTop

                              -114

                              Mid = 75 mg46 mgTop = 15 mg92 mg

                              CONQUER Significant Improvement in Cardiovascular Risk Factors

                              (LS Mean Wt Loss)

                              QNEXAMid(78)

                              P valueQNEXATop

                              (98) P value

                              Waist Circumference (cm) ‐52 lt00001 ‐68 lt00001

                              Systolic BP (mmHg) ‐23 00008 ‐32 lt00001

                              Diastolic BP (mmHg) ‐07 NS ‐11 00031

                              Triglycerides ( ∆) ‐133 lt00001 ‐153 lt00001

                              Total Cholesterol ( ∆) ‐16 00345 ‐30 lt00001

                              LDL ( ∆) 04 NS ‐28 00069

                              HDL ( ∆) 40 lt00001 56 lt00001

                              P values represent comparisons to placebo NS= non‐significant

                              ITT‐LOCF Placebo ComparisonsTotal Study Population

                              Davidson MH et al Am J Cardiol 2013 Jan 29 pii S0002‐9149(12)02641‐0 doi 101016jamjcard201212038

                              Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors

                              Risk FactorsPhenTPMMid

                              p-valuePhenTPMTop

                              p-value

                              CRP lt0001 lt0001Fibrinogen lt005 lt005Adiponectin lt00001 lt00001

                              p-values represent comparisons to placebo

                              ITT-LOCF Placebo Comparisons

                              Gadde KM et al Lancet 2011377(9774)1341-52

                              Mid = 75 mg46 mgTop = 15 mg92 mg

                              Lorcaserin

                              bull Selective 5‐HT2C receptor agonist designed to promote weight loss

                              bull Schedule IV ndash Expected soonbull Indication weight loss and maintenance of

                              weight loss in patients with BMI gt30 kgm2 or BMI gt27 kgm2 + weight-related comorbidcondition(s)

                              bull Dose - 10 mg BIDbull Most common side effects headache nausea

                              dizziness dry mouth

                              BLOOM Study Body Weight Over Years 1 and 2

                              Smith SR et al N Engl J Med 2010363245-256 Study Week0 8 16 24 32 40 48 56 64 72 80 88 96 104

                              Bod

                              y W

                              eigh

                              t (kg

                              )

                              102

                              100

                              98

                              96

                              94

                              92

                              90

                              0

                              Year 1

                              Placebo in year 1 and 2 (n = 684)Lorcaserin in year 1 placebo in year 2 (n = 275)Lorcaserin in year 1 and 2 (n = 564)

                              Year 2

                              Endpoint Lorcaserin Placebo P valueWaist circumference (cm) minus68plusmn02 minus39plusmn02 lt001BMI (kgm2) minus209plusmn006 minus078plusmn005 lt001SBPDBP (mm Hg) minus14plusmn03minus11plusmn02 minus08plusmn03minus06plusmn02 0401Cholesterol ( ∆)Total LDLHDL

                              minus090plusmn033287plusmn056005plusmn033

                              057plusmn034403plusmn058minus021plusmn034

                              001

                              049

                              72Triglycerides minus615plusmn103 minus014plusmn099 lt001SafetyHR (beatsmin)PASP (mm Hg)Beck depression II score

                              minus20plusmn03minus092plusmn023minus11plusmn01

                              minus16plusmn04 minus023plusmn023 minus09plusmn01

                              0499014026

                              BLOOM StudyKey Secondary Endpoints

                              Smith SR et al N Engl J Med 2010363245-256

                              BLOOM-DMChange in Glycemic Parameters

                              P lt001 P lt05 LS mean change plusmn SEMOrsquoNeil PM et al Obesity 201220(7)1426-36 httpwwwnaturecomdoifinder101038oby201266

                              00

                              -05

                              -10

                              -150 12 24 36 52

                              Cha

                              nge

                              from

                              bas

                              elin

                              e (

                              )

                              A1c

                              Study week

                              0

                              -10

                              -20

                              -30

                              -400 12 24 52

                              Cha

                              nge

                              from

                              bas

                              elin

                              e m

                              gdl

                              )

                              Fasting plasma glucose

                              Study week

                              Lorcaserin 10 mg BID Lorcaserin 10 mg Placebo

                              Lorcaserin Adverse Events Reported by 5 or More in Any Group in Year 1

                              55

                              N () Lorcaserin(N = 1593)

                              Placebo(N = 1584)

                              Headache 287 (180) 175 (110)

                              Dizziness 130 (82) 60 (38)

                              Nausea 119 (75) 85 (54)

                              Constipation 106 (67) 64 (40)

                              Fatigue 95 (60) 48 (30)

                              Dry mouth 83 (52) 37 (23)

                              Smith SR et al ADA 2009 Late‐Breaking Abstract 96

                              LorcaserinNo Increase in Rate of Valvulopathy

                              Smith SR et al N Engl J Med 2010363245-256

                              10

                              8

                              6

                              4

                              2

                              024 52 76 104

                              1351714

                              9

                              19

                              3421Patie

                              nts

                              ()

                              Week

                              Lorcaserin in yr 1 and 2

                              Lorcaserin in yr 1 Placebo in yr 2

                              Placebo in yr 1 and 2

                              Phase III Study Outcomes Compared

                              Buproprion SR (360 mgd) Naltrexone SR (32 mgd)

                              Lorcaserin(20 mgd)

                              Phentermine Topiramate CR

                              COR1 COR-I2 COR-II3 NB3043 BLOOM4 BLOSSOM5 EQUIP CONQUER

                              Number of patients (ITT-LOCF)

                              793 obese 1453 obese

                              1281 obese

                              502 type II diabetes

                              3182 obese 4008 obese

                              1230 obese BMI 44

                              2448 comorbidBMI 36

                              Mean change compared with placebo from base

                              93 vs5 1c

                              61a vs13c

                              64a vs12

                              50 a vs12c

                              58 vs22c

                              48 vs28c

                              11 Fullbvs 16

                              104 Fullb 84 Midb

                              vs 18

                              51 Lowb vs16c

                              Categorical change 5 compared with placebo from base

                              56 vs43

                              48a vs164

                              563a

                              vs 171445a vs189

                              475b

                              vs 203472b vs25

                              67 Fullb 45 Lowb vs17

                              70 Fullb 62 Midb

                              vs 21

                              Phenterminetopiramate doses Low 375 mg phentermine23 mg topiramate Mid 75 mg phentermine 46 mg topiramate Full 15 mg phentermine 92 mg topiramateITT-LOCF intent-to-treat last observation carried forwardData not available aP lt 001 vs placebo bP lt 0001 vs placebo

                              Obesity Treatments in Late Development

                              Kushner RF Expert Opin Pharmacother 200891339-1350

                              Agents ActionBupropionNaltrexone

                              bull Dopaminenoradrenaline reuptake inhibitorbull Opioid receptor antagonist

                              Liraglutide bull GLP-1 agonist

                              BupropionNaltrexone

                              bull Mechanism of Actionndash Bupropion - Dopaminenoradrenaline reuptake inhibitorndash Naltrexone- Opioid receptor antagonist

                              bull Was approved by FDA committee but FDA did not approve until a CV outcome study is performed 2nd concerns about BP and P in some patients

                              bull The Light Study is now underway and reported to be enrolling well under PI Dr Nissen

                              bull BupropionNaltrexone will have first completed CV outcome study

                              Buproprion ndash Naltrexone

                              Greenway FL et al Lancet 2010376(9741)595-605

                              0

                              -2

                              -4

                              -6

                              -8

                              -100 4 8 12 16 20 24 28 32 36 40 44 48 52 56

                              Weeks

                              Wei

                              ght c

                              hang

                              e fro

                              m b

                              asel

                              ine

                              ()

                              Placebo

                              Naltrexone 16 mg plus bupropion

                              Naltrexone 32 mg plus bupropion

                              Liraglutide for Weight Loss in Patients with Type 2 Diabetes

                              bull GLP-1 analog approved for treatment of type 2 diabetes

                              bull Anorectic effect mediated both by the activation of GLP-1 receptor expressed on vagal afferents and by the GLP-1R activation in CNS

                              bull Affects visceral fat adiposity appetite food preference and cardiovascular biomarkers in patients with type 2 diabetes

                              Inoue K et al Cardiovasc Diabetol 2011 10109 doi1011861475-2840-10-109

                              Liraglutide Weight Loss Over 2 Years ITT Observed Means

                              Astrup A et al Int J Obes (Lond) 201236(6)843-54

                              FromScreening

                              -94 kg

                              -67 kg-88 kg

                              -99 kg-94 kg

                              -103 kg

                              ITT intention to treat

                              Phase III Study Outcomes Compared

                              Buproprion SR (360 mgd) Naltrexone SR (32 mgd)

                              Lorcaserin(20 mgd)

                              Phentermine Topiramate CR

                              COR1 COR-I2 COR-II3 NB3043 BLOOM4 BLOSSOM5 EQUIP CONQUER

                              Number of patients (ITT-LOCF)

                              793 obese 1453 obese

                              1281 obese

                              502 type II diabetes

                              3182 obese 4008 obese

                              1230 obese BMI 44

                              2448 comorbidBMI 36

                              Mean change compared with placebo from base

                              93 vs5 1c

                              61a vs13c

                              64a vs12

                              50 a vs12c

                              58 vs22c

                              48 vs28c

                              11 Fullbvs 16

                              104 Fullb 84 Midb

                              vs 18

                              51 Lowb vs16c

                              Categorical change 5 compared with placebo from base

                              56 vs43

                              48a vs164

                              563a

                              vs 171445a vs189

                              475b

                              vs 203472b vs25

                              67 Fullb 45 Lowb vs17

                              70 Fullb 62 Midb

                              vs 21

                              Phenterminetopiramate doses Low 375 mg phentermine23 mg topiramate Mid 75 mg phentermine 46 mg topiramate Full 15 mg phentermine 92 mg topiramateITT-LOCF intent-to-treat last observation carried forwardData not available aP lt 001 vs placebo bP lt 0001 vs placebo

                              Treatment Gap in theManagement of Obesity

                              Physicians Need Effective Pharmacotherapies That Will Reduce Weight Significantly and Reduce Weight-related Comorbidities

                              0 5 10 15 20 25 30 35

                              Diet and Lifestyle Lap Band Gastric Bypass

                              TreatmentGap

                              What will fill the gap

                              Too risky for many peopleNot effective enoughfor many people

                              Treatment Gap in theManagement of Obesity

                              0 5 10 15 20 25 30 35

                              Diet and Lifestyle Lap Band Gastric Bypass

                              TreatmentGap

                              Too risky for many peopleNot effective enoughfor many people Pharmacotherapy

                              Less invasive procedures

                              Physicians Need Effective Pharmacotherapies That Will Reduce Weight Significantly and Reduce Weight-related Comorbidities

                              What will fill the gap

                              • Slide Number 1
                              • Slide Number 2
                              • Weight Management is Moving into the Workplace and Mainstream of Healthcare
                              • US Preventative Services Task Force
                              • A Proposal from CMS about Coverage for Intensive Behavioral Therapy for Obesity
                              • Slide Number 6
                              • Biggest Increases in Clinically Severe Obesity US 1987-2005
                              • Relationship Between BMI and Risk of Type 2 Diabetes
                              • Slide Number 9
                              • Medical Complications of Obesity Almost every organ system is affected
                              • Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and disease
                              • Current Therapies Often Address Individual Risk Factors Cardiometabolic risk
                              • Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and disease
                              • Are You Treating These Drivers of Cardiometabolic Risk Should You Treat The Underlying Cause
                              • Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors
                              • In My Opinion The Winds of Change are Blowing in the Treatment of Chronic Diseases
                              • Bariatric Surgery Reduces Overall Mortality Diabetes Mortality by 88
                              • Health Care Costs Attributable to ObesityEstimates of what various conditions add to health-care service costs over a 12-month period
                              • What-if scenarios (The Lancet forthcoming)
                              • How Much Weight Loss Is Needed to Prevent T2DMndashNot Very Much The DPP Experience
                              • In the Da Qing Study 6-year Intervention Led to Lower Incidence of Type 2 Diabetes 14 Years Later
                              • Slide Number 22
                              • Slide Number 23
                              • New Compounds andCombination Interventions
                              • Phentermine and Topiramate Extended-Release
                              • Phentermine and Topiramate Extended-Release
                              • EQUIP amp CONQUER Discontinuation RateDue to AEs in All Doses Studied
                              • Phentermine and Topiramate SEQUELWeight Loss Over Time
                              • CONQUER Significant Improvement in Cardiovascular Risk Factors
                              • Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors
                              • Lorcaserin
                              • BLOOM Study Body Weight Over Years 1 and 2
                              • BLOOM StudyKey Secondary Endpoints
                              • BLOOM-DMChange in Glycemic Parameters
                              • Lorcaserin Adverse Events Reported by 5 or More in Any Group in Year 1
                              • LorcaserinNo Increase in Rate of Valvulopathy
                              • Phase III Study Outcomes Compared
                              • Obesity Treatments in Late Development
                              • BupropionNaltrexone
                              • Buproprion ndash Naltrexone
                              • Liraglutide for Weight Loss in Patients with Type 2 Diabetes
                              • Liraglutide Weight Loss Over 2 Years ITT Observed Means
                              • Phase III Study Outcomes Compared
                              • Treatment Gap in theManagement of Obesity
                              • Treatment Gap in theManagement of Obesity

                                -34-48-48-88-59-29+73

                                Adams TD et al N Engl J Med 2007357(8)753-761

                                Bariatric Surgery Reduces Overall Mortality Diabetes Mortality by 88

                                Matched SubjectsSurgery Group (n=7925)

                                Co(n=

                                ntrol Group7925)

                                NoNo10000 person-yr No

                                No10000 person-yr

                                All causes of death 213 376 321 571All deaths caused by disease 150 265 285 507Cardiovascular diseases 55 97 104 185Diabetes 2 04 19 34Cancer 31 55 73 133Other diseases 62 11 89 155All non-disease causes 63 111 36 64Accident unrelated to drugs 21 37 17 30Poisoning of undetermined intent 9 16 4 07Suicide 15 26 5 09Other nondisease cause 18 32 10 18

                                CC-18

                                Health Care Costs Attributable to ObesityEstimates of what various conditions add to health-care service costs over a 12-month period

                                $395

                                $230

                                $225

                                $150

                                $125

                                $0 $100 $200 $300 $400 $500

                                Obesity

                                Smoking

                                20 years aging

                                Problem drinking

                                Overweight

                                Sturm R Health Aff (Millwood) 2002 Mar-Apr21(2)245-53 Table Wall Street Journal 3132002

                                Obesity increased medication costs 77inpatient and outpatient costs 36

                                What-if scenarios (The Lancet forthcoming)

                                Redrawn from Hamman RF et al Diabetes Care 2006292102‐2107

                                Change in Weight from Baseline (kg)0‐10 ‐5 +5In

                                cide

                                nce Ra

                                te per 100

                                Person‐Years

                                10

                                20

                                15

                                5

                                0

                                How Much Weight Loss Is Needed to Prevent T2DMndashNot Very Much The DPP Experience

                                In the Da Qing Study 6-year Intervention Led to Lower Incidence of Type 2 Diabetes 14 Years Later

                                n=530 overweight Chinese men and women with IGT mean BMI=26

                                17

                                0

                                20

                                40

                                60

                                80

                                100

                                2 4 6 8 10 12 14 16 18 20Years of follow‐up

                                6‐year intervention hazard ratio = 049 (95 CI 033ndash073)20‐year follow‐up hazard ratio = 057 (95 CI 041ndash081)

                                Cumulative Incide

                                nce of Type 2 Diabe

                                tes ()

                                0

                                Lifestyle interventionControl

                                Treatment Follow‐up

                                Li et al Lancet 20083711783ndash9

                                Pharmacotherapy for Weight LossLouis J Aronne MD FACP

                                Professor of Clinical Medicine Weill Cornell Medical College

                                Adjunct Associate Professor of Clinical Medicine Columbia University College of Physicians and Surgeons

                                Director Comprehensive Weight Control Program

                                New York-Presbyterian HospitalWeill Cornell Medical Center New York NY

                                As faculty of Weill Cornell Medical College we are committed to providing transparency for any and all external relationships prior to giving an academic presentation

                                I am a consultant speaker advisor or receive research support fromBMS

                                Arena Aspire BariatricsMyos

                                GI Dynamics Novo NordiskOrexigenVivusZafgen

                                I may discuss off-label use of medications

                                Disclosure Page

                                uarrFood intakedarr energy expenditure

                                darrfood intake uarrenergy expenditure

                                Topiramate

                                Naltrexone

                                LorcaserinPramlintideGLP-1Leptin

                                BupropionPhentermine

                                New Compounds andCombination Interventions

                                c Louis J Aronne MDScience Feb 7 2003 Vol 299Illustration by Katharine Sutliff

                                Phentermine and TopiramateExtended-Release

                                bull Mechanism of actionndash Phentermine Sympathomimetic amine - releaserndash Topiramate Gabaergicglutamate modulation and carbonic

                                anhydrase inhibitionbull February 2012 FDA advisory committee votes 20-2 for

                                approval bull FDA approved July 2012

                                ndash Schedule IVndash Pregnancy Category X = REMS

                                Topiramate monotherapy exposure in pregnancy associated with 2- to 5-fold increased prevalence of oral clefts

                                bull 4 doses Titrate upbull Available only by mail orderbull Covered through Medco Express Scripts

                                Phentermine and TopiramateExtended-Release

                                bull Dose titrationndash Once dailyndash Start treatment with phentermine 375 mgtopiramate

                                23 mg extended-release daily for 14 daysndash After 14 days increase to the recommended dose of

                                phentermine 75 mgtopiramate 46 mg extended-release once daily

                                ndash May titrate upwards if needed to phen 15 top 92 mg strength

                                EQUIP amp CONQUER Discontinuation RateDue to AEs in All Doses Studied

                                Placebo Low Mid Full

                                Number of patients 1508 241 498 1507Discontinuation due to AEs 9 12 12 18Blurred vision 05 21 08 07Headache 07 17 02 09Insomnia 04 00 04 17Depression 02 00 08 14Tingling 00 04 10 12Irritability 01 08 08 12Anxiety 03 00 02 11Dizziness 02 04 12 08

                                Includes adverse events (AEs) by dose for EQUIP amp CONQUER which lead to discontinuation in gt 1 of patientsPress release Sept 9 2009 Available at httpirvivuscomreleasedetailcfmReleaseID=420114Accessed April 27 2010

                                PhenTPMMid

                                -104

                                Phentermine and Topiramate SEQUELWeight Loss Over Time

                                Garvey WT Ryan DH Look M Gadde KM Am J Clin Nutr 201295(2)297-308

                                Placebo-25

                                Plt00001 v placebo

                                Weight Loss

                                Week

                                Total Population

                                0

                                -2

                                -4

                                -6

                                -8

                                -10

                                -12

                                -14

                                -16

                                0 12 24 36 48 60 72 84 96 108

                                Weight Loss ITT-LOCF

                                PhenTPMTop

                                -114

                                Mid = 75 mg46 mgTop = 15 mg92 mg

                                CONQUER Significant Improvement in Cardiovascular Risk Factors

                                (LS Mean Wt Loss)

                                QNEXAMid(78)

                                P valueQNEXATop

                                (98) P value

                                Waist Circumference (cm) ‐52 lt00001 ‐68 lt00001

                                Systolic BP (mmHg) ‐23 00008 ‐32 lt00001

                                Diastolic BP (mmHg) ‐07 NS ‐11 00031

                                Triglycerides ( ∆) ‐133 lt00001 ‐153 lt00001

                                Total Cholesterol ( ∆) ‐16 00345 ‐30 lt00001

                                LDL ( ∆) 04 NS ‐28 00069

                                HDL ( ∆) 40 lt00001 56 lt00001

                                P values represent comparisons to placebo NS= non‐significant

                                ITT‐LOCF Placebo ComparisonsTotal Study Population

                                Davidson MH et al Am J Cardiol 2013 Jan 29 pii S0002‐9149(12)02641‐0 doi 101016jamjcard201212038

                                Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors

                                Risk FactorsPhenTPMMid

                                p-valuePhenTPMTop

                                p-value

                                CRP lt0001 lt0001Fibrinogen lt005 lt005Adiponectin lt00001 lt00001

                                p-values represent comparisons to placebo

                                ITT-LOCF Placebo Comparisons

                                Gadde KM et al Lancet 2011377(9774)1341-52

                                Mid = 75 mg46 mgTop = 15 mg92 mg

                                Lorcaserin

                                bull Selective 5‐HT2C receptor agonist designed to promote weight loss

                                bull Schedule IV ndash Expected soonbull Indication weight loss and maintenance of

                                weight loss in patients with BMI gt30 kgm2 or BMI gt27 kgm2 + weight-related comorbidcondition(s)

                                bull Dose - 10 mg BIDbull Most common side effects headache nausea

                                dizziness dry mouth

                                BLOOM Study Body Weight Over Years 1 and 2

                                Smith SR et al N Engl J Med 2010363245-256 Study Week0 8 16 24 32 40 48 56 64 72 80 88 96 104

                                Bod

                                y W

                                eigh

                                t (kg

                                )

                                102

                                100

                                98

                                96

                                94

                                92

                                90

                                0

                                Year 1

                                Placebo in year 1 and 2 (n = 684)Lorcaserin in year 1 placebo in year 2 (n = 275)Lorcaserin in year 1 and 2 (n = 564)

                                Year 2

                                Endpoint Lorcaserin Placebo P valueWaist circumference (cm) minus68plusmn02 minus39plusmn02 lt001BMI (kgm2) minus209plusmn006 minus078plusmn005 lt001SBPDBP (mm Hg) minus14plusmn03minus11plusmn02 minus08plusmn03minus06plusmn02 0401Cholesterol ( ∆)Total LDLHDL

                                minus090plusmn033287plusmn056005plusmn033

                                057plusmn034403plusmn058minus021plusmn034

                                001

                                049

                                72Triglycerides minus615plusmn103 minus014plusmn099 lt001SafetyHR (beatsmin)PASP (mm Hg)Beck depression II score

                                minus20plusmn03minus092plusmn023minus11plusmn01

                                minus16plusmn04 minus023plusmn023 minus09plusmn01

                                0499014026

                                BLOOM StudyKey Secondary Endpoints

                                Smith SR et al N Engl J Med 2010363245-256

                                BLOOM-DMChange in Glycemic Parameters

                                P lt001 P lt05 LS mean change plusmn SEMOrsquoNeil PM et al Obesity 201220(7)1426-36 httpwwwnaturecomdoifinder101038oby201266

                                00

                                -05

                                -10

                                -150 12 24 36 52

                                Cha

                                nge

                                from

                                bas

                                elin

                                e (

                                )

                                A1c

                                Study week

                                0

                                -10

                                -20

                                -30

                                -400 12 24 52

                                Cha

                                nge

                                from

                                bas

                                elin

                                e m

                                gdl

                                )

                                Fasting plasma glucose

                                Study week

                                Lorcaserin 10 mg BID Lorcaserin 10 mg Placebo

                                Lorcaserin Adverse Events Reported by 5 or More in Any Group in Year 1

                                55

                                N () Lorcaserin(N = 1593)

                                Placebo(N = 1584)

                                Headache 287 (180) 175 (110)

                                Dizziness 130 (82) 60 (38)

                                Nausea 119 (75) 85 (54)

                                Constipation 106 (67) 64 (40)

                                Fatigue 95 (60) 48 (30)

                                Dry mouth 83 (52) 37 (23)

                                Smith SR et al ADA 2009 Late‐Breaking Abstract 96

                                LorcaserinNo Increase in Rate of Valvulopathy

                                Smith SR et al N Engl J Med 2010363245-256

                                10

                                8

                                6

                                4

                                2

                                024 52 76 104

                                1351714

                                9

                                19

                                3421Patie

                                nts

                                ()

                                Week

                                Lorcaserin in yr 1 and 2

                                Lorcaserin in yr 1 Placebo in yr 2

                                Placebo in yr 1 and 2

                                Phase III Study Outcomes Compared

                                Buproprion SR (360 mgd) Naltrexone SR (32 mgd)

                                Lorcaserin(20 mgd)

                                Phentermine Topiramate CR

                                COR1 COR-I2 COR-II3 NB3043 BLOOM4 BLOSSOM5 EQUIP CONQUER

                                Number of patients (ITT-LOCF)

                                793 obese 1453 obese

                                1281 obese

                                502 type II diabetes

                                3182 obese 4008 obese

                                1230 obese BMI 44

                                2448 comorbidBMI 36

                                Mean change compared with placebo from base

                                93 vs5 1c

                                61a vs13c

                                64a vs12

                                50 a vs12c

                                58 vs22c

                                48 vs28c

                                11 Fullbvs 16

                                104 Fullb 84 Midb

                                vs 18

                                51 Lowb vs16c

                                Categorical change 5 compared with placebo from base

                                56 vs43

                                48a vs164

                                563a

                                vs 171445a vs189

                                475b

                                vs 203472b vs25

                                67 Fullb 45 Lowb vs17

                                70 Fullb 62 Midb

                                vs 21

                                Phenterminetopiramate doses Low 375 mg phentermine23 mg topiramate Mid 75 mg phentermine 46 mg topiramate Full 15 mg phentermine 92 mg topiramateITT-LOCF intent-to-treat last observation carried forwardData not available aP lt 001 vs placebo bP lt 0001 vs placebo

                                Obesity Treatments in Late Development

                                Kushner RF Expert Opin Pharmacother 200891339-1350

                                Agents ActionBupropionNaltrexone

                                bull Dopaminenoradrenaline reuptake inhibitorbull Opioid receptor antagonist

                                Liraglutide bull GLP-1 agonist

                                BupropionNaltrexone

                                bull Mechanism of Actionndash Bupropion - Dopaminenoradrenaline reuptake inhibitorndash Naltrexone- Opioid receptor antagonist

                                bull Was approved by FDA committee but FDA did not approve until a CV outcome study is performed 2nd concerns about BP and P in some patients

                                bull The Light Study is now underway and reported to be enrolling well under PI Dr Nissen

                                bull BupropionNaltrexone will have first completed CV outcome study

                                Buproprion ndash Naltrexone

                                Greenway FL et al Lancet 2010376(9741)595-605

                                0

                                -2

                                -4

                                -6

                                -8

                                -100 4 8 12 16 20 24 28 32 36 40 44 48 52 56

                                Weeks

                                Wei

                                ght c

                                hang

                                e fro

                                m b

                                asel

                                ine

                                ()

                                Placebo

                                Naltrexone 16 mg plus bupropion

                                Naltrexone 32 mg plus bupropion

                                Liraglutide for Weight Loss in Patients with Type 2 Diabetes

                                bull GLP-1 analog approved for treatment of type 2 diabetes

                                bull Anorectic effect mediated both by the activation of GLP-1 receptor expressed on vagal afferents and by the GLP-1R activation in CNS

                                bull Affects visceral fat adiposity appetite food preference and cardiovascular biomarkers in patients with type 2 diabetes

                                Inoue K et al Cardiovasc Diabetol 2011 10109 doi1011861475-2840-10-109

                                Liraglutide Weight Loss Over 2 Years ITT Observed Means

                                Astrup A et al Int J Obes (Lond) 201236(6)843-54

                                FromScreening

                                -94 kg

                                -67 kg-88 kg

                                -99 kg-94 kg

                                -103 kg

                                ITT intention to treat

                                Phase III Study Outcomes Compared

                                Buproprion SR (360 mgd) Naltrexone SR (32 mgd)

                                Lorcaserin(20 mgd)

                                Phentermine Topiramate CR

                                COR1 COR-I2 COR-II3 NB3043 BLOOM4 BLOSSOM5 EQUIP CONQUER

                                Number of patients (ITT-LOCF)

                                793 obese 1453 obese

                                1281 obese

                                502 type II diabetes

                                3182 obese 4008 obese

                                1230 obese BMI 44

                                2448 comorbidBMI 36

                                Mean change compared with placebo from base

                                93 vs5 1c

                                61a vs13c

                                64a vs12

                                50 a vs12c

                                58 vs22c

                                48 vs28c

                                11 Fullbvs 16

                                104 Fullb 84 Midb

                                vs 18

                                51 Lowb vs16c

                                Categorical change 5 compared with placebo from base

                                56 vs43

                                48a vs164

                                563a

                                vs 171445a vs189

                                475b

                                vs 203472b vs25

                                67 Fullb 45 Lowb vs17

                                70 Fullb 62 Midb

                                vs 21

                                Phenterminetopiramate doses Low 375 mg phentermine23 mg topiramate Mid 75 mg phentermine 46 mg topiramate Full 15 mg phentermine 92 mg topiramateITT-LOCF intent-to-treat last observation carried forwardData not available aP lt 001 vs placebo bP lt 0001 vs placebo

                                Treatment Gap in theManagement of Obesity

                                Physicians Need Effective Pharmacotherapies That Will Reduce Weight Significantly and Reduce Weight-related Comorbidities

                                0 5 10 15 20 25 30 35

                                Diet and Lifestyle Lap Band Gastric Bypass

                                TreatmentGap

                                What will fill the gap

                                Too risky for many peopleNot effective enoughfor many people

                                Treatment Gap in theManagement of Obesity

                                0 5 10 15 20 25 30 35

                                Diet and Lifestyle Lap Band Gastric Bypass

                                TreatmentGap

                                Too risky for many peopleNot effective enoughfor many people Pharmacotherapy

                                Less invasive procedures

                                Physicians Need Effective Pharmacotherapies That Will Reduce Weight Significantly and Reduce Weight-related Comorbidities

                                What will fill the gap

                                • Slide Number 1
                                • Slide Number 2
                                • Weight Management is Moving into the Workplace and Mainstream of Healthcare
                                • US Preventative Services Task Force
                                • A Proposal from CMS about Coverage for Intensive Behavioral Therapy for Obesity
                                • Slide Number 6
                                • Biggest Increases in Clinically Severe Obesity US 1987-2005
                                • Relationship Between BMI and Risk of Type 2 Diabetes
                                • Slide Number 9
                                • Medical Complications of Obesity Almost every organ system is affected
                                • Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and disease
                                • Current Therapies Often Address Individual Risk Factors Cardiometabolic risk
                                • Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and disease
                                • Are You Treating These Drivers of Cardiometabolic Risk Should You Treat The Underlying Cause
                                • Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors
                                • In My Opinion The Winds of Change are Blowing in the Treatment of Chronic Diseases
                                • Bariatric Surgery Reduces Overall Mortality Diabetes Mortality by 88
                                • Health Care Costs Attributable to ObesityEstimates of what various conditions add to health-care service costs over a 12-month period
                                • What-if scenarios (The Lancet forthcoming)
                                • How Much Weight Loss Is Needed to Prevent T2DMndashNot Very Much The DPP Experience
                                • In the Da Qing Study 6-year Intervention Led to Lower Incidence of Type 2 Diabetes 14 Years Later
                                • Slide Number 22
                                • Slide Number 23
                                • New Compounds andCombination Interventions
                                • Phentermine and Topiramate Extended-Release
                                • Phentermine and Topiramate Extended-Release
                                • EQUIP amp CONQUER Discontinuation RateDue to AEs in All Doses Studied
                                • Phentermine and Topiramate SEQUELWeight Loss Over Time
                                • CONQUER Significant Improvement in Cardiovascular Risk Factors
                                • Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors
                                • Lorcaserin
                                • BLOOM Study Body Weight Over Years 1 and 2
                                • BLOOM StudyKey Secondary Endpoints
                                • BLOOM-DMChange in Glycemic Parameters
                                • Lorcaserin Adverse Events Reported by 5 or More in Any Group in Year 1
                                • LorcaserinNo Increase in Rate of Valvulopathy
                                • Phase III Study Outcomes Compared
                                • Obesity Treatments in Late Development
                                • BupropionNaltrexone
                                • Buproprion ndash Naltrexone
                                • Liraglutide for Weight Loss in Patients with Type 2 Diabetes
                                • Liraglutide Weight Loss Over 2 Years ITT Observed Means
                                • Phase III Study Outcomes Compared
                                • Treatment Gap in theManagement of Obesity
                                • Treatment Gap in theManagement of Obesity

                                  CC-18

                                  Health Care Costs Attributable to ObesityEstimates of what various conditions add to health-care service costs over a 12-month period

                                  $395

                                  $230

                                  $225

                                  $150

                                  $125

                                  $0 $100 $200 $300 $400 $500

                                  Obesity

                                  Smoking

                                  20 years aging

                                  Problem drinking

                                  Overweight

                                  Sturm R Health Aff (Millwood) 2002 Mar-Apr21(2)245-53 Table Wall Street Journal 3132002

                                  Obesity increased medication costs 77inpatient and outpatient costs 36

                                  What-if scenarios (The Lancet forthcoming)

                                  Redrawn from Hamman RF et al Diabetes Care 2006292102‐2107

                                  Change in Weight from Baseline (kg)0‐10 ‐5 +5In

                                  cide

                                  nce Ra

                                  te per 100

                                  Person‐Years

                                  10

                                  20

                                  15

                                  5

                                  0

                                  How Much Weight Loss Is Needed to Prevent T2DMndashNot Very Much The DPP Experience

                                  In the Da Qing Study 6-year Intervention Led to Lower Incidence of Type 2 Diabetes 14 Years Later

                                  n=530 overweight Chinese men and women with IGT mean BMI=26

                                  17

                                  0

                                  20

                                  40

                                  60

                                  80

                                  100

                                  2 4 6 8 10 12 14 16 18 20Years of follow‐up

                                  6‐year intervention hazard ratio = 049 (95 CI 033ndash073)20‐year follow‐up hazard ratio = 057 (95 CI 041ndash081)

                                  Cumulative Incide

                                  nce of Type 2 Diabe

                                  tes ()

                                  0

                                  Lifestyle interventionControl

                                  Treatment Follow‐up

                                  Li et al Lancet 20083711783ndash9

                                  Pharmacotherapy for Weight LossLouis J Aronne MD FACP

                                  Professor of Clinical Medicine Weill Cornell Medical College

                                  Adjunct Associate Professor of Clinical Medicine Columbia University College of Physicians and Surgeons

                                  Director Comprehensive Weight Control Program

                                  New York-Presbyterian HospitalWeill Cornell Medical Center New York NY

                                  As faculty of Weill Cornell Medical College we are committed to providing transparency for any and all external relationships prior to giving an academic presentation

                                  I am a consultant speaker advisor or receive research support fromBMS

                                  Arena Aspire BariatricsMyos

                                  GI Dynamics Novo NordiskOrexigenVivusZafgen

                                  I may discuss off-label use of medications

                                  Disclosure Page

                                  uarrFood intakedarr energy expenditure

                                  darrfood intake uarrenergy expenditure

                                  Topiramate

                                  Naltrexone

                                  LorcaserinPramlintideGLP-1Leptin

                                  BupropionPhentermine

                                  New Compounds andCombination Interventions

                                  c Louis J Aronne MDScience Feb 7 2003 Vol 299Illustration by Katharine Sutliff

                                  Phentermine and TopiramateExtended-Release

                                  bull Mechanism of actionndash Phentermine Sympathomimetic amine - releaserndash Topiramate Gabaergicglutamate modulation and carbonic

                                  anhydrase inhibitionbull February 2012 FDA advisory committee votes 20-2 for

                                  approval bull FDA approved July 2012

                                  ndash Schedule IVndash Pregnancy Category X = REMS

                                  Topiramate monotherapy exposure in pregnancy associated with 2- to 5-fold increased prevalence of oral clefts

                                  bull 4 doses Titrate upbull Available only by mail orderbull Covered through Medco Express Scripts

                                  Phentermine and TopiramateExtended-Release

                                  bull Dose titrationndash Once dailyndash Start treatment with phentermine 375 mgtopiramate

                                  23 mg extended-release daily for 14 daysndash After 14 days increase to the recommended dose of

                                  phentermine 75 mgtopiramate 46 mg extended-release once daily

                                  ndash May titrate upwards if needed to phen 15 top 92 mg strength

                                  EQUIP amp CONQUER Discontinuation RateDue to AEs in All Doses Studied

                                  Placebo Low Mid Full

                                  Number of patients 1508 241 498 1507Discontinuation due to AEs 9 12 12 18Blurred vision 05 21 08 07Headache 07 17 02 09Insomnia 04 00 04 17Depression 02 00 08 14Tingling 00 04 10 12Irritability 01 08 08 12Anxiety 03 00 02 11Dizziness 02 04 12 08

                                  Includes adverse events (AEs) by dose for EQUIP amp CONQUER which lead to discontinuation in gt 1 of patientsPress release Sept 9 2009 Available at httpirvivuscomreleasedetailcfmReleaseID=420114Accessed April 27 2010

                                  PhenTPMMid

                                  -104

                                  Phentermine and Topiramate SEQUELWeight Loss Over Time

                                  Garvey WT Ryan DH Look M Gadde KM Am J Clin Nutr 201295(2)297-308

                                  Placebo-25

                                  Plt00001 v placebo

                                  Weight Loss

                                  Week

                                  Total Population

                                  0

                                  -2

                                  -4

                                  -6

                                  -8

                                  -10

                                  -12

                                  -14

                                  -16

                                  0 12 24 36 48 60 72 84 96 108

                                  Weight Loss ITT-LOCF

                                  PhenTPMTop

                                  -114

                                  Mid = 75 mg46 mgTop = 15 mg92 mg

                                  CONQUER Significant Improvement in Cardiovascular Risk Factors

                                  (LS Mean Wt Loss)

                                  QNEXAMid(78)

                                  P valueQNEXATop

                                  (98) P value

                                  Waist Circumference (cm) ‐52 lt00001 ‐68 lt00001

                                  Systolic BP (mmHg) ‐23 00008 ‐32 lt00001

                                  Diastolic BP (mmHg) ‐07 NS ‐11 00031

                                  Triglycerides ( ∆) ‐133 lt00001 ‐153 lt00001

                                  Total Cholesterol ( ∆) ‐16 00345 ‐30 lt00001

                                  LDL ( ∆) 04 NS ‐28 00069

                                  HDL ( ∆) 40 lt00001 56 lt00001

                                  P values represent comparisons to placebo NS= non‐significant

                                  ITT‐LOCF Placebo ComparisonsTotal Study Population

                                  Davidson MH et al Am J Cardiol 2013 Jan 29 pii S0002‐9149(12)02641‐0 doi 101016jamjcard201212038

                                  Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors

                                  Risk FactorsPhenTPMMid

                                  p-valuePhenTPMTop

                                  p-value

                                  CRP lt0001 lt0001Fibrinogen lt005 lt005Adiponectin lt00001 lt00001

                                  p-values represent comparisons to placebo

                                  ITT-LOCF Placebo Comparisons

                                  Gadde KM et al Lancet 2011377(9774)1341-52

                                  Mid = 75 mg46 mgTop = 15 mg92 mg

                                  Lorcaserin

                                  bull Selective 5‐HT2C receptor agonist designed to promote weight loss

                                  bull Schedule IV ndash Expected soonbull Indication weight loss and maintenance of

                                  weight loss in patients with BMI gt30 kgm2 or BMI gt27 kgm2 + weight-related comorbidcondition(s)

                                  bull Dose - 10 mg BIDbull Most common side effects headache nausea

                                  dizziness dry mouth

                                  BLOOM Study Body Weight Over Years 1 and 2

                                  Smith SR et al N Engl J Med 2010363245-256 Study Week0 8 16 24 32 40 48 56 64 72 80 88 96 104

                                  Bod

                                  y W

                                  eigh

                                  t (kg

                                  )

                                  102

                                  100

                                  98

                                  96

                                  94

                                  92

                                  90

                                  0

                                  Year 1

                                  Placebo in year 1 and 2 (n = 684)Lorcaserin in year 1 placebo in year 2 (n = 275)Lorcaserin in year 1 and 2 (n = 564)

                                  Year 2

                                  Endpoint Lorcaserin Placebo P valueWaist circumference (cm) minus68plusmn02 minus39plusmn02 lt001BMI (kgm2) minus209plusmn006 minus078plusmn005 lt001SBPDBP (mm Hg) minus14plusmn03minus11plusmn02 minus08plusmn03minus06plusmn02 0401Cholesterol ( ∆)Total LDLHDL

                                  minus090plusmn033287plusmn056005plusmn033

                                  057plusmn034403plusmn058minus021plusmn034

                                  001

                                  049

                                  72Triglycerides minus615plusmn103 minus014plusmn099 lt001SafetyHR (beatsmin)PASP (mm Hg)Beck depression II score

                                  minus20plusmn03minus092plusmn023minus11plusmn01

                                  minus16plusmn04 minus023plusmn023 minus09plusmn01

                                  0499014026

                                  BLOOM StudyKey Secondary Endpoints

                                  Smith SR et al N Engl J Med 2010363245-256

                                  BLOOM-DMChange in Glycemic Parameters

                                  P lt001 P lt05 LS mean change plusmn SEMOrsquoNeil PM et al Obesity 201220(7)1426-36 httpwwwnaturecomdoifinder101038oby201266

                                  00

                                  -05

                                  -10

                                  -150 12 24 36 52

                                  Cha

                                  nge

                                  from

                                  bas

                                  elin

                                  e (

                                  )

                                  A1c

                                  Study week

                                  0

                                  -10

                                  -20

                                  -30

                                  -400 12 24 52

                                  Cha

                                  nge

                                  from

                                  bas

                                  elin

                                  e m

                                  gdl

                                  )

                                  Fasting plasma glucose

                                  Study week

                                  Lorcaserin 10 mg BID Lorcaserin 10 mg Placebo

                                  Lorcaserin Adverse Events Reported by 5 or More in Any Group in Year 1

                                  55

                                  N () Lorcaserin(N = 1593)

                                  Placebo(N = 1584)

                                  Headache 287 (180) 175 (110)

                                  Dizziness 130 (82) 60 (38)

                                  Nausea 119 (75) 85 (54)

                                  Constipation 106 (67) 64 (40)

                                  Fatigue 95 (60) 48 (30)

                                  Dry mouth 83 (52) 37 (23)

                                  Smith SR et al ADA 2009 Late‐Breaking Abstract 96

                                  LorcaserinNo Increase in Rate of Valvulopathy

                                  Smith SR et al N Engl J Med 2010363245-256

                                  10

                                  8

                                  6

                                  4

                                  2

                                  024 52 76 104

                                  1351714

                                  9

                                  19

                                  3421Patie

                                  nts

                                  ()

                                  Week

                                  Lorcaserin in yr 1 and 2

                                  Lorcaserin in yr 1 Placebo in yr 2

                                  Placebo in yr 1 and 2

                                  Phase III Study Outcomes Compared

                                  Buproprion SR (360 mgd) Naltrexone SR (32 mgd)

                                  Lorcaserin(20 mgd)

                                  Phentermine Topiramate CR

                                  COR1 COR-I2 COR-II3 NB3043 BLOOM4 BLOSSOM5 EQUIP CONQUER

                                  Number of patients (ITT-LOCF)

                                  793 obese 1453 obese

                                  1281 obese

                                  502 type II diabetes

                                  3182 obese 4008 obese

                                  1230 obese BMI 44

                                  2448 comorbidBMI 36

                                  Mean change compared with placebo from base

                                  93 vs5 1c

                                  61a vs13c

                                  64a vs12

                                  50 a vs12c

                                  58 vs22c

                                  48 vs28c

                                  11 Fullbvs 16

                                  104 Fullb 84 Midb

                                  vs 18

                                  51 Lowb vs16c

                                  Categorical change 5 compared with placebo from base

                                  56 vs43

                                  48a vs164

                                  563a

                                  vs 171445a vs189

                                  475b

                                  vs 203472b vs25

                                  67 Fullb 45 Lowb vs17

                                  70 Fullb 62 Midb

                                  vs 21

                                  Phenterminetopiramate doses Low 375 mg phentermine23 mg topiramate Mid 75 mg phentermine 46 mg topiramate Full 15 mg phentermine 92 mg topiramateITT-LOCF intent-to-treat last observation carried forwardData not available aP lt 001 vs placebo bP lt 0001 vs placebo

                                  Obesity Treatments in Late Development

                                  Kushner RF Expert Opin Pharmacother 200891339-1350

                                  Agents ActionBupropionNaltrexone

                                  bull Dopaminenoradrenaline reuptake inhibitorbull Opioid receptor antagonist

                                  Liraglutide bull GLP-1 agonist

                                  BupropionNaltrexone

                                  bull Mechanism of Actionndash Bupropion - Dopaminenoradrenaline reuptake inhibitorndash Naltrexone- Opioid receptor antagonist

                                  bull Was approved by FDA committee but FDA did not approve until a CV outcome study is performed 2nd concerns about BP and P in some patients

                                  bull The Light Study is now underway and reported to be enrolling well under PI Dr Nissen

                                  bull BupropionNaltrexone will have first completed CV outcome study

                                  Buproprion ndash Naltrexone

                                  Greenway FL et al Lancet 2010376(9741)595-605

                                  0

                                  -2

                                  -4

                                  -6

                                  -8

                                  -100 4 8 12 16 20 24 28 32 36 40 44 48 52 56

                                  Weeks

                                  Wei

                                  ght c

                                  hang

                                  e fro

                                  m b

                                  asel

                                  ine

                                  ()

                                  Placebo

                                  Naltrexone 16 mg plus bupropion

                                  Naltrexone 32 mg plus bupropion

                                  Liraglutide for Weight Loss in Patients with Type 2 Diabetes

                                  bull GLP-1 analog approved for treatment of type 2 diabetes

                                  bull Anorectic effect mediated both by the activation of GLP-1 receptor expressed on vagal afferents and by the GLP-1R activation in CNS

                                  bull Affects visceral fat adiposity appetite food preference and cardiovascular biomarkers in patients with type 2 diabetes

                                  Inoue K et al Cardiovasc Diabetol 2011 10109 doi1011861475-2840-10-109

                                  Liraglutide Weight Loss Over 2 Years ITT Observed Means

                                  Astrup A et al Int J Obes (Lond) 201236(6)843-54

                                  FromScreening

                                  -94 kg

                                  -67 kg-88 kg

                                  -99 kg-94 kg

                                  -103 kg

                                  ITT intention to treat

                                  Phase III Study Outcomes Compared

                                  Buproprion SR (360 mgd) Naltrexone SR (32 mgd)

                                  Lorcaserin(20 mgd)

                                  Phentermine Topiramate CR

                                  COR1 COR-I2 COR-II3 NB3043 BLOOM4 BLOSSOM5 EQUIP CONQUER

                                  Number of patients (ITT-LOCF)

                                  793 obese 1453 obese

                                  1281 obese

                                  502 type II diabetes

                                  3182 obese 4008 obese

                                  1230 obese BMI 44

                                  2448 comorbidBMI 36

                                  Mean change compared with placebo from base

                                  93 vs5 1c

                                  61a vs13c

                                  64a vs12

                                  50 a vs12c

                                  58 vs22c

                                  48 vs28c

                                  11 Fullbvs 16

                                  104 Fullb 84 Midb

                                  vs 18

                                  51 Lowb vs16c

                                  Categorical change 5 compared with placebo from base

                                  56 vs43

                                  48a vs164

                                  563a

                                  vs 171445a vs189

                                  475b

                                  vs 203472b vs25

                                  67 Fullb 45 Lowb vs17

                                  70 Fullb 62 Midb

                                  vs 21

                                  Phenterminetopiramate doses Low 375 mg phentermine23 mg topiramate Mid 75 mg phentermine 46 mg topiramate Full 15 mg phentermine 92 mg topiramateITT-LOCF intent-to-treat last observation carried forwardData not available aP lt 001 vs placebo bP lt 0001 vs placebo

                                  Treatment Gap in theManagement of Obesity

                                  Physicians Need Effective Pharmacotherapies That Will Reduce Weight Significantly and Reduce Weight-related Comorbidities

                                  0 5 10 15 20 25 30 35

                                  Diet and Lifestyle Lap Band Gastric Bypass

                                  TreatmentGap

                                  What will fill the gap

                                  Too risky for many peopleNot effective enoughfor many people

                                  Treatment Gap in theManagement of Obesity

                                  0 5 10 15 20 25 30 35

                                  Diet and Lifestyle Lap Band Gastric Bypass

                                  TreatmentGap

                                  Too risky for many peopleNot effective enoughfor many people Pharmacotherapy

                                  Less invasive procedures

                                  Physicians Need Effective Pharmacotherapies That Will Reduce Weight Significantly and Reduce Weight-related Comorbidities

                                  What will fill the gap

                                  • Slide Number 1
                                  • Slide Number 2
                                  • Weight Management is Moving into the Workplace and Mainstream of Healthcare
                                  • US Preventative Services Task Force
                                  • A Proposal from CMS about Coverage for Intensive Behavioral Therapy for Obesity
                                  • Slide Number 6
                                  • Biggest Increases in Clinically Severe Obesity US 1987-2005
                                  • Relationship Between BMI and Risk of Type 2 Diabetes
                                  • Slide Number 9
                                  • Medical Complications of Obesity Almost every organ system is affected
                                  • Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and disease
                                  • Current Therapies Often Address Individual Risk Factors Cardiometabolic risk
                                  • Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and disease
                                  • Are You Treating These Drivers of Cardiometabolic Risk Should You Treat The Underlying Cause
                                  • Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors
                                  • In My Opinion The Winds of Change are Blowing in the Treatment of Chronic Diseases
                                  • Bariatric Surgery Reduces Overall Mortality Diabetes Mortality by 88
                                  • Health Care Costs Attributable to ObesityEstimates of what various conditions add to health-care service costs over a 12-month period
                                  • What-if scenarios (The Lancet forthcoming)
                                  • How Much Weight Loss Is Needed to Prevent T2DMndashNot Very Much The DPP Experience
                                  • In the Da Qing Study 6-year Intervention Led to Lower Incidence of Type 2 Diabetes 14 Years Later
                                  • Slide Number 22
                                  • Slide Number 23
                                  • New Compounds andCombination Interventions
                                  • Phentermine and Topiramate Extended-Release
                                  • Phentermine and Topiramate Extended-Release
                                  • EQUIP amp CONQUER Discontinuation RateDue to AEs in All Doses Studied
                                  • Phentermine and Topiramate SEQUELWeight Loss Over Time
                                  • CONQUER Significant Improvement in Cardiovascular Risk Factors
                                  • Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors
                                  • Lorcaserin
                                  • BLOOM Study Body Weight Over Years 1 and 2
                                  • BLOOM StudyKey Secondary Endpoints
                                  • BLOOM-DMChange in Glycemic Parameters
                                  • Lorcaserin Adverse Events Reported by 5 or More in Any Group in Year 1
                                  • LorcaserinNo Increase in Rate of Valvulopathy
                                  • Phase III Study Outcomes Compared
                                  • Obesity Treatments in Late Development
                                  • BupropionNaltrexone
                                  • Buproprion ndash Naltrexone
                                  • Liraglutide for Weight Loss in Patients with Type 2 Diabetes
                                  • Liraglutide Weight Loss Over 2 Years ITT Observed Means
                                  • Phase III Study Outcomes Compared
                                  • Treatment Gap in theManagement of Obesity
                                  • Treatment Gap in theManagement of Obesity

                                    What-if scenarios (The Lancet forthcoming)

                                    Redrawn from Hamman RF et al Diabetes Care 2006292102‐2107

                                    Change in Weight from Baseline (kg)0‐10 ‐5 +5In

                                    cide

                                    nce Ra

                                    te per 100

                                    Person‐Years

                                    10

                                    20

                                    15

                                    5

                                    0

                                    How Much Weight Loss Is Needed to Prevent T2DMndashNot Very Much The DPP Experience

                                    In the Da Qing Study 6-year Intervention Led to Lower Incidence of Type 2 Diabetes 14 Years Later

                                    n=530 overweight Chinese men and women with IGT mean BMI=26

                                    17

                                    0

                                    20

                                    40

                                    60

                                    80

                                    100

                                    2 4 6 8 10 12 14 16 18 20Years of follow‐up

                                    6‐year intervention hazard ratio = 049 (95 CI 033ndash073)20‐year follow‐up hazard ratio = 057 (95 CI 041ndash081)

                                    Cumulative Incide

                                    nce of Type 2 Diabe

                                    tes ()

                                    0

                                    Lifestyle interventionControl

                                    Treatment Follow‐up

                                    Li et al Lancet 20083711783ndash9

                                    Pharmacotherapy for Weight LossLouis J Aronne MD FACP

                                    Professor of Clinical Medicine Weill Cornell Medical College

                                    Adjunct Associate Professor of Clinical Medicine Columbia University College of Physicians and Surgeons

                                    Director Comprehensive Weight Control Program

                                    New York-Presbyterian HospitalWeill Cornell Medical Center New York NY

                                    As faculty of Weill Cornell Medical College we are committed to providing transparency for any and all external relationships prior to giving an academic presentation

                                    I am a consultant speaker advisor or receive research support fromBMS

                                    Arena Aspire BariatricsMyos

                                    GI Dynamics Novo NordiskOrexigenVivusZafgen

                                    I may discuss off-label use of medications

                                    Disclosure Page

                                    uarrFood intakedarr energy expenditure

                                    darrfood intake uarrenergy expenditure

                                    Topiramate

                                    Naltrexone

                                    LorcaserinPramlintideGLP-1Leptin

                                    BupropionPhentermine

                                    New Compounds andCombination Interventions

                                    c Louis J Aronne MDScience Feb 7 2003 Vol 299Illustration by Katharine Sutliff

                                    Phentermine and TopiramateExtended-Release

                                    bull Mechanism of actionndash Phentermine Sympathomimetic amine - releaserndash Topiramate Gabaergicglutamate modulation and carbonic

                                    anhydrase inhibitionbull February 2012 FDA advisory committee votes 20-2 for

                                    approval bull FDA approved July 2012

                                    ndash Schedule IVndash Pregnancy Category X = REMS

                                    Topiramate monotherapy exposure in pregnancy associated with 2- to 5-fold increased prevalence of oral clefts

                                    bull 4 doses Titrate upbull Available only by mail orderbull Covered through Medco Express Scripts

                                    Phentermine and TopiramateExtended-Release

                                    bull Dose titrationndash Once dailyndash Start treatment with phentermine 375 mgtopiramate

                                    23 mg extended-release daily for 14 daysndash After 14 days increase to the recommended dose of

                                    phentermine 75 mgtopiramate 46 mg extended-release once daily

                                    ndash May titrate upwards if needed to phen 15 top 92 mg strength

                                    EQUIP amp CONQUER Discontinuation RateDue to AEs in All Doses Studied

                                    Placebo Low Mid Full

                                    Number of patients 1508 241 498 1507Discontinuation due to AEs 9 12 12 18Blurred vision 05 21 08 07Headache 07 17 02 09Insomnia 04 00 04 17Depression 02 00 08 14Tingling 00 04 10 12Irritability 01 08 08 12Anxiety 03 00 02 11Dizziness 02 04 12 08

                                    Includes adverse events (AEs) by dose for EQUIP amp CONQUER which lead to discontinuation in gt 1 of patientsPress release Sept 9 2009 Available at httpirvivuscomreleasedetailcfmReleaseID=420114Accessed April 27 2010

                                    PhenTPMMid

                                    -104

                                    Phentermine and Topiramate SEQUELWeight Loss Over Time

                                    Garvey WT Ryan DH Look M Gadde KM Am J Clin Nutr 201295(2)297-308

                                    Placebo-25

                                    Plt00001 v placebo

                                    Weight Loss

                                    Week

                                    Total Population

                                    0

                                    -2

                                    -4

                                    -6

                                    -8

                                    -10

                                    -12

                                    -14

                                    -16

                                    0 12 24 36 48 60 72 84 96 108

                                    Weight Loss ITT-LOCF

                                    PhenTPMTop

                                    -114

                                    Mid = 75 mg46 mgTop = 15 mg92 mg

                                    CONQUER Significant Improvement in Cardiovascular Risk Factors

                                    (LS Mean Wt Loss)

                                    QNEXAMid(78)

                                    P valueQNEXATop

                                    (98) P value

                                    Waist Circumference (cm) ‐52 lt00001 ‐68 lt00001

                                    Systolic BP (mmHg) ‐23 00008 ‐32 lt00001

                                    Diastolic BP (mmHg) ‐07 NS ‐11 00031

                                    Triglycerides ( ∆) ‐133 lt00001 ‐153 lt00001

                                    Total Cholesterol ( ∆) ‐16 00345 ‐30 lt00001

                                    LDL ( ∆) 04 NS ‐28 00069

                                    HDL ( ∆) 40 lt00001 56 lt00001

                                    P values represent comparisons to placebo NS= non‐significant

                                    ITT‐LOCF Placebo ComparisonsTotal Study Population

                                    Davidson MH et al Am J Cardiol 2013 Jan 29 pii S0002‐9149(12)02641‐0 doi 101016jamjcard201212038

                                    Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors

                                    Risk FactorsPhenTPMMid

                                    p-valuePhenTPMTop

                                    p-value

                                    CRP lt0001 lt0001Fibrinogen lt005 lt005Adiponectin lt00001 lt00001

                                    p-values represent comparisons to placebo

                                    ITT-LOCF Placebo Comparisons

                                    Gadde KM et al Lancet 2011377(9774)1341-52

                                    Mid = 75 mg46 mgTop = 15 mg92 mg

                                    Lorcaserin

                                    bull Selective 5‐HT2C receptor agonist designed to promote weight loss

                                    bull Schedule IV ndash Expected soonbull Indication weight loss and maintenance of

                                    weight loss in patients with BMI gt30 kgm2 or BMI gt27 kgm2 + weight-related comorbidcondition(s)

                                    bull Dose - 10 mg BIDbull Most common side effects headache nausea

                                    dizziness dry mouth

                                    BLOOM Study Body Weight Over Years 1 and 2

                                    Smith SR et al N Engl J Med 2010363245-256 Study Week0 8 16 24 32 40 48 56 64 72 80 88 96 104

                                    Bod

                                    y W

                                    eigh

                                    t (kg

                                    )

                                    102

                                    100

                                    98

                                    96

                                    94

                                    92

                                    90

                                    0

                                    Year 1

                                    Placebo in year 1 and 2 (n = 684)Lorcaserin in year 1 placebo in year 2 (n = 275)Lorcaserin in year 1 and 2 (n = 564)

                                    Year 2

                                    Endpoint Lorcaserin Placebo P valueWaist circumference (cm) minus68plusmn02 minus39plusmn02 lt001BMI (kgm2) minus209plusmn006 minus078plusmn005 lt001SBPDBP (mm Hg) minus14plusmn03minus11plusmn02 minus08plusmn03minus06plusmn02 0401Cholesterol ( ∆)Total LDLHDL

                                    minus090plusmn033287plusmn056005plusmn033

                                    057plusmn034403plusmn058minus021plusmn034

                                    001

                                    049

                                    72Triglycerides minus615plusmn103 minus014plusmn099 lt001SafetyHR (beatsmin)PASP (mm Hg)Beck depression II score

                                    minus20plusmn03minus092plusmn023minus11plusmn01

                                    minus16plusmn04 minus023plusmn023 minus09plusmn01

                                    0499014026

                                    BLOOM StudyKey Secondary Endpoints

                                    Smith SR et al N Engl J Med 2010363245-256

                                    BLOOM-DMChange in Glycemic Parameters

                                    P lt001 P lt05 LS mean change plusmn SEMOrsquoNeil PM et al Obesity 201220(7)1426-36 httpwwwnaturecomdoifinder101038oby201266

                                    00

                                    -05

                                    -10

                                    -150 12 24 36 52

                                    Cha

                                    nge

                                    from

                                    bas

                                    elin

                                    e (

                                    )

                                    A1c

                                    Study week

                                    0

                                    -10

                                    -20

                                    -30

                                    -400 12 24 52

                                    Cha

                                    nge

                                    from

                                    bas

                                    elin

                                    e m

                                    gdl

                                    )

                                    Fasting plasma glucose

                                    Study week

                                    Lorcaserin 10 mg BID Lorcaserin 10 mg Placebo

                                    Lorcaserin Adverse Events Reported by 5 or More in Any Group in Year 1

                                    55

                                    N () Lorcaserin(N = 1593)

                                    Placebo(N = 1584)

                                    Headache 287 (180) 175 (110)

                                    Dizziness 130 (82) 60 (38)

                                    Nausea 119 (75) 85 (54)

                                    Constipation 106 (67) 64 (40)

                                    Fatigue 95 (60) 48 (30)

                                    Dry mouth 83 (52) 37 (23)

                                    Smith SR et al ADA 2009 Late‐Breaking Abstract 96

                                    LorcaserinNo Increase in Rate of Valvulopathy

                                    Smith SR et al N Engl J Med 2010363245-256

                                    10

                                    8

                                    6

                                    4

                                    2

                                    024 52 76 104

                                    1351714

                                    9

                                    19

                                    3421Patie

                                    nts

                                    ()

                                    Week

                                    Lorcaserin in yr 1 and 2

                                    Lorcaserin in yr 1 Placebo in yr 2

                                    Placebo in yr 1 and 2

                                    Phase III Study Outcomes Compared

                                    Buproprion SR (360 mgd) Naltrexone SR (32 mgd)

                                    Lorcaserin(20 mgd)

                                    Phentermine Topiramate CR

                                    COR1 COR-I2 COR-II3 NB3043 BLOOM4 BLOSSOM5 EQUIP CONQUER

                                    Number of patients (ITT-LOCF)

                                    793 obese 1453 obese

                                    1281 obese

                                    502 type II diabetes

                                    3182 obese 4008 obese

                                    1230 obese BMI 44

                                    2448 comorbidBMI 36

                                    Mean change compared with placebo from base

                                    93 vs5 1c

                                    61a vs13c

                                    64a vs12

                                    50 a vs12c

                                    58 vs22c

                                    48 vs28c

                                    11 Fullbvs 16

                                    104 Fullb 84 Midb

                                    vs 18

                                    51 Lowb vs16c

                                    Categorical change 5 compared with placebo from base

                                    56 vs43

                                    48a vs164

                                    563a

                                    vs 171445a vs189

                                    475b

                                    vs 203472b vs25

                                    67 Fullb 45 Lowb vs17

                                    70 Fullb 62 Midb

                                    vs 21

                                    Phenterminetopiramate doses Low 375 mg phentermine23 mg topiramate Mid 75 mg phentermine 46 mg topiramate Full 15 mg phentermine 92 mg topiramateITT-LOCF intent-to-treat last observation carried forwardData not available aP lt 001 vs placebo bP lt 0001 vs placebo

                                    Obesity Treatments in Late Development

                                    Kushner RF Expert Opin Pharmacother 200891339-1350

                                    Agents ActionBupropionNaltrexone

                                    bull Dopaminenoradrenaline reuptake inhibitorbull Opioid receptor antagonist

                                    Liraglutide bull GLP-1 agonist

                                    BupropionNaltrexone

                                    bull Mechanism of Actionndash Bupropion - Dopaminenoradrenaline reuptake inhibitorndash Naltrexone- Opioid receptor antagonist

                                    bull Was approved by FDA committee but FDA did not approve until a CV outcome study is performed 2nd concerns about BP and P in some patients

                                    bull The Light Study is now underway and reported to be enrolling well under PI Dr Nissen

                                    bull BupropionNaltrexone will have first completed CV outcome study

                                    Buproprion ndash Naltrexone

                                    Greenway FL et al Lancet 2010376(9741)595-605

                                    0

                                    -2

                                    -4

                                    -6

                                    -8

                                    -100 4 8 12 16 20 24 28 32 36 40 44 48 52 56

                                    Weeks

                                    Wei

                                    ght c

                                    hang

                                    e fro

                                    m b

                                    asel

                                    ine

                                    ()

                                    Placebo

                                    Naltrexone 16 mg plus bupropion

                                    Naltrexone 32 mg plus bupropion

                                    Liraglutide for Weight Loss in Patients with Type 2 Diabetes

                                    bull GLP-1 analog approved for treatment of type 2 diabetes

                                    bull Anorectic effect mediated both by the activation of GLP-1 receptor expressed on vagal afferents and by the GLP-1R activation in CNS

                                    bull Affects visceral fat adiposity appetite food preference and cardiovascular biomarkers in patients with type 2 diabetes

                                    Inoue K et al Cardiovasc Diabetol 2011 10109 doi1011861475-2840-10-109

                                    Liraglutide Weight Loss Over 2 Years ITT Observed Means

                                    Astrup A et al Int J Obes (Lond) 201236(6)843-54

                                    FromScreening

                                    -94 kg

                                    -67 kg-88 kg

                                    -99 kg-94 kg

                                    -103 kg

                                    ITT intention to treat

                                    Phase III Study Outcomes Compared

                                    Buproprion SR (360 mgd) Naltrexone SR (32 mgd)

                                    Lorcaserin(20 mgd)

                                    Phentermine Topiramate CR

                                    COR1 COR-I2 COR-II3 NB3043 BLOOM4 BLOSSOM5 EQUIP CONQUER

                                    Number of patients (ITT-LOCF)

                                    793 obese 1453 obese

                                    1281 obese

                                    502 type II diabetes

                                    3182 obese 4008 obese

                                    1230 obese BMI 44

                                    2448 comorbidBMI 36

                                    Mean change compared with placebo from base

                                    93 vs5 1c

                                    61a vs13c

                                    64a vs12

                                    50 a vs12c

                                    58 vs22c

                                    48 vs28c

                                    11 Fullbvs 16

                                    104 Fullb 84 Midb

                                    vs 18

                                    51 Lowb vs16c

                                    Categorical change 5 compared with placebo from base

                                    56 vs43

                                    48a vs164

                                    563a

                                    vs 171445a vs189

                                    475b

                                    vs 203472b vs25

                                    67 Fullb 45 Lowb vs17

                                    70 Fullb 62 Midb

                                    vs 21

                                    Phenterminetopiramate doses Low 375 mg phentermine23 mg topiramate Mid 75 mg phentermine 46 mg topiramate Full 15 mg phentermine 92 mg topiramateITT-LOCF intent-to-treat last observation carried forwardData not available aP lt 001 vs placebo bP lt 0001 vs placebo

                                    Treatment Gap in theManagement of Obesity

                                    Physicians Need Effective Pharmacotherapies That Will Reduce Weight Significantly and Reduce Weight-related Comorbidities

                                    0 5 10 15 20 25 30 35

                                    Diet and Lifestyle Lap Band Gastric Bypass

                                    TreatmentGap

                                    What will fill the gap

                                    Too risky for many peopleNot effective enoughfor many people

                                    Treatment Gap in theManagement of Obesity

                                    0 5 10 15 20 25 30 35

                                    Diet and Lifestyle Lap Band Gastric Bypass

                                    TreatmentGap

                                    Too risky for many peopleNot effective enoughfor many people Pharmacotherapy

                                    Less invasive procedures

                                    Physicians Need Effective Pharmacotherapies That Will Reduce Weight Significantly and Reduce Weight-related Comorbidities

                                    What will fill the gap

                                    • Slide Number 1
                                    • Slide Number 2
                                    • Weight Management is Moving into the Workplace and Mainstream of Healthcare
                                    • US Preventative Services Task Force
                                    • A Proposal from CMS about Coverage for Intensive Behavioral Therapy for Obesity
                                    • Slide Number 6
                                    • Biggest Increases in Clinically Severe Obesity US 1987-2005
                                    • Relationship Between BMI and Risk of Type 2 Diabetes
                                    • Slide Number 9
                                    • Medical Complications of Obesity Almost every organ system is affected
                                    • Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and disease
                                    • Current Therapies Often Address Individual Risk Factors Cardiometabolic risk
                                    • Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and disease
                                    • Are You Treating These Drivers of Cardiometabolic Risk Should You Treat The Underlying Cause
                                    • Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors
                                    • In My Opinion The Winds of Change are Blowing in the Treatment of Chronic Diseases
                                    • Bariatric Surgery Reduces Overall Mortality Diabetes Mortality by 88
                                    • Health Care Costs Attributable to ObesityEstimates of what various conditions add to health-care service costs over a 12-month period
                                    • What-if scenarios (The Lancet forthcoming)
                                    • How Much Weight Loss Is Needed to Prevent T2DMndashNot Very Much The DPP Experience
                                    • In the Da Qing Study 6-year Intervention Led to Lower Incidence of Type 2 Diabetes 14 Years Later
                                    • Slide Number 22
                                    • Slide Number 23
                                    • New Compounds andCombination Interventions
                                    • Phentermine and Topiramate Extended-Release
                                    • Phentermine and Topiramate Extended-Release
                                    • EQUIP amp CONQUER Discontinuation RateDue to AEs in All Doses Studied
                                    • Phentermine and Topiramate SEQUELWeight Loss Over Time
                                    • CONQUER Significant Improvement in Cardiovascular Risk Factors
                                    • Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors
                                    • Lorcaserin
                                    • BLOOM Study Body Weight Over Years 1 and 2
                                    • BLOOM StudyKey Secondary Endpoints
                                    • BLOOM-DMChange in Glycemic Parameters
                                    • Lorcaserin Adverse Events Reported by 5 or More in Any Group in Year 1
                                    • LorcaserinNo Increase in Rate of Valvulopathy
                                    • Phase III Study Outcomes Compared
                                    • Obesity Treatments in Late Development
                                    • BupropionNaltrexone
                                    • Buproprion ndash Naltrexone
                                    • Liraglutide for Weight Loss in Patients with Type 2 Diabetes
                                    • Liraglutide Weight Loss Over 2 Years ITT Observed Means
                                    • Phase III Study Outcomes Compared
                                    • Treatment Gap in theManagement of Obesity
                                    • Treatment Gap in theManagement of Obesity

                                      Redrawn from Hamman RF et al Diabetes Care 2006292102‐2107

                                      Change in Weight from Baseline (kg)0‐10 ‐5 +5In

                                      cide

                                      nce Ra

                                      te per 100

                                      Person‐Years

                                      10

                                      20

                                      15

                                      5

                                      0

                                      How Much Weight Loss Is Needed to Prevent T2DMndashNot Very Much The DPP Experience

                                      In the Da Qing Study 6-year Intervention Led to Lower Incidence of Type 2 Diabetes 14 Years Later

                                      n=530 overweight Chinese men and women with IGT mean BMI=26

                                      17

                                      0

                                      20

                                      40

                                      60

                                      80

                                      100

                                      2 4 6 8 10 12 14 16 18 20Years of follow‐up

                                      6‐year intervention hazard ratio = 049 (95 CI 033ndash073)20‐year follow‐up hazard ratio = 057 (95 CI 041ndash081)

                                      Cumulative Incide

                                      nce of Type 2 Diabe

                                      tes ()

                                      0

                                      Lifestyle interventionControl

                                      Treatment Follow‐up

                                      Li et al Lancet 20083711783ndash9

                                      Pharmacotherapy for Weight LossLouis J Aronne MD FACP

                                      Professor of Clinical Medicine Weill Cornell Medical College

                                      Adjunct Associate Professor of Clinical Medicine Columbia University College of Physicians and Surgeons

                                      Director Comprehensive Weight Control Program

                                      New York-Presbyterian HospitalWeill Cornell Medical Center New York NY

                                      As faculty of Weill Cornell Medical College we are committed to providing transparency for any and all external relationships prior to giving an academic presentation

                                      I am a consultant speaker advisor or receive research support fromBMS

                                      Arena Aspire BariatricsMyos

                                      GI Dynamics Novo NordiskOrexigenVivusZafgen

                                      I may discuss off-label use of medications

                                      Disclosure Page

                                      uarrFood intakedarr energy expenditure

                                      darrfood intake uarrenergy expenditure

                                      Topiramate

                                      Naltrexone

                                      LorcaserinPramlintideGLP-1Leptin

                                      BupropionPhentermine

                                      New Compounds andCombination Interventions

                                      c Louis J Aronne MDScience Feb 7 2003 Vol 299Illustration by Katharine Sutliff

                                      Phentermine and TopiramateExtended-Release

                                      bull Mechanism of actionndash Phentermine Sympathomimetic amine - releaserndash Topiramate Gabaergicglutamate modulation and carbonic

                                      anhydrase inhibitionbull February 2012 FDA advisory committee votes 20-2 for

                                      approval bull FDA approved July 2012

                                      ndash Schedule IVndash Pregnancy Category X = REMS

                                      Topiramate monotherapy exposure in pregnancy associated with 2- to 5-fold increased prevalence of oral clefts

                                      bull 4 doses Titrate upbull Available only by mail orderbull Covered through Medco Express Scripts

                                      Phentermine and TopiramateExtended-Release

                                      bull Dose titrationndash Once dailyndash Start treatment with phentermine 375 mgtopiramate

                                      23 mg extended-release daily for 14 daysndash After 14 days increase to the recommended dose of

                                      phentermine 75 mgtopiramate 46 mg extended-release once daily

                                      ndash May titrate upwards if needed to phen 15 top 92 mg strength

                                      EQUIP amp CONQUER Discontinuation RateDue to AEs in All Doses Studied

                                      Placebo Low Mid Full

                                      Number of patients 1508 241 498 1507Discontinuation due to AEs 9 12 12 18Blurred vision 05 21 08 07Headache 07 17 02 09Insomnia 04 00 04 17Depression 02 00 08 14Tingling 00 04 10 12Irritability 01 08 08 12Anxiety 03 00 02 11Dizziness 02 04 12 08

                                      Includes adverse events (AEs) by dose for EQUIP amp CONQUER which lead to discontinuation in gt 1 of patientsPress release Sept 9 2009 Available at httpirvivuscomreleasedetailcfmReleaseID=420114Accessed April 27 2010

                                      PhenTPMMid

                                      -104

                                      Phentermine and Topiramate SEQUELWeight Loss Over Time

                                      Garvey WT Ryan DH Look M Gadde KM Am J Clin Nutr 201295(2)297-308

                                      Placebo-25

                                      Plt00001 v placebo

                                      Weight Loss

                                      Week

                                      Total Population

                                      0

                                      -2

                                      -4

                                      -6

                                      -8

                                      -10

                                      -12

                                      -14

                                      -16

                                      0 12 24 36 48 60 72 84 96 108

                                      Weight Loss ITT-LOCF

                                      PhenTPMTop

                                      -114

                                      Mid = 75 mg46 mgTop = 15 mg92 mg

                                      CONQUER Significant Improvement in Cardiovascular Risk Factors

                                      (LS Mean Wt Loss)

                                      QNEXAMid(78)

                                      P valueQNEXATop

                                      (98) P value

                                      Waist Circumference (cm) ‐52 lt00001 ‐68 lt00001

                                      Systolic BP (mmHg) ‐23 00008 ‐32 lt00001

                                      Diastolic BP (mmHg) ‐07 NS ‐11 00031

                                      Triglycerides ( ∆) ‐133 lt00001 ‐153 lt00001

                                      Total Cholesterol ( ∆) ‐16 00345 ‐30 lt00001

                                      LDL ( ∆) 04 NS ‐28 00069

                                      HDL ( ∆) 40 lt00001 56 lt00001

                                      P values represent comparisons to placebo NS= non‐significant

                                      ITT‐LOCF Placebo ComparisonsTotal Study Population

                                      Davidson MH et al Am J Cardiol 2013 Jan 29 pii S0002‐9149(12)02641‐0 doi 101016jamjcard201212038

                                      Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors

                                      Risk FactorsPhenTPMMid

                                      p-valuePhenTPMTop

                                      p-value

                                      CRP lt0001 lt0001Fibrinogen lt005 lt005Adiponectin lt00001 lt00001

                                      p-values represent comparisons to placebo

                                      ITT-LOCF Placebo Comparisons

                                      Gadde KM et al Lancet 2011377(9774)1341-52

                                      Mid = 75 mg46 mgTop = 15 mg92 mg

                                      Lorcaserin

                                      bull Selective 5‐HT2C receptor agonist designed to promote weight loss

                                      bull Schedule IV ndash Expected soonbull Indication weight loss and maintenance of

                                      weight loss in patients with BMI gt30 kgm2 or BMI gt27 kgm2 + weight-related comorbidcondition(s)

                                      bull Dose - 10 mg BIDbull Most common side effects headache nausea

                                      dizziness dry mouth

                                      BLOOM Study Body Weight Over Years 1 and 2

                                      Smith SR et al N Engl J Med 2010363245-256 Study Week0 8 16 24 32 40 48 56 64 72 80 88 96 104

                                      Bod

                                      y W

                                      eigh

                                      t (kg

                                      )

                                      102

                                      100

                                      98

                                      96

                                      94

                                      92

                                      90

                                      0

                                      Year 1

                                      Placebo in year 1 and 2 (n = 684)Lorcaserin in year 1 placebo in year 2 (n = 275)Lorcaserin in year 1 and 2 (n = 564)

                                      Year 2

                                      Endpoint Lorcaserin Placebo P valueWaist circumference (cm) minus68plusmn02 minus39plusmn02 lt001BMI (kgm2) minus209plusmn006 minus078plusmn005 lt001SBPDBP (mm Hg) minus14plusmn03minus11plusmn02 minus08plusmn03minus06plusmn02 0401Cholesterol ( ∆)Total LDLHDL

                                      minus090plusmn033287plusmn056005plusmn033

                                      057plusmn034403plusmn058minus021plusmn034

                                      001

                                      049

                                      72Triglycerides minus615plusmn103 minus014plusmn099 lt001SafetyHR (beatsmin)PASP (mm Hg)Beck depression II score

                                      minus20plusmn03minus092plusmn023minus11plusmn01

                                      minus16plusmn04 minus023plusmn023 minus09plusmn01

                                      0499014026

                                      BLOOM StudyKey Secondary Endpoints

                                      Smith SR et al N Engl J Med 2010363245-256

                                      BLOOM-DMChange in Glycemic Parameters

                                      P lt001 P lt05 LS mean change plusmn SEMOrsquoNeil PM et al Obesity 201220(7)1426-36 httpwwwnaturecomdoifinder101038oby201266

                                      00

                                      -05

                                      -10

                                      -150 12 24 36 52

                                      Cha

                                      nge

                                      from

                                      bas

                                      elin

                                      e (

                                      )

                                      A1c

                                      Study week

                                      0

                                      -10

                                      -20

                                      -30

                                      -400 12 24 52

                                      Cha

                                      nge

                                      from

                                      bas

                                      elin

                                      e m

                                      gdl

                                      )

                                      Fasting plasma glucose

                                      Study week

                                      Lorcaserin 10 mg BID Lorcaserin 10 mg Placebo

                                      Lorcaserin Adverse Events Reported by 5 or More in Any Group in Year 1

                                      55

                                      N () Lorcaserin(N = 1593)

                                      Placebo(N = 1584)

                                      Headache 287 (180) 175 (110)

                                      Dizziness 130 (82) 60 (38)

                                      Nausea 119 (75) 85 (54)

                                      Constipation 106 (67) 64 (40)

                                      Fatigue 95 (60) 48 (30)

                                      Dry mouth 83 (52) 37 (23)

                                      Smith SR et al ADA 2009 Late‐Breaking Abstract 96

                                      LorcaserinNo Increase in Rate of Valvulopathy

                                      Smith SR et al N Engl J Med 2010363245-256

                                      10

                                      8

                                      6

                                      4

                                      2

                                      024 52 76 104

                                      1351714

                                      9

                                      19

                                      3421Patie

                                      nts

                                      ()

                                      Week

                                      Lorcaserin in yr 1 and 2

                                      Lorcaserin in yr 1 Placebo in yr 2

                                      Placebo in yr 1 and 2

                                      Phase III Study Outcomes Compared

                                      Buproprion SR (360 mgd) Naltrexone SR (32 mgd)

                                      Lorcaserin(20 mgd)

                                      Phentermine Topiramate CR

                                      COR1 COR-I2 COR-II3 NB3043 BLOOM4 BLOSSOM5 EQUIP CONQUER

                                      Number of patients (ITT-LOCF)

                                      793 obese 1453 obese

                                      1281 obese

                                      502 type II diabetes

                                      3182 obese 4008 obese

                                      1230 obese BMI 44

                                      2448 comorbidBMI 36

                                      Mean change compared with placebo from base

                                      93 vs5 1c

                                      61a vs13c

                                      64a vs12

                                      50 a vs12c

                                      58 vs22c

                                      48 vs28c

                                      11 Fullbvs 16

                                      104 Fullb 84 Midb

                                      vs 18

                                      51 Lowb vs16c

                                      Categorical change 5 compared with placebo from base

                                      56 vs43

                                      48a vs164

                                      563a

                                      vs 171445a vs189

                                      475b

                                      vs 203472b vs25

                                      67 Fullb 45 Lowb vs17

                                      70 Fullb 62 Midb

                                      vs 21

                                      Phenterminetopiramate doses Low 375 mg phentermine23 mg topiramate Mid 75 mg phentermine 46 mg topiramate Full 15 mg phentermine 92 mg topiramateITT-LOCF intent-to-treat last observation carried forwardData not available aP lt 001 vs placebo bP lt 0001 vs placebo

                                      Obesity Treatments in Late Development

                                      Kushner RF Expert Opin Pharmacother 200891339-1350

                                      Agents ActionBupropionNaltrexone

                                      bull Dopaminenoradrenaline reuptake inhibitorbull Opioid receptor antagonist

                                      Liraglutide bull GLP-1 agonist

                                      BupropionNaltrexone

                                      bull Mechanism of Actionndash Bupropion - Dopaminenoradrenaline reuptake inhibitorndash Naltrexone- Opioid receptor antagonist

                                      bull Was approved by FDA committee but FDA did not approve until a CV outcome study is performed 2nd concerns about BP and P in some patients

                                      bull The Light Study is now underway and reported to be enrolling well under PI Dr Nissen

                                      bull BupropionNaltrexone will have first completed CV outcome study

                                      Buproprion ndash Naltrexone

                                      Greenway FL et al Lancet 2010376(9741)595-605

                                      0

                                      -2

                                      -4

                                      -6

                                      -8

                                      -100 4 8 12 16 20 24 28 32 36 40 44 48 52 56

                                      Weeks

                                      Wei

                                      ght c

                                      hang

                                      e fro

                                      m b

                                      asel

                                      ine

                                      ()

                                      Placebo

                                      Naltrexone 16 mg plus bupropion

                                      Naltrexone 32 mg plus bupropion

                                      Liraglutide for Weight Loss in Patients with Type 2 Diabetes

                                      bull GLP-1 analog approved for treatment of type 2 diabetes

                                      bull Anorectic effect mediated both by the activation of GLP-1 receptor expressed on vagal afferents and by the GLP-1R activation in CNS

                                      bull Affects visceral fat adiposity appetite food preference and cardiovascular biomarkers in patients with type 2 diabetes

                                      Inoue K et al Cardiovasc Diabetol 2011 10109 doi1011861475-2840-10-109

                                      Liraglutide Weight Loss Over 2 Years ITT Observed Means

                                      Astrup A et al Int J Obes (Lond) 201236(6)843-54

                                      FromScreening

                                      -94 kg

                                      -67 kg-88 kg

                                      -99 kg-94 kg

                                      -103 kg

                                      ITT intention to treat

                                      Phase III Study Outcomes Compared

                                      Buproprion SR (360 mgd) Naltrexone SR (32 mgd)

                                      Lorcaserin(20 mgd)

                                      Phentermine Topiramate CR

                                      COR1 COR-I2 COR-II3 NB3043 BLOOM4 BLOSSOM5 EQUIP CONQUER

                                      Number of patients (ITT-LOCF)

                                      793 obese 1453 obese

                                      1281 obese

                                      502 type II diabetes

                                      3182 obese 4008 obese

                                      1230 obese BMI 44

                                      2448 comorbidBMI 36

                                      Mean change compared with placebo from base

                                      93 vs5 1c

                                      61a vs13c

                                      64a vs12

                                      50 a vs12c

                                      58 vs22c

                                      48 vs28c

                                      11 Fullbvs 16

                                      104 Fullb 84 Midb

                                      vs 18

                                      51 Lowb vs16c

                                      Categorical change 5 compared with placebo from base

                                      56 vs43

                                      48a vs164

                                      563a

                                      vs 171445a vs189

                                      475b

                                      vs 203472b vs25

                                      67 Fullb 45 Lowb vs17

                                      70 Fullb 62 Midb

                                      vs 21

                                      Phenterminetopiramate doses Low 375 mg phentermine23 mg topiramate Mid 75 mg phentermine 46 mg topiramate Full 15 mg phentermine 92 mg topiramateITT-LOCF intent-to-treat last observation carried forwardData not available aP lt 001 vs placebo bP lt 0001 vs placebo

                                      Treatment Gap in theManagement of Obesity

                                      Physicians Need Effective Pharmacotherapies That Will Reduce Weight Significantly and Reduce Weight-related Comorbidities

                                      0 5 10 15 20 25 30 35

                                      Diet and Lifestyle Lap Band Gastric Bypass

                                      TreatmentGap

                                      What will fill the gap

                                      Too risky for many peopleNot effective enoughfor many people

                                      Treatment Gap in theManagement of Obesity

                                      0 5 10 15 20 25 30 35

                                      Diet and Lifestyle Lap Band Gastric Bypass

                                      TreatmentGap

                                      Too risky for many peopleNot effective enoughfor many people Pharmacotherapy

                                      Less invasive procedures

                                      Physicians Need Effective Pharmacotherapies That Will Reduce Weight Significantly and Reduce Weight-related Comorbidities

                                      What will fill the gap

                                      • Slide Number 1
                                      • Slide Number 2
                                      • Weight Management is Moving into the Workplace and Mainstream of Healthcare
                                      • US Preventative Services Task Force
                                      • A Proposal from CMS about Coverage for Intensive Behavioral Therapy for Obesity
                                      • Slide Number 6
                                      • Biggest Increases in Clinically Severe Obesity US 1987-2005
                                      • Relationship Between BMI and Risk of Type 2 Diabetes
                                      • Slide Number 9
                                      • Medical Complications of Obesity Almost every organ system is affected
                                      • Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and disease
                                      • Current Therapies Often Address Individual Risk Factors Cardiometabolic risk
                                      • Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and disease
                                      • Are You Treating These Drivers of Cardiometabolic Risk Should You Treat The Underlying Cause
                                      • Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors
                                      • In My Opinion The Winds of Change are Blowing in the Treatment of Chronic Diseases
                                      • Bariatric Surgery Reduces Overall Mortality Diabetes Mortality by 88
                                      • Health Care Costs Attributable to ObesityEstimates of what various conditions add to health-care service costs over a 12-month period
                                      • What-if scenarios (The Lancet forthcoming)
                                      • How Much Weight Loss Is Needed to Prevent T2DMndashNot Very Much The DPP Experience
                                      • In the Da Qing Study 6-year Intervention Led to Lower Incidence of Type 2 Diabetes 14 Years Later
                                      • Slide Number 22
                                      • Slide Number 23
                                      • New Compounds andCombination Interventions
                                      • Phentermine and Topiramate Extended-Release
                                      • Phentermine and Topiramate Extended-Release
                                      • EQUIP amp CONQUER Discontinuation RateDue to AEs in All Doses Studied
                                      • Phentermine and Topiramate SEQUELWeight Loss Over Time
                                      • CONQUER Significant Improvement in Cardiovascular Risk Factors
                                      • Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors
                                      • Lorcaserin
                                      • BLOOM Study Body Weight Over Years 1 and 2
                                      • BLOOM StudyKey Secondary Endpoints
                                      • BLOOM-DMChange in Glycemic Parameters
                                      • Lorcaserin Adverse Events Reported by 5 or More in Any Group in Year 1
                                      • LorcaserinNo Increase in Rate of Valvulopathy
                                      • Phase III Study Outcomes Compared
                                      • Obesity Treatments in Late Development
                                      • BupropionNaltrexone
                                      • Buproprion ndash Naltrexone
                                      • Liraglutide for Weight Loss in Patients with Type 2 Diabetes
                                      • Liraglutide Weight Loss Over 2 Years ITT Observed Means
                                      • Phase III Study Outcomes Compared
                                      • Treatment Gap in theManagement of Obesity
                                      • Treatment Gap in theManagement of Obesity

                                        In the Da Qing Study 6-year Intervention Led to Lower Incidence of Type 2 Diabetes 14 Years Later

                                        n=530 overweight Chinese men and women with IGT mean BMI=26

                                        17

                                        0

                                        20

                                        40

                                        60

                                        80

                                        100

                                        2 4 6 8 10 12 14 16 18 20Years of follow‐up

                                        6‐year intervention hazard ratio = 049 (95 CI 033ndash073)20‐year follow‐up hazard ratio = 057 (95 CI 041ndash081)

                                        Cumulative Incide

                                        nce of Type 2 Diabe

                                        tes ()

                                        0

                                        Lifestyle interventionControl

                                        Treatment Follow‐up

                                        Li et al Lancet 20083711783ndash9

                                        Pharmacotherapy for Weight LossLouis J Aronne MD FACP

                                        Professor of Clinical Medicine Weill Cornell Medical College

                                        Adjunct Associate Professor of Clinical Medicine Columbia University College of Physicians and Surgeons

                                        Director Comprehensive Weight Control Program

                                        New York-Presbyterian HospitalWeill Cornell Medical Center New York NY

                                        As faculty of Weill Cornell Medical College we are committed to providing transparency for any and all external relationships prior to giving an academic presentation

                                        I am a consultant speaker advisor or receive research support fromBMS

                                        Arena Aspire BariatricsMyos

                                        GI Dynamics Novo NordiskOrexigenVivusZafgen

                                        I may discuss off-label use of medications

                                        Disclosure Page

                                        uarrFood intakedarr energy expenditure

                                        darrfood intake uarrenergy expenditure

                                        Topiramate

                                        Naltrexone

                                        LorcaserinPramlintideGLP-1Leptin

                                        BupropionPhentermine

                                        New Compounds andCombination Interventions

                                        c Louis J Aronne MDScience Feb 7 2003 Vol 299Illustration by Katharine Sutliff

                                        Phentermine and TopiramateExtended-Release

                                        bull Mechanism of actionndash Phentermine Sympathomimetic amine - releaserndash Topiramate Gabaergicglutamate modulation and carbonic

                                        anhydrase inhibitionbull February 2012 FDA advisory committee votes 20-2 for

                                        approval bull FDA approved July 2012

                                        ndash Schedule IVndash Pregnancy Category X = REMS

                                        Topiramate monotherapy exposure in pregnancy associated with 2- to 5-fold increased prevalence of oral clefts

                                        bull 4 doses Titrate upbull Available only by mail orderbull Covered through Medco Express Scripts

                                        Phentermine and TopiramateExtended-Release

                                        bull Dose titrationndash Once dailyndash Start treatment with phentermine 375 mgtopiramate

                                        23 mg extended-release daily for 14 daysndash After 14 days increase to the recommended dose of

                                        phentermine 75 mgtopiramate 46 mg extended-release once daily

                                        ndash May titrate upwards if needed to phen 15 top 92 mg strength

                                        EQUIP amp CONQUER Discontinuation RateDue to AEs in All Doses Studied

                                        Placebo Low Mid Full

                                        Number of patients 1508 241 498 1507Discontinuation due to AEs 9 12 12 18Blurred vision 05 21 08 07Headache 07 17 02 09Insomnia 04 00 04 17Depression 02 00 08 14Tingling 00 04 10 12Irritability 01 08 08 12Anxiety 03 00 02 11Dizziness 02 04 12 08

                                        Includes adverse events (AEs) by dose for EQUIP amp CONQUER which lead to discontinuation in gt 1 of patientsPress release Sept 9 2009 Available at httpirvivuscomreleasedetailcfmReleaseID=420114Accessed April 27 2010

                                        PhenTPMMid

                                        -104

                                        Phentermine and Topiramate SEQUELWeight Loss Over Time

                                        Garvey WT Ryan DH Look M Gadde KM Am J Clin Nutr 201295(2)297-308

                                        Placebo-25

                                        Plt00001 v placebo

                                        Weight Loss

                                        Week

                                        Total Population

                                        0

                                        -2

                                        -4

                                        -6

                                        -8

                                        -10

                                        -12

                                        -14

                                        -16

                                        0 12 24 36 48 60 72 84 96 108

                                        Weight Loss ITT-LOCF

                                        PhenTPMTop

                                        -114

                                        Mid = 75 mg46 mgTop = 15 mg92 mg

                                        CONQUER Significant Improvement in Cardiovascular Risk Factors

                                        (LS Mean Wt Loss)

                                        QNEXAMid(78)

                                        P valueQNEXATop

                                        (98) P value

                                        Waist Circumference (cm) ‐52 lt00001 ‐68 lt00001

                                        Systolic BP (mmHg) ‐23 00008 ‐32 lt00001

                                        Diastolic BP (mmHg) ‐07 NS ‐11 00031

                                        Triglycerides ( ∆) ‐133 lt00001 ‐153 lt00001

                                        Total Cholesterol ( ∆) ‐16 00345 ‐30 lt00001

                                        LDL ( ∆) 04 NS ‐28 00069

                                        HDL ( ∆) 40 lt00001 56 lt00001

                                        P values represent comparisons to placebo NS= non‐significant

                                        ITT‐LOCF Placebo ComparisonsTotal Study Population

                                        Davidson MH et al Am J Cardiol 2013 Jan 29 pii S0002‐9149(12)02641‐0 doi 101016jamjcard201212038

                                        Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors

                                        Risk FactorsPhenTPMMid

                                        p-valuePhenTPMTop

                                        p-value

                                        CRP lt0001 lt0001Fibrinogen lt005 lt005Adiponectin lt00001 lt00001

                                        p-values represent comparisons to placebo

                                        ITT-LOCF Placebo Comparisons

                                        Gadde KM et al Lancet 2011377(9774)1341-52

                                        Mid = 75 mg46 mgTop = 15 mg92 mg

                                        Lorcaserin

                                        bull Selective 5‐HT2C receptor agonist designed to promote weight loss

                                        bull Schedule IV ndash Expected soonbull Indication weight loss and maintenance of

                                        weight loss in patients with BMI gt30 kgm2 or BMI gt27 kgm2 + weight-related comorbidcondition(s)

                                        bull Dose - 10 mg BIDbull Most common side effects headache nausea

                                        dizziness dry mouth

                                        BLOOM Study Body Weight Over Years 1 and 2

                                        Smith SR et al N Engl J Med 2010363245-256 Study Week0 8 16 24 32 40 48 56 64 72 80 88 96 104

                                        Bod

                                        y W

                                        eigh

                                        t (kg

                                        )

                                        102

                                        100

                                        98

                                        96

                                        94

                                        92

                                        90

                                        0

                                        Year 1

                                        Placebo in year 1 and 2 (n = 684)Lorcaserin in year 1 placebo in year 2 (n = 275)Lorcaserin in year 1 and 2 (n = 564)

                                        Year 2

                                        Endpoint Lorcaserin Placebo P valueWaist circumference (cm) minus68plusmn02 minus39plusmn02 lt001BMI (kgm2) minus209plusmn006 minus078plusmn005 lt001SBPDBP (mm Hg) minus14plusmn03minus11plusmn02 minus08plusmn03minus06plusmn02 0401Cholesterol ( ∆)Total LDLHDL

                                        minus090plusmn033287plusmn056005plusmn033

                                        057plusmn034403plusmn058minus021plusmn034

                                        001

                                        049

                                        72Triglycerides minus615plusmn103 minus014plusmn099 lt001SafetyHR (beatsmin)PASP (mm Hg)Beck depression II score

                                        minus20plusmn03minus092plusmn023minus11plusmn01

                                        minus16plusmn04 minus023plusmn023 minus09plusmn01

                                        0499014026

                                        BLOOM StudyKey Secondary Endpoints

                                        Smith SR et al N Engl J Med 2010363245-256

                                        BLOOM-DMChange in Glycemic Parameters

                                        P lt001 P lt05 LS mean change plusmn SEMOrsquoNeil PM et al Obesity 201220(7)1426-36 httpwwwnaturecomdoifinder101038oby201266

                                        00

                                        -05

                                        -10

                                        -150 12 24 36 52

                                        Cha

                                        nge

                                        from

                                        bas

                                        elin

                                        e (

                                        )

                                        A1c

                                        Study week

                                        0

                                        -10

                                        -20

                                        -30

                                        -400 12 24 52

                                        Cha

                                        nge

                                        from

                                        bas

                                        elin

                                        e m

                                        gdl

                                        )

                                        Fasting plasma glucose

                                        Study week

                                        Lorcaserin 10 mg BID Lorcaserin 10 mg Placebo

                                        Lorcaserin Adverse Events Reported by 5 or More in Any Group in Year 1

                                        55

                                        N () Lorcaserin(N = 1593)

                                        Placebo(N = 1584)

                                        Headache 287 (180) 175 (110)

                                        Dizziness 130 (82) 60 (38)

                                        Nausea 119 (75) 85 (54)

                                        Constipation 106 (67) 64 (40)

                                        Fatigue 95 (60) 48 (30)

                                        Dry mouth 83 (52) 37 (23)

                                        Smith SR et al ADA 2009 Late‐Breaking Abstract 96

                                        LorcaserinNo Increase in Rate of Valvulopathy

                                        Smith SR et al N Engl J Med 2010363245-256

                                        10

                                        8

                                        6

                                        4

                                        2

                                        024 52 76 104

                                        1351714

                                        9

                                        19

                                        3421Patie

                                        nts

                                        ()

                                        Week

                                        Lorcaserin in yr 1 and 2

                                        Lorcaserin in yr 1 Placebo in yr 2

                                        Placebo in yr 1 and 2

                                        Phase III Study Outcomes Compared

                                        Buproprion SR (360 mgd) Naltrexone SR (32 mgd)

                                        Lorcaserin(20 mgd)

                                        Phentermine Topiramate CR

                                        COR1 COR-I2 COR-II3 NB3043 BLOOM4 BLOSSOM5 EQUIP CONQUER

                                        Number of patients (ITT-LOCF)

                                        793 obese 1453 obese

                                        1281 obese

                                        502 type II diabetes

                                        3182 obese 4008 obese

                                        1230 obese BMI 44

                                        2448 comorbidBMI 36

                                        Mean change compared with placebo from base

                                        93 vs5 1c

                                        61a vs13c

                                        64a vs12

                                        50 a vs12c

                                        58 vs22c

                                        48 vs28c

                                        11 Fullbvs 16

                                        104 Fullb 84 Midb

                                        vs 18

                                        51 Lowb vs16c

                                        Categorical change 5 compared with placebo from base

                                        56 vs43

                                        48a vs164

                                        563a

                                        vs 171445a vs189

                                        475b

                                        vs 203472b vs25

                                        67 Fullb 45 Lowb vs17

                                        70 Fullb 62 Midb

                                        vs 21

                                        Phenterminetopiramate doses Low 375 mg phentermine23 mg topiramate Mid 75 mg phentermine 46 mg topiramate Full 15 mg phentermine 92 mg topiramateITT-LOCF intent-to-treat last observation carried forwardData not available aP lt 001 vs placebo bP lt 0001 vs placebo

                                        Obesity Treatments in Late Development

                                        Kushner RF Expert Opin Pharmacother 200891339-1350

                                        Agents ActionBupropionNaltrexone

                                        bull Dopaminenoradrenaline reuptake inhibitorbull Opioid receptor antagonist

                                        Liraglutide bull GLP-1 agonist

                                        BupropionNaltrexone

                                        bull Mechanism of Actionndash Bupropion - Dopaminenoradrenaline reuptake inhibitorndash Naltrexone- Opioid receptor antagonist

                                        bull Was approved by FDA committee but FDA did not approve until a CV outcome study is performed 2nd concerns about BP and P in some patients

                                        bull The Light Study is now underway and reported to be enrolling well under PI Dr Nissen

                                        bull BupropionNaltrexone will have first completed CV outcome study

                                        Buproprion ndash Naltrexone

                                        Greenway FL et al Lancet 2010376(9741)595-605

                                        0

                                        -2

                                        -4

                                        -6

                                        -8

                                        -100 4 8 12 16 20 24 28 32 36 40 44 48 52 56

                                        Weeks

                                        Wei

                                        ght c

                                        hang

                                        e fro

                                        m b

                                        asel

                                        ine

                                        ()

                                        Placebo

                                        Naltrexone 16 mg plus bupropion

                                        Naltrexone 32 mg plus bupropion

                                        Liraglutide for Weight Loss in Patients with Type 2 Diabetes

                                        bull GLP-1 analog approved for treatment of type 2 diabetes

                                        bull Anorectic effect mediated both by the activation of GLP-1 receptor expressed on vagal afferents and by the GLP-1R activation in CNS

                                        bull Affects visceral fat adiposity appetite food preference and cardiovascular biomarkers in patients with type 2 diabetes

                                        Inoue K et al Cardiovasc Diabetol 2011 10109 doi1011861475-2840-10-109

                                        Liraglutide Weight Loss Over 2 Years ITT Observed Means

                                        Astrup A et al Int J Obes (Lond) 201236(6)843-54

                                        FromScreening

                                        -94 kg

                                        -67 kg-88 kg

                                        -99 kg-94 kg

                                        -103 kg

                                        ITT intention to treat

                                        Phase III Study Outcomes Compared

                                        Buproprion SR (360 mgd) Naltrexone SR (32 mgd)

                                        Lorcaserin(20 mgd)

                                        Phentermine Topiramate CR

                                        COR1 COR-I2 COR-II3 NB3043 BLOOM4 BLOSSOM5 EQUIP CONQUER

                                        Number of patients (ITT-LOCF)

                                        793 obese 1453 obese

                                        1281 obese

                                        502 type II diabetes

                                        3182 obese 4008 obese

                                        1230 obese BMI 44

                                        2448 comorbidBMI 36

                                        Mean change compared with placebo from base

                                        93 vs5 1c

                                        61a vs13c

                                        64a vs12

                                        50 a vs12c

                                        58 vs22c

                                        48 vs28c

                                        11 Fullbvs 16

                                        104 Fullb 84 Midb

                                        vs 18

                                        51 Lowb vs16c

                                        Categorical change 5 compared with placebo from base

                                        56 vs43

                                        48a vs164

                                        563a

                                        vs 171445a vs189

                                        475b

                                        vs 203472b vs25

                                        67 Fullb 45 Lowb vs17

                                        70 Fullb 62 Midb

                                        vs 21

                                        Phenterminetopiramate doses Low 375 mg phentermine23 mg topiramate Mid 75 mg phentermine 46 mg topiramate Full 15 mg phentermine 92 mg topiramateITT-LOCF intent-to-treat last observation carried forwardData not available aP lt 001 vs placebo bP lt 0001 vs placebo

                                        Treatment Gap in theManagement of Obesity

                                        Physicians Need Effective Pharmacotherapies That Will Reduce Weight Significantly and Reduce Weight-related Comorbidities

                                        0 5 10 15 20 25 30 35

                                        Diet and Lifestyle Lap Band Gastric Bypass

                                        TreatmentGap

                                        What will fill the gap

                                        Too risky for many peopleNot effective enoughfor many people

                                        Treatment Gap in theManagement of Obesity

                                        0 5 10 15 20 25 30 35

                                        Diet and Lifestyle Lap Band Gastric Bypass

                                        TreatmentGap

                                        Too risky for many peopleNot effective enoughfor many people Pharmacotherapy

                                        Less invasive procedures

                                        Physicians Need Effective Pharmacotherapies That Will Reduce Weight Significantly and Reduce Weight-related Comorbidities

                                        What will fill the gap

                                        • Slide Number 1
                                        • Slide Number 2
                                        • Weight Management is Moving into the Workplace and Mainstream of Healthcare
                                        • US Preventative Services Task Force
                                        • A Proposal from CMS about Coverage for Intensive Behavioral Therapy for Obesity
                                        • Slide Number 6
                                        • Biggest Increases in Clinically Severe Obesity US 1987-2005
                                        • Relationship Between BMI and Risk of Type 2 Diabetes
                                        • Slide Number 9
                                        • Medical Complications of Obesity Almost every organ system is affected
                                        • Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and disease
                                        • Current Therapies Often Address Individual Risk Factors Cardiometabolic risk
                                        • Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and disease
                                        • Are You Treating These Drivers of Cardiometabolic Risk Should You Treat The Underlying Cause
                                        • Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors
                                        • In My Opinion The Winds of Change are Blowing in the Treatment of Chronic Diseases
                                        • Bariatric Surgery Reduces Overall Mortality Diabetes Mortality by 88
                                        • Health Care Costs Attributable to ObesityEstimates of what various conditions add to health-care service costs over a 12-month period
                                        • What-if scenarios (The Lancet forthcoming)
                                        • How Much Weight Loss Is Needed to Prevent T2DMndashNot Very Much The DPP Experience
                                        • In the Da Qing Study 6-year Intervention Led to Lower Incidence of Type 2 Diabetes 14 Years Later
                                        • Slide Number 22
                                        • Slide Number 23
                                        • New Compounds andCombination Interventions
                                        • Phentermine and Topiramate Extended-Release
                                        • Phentermine and Topiramate Extended-Release
                                        • EQUIP amp CONQUER Discontinuation RateDue to AEs in All Doses Studied
                                        • Phentermine and Topiramate SEQUELWeight Loss Over Time
                                        • CONQUER Significant Improvement in Cardiovascular Risk Factors
                                        • Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors
                                        • Lorcaserin
                                        • BLOOM Study Body Weight Over Years 1 and 2
                                        • BLOOM StudyKey Secondary Endpoints
                                        • BLOOM-DMChange in Glycemic Parameters
                                        • Lorcaserin Adverse Events Reported by 5 or More in Any Group in Year 1
                                        • LorcaserinNo Increase in Rate of Valvulopathy
                                        • Phase III Study Outcomes Compared
                                        • Obesity Treatments in Late Development
                                        • BupropionNaltrexone
                                        • Buproprion ndash Naltrexone
                                        • Liraglutide for Weight Loss in Patients with Type 2 Diabetes
                                        • Liraglutide Weight Loss Over 2 Years ITT Observed Means
                                        • Phase III Study Outcomes Compared
                                        • Treatment Gap in theManagement of Obesity
                                        • Treatment Gap in theManagement of Obesity

                                          Pharmacotherapy for Weight LossLouis J Aronne MD FACP

                                          Professor of Clinical Medicine Weill Cornell Medical College

                                          Adjunct Associate Professor of Clinical Medicine Columbia University College of Physicians and Surgeons

                                          Director Comprehensive Weight Control Program

                                          New York-Presbyterian HospitalWeill Cornell Medical Center New York NY

                                          As faculty of Weill Cornell Medical College we are committed to providing transparency for any and all external relationships prior to giving an academic presentation

                                          I am a consultant speaker advisor or receive research support fromBMS

                                          Arena Aspire BariatricsMyos

                                          GI Dynamics Novo NordiskOrexigenVivusZafgen

                                          I may discuss off-label use of medications

                                          Disclosure Page

                                          uarrFood intakedarr energy expenditure

                                          darrfood intake uarrenergy expenditure

                                          Topiramate

                                          Naltrexone

                                          LorcaserinPramlintideGLP-1Leptin

                                          BupropionPhentermine

                                          New Compounds andCombination Interventions

                                          c Louis J Aronne MDScience Feb 7 2003 Vol 299Illustration by Katharine Sutliff

                                          Phentermine and TopiramateExtended-Release

                                          bull Mechanism of actionndash Phentermine Sympathomimetic amine - releaserndash Topiramate Gabaergicglutamate modulation and carbonic

                                          anhydrase inhibitionbull February 2012 FDA advisory committee votes 20-2 for

                                          approval bull FDA approved July 2012

                                          ndash Schedule IVndash Pregnancy Category X = REMS

                                          Topiramate monotherapy exposure in pregnancy associated with 2- to 5-fold increased prevalence of oral clefts

                                          bull 4 doses Titrate upbull Available only by mail orderbull Covered through Medco Express Scripts

                                          Phentermine and TopiramateExtended-Release

                                          bull Dose titrationndash Once dailyndash Start treatment with phentermine 375 mgtopiramate

                                          23 mg extended-release daily for 14 daysndash After 14 days increase to the recommended dose of

                                          phentermine 75 mgtopiramate 46 mg extended-release once daily

                                          ndash May titrate upwards if needed to phen 15 top 92 mg strength

                                          EQUIP amp CONQUER Discontinuation RateDue to AEs in All Doses Studied

                                          Placebo Low Mid Full

                                          Number of patients 1508 241 498 1507Discontinuation due to AEs 9 12 12 18Blurred vision 05 21 08 07Headache 07 17 02 09Insomnia 04 00 04 17Depression 02 00 08 14Tingling 00 04 10 12Irritability 01 08 08 12Anxiety 03 00 02 11Dizziness 02 04 12 08

                                          Includes adverse events (AEs) by dose for EQUIP amp CONQUER which lead to discontinuation in gt 1 of patientsPress release Sept 9 2009 Available at httpirvivuscomreleasedetailcfmReleaseID=420114Accessed April 27 2010

                                          PhenTPMMid

                                          -104

                                          Phentermine and Topiramate SEQUELWeight Loss Over Time

                                          Garvey WT Ryan DH Look M Gadde KM Am J Clin Nutr 201295(2)297-308

                                          Placebo-25

                                          Plt00001 v placebo

                                          Weight Loss

                                          Week

                                          Total Population

                                          0

                                          -2

                                          -4

                                          -6

                                          -8

                                          -10

                                          -12

                                          -14

                                          -16

                                          0 12 24 36 48 60 72 84 96 108

                                          Weight Loss ITT-LOCF

                                          PhenTPMTop

                                          -114

                                          Mid = 75 mg46 mgTop = 15 mg92 mg

                                          CONQUER Significant Improvement in Cardiovascular Risk Factors

                                          (LS Mean Wt Loss)

                                          QNEXAMid(78)

                                          P valueQNEXATop

                                          (98) P value

                                          Waist Circumference (cm) ‐52 lt00001 ‐68 lt00001

                                          Systolic BP (mmHg) ‐23 00008 ‐32 lt00001

                                          Diastolic BP (mmHg) ‐07 NS ‐11 00031

                                          Triglycerides ( ∆) ‐133 lt00001 ‐153 lt00001

                                          Total Cholesterol ( ∆) ‐16 00345 ‐30 lt00001

                                          LDL ( ∆) 04 NS ‐28 00069

                                          HDL ( ∆) 40 lt00001 56 lt00001

                                          P values represent comparisons to placebo NS= non‐significant

                                          ITT‐LOCF Placebo ComparisonsTotal Study Population

                                          Davidson MH et al Am J Cardiol 2013 Jan 29 pii S0002‐9149(12)02641‐0 doi 101016jamjcard201212038

                                          Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors

                                          Risk FactorsPhenTPMMid

                                          p-valuePhenTPMTop

                                          p-value

                                          CRP lt0001 lt0001Fibrinogen lt005 lt005Adiponectin lt00001 lt00001

                                          p-values represent comparisons to placebo

                                          ITT-LOCF Placebo Comparisons

                                          Gadde KM et al Lancet 2011377(9774)1341-52

                                          Mid = 75 mg46 mgTop = 15 mg92 mg

                                          Lorcaserin

                                          bull Selective 5‐HT2C receptor agonist designed to promote weight loss

                                          bull Schedule IV ndash Expected soonbull Indication weight loss and maintenance of

                                          weight loss in patients with BMI gt30 kgm2 or BMI gt27 kgm2 + weight-related comorbidcondition(s)

                                          bull Dose - 10 mg BIDbull Most common side effects headache nausea

                                          dizziness dry mouth

                                          BLOOM Study Body Weight Over Years 1 and 2

                                          Smith SR et al N Engl J Med 2010363245-256 Study Week0 8 16 24 32 40 48 56 64 72 80 88 96 104

                                          Bod

                                          y W

                                          eigh

                                          t (kg

                                          )

                                          102

                                          100

                                          98

                                          96

                                          94

                                          92

                                          90

                                          0

                                          Year 1

                                          Placebo in year 1 and 2 (n = 684)Lorcaserin in year 1 placebo in year 2 (n = 275)Lorcaserin in year 1 and 2 (n = 564)

                                          Year 2

                                          Endpoint Lorcaserin Placebo P valueWaist circumference (cm) minus68plusmn02 minus39plusmn02 lt001BMI (kgm2) minus209plusmn006 minus078plusmn005 lt001SBPDBP (mm Hg) minus14plusmn03minus11plusmn02 minus08plusmn03minus06plusmn02 0401Cholesterol ( ∆)Total LDLHDL

                                          minus090plusmn033287plusmn056005plusmn033

                                          057plusmn034403plusmn058minus021plusmn034

                                          001

                                          049

                                          72Triglycerides minus615plusmn103 minus014plusmn099 lt001SafetyHR (beatsmin)PASP (mm Hg)Beck depression II score

                                          minus20plusmn03minus092plusmn023minus11plusmn01

                                          minus16plusmn04 minus023plusmn023 minus09plusmn01

                                          0499014026

                                          BLOOM StudyKey Secondary Endpoints

                                          Smith SR et al N Engl J Med 2010363245-256

                                          BLOOM-DMChange in Glycemic Parameters

                                          P lt001 P lt05 LS mean change plusmn SEMOrsquoNeil PM et al Obesity 201220(7)1426-36 httpwwwnaturecomdoifinder101038oby201266

                                          00

                                          -05

                                          -10

                                          -150 12 24 36 52

                                          Cha

                                          nge

                                          from

                                          bas

                                          elin

                                          e (

                                          )

                                          A1c

                                          Study week

                                          0

                                          -10

                                          -20

                                          -30

                                          -400 12 24 52

                                          Cha

                                          nge

                                          from

                                          bas

                                          elin

                                          e m

                                          gdl

                                          )

                                          Fasting plasma glucose

                                          Study week

                                          Lorcaserin 10 mg BID Lorcaserin 10 mg Placebo

                                          Lorcaserin Adverse Events Reported by 5 or More in Any Group in Year 1

                                          55

                                          N () Lorcaserin(N = 1593)

                                          Placebo(N = 1584)

                                          Headache 287 (180) 175 (110)

                                          Dizziness 130 (82) 60 (38)

                                          Nausea 119 (75) 85 (54)

                                          Constipation 106 (67) 64 (40)

                                          Fatigue 95 (60) 48 (30)

                                          Dry mouth 83 (52) 37 (23)

                                          Smith SR et al ADA 2009 Late‐Breaking Abstract 96

                                          LorcaserinNo Increase in Rate of Valvulopathy

                                          Smith SR et al N Engl J Med 2010363245-256

                                          10

                                          8

                                          6

                                          4

                                          2

                                          024 52 76 104

                                          1351714

                                          9

                                          19

                                          3421Patie

                                          nts

                                          ()

                                          Week

                                          Lorcaserin in yr 1 and 2

                                          Lorcaserin in yr 1 Placebo in yr 2

                                          Placebo in yr 1 and 2

                                          Phase III Study Outcomes Compared

                                          Buproprion SR (360 mgd) Naltrexone SR (32 mgd)

                                          Lorcaserin(20 mgd)

                                          Phentermine Topiramate CR

                                          COR1 COR-I2 COR-II3 NB3043 BLOOM4 BLOSSOM5 EQUIP CONQUER

                                          Number of patients (ITT-LOCF)

                                          793 obese 1453 obese

                                          1281 obese

                                          502 type II diabetes

                                          3182 obese 4008 obese

                                          1230 obese BMI 44

                                          2448 comorbidBMI 36

                                          Mean change compared with placebo from base

                                          93 vs5 1c

                                          61a vs13c

                                          64a vs12

                                          50 a vs12c

                                          58 vs22c

                                          48 vs28c

                                          11 Fullbvs 16

                                          104 Fullb 84 Midb

                                          vs 18

                                          51 Lowb vs16c

                                          Categorical change 5 compared with placebo from base

                                          56 vs43

                                          48a vs164

                                          563a

                                          vs 171445a vs189

                                          475b

                                          vs 203472b vs25

                                          67 Fullb 45 Lowb vs17

                                          70 Fullb 62 Midb

                                          vs 21

                                          Phenterminetopiramate doses Low 375 mg phentermine23 mg topiramate Mid 75 mg phentermine 46 mg topiramate Full 15 mg phentermine 92 mg topiramateITT-LOCF intent-to-treat last observation carried forwardData not available aP lt 001 vs placebo bP lt 0001 vs placebo

                                          Obesity Treatments in Late Development

                                          Kushner RF Expert Opin Pharmacother 200891339-1350

                                          Agents ActionBupropionNaltrexone

                                          bull Dopaminenoradrenaline reuptake inhibitorbull Opioid receptor antagonist

                                          Liraglutide bull GLP-1 agonist

                                          BupropionNaltrexone

                                          bull Mechanism of Actionndash Bupropion - Dopaminenoradrenaline reuptake inhibitorndash Naltrexone- Opioid receptor antagonist

                                          bull Was approved by FDA committee but FDA did not approve until a CV outcome study is performed 2nd concerns about BP and P in some patients

                                          bull The Light Study is now underway and reported to be enrolling well under PI Dr Nissen

                                          bull BupropionNaltrexone will have first completed CV outcome study

                                          Buproprion ndash Naltrexone

                                          Greenway FL et al Lancet 2010376(9741)595-605

                                          0

                                          -2

                                          -4

                                          -6

                                          -8

                                          -100 4 8 12 16 20 24 28 32 36 40 44 48 52 56

                                          Weeks

                                          Wei

                                          ght c

                                          hang

                                          e fro

                                          m b

                                          asel

                                          ine

                                          ()

                                          Placebo

                                          Naltrexone 16 mg plus bupropion

                                          Naltrexone 32 mg plus bupropion

                                          Liraglutide for Weight Loss in Patients with Type 2 Diabetes

                                          bull GLP-1 analog approved for treatment of type 2 diabetes

                                          bull Anorectic effect mediated both by the activation of GLP-1 receptor expressed on vagal afferents and by the GLP-1R activation in CNS

                                          bull Affects visceral fat adiposity appetite food preference and cardiovascular biomarkers in patients with type 2 diabetes

                                          Inoue K et al Cardiovasc Diabetol 2011 10109 doi1011861475-2840-10-109

                                          Liraglutide Weight Loss Over 2 Years ITT Observed Means

                                          Astrup A et al Int J Obes (Lond) 201236(6)843-54

                                          FromScreening

                                          -94 kg

                                          -67 kg-88 kg

                                          -99 kg-94 kg

                                          -103 kg

                                          ITT intention to treat

                                          Phase III Study Outcomes Compared

                                          Buproprion SR (360 mgd) Naltrexone SR (32 mgd)

                                          Lorcaserin(20 mgd)

                                          Phentermine Topiramate CR

                                          COR1 COR-I2 COR-II3 NB3043 BLOOM4 BLOSSOM5 EQUIP CONQUER

                                          Number of patients (ITT-LOCF)

                                          793 obese 1453 obese

                                          1281 obese

                                          502 type II diabetes

                                          3182 obese 4008 obese

                                          1230 obese BMI 44

                                          2448 comorbidBMI 36

                                          Mean change compared with placebo from base

                                          93 vs5 1c

                                          61a vs13c

                                          64a vs12

                                          50 a vs12c

                                          58 vs22c

                                          48 vs28c

                                          11 Fullbvs 16

                                          104 Fullb 84 Midb

                                          vs 18

                                          51 Lowb vs16c

                                          Categorical change 5 compared with placebo from base

                                          56 vs43

                                          48a vs164

                                          563a

                                          vs 171445a vs189

                                          475b

                                          vs 203472b vs25

                                          67 Fullb 45 Lowb vs17

                                          70 Fullb 62 Midb

                                          vs 21

                                          Phenterminetopiramate doses Low 375 mg phentermine23 mg topiramate Mid 75 mg phentermine 46 mg topiramate Full 15 mg phentermine 92 mg topiramateITT-LOCF intent-to-treat last observation carried forwardData not available aP lt 001 vs placebo bP lt 0001 vs placebo

                                          Treatment Gap in theManagement of Obesity

                                          Physicians Need Effective Pharmacotherapies That Will Reduce Weight Significantly and Reduce Weight-related Comorbidities

                                          0 5 10 15 20 25 30 35

                                          Diet and Lifestyle Lap Band Gastric Bypass

                                          TreatmentGap

                                          What will fill the gap

                                          Too risky for many peopleNot effective enoughfor many people

                                          Treatment Gap in theManagement of Obesity

                                          0 5 10 15 20 25 30 35

                                          Diet and Lifestyle Lap Band Gastric Bypass

                                          TreatmentGap

                                          Too risky for many peopleNot effective enoughfor many people Pharmacotherapy

                                          Less invasive procedures

                                          Physicians Need Effective Pharmacotherapies That Will Reduce Weight Significantly and Reduce Weight-related Comorbidities

                                          What will fill the gap

                                          • Slide Number 1
                                          • Slide Number 2
                                          • Weight Management is Moving into the Workplace and Mainstream of Healthcare
                                          • US Preventative Services Task Force
                                          • A Proposal from CMS about Coverage for Intensive Behavioral Therapy for Obesity
                                          • Slide Number 6
                                          • Biggest Increases in Clinically Severe Obesity US 1987-2005
                                          • Relationship Between BMI and Risk of Type 2 Diabetes
                                          • Slide Number 9
                                          • Medical Complications of Obesity Almost every organ system is affected
                                          • Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and disease
                                          • Current Therapies Often Address Individual Risk Factors Cardiometabolic risk
                                          • Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and disease
                                          • Are You Treating These Drivers of Cardiometabolic Risk Should You Treat The Underlying Cause
                                          • Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors
                                          • In My Opinion The Winds of Change are Blowing in the Treatment of Chronic Diseases
                                          • Bariatric Surgery Reduces Overall Mortality Diabetes Mortality by 88
                                          • Health Care Costs Attributable to ObesityEstimates of what various conditions add to health-care service costs over a 12-month period
                                          • What-if scenarios (The Lancet forthcoming)
                                          • How Much Weight Loss Is Needed to Prevent T2DMndashNot Very Much The DPP Experience
                                          • In the Da Qing Study 6-year Intervention Led to Lower Incidence of Type 2 Diabetes 14 Years Later
                                          • Slide Number 22
                                          • Slide Number 23
                                          • New Compounds andCombination Interventions
                                          • Phentermine and Topiramate Extended-Release
                                          • Phentermine and Topiramate Extended-Release
                                          • EQUIP amp CONQUER Discontinuation RateDue to AEs in All Doses Studied
                                          • Phentermine and Topiramate SEQUELWeight Loss Over Time
                                          • CONQUER Significant Improvement in Cardiovascular Risk Factors
                                          • Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors
                                          • Lorcaserin
                                          • BLOOM Study Body Weight Over Years 1 and 2
                                          • BLOOM StudyKey Secondary Endpoints
                                          • BLOOM-DMChange in Glycemic Parameters
                                          • Lorcaserin Adverse Events Reported by 5 or More in Any Group in Year 1
                                          • LorcaserinNo Increase in Rate of Valvulopathy
                                          • Phase III Study Outcomes Compared
                                          • Obesity Treatments in Late Development
                                          • BupropionNaltrexone
                                          • Buproprion ndash Naltrexone
                                          • Liraglutide for Weight Loss in Patients with Type 2 Diabetes
                                          • Liraglutide Weight Loss Over 2 Years ITT Observed Means
                                          • Phase III Study Outcomes Compared
                                          • Treatment Gap in theManagement of Obesity
                                          • Treatment Gap in theManagement of Obesity

                                            As faculty of Weill Cornell Medical College we are committed to providing transparency for any and all external relationships prior to giving an academic presentation

                                            I am a consultant speaker advisor or receive research support fromBMS

                                            Arena Aspire BariatricsMyos

                                            GI Dynamics Novo NordiskOrexigenVivusZafgen

                                            I may discuss off-label use of medications

                                            Disclosure Page

                                            uarrFood intakedarr energy expenditure

                                            darrfood intake uarrenergy expenditure

                                            Topiramate

                                            Naltrexone

                                            LorcaserinPramlintideGLP-1Leptin

                                            BupropionPhentermine

                                            New Compounds andCombination Interventions

                                            c Louis J Aronne MDScience Feb 7 2003 Vol 299Illustration by Katharine Sutliff

                                            Phentermine and TopiramateExtended-Release

                                            bull Mechanism of actionndash Phentermine Sympathomimetic amine - releaserndash Topiramate Gabaergicglutamate modulation and carbonic

                                            anhydrase inhibitionbull February 2012 FDA advisory committee votes 20-2 for

                                            approval bull FDA approved July 2012

                                            ndash Schedule IVndash Pregnancy Category X = REMS

                                            Topiramate monotherapy exposure in pregnancy associated with 2- to 5-fold increased prevalence of oral clefts

                                            bull 4 doses Titrate upbull Available only by mail orderbull Covered through Medco Express Scripts

                                            Phentermine and TopiramateExtended-Release

                                            bull Dose titrationndash Once dailyndash Start treatment with phentermine 375 mgtopiramate

                                            23 mg extended-release daily for 14 daysndash After 14 days increase to the recommended dose of

                                            phentermine 75 mgtopiramate 46 mg extended-release once daily

                                            ndash May titrate upwards if needed to phen 15 top 92 mg strength

                                            EQUIP amp CONQUER Discontinuation RateDue to AEs in All Doses Studied

                                            Placebo Low Mid Full

                                            Number of patients 1508 241 498 1507Discontinuation due to AEs 9 12 12 18Blurred vision 05 21 08 07Headache 07 17 02 09Insomnia 04 00 04 17Depression 02 00 08 14Tingling 00 04 10 12Irritability 01 08 08 12Anxiety 03 00 02 11Dizziness 02 04 12 08

                                            Includes adverse events (AEs) by dose for EQUIP amp CONQUER which lead to discontinuation in gt 1 of patientsPress release Sept 9 2009 Available at httpirvivuscomreleasedetailcfmReleaseID=420114Accessed April 27 2010

                                            PhenTPMMid

                                            -104

                                            Phentermine and Topiramate SEQUELWeight Loss Over Time

                                            Garvey WT Ryan DH Look M Gadde KM Am J Clin Nutr 201295(2)297-308

                                            Placebo-25

                                            Plt00001 v placebo

                                            Weight Loss

                                            Week

                                            Total Population

                                            0

                                            -2

                                            -4

                                            -6

                                            -8

                                            -10

                                            -12

                                            -14

                                            -16

                                            0 12 24 36 48 60 72 84 96 108

                                            Weight Loss ITT-LOCF

                                            PhenTPMTop

                                            -114

                                            Mid = 75 mg46 mgTop = 15 mg92 mg

                                            CONQUER Significant Improvement in Cardiovascular Risk Factors

                                            (LS Mean Wt Loss)

                                            QNEXAMid(78)

                                            P valueQNEXATop

                                            (98) P value

                                            Waist Circumference (cm) ‐52 lt00001 ‐68 lt00001

                                            Systolic BP (mmHg) ‐23 00008 ‐32 lt00001

                                            Diastolic BP (mmHg) ‐07 NS ‐11 00031

                                            Triglycerides ( ∆) ‐133 lt00001 ‐153 lt00001

                                            Total Cholesterol ( ∆) ‐16 00345 ‐30 lt00001

                                            LDL ( ∆) 04 NS ‐28 00069

                                            HDL ( ∆) 40 lt00001 56 lt00001

                                            P values represent comparisons to placebo NS= non‐significant

                                            ITT‐LOCF Placebo ComparisonsTotal Study Population

                                            Davidson MH et al Am J Cardiol 2013 Jan 29 pii S0002‐9149(12)02641‐0 doi 101016jamjcard201212038

                                            Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors

                                            Risk FactorsPhenTPMMid

                                            p-valuePhenTPMTop

                                            p-value

                                            CRP lt0001 lt0001Fibrinogen lt005 lt005Adiponectin lt00001 lt00001

                                            p-values represent comparisons to placebo

                                            ITT-LOCF Placebo Comparisons

                                            Gadde KM et al Lancet 2011377(9774)1341-52

                                            Mid = 75 mg46 mgTop = 15 mg92 mg

                                            Lorcaserin

                                            bull Selective 5‐HT2C receptor agonist designed to promote weight loss

                                            bull Schedule IV ndash Expected soonbull Indication weight loss and maintenance of

                                            weight loss in patients with BMI gt30 kgm2 or BMI gt27 kgm2 + weight-related comorbidcondition(s)

                                            bull Dose - 10 mg BIDbull Most common side effects headache nausea

                                            dizziness dry mouth

                                            BLOOM Study Body Weight Over Years 1 and 2

                                            Smith SR et al N Engl J Med 2010363245-256 Study Week0 8 16 24 32 40 48 56 64 72 80 88 96 104

                                            Bod

                                            y W

                                            eigh

                                            t (kg

                                            )

                                            102

                                            100

                                            98

                                            96

                                            94

                                            92

                                            90

                                            0

                                            Year 1

                                            Placebo in year 1 and 2 (n = 684)Lorcaserin in year 1 placebo in year 2 (n = 275)Lorcaserin in year 1 and 2 (n = 564)

                                            Year 2

                                            Endpoint Lorcaserin Placebo P valueWaist circumference (cm) minus68plusmn02 minus39plusmn02 lt001BMI (kgm2) minus209plusmn006 minus078plusmn005 lt001SBPDBP (mm Hg) minus14plusmn03minus11plusmn02 minus08plusmn03minus06plusmn02 0401Cholesterol ( ∆)Total LDLHDL

                                            minus090plusmn033287plusmn056005plusmn033

                                            057plusmn034403plusmn058minus021plusmn034

                                            001

                                            049

                                            72Triglycerides minus615plusmn103 minus014plusmn099 lt001SafetyHR (beatsmin)PASP (mm Hg)Beck depression II score

                                            minus20plusmn03minus092plusmn023minus11plusmn01

                                            minus16plusmn04 minus023plusmn023 minus09plusmn01

                                            0499014026

                                            BLOOM StudyKey Secondary Endpoints

                                            Smith SR et al N Engl J Med 2010363245-256

                                            BLOOM-DMChange in Glycemic Parameters

                                            P lt001 P lt05 LS mean change plusmn SEMOrsquoNeil PM et al Obesity 201220(7)1426-36 httpwwwnaturecomdoifinder101038oby201266

                                            00

                                            -05

                                            -10

                                            -150 12 24 36 52

                                            Cha

                                            nge

                                            from

                                            bas

                                            elin

                                            e (

                                            )

                                            A1c

                                            Study week

                                            0

                                            -10

                                            -20

                                            -30

                                            -400 12 24 52

                                            Cha

                                            nge

                                            from

                                            bas

                                            elin

                                            e m

                                            gdl

                                            )

                                            Fasting plasma glucose

                                            Study week

                                            Lorcaserin 10 mg BID Lorcaserin 10 mg Placebo

                                            Lorcaserin Adverse Events Reported by 5 or More in Any Group in Year 1

                                            55

                                            N () Lorcaserin(N = 1593)

                                            Placebo(N = 1584)

                                            Headache 287 (180) 175 (110)

                                            Dizziness 130 (82) 60 (38)

                                            Nausea 119 (75) 85 (54)

                                            Constipation 106 (67) 64 (40)

                                            Fatigue 95 (60) 48 (30)

                                            Dry mouth 83 (52) 37 (23)

                                            Smith SR et al ADA 2009 Late‐Breaking Abstract 96

                                            LorcaserinNo Increase in Rate of Valvulopathy

                                            Smith SR et al N Engl J Med 2010363245-256

                                            10

                                            8

                                            6

                                            4

                                            2

                                            024 52 76 104

                                            1351714

                                            9

                                            19

                                            3421Patie

                                            nts

                                            ()

                                            Week

                                            Lorcaserin in yr 1 and 2

                                            Lorcaserin in yr 1 Placebo in yr 2

                                            Placebo in yr 1 and 2

                                            Phase III Study Outcomes Compared

                                            Buproprion SR (360 mgd) Naltrexone SR (32 mgd)

                                            Lorcaserin(20 mgd)

                                            Phentermine Topiramate CR

                                            COR1 COR-I2 COR-II3 NB3043 BLOOM4 BLOSSOM5 EQUIP CONQUER

                                            Number of patients (ITT-LOCF)

                                            793 obese 1453 obese

                                            1281 obese

                                            502 type II diabetes

                                            3182 obese 4008 obese

                                            1230 obese BMI 44

                                            2448 comorbidBMI 36

                                            Mean change compared with placebo from base

                                            93 vs5 1c

                                            61a vs13c

                                            64a vs12

                                            50 a vs12c

                                            58 vs22c

                                            48 vs28c

                                            11 Fullbvs 16

                                            104 Fullb 84 Midb

                                            vs 18

                                            51 Lowb vs16c

                                            Categorical change 5 compared with placebo from base

                                            56 vs43

                                            48a vs164

                                            563a

                                            vs 171445a vs189

                                            475b

                                            vs 203472b vs25

                                            67 Fullb 45 Lowb vs17

                                            70 Fullb 62 Midb

                                            vs 21

                                            Phenterminetopiramate doses Low 375 mg phentermine23 mg topiramate Mid 75 mg phentermine 46 mg topiramate Full 15 mg phentermine 92 mg topiramateITT-LOCF intent-to-treat last observation carried forwardData not available aP lt 001 vs placebo bP lt 0001 vs placebo

                                            Obesity Treatments in Late Development

                                            Kushner RF Expert Opin Pharmacother 200891339-1350

                                            Agents ActionBupropionNaltrexone

                                            bull Dopaminenoradrenaline reuptake inhibitorbull Opioid receptor antagonist

                                            Liraglutide bull GLP-1 agonist

                                            BupropionNaltrexone

                                            bull Mechanism of Actionndash Bupropion - Dopaminenoradrenaline reuptake inhibitorndash Naltrexone- Opioid receptor antagonist

                                            bull Was approved by FDA committee but FDA did not approve until a CV outcome study is performed 2nd concerns about BP and P in some patients

                                            bull The Light Study is now underway and reported to be enrolling well under PI Dr Nissen

                                            bull BupropionNaltrexone will have first completed CV outcome study

                                            Buproprion ndash Naltrexone

                                            Greenway FL et al Lancet 2010376(9741)595-605

                                            0

                                            -2

                                            -4

                                            -6

                                            -8

                                            -100 4 8 12 16 20 24 28 32 36 40 44 48 52 56

                                            Weeks

                                            Wei

                                            ght c

                                            hang

                                            e fro

                                            m b

                                            asel

                                            ine

                                            ()

                                            Placebo

                                            Naltrexone 16 mg plus bupropion

                                            Naltrexone 32 mg plus bupropion

                                            Liraglutide for Weight Loss in Patients with Type 2 Diabetes

                                            bull GLP-1 analog approved for treatment of type 2 diabetes

                                            bull Anorectic effect mediated both by the activation of GLP-1 receptor expressed on vagal afferents and by the GLP-1R activation in CNS

                                            bull Affects visceral fat adiposity appetite food preference and cardiovascular biomarkers in patients with type 2 diabetes

                                            Inoue K et al Cardiovasc Diabetol 2011 10109 doi1011861475-2840-10-109

                                            Liraglutide Weight Loss Over 2 Years ITT Observed Means

                                            Astrup A et al Int J Obes (Lond) 201236(6)843-54

                                            FromScreening

                                            -94 kg

                                            -67 kg-88 kg

                                            -99 kg-94 kg

                                            -103 kg

                                            ITT intention to treat

                                            Phase III Study Outcomes Compared

                                            Buproprion SR (360 mgd) Naltrexone SR (32 mgd)

                                            Lorcaserin(20 mgd)

                                            Phentermine Topiramate CR

                                            COR1 COR-I2 COR-II3 NB3043 BLOOM4 BLOSSOM5 EQUIP CONQUER

                                            Number of patients (ITT-LOCF)

                                            793 obese 1453 obese

                                            1281 obese

                                            502 type II diabetes

                                            3182 obese 4008 obese

                                            1230 obese BMI 44

                                            2448 comorbidBMI 36

                                            Mean change compared with placebo from base

                                            93 vs5 1c

                                            61a vs13c

                                            64a vs12

                                            50 a vs12c

                                            58 vs22c

                                            48 vs28c

                                            11 Fullbvs 16

                                            104 Fullb 84 Midb

                                            vs 18

                                            51 Lowb vs16c

                                            Categorical change 5 compared with placebo from base

                                            56 vs43

                                            48a vs164

                                            563a

                                            vs 171445a vs189

                                            475b

                                            vs 203472b vs25

                                            67 Fullb 45 Lowb vs17

                                            70 Fullb 62 Midb

                                            vs 21

                                            Phenterminetopiramate doses Low 375 mg phentermine23 mg topiramate Mid 75 mg phentermine 46 mg topiramate Full 15 mg phentermine 92 mg topiramateITT-LOCF intent-to-treat last observation carried forwardData not available aP lt 001 vs placebo bP lt 0001 vs placebo

                                            Treatment Gap in theManagement of Obesity

                                            Physicians Need Effective Pharmacotherapies That Will Reduce Weight Significantly and Reduce Weight-related Comorbidities

                                            0 5 10 15 20 25 30 35

                                            Diet and Lifestyle Lap Band Gastric Bypass

                                            TreatmentGap

                                            What will fill the gap

                                            Too risky for many peopleNot effective enoughfor many people

                                            Treatment Gap in theManagement of Obesity

                                            0 5 10 15 20 25 30 35

                                            Diet and Lifestyle Lap Band Gastric Bypass

                                            TreatmentGap

                                            Too risky for many peopleNot effective enoughfor many people Pharmacotherapy

                                            Less invasive procedures

                                            Physicians Need Effective Pharmacotherapies That Will Reduce Weight Significantly and Reduce Weight-related Comorbidities

                                            What will fill the gap

                                            • Slide Number 1
                                            • Slide Number 2
                                            • Weight Management is Moving into the Workplace and Mainstream of Healthcare
                                            • US Preventative Services Task Force
                                            • A Proposal from CMS about Coverage for Intensive Behavioral Therapy for Obesity
                                            • Slide Number 6
                                            • Biggest Increases in Clinically Severe Obesity US 1987-2005
                                            • Relationship Between BMI and Risk of Type 2 Diabetes
                                            • Slide Number 9
                                            • Medical Complications of Obesity Almost every organ system is affected
                                            • Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and disease
                                            • Current Therapies Often Address Individual Risk Factors Cardiometabolic risk
                                            • Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and disease
                                            • Are You Treating These Drivers of Cardiometabolic Risk Should You Treat The Underlying Cause
                                            • Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors
                                            • In My Opinion The Winds of Change are Blowing in the Treatment of Chronic Diseases
                                            • Bariatric Surgery Reduces Overall Mortality Diabetes Mortality by 88
                                            • Health Care Costs Attributable to ObesityEstimates of what various conditions add to health-care service costs over a 12-month period
                                            • What-if scenarios (The Lancet forthcoming)
                                            • How Much Weight Loss Is Needed to Prevent T2DMndashNot Very Much The DPP Experience
                                            • In the Da Qing Study 6-year Intervention Led to Lower Incidence of Type 2 Diabetes 14 Years Later
                                            • Slide Number 22
                                            • Slide Number 23
                                            • New Compounds andCombination Interventions
                                            • Phentermine and Topiramate Extended-Release
                                            • Phentermine and Topiramate Extended-Release
                                            • EQUIP amp CONQUER Discontinuation RateDue to AEs in All Doses Studied
                                            • Phentermine and Topiramate SEQUELWeight Loss Over Time
                                            • CONQUER Significant Improvement in Cardiovascular Risk Factors
                                            • Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors
                                            • Lorcaserin
                                            • BLOOM Study Body Weight Over Years 1 and 2
                                            • BLOOM StudyKey Secondary Endpoints
                                            • BLOOM-DMChange in Glycemic Parameters
                                            • Lorcaserin Adverse Events Reported by 5 or More in Any Group in Year 1
                                            • LorcaserinNo Increase in Rate of Valvulopathy
                                            • Phase III Study Outcomes Compared
                                            • Obesity Treatments in Late Development
                                            • BupropionNaltrexone
                                            • Buproprion ndash Naltrexone
                                            • Liraglutide for Weight Loss in Patients with Type 2 Diabetes
                                            • Liraglutide Weight Loss Over 2 Years ITT Observed Means
                                            • Phase III Study Outcomes Compared
                                            • Treatment Gap in theManagement of Obesity
                                            • Treatment Gap in theManagement of Obesity

                                              uarrFood intakedarr energy expenditure

                                              darrfood intake uarrenergy expenditure

                                              Topiramate

                                              Naltrexone

                                              LorcaserinPramlintideGLP-1Leptin

                                              BupropionPhentermine

                                              New Compounds andCombination Interventions

                                              c Louis J Aronne MDScience Feb 7 2003 Vol 299Illustration by Katharine Sutliff

                                              Phentermine and TopiramateExtended-Release

                                              bull Mechanism of actionndash Phentermine Sympathomimetic amine - releaserndash Topiramate Gabaergicglutamate modulation and carbonic

                                              anhydrase inhibitionbull February 2012 FDA advisory committee votes 20-2 for

                                              approval bull FDA approved July 2012

                                              ndash Schedule IVndash Pregnancy Category X = REMS

                                              Topiramate monotherapy exposure in pregnancy associated with 2- to 5-fold increased prevalence of oral clefts

                                              bull 4 doses Titrate upbull Available only by mail orderbull Covered through Medco Express Scripts

                                              Phentermine and TopiramateExtended-Release

                                              bull Dose titrationndash Once dailyndash Start treatment with phentermine 375 mgtopiramate

                                              23 mg extended-release daily for 14 daysndash After 14 days increase to the recommended dose of

                                              phentermine 75 mgtopiramate 46 mg extended-release once daily

                                              ndash May titrate upwards if needed to phen 15 top 92 mg strength

                                              EQUIP amp CONQUER Discontinuation RateDue to AEs in All Doses Studied

                                              Placebo Low Mid Full

                                              Number of patients 1508 241 498 1507Discontinuation due to AEs 9 12 12 18Blurred vision 05 21 08 07Headache 07 17 02 09Insomnia 04 00 04 17Depression 02 00 08 14Tingling 00 04 10 12Irritability 01 08 08 12Anxiety 03 00 02 11Dizziness 02 04 12 08

                                              Includes adverse events (AEs) by dose for EQUIP amp CONQUER which lead to discontinuation in gt 1 of patientsPress release Sept 9 2009 Available at httpirvivuscomreleasedetailcfmReleaseID=420114Accessed April 27 2010

                                              PhenTPMMid

                                              -104

                                              Phentermine and Topiramate SEQUELWeight Loss Over Time

                                              Garvey WT Ryan DH Look M Gadde KM Am J Clin Nutr 201295(2)297-308

                                              Placebo-25

                                              Plt00001 v placebo

                                              Weight Loss

                                              Week

                                              Total Population

                                              0

                                              -2

                                              -4

                                              -6

                                              -8

                                              -10

                                              -12

                                              -14

                                              -16

                                              0 12 24 36 48 60 72 84 96 108

                                              Weight Loss ITT-LOCF

                                              PhenTPMTop

                                              -114

                                              Mid = 75 mg46 mgTop = 15 mg92 mg

                                              CONQUER Significant Improvement in Cardiovascular Risk Factors

                                              (LS Mean Wt Loss)

                                              QNEXAMid(78)

                                              P valueQNEXATop

                                              (98) P value

                                              Waist Circumference (cm) ‐52 lt00001 ‐68 lt00001

                                              Systolic BP (mmHg) ‐23 00008 ‐32 lt00001

                                              Diastolic BP (mmHg) ‐07 NS ‐11 00031

                                              Triglycerides ( ∆) ‐133 lt00001 ‐153 lt00001

                                              Total Cholesterol ( ∆) ‐16 00345 ‐30 lt00001

                                              LDL ( ∆) 04 NS ‐28 00069

                                              HDL ( ∆) 40 lt00001 56 lt00001

                                              P values represent comparisons to placebo NS= non‐significant

                                              ITT‐LOCF Placebo ComparisonsTotal Study Population

                                              Davidson MH et al Am J Cardiol 2013 Jan 29 pii S0002‐9149(12)02641‐0 doi 101016jamjcard201212038

                                              Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors

                                              Risk FactorsPhenTPMMid

                                              p-valuePhenTPMTop

                                              p-value

                                              CRP lt0001 lt0001Fibrinogen lt005 lt005Adiponectin lt00001 lt00001

                                              p-values represent comparisons to placebo

                                              ITT-LOCF Placebo Comparisons

                                              Gadde KM et al Lancet 2011377(9774)1341-52

                                              Mid = 75 mg46 mgTop = 15 mg92 mg

                                              Lorcaserin

                                              bull Selective 5‐HT2C receptor agonist designed to promote weight loss

                                              bull Schedule IV ndash Expected soonbull Indication weight loss and maintenance of

                                              weight loss in patients with BMI gt30 kgm2 or BMI gt27 kgm2 + weight-related comorbidcondition(s)

                                              bull Dose - 10 mg BIDbull Most common side effects headache nausea

                                              dizziness dry mouth

                                              BLOOM Study Body Weight Over Years 1 and 2

                                              Smith SR et al N Engl J Med 2010363245-256 Study Week0 8 16 24 32 40 48 56 64 72 80 88 96 104

                                              Bod

                                              y W

                                              eigh

                                              t (kg

                                              )

                                              102

                                              100

                                              98

                                              96

                                              94

                                              92

                                              90

                                              0

                                              Year 1

                                              Placebo in year 1 and 2 (n = 684)Lorcaserin in year 1 placebo in year 2 (n = 275)Lorcaserin in year 1 and 2 (n = 564)

                                              Year 2

                                              Endpoint Lorcaserin Placebo P valueWaist circumference (cm) minus68plusmn02 minus39plusmn02 lt001BMI (kgm2) minus209plusmn006 minus078plusmn005 lt001SBPDBP (mm Hg) minus14plusmn03minus11plusmn02 minus08plusmn03minus06plusmn02 0401Cholesterol ( ∆)Total LDLHDL

                                              minus090plusmn033287plusmn056005plusmn033

                                              057plusmn034403plusmn058minus021plusmn034

                                              001

                                              049

                                              72Triglycerides minus615plusmn103 minus014plusmn099 lt001SafetyHR (beatsmin)PASP (mm Hg)Beck depression II score

                                              minus20plusmn03minus092plusmn023minus11plusmn01

                                              minus16plusmn04 minus023plusmn023 minus09plusmn01

                                              0499014026

                                              BLOOM StudyKey Secondary Endpoints

                                              Smith SR et al N Engl J Med 2010363245-256

                                              BLOOM-DMChange in Glycemic Parameters

                                              P lt001 P lt05 LS mean change plusmn SEMOrsquoNeil PM et al Obesity 201220(7)1426-36 httpwwwnaturecomdoifinder101038oby201266

                                              00

                                              -05

                                              -10

                                              -150 12 24 36 52

                                              Cha

                                              nge

                                              from

                                              bas

                                              elin

                                              e (

                                              )

                                              A1c

                                              Study week

                                              0

                                              -10

                                              -20

                                              -30

                                              -400 12 24 52

                                              Cha

                                              nge

                                              from

                                              bas

                                              elin

                                              e m

                                              gdl

                                              )

                                              Fasting plasma glucose

                                              Study week

                                              Lorcaserin 10 mg BID Lorcaserin 10 mg Placebo

                                              Lorcaserin Adverse Events Reported by 5 or More in Any Group in Year 1

                                              55

                                              N () Lorcaserin(N = 1593)

                                              Placebo(N = 1584)

                                              Headache 287 (180) 175 (110)

                                              Dizziness 130 (82) 60 (38)

                                              Nausea 119 (75) 85 (54)

                                              Constipation 106 (67) 64 (40)

                                              Fatigue 95 (60) 48 (30)

                                              Dry mouth 83 (52) 37 (23)

                                              Smith SR et al ADA 2009 Late‐Breaking Abstract 96

                                              LorcaserinNo Increase in Rate of Valvulopathy

                                              Smith SR et al N Engl J Med 2010363245-256

                                              10

                                              8

                                              6

                                              4

                                              2

                                              024 52 76 104

                                              1351714

                                              9

                                              19

                                              3421Patie

                                              nts

                                              ()

                                              Week

                                              Lorcaserin in yr 1 and 2

                                              Lorcaserin in yr 1 Placebo in yr 2

                                              Placebo in yr 1 and 2

                                              Phase III Study Outcomes Compared

                                              Buproprion SR (360 mgd) Naltrexone SR (32 mgd)

                                              Lorcaserin(20 mgd)

                                              Phentermine Topiramate CR

                                              COR1 COR-I2 COR-II3 NB3043 BLOOM4 BLOSSOM5 EQUIP CONQUER

                                              Number of patients (ITT-LOCF)

                                              793 obese 1453 obese

                                              1281 obese

                                              502 type II diabetes

                                              3182 obese 4008 obese

                                              1230 obese BMI 44

                                              2448 comorbidBMI 36

                                              Mean change compared with placebo from base

                                              93 vs5 1c

                                              61a vs13c

                                              64a vs12

                                              50 a vs12c

                                              58 vs22c

                                              48 vs28c

                                              11 Fullbvs 16

                                              104 Fullb 84 Midb

                                              vs 18

                                              51 Lowb vs16c

                                              Categorical change 5 compared with placebo from base

                                              56 vs43

                                              48a vs164

                                              563a

                                              vs 171445a vs189

                                              475b

                                              vs 203472b vs25

                                              67 Fullb 45 Lowb vs17

                                              70 Fullb 62 Midb

                                              vs 21

                                              Phenterminetopiramate doses Low 375 mg phentermine23 mg topiramate Mid 75 mg phentermine 46 mg topiramate Full 15 mg phentermine 92 mg topiramateITT-LOCF intent-to-treat last observation carried forwardData not available aP lt 001 vs placebo bP lt 0001 vs placebo

                                              Obesity Treatments in Late Development

                                              Kushner RF Expert Opin Pharmacother 200891339-1350

                                              Agents ActionBupropionNaltrexone

                                              bull Dopaminenoradrenaline reuptake inhibitorbull Opioid receptor antagonist

                                              Liraglutide bull GLP-1 agonist

                                              BupropionNaltrexone

                                              bull Mechanism of Actionndash Bupropion - Dopaminenoradrenaline reuptake inhibitorndash Naltrexone- Opioid receptor antagonist

                                              bull Was approved by FDA committee but FDA did not approve until a CV outcome study is performed 2nd concerns about BP and P in some patients

                                              bull The Light Study is now underway and reported to be enrolling well under PI Dr Nissen

                                              bull BupropionNaltrexone will have first completed CV outcome study

                                              Buproprion ndash Naltrexone

                                              Greenway FL et al Lancet 2010376(9741)595-605

                                              0

                                              -2

                                              -4

                                              -6

                                              -8

                                              -100 4 8 12 16 20 24 28 32 36 40 44 48 52 56

                                              Weeks

                                              Wei

                                              ght c

                                              hang

                                              e fro

                                              m b

                                              asel

                                              ine

                                              ()

                                              Placebo

                                              Naltrexone 16 mg plus bupropion

                                              Naltrexone 32 mg plus bupropion

                                              Liraglutide for Weight Loss in Patients with Type 2 Diabetes

                                              bull GLP-1 analog approved for treatment of type 2 diabetes

                                              bull Anorectic effect mediated both by the activation of GLP-1 receptor expressed on vagal afferents and by the GLP-1R activation in CNS

                                              bull Affects visceral fat adiposity appetite food preference and cardiovascular biomarkers in patients with type 2 diabetes

                                              Inoue K et al Cardiovasc Diabetol 2011 10109 doi1011861475-2840-10-109

                                              Liraglutide Weight Loss Over 2 Years ITT Observed Means

                                              Astrup A et al Int J Obes (Lond) 201236(6)843-54

                                              FromScreening

                                              -94 kg

                                              -67 kg-88 kg

                                              -99 kg-94 kg

                                              -103 kg

                                              ITT intention to treat

                                              Phase III Study Outcomes Compared

                                              Buproprion SR (360 mgd) Naltrexone SR (32 mgd)

                                              Lorcaserin(20 mgd)

                                              Phentermine Topiramate CR

                                              COR1 COR-I2 COR-II3 NB3043 BLOOM4 BLOSSOM5 EQUIP CONQUER

                                              Number of patients (ITT-LOCF)

                                              793 obese 1453 obese

                                              1281 obese

                                              502 type II diabetes

                                              3182 obese 4008 obese

                                              1230 obese BMI 44

                                              2448 comorbidBMI 36

                                              Mean change compared with placebo from base

                                              93 vs5 1c

                                              61a vs13c

                                              64a vs12

                                              50 a vs12c

                                              58 vs22c

                                              48 vs28c

                                              11 Fullbvs 16

                                              104 Fullb 84 Midb

                                              vs 18

                                              51 Lowb vs16c

                                              Categorical change 5 compared with placebo from base

                                              56 vs43

                                              48a vs164

                                              563a

                                              vs 171445a vs189

                                              475b

                                              vs 203472b vs25

                                              67 Fullb 45 Lowb vs17

                                              70 Fullb 62 Midb

                                              vs 21

                                              Phenterminetopiramate doses Low 375 mg phentermine23 mg topiramate Mid 75 mg phentermine 46 mg topiramate Full 15 mg phentermine 92 mg topiramateITT-LOCF intent-to-treat last observation carried forwardData not available aP lt 001 vs placebo bP lt 0001 vs placebo

                                              Treatment Gap in theManagement of Obesity

                                              Physicians Need Effective Pharmacotherapies That Will Reduce Weight Significantly and Reduce Weight-related Comorbidities

                                              0 5 10 15 20 25 30 35

                                              Diet and Lifestyle Lap Band Gastric Bypass

                                              TreatmentGap

                                              What will fill the gap

                                              Too risky for many peopleNot effective enoughfor many people

                                              Treatment Gap in theManagement of Obesity

                                              0 5 10 15 20 25 30 35

                                              Diet and Lifestyle Lap Band Gastric Bypass

                                              TreatmentGap

                                              Too risky for many peopleNot effective enoughfor many people Pharmacotherapy

                                              Less invasive procedures

                                              Physicians Need Effective Pharmacotherapies That Will Reduce Weight Significantly and Reduce Weight-related Comorbidities

                                              What will fill the gap

                                              • Slide Number 1
                                              • Slide Number 2
                                              • Weight Management is Moving into the Workplace and Mainstream of Healthcare
                                              • US Preventative Services Task Force
                                              • A Proposal from CMS about Coverage for Intensive Behavioral Therapy for Obesity
                                              • Slide Number 6
                                              • Biggest Increases in Clinically Severe Obesity US 1987-2005
                                              • Relationship Between BMI and Risk of Type 2 Diabetes
                                              • Slide Number 9
                                              • Medical Complications of Obesity Almost every organ system is affected
                                              • Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and disease
                                              • Current Therapies Often Address Individual Risk Factors Cardiometabolic risk
                                              • Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and disease
                                              • Are You Treating These Drivers of Cardiometabolic Risk Should You Treat The Underlying Cause
                                              • Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors
                                              • In My Opinion The Winds of Change are Blowing in the Treatment of Chronic Diseases
                                              • Bariatric Surgery Reduces Overall Mortality Diabetes Mortality by 88
                                              • Health Care Costs Attributable to ObesityEstimates of what various conditions add to health-care service costs over a 12-month period
                                              • What-if scenarios (The Lancet forthcoming)
                                              • How Much Weight Loss Is Needed to Prevent T2DMndashNot Very Much The DPP Experience
                                              • In the Da Qing Study 6-year Intervention Led to Lower Incidence of Type 2 Diabetes 14 Years Later
                                              • Slide Number 22
                                              • Slide Number 23
                                              • New Compounds andCombination Interventions
                                              • Phentermine and Topiramate Extended-Release
                                              • Phentermine and Topiramate Extended-Release
                                              • EQUIP amp CONQUER Discontinuation RateDue to AEs in All Doses Studied
                                              • Phentermine and Topiramate SEQUELWeight Loss Over Time
                                              • CONQUER Significant Improvement in Cardiovascular Risk Factors
                                              • Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors
                                              • Lorcaserin
                                              • BLOOM Study Body Weight Over Years 1 and 2
                                              • BLOOM StudyKey Secondary Endpoints
                                              • BLOOM-DMChange in Glycemic Parameters
                                              • Lorcaserin Adverse Events Reported by 5 or More in Any Group in Year 1
                                              • LorcaserinNo Increase in Rate of Valvulopathy
                                              • Phase III Study Outcomes Compared
                                              • Obesity Treatments in Late Development
                                              • BupropionNaltrexone
                                              • Buproprion ndash Naltrexone
                                              • Liraglutide for Weight Loss in Patients with Type 2 Diabetes
                                              • Liraglutide Weight Loss Over 2 Years ITT Observed Means
                                              • Phase III Study Outcomes Compared
                                              • Treatment Gap in theManagement of Obesity
                                              • Treatment Gap in theManagement of Obesity

                                                Phentermine and TopiramateExtended-Release

                                                bull Mechanism of actionndash Phentermine Sympathomimetic amine - releaserndash Topiramate Gabaergicglutamate modulation and carbonic

                                                anhydrase inhibitionbull February 2012 FDA advisory committee votes 20-2 for

                                                approval bull FDA approved July 2012

                                                ndash Schedule IVndash Pregnancy Category X = REMS

                                                Topiramate monotherapy exposure in pregnancy associated with 2- to 5-fold increased prevalence of oral clefts

                                                bull 4 doses Titrate upbull Available only by mail orderbull Covered through Medco Express Scripts

                                                Phentermine and TopiramateExtended-Release

                                                bull Dose titrationndash Once dailyndash Start treatment with phentermine 375 mgtopiramate

                                                23 mg extended-release daily for 14 daysndash After 14 days increase to the recommended dose of

                                                phentermine 75 mgtopiramate 46 mg extended-release once daily

                                                ndash May titrate upwards if needed to phen 15 top 92 mg strength

                                                EQUIP amp CONQUER Discontinuation RateDue to AEs in All Doses Studied

                                                Placebo Low Mid Full

                                                Number of patients 1508 241 498 1507Discontinuation due to AEs 9 12 12 18Blurred vision 05 21 08 07Headache 07 17 02 09Insomnia 04 00 04 17Depression 02 00 08 14Tingling 00 04 10 12Irritability 01 08 08 12Anxiety 03 00 02 11Dizziness 02 04 12 08

                                                Includes adverse events (AEs) by dose for EQUIP amp CONQUER which lead to discontinuation in gt 1 of patientsPress release Sept 9 2009 Available at httpirvivuscomreleasedetailcfmReleaseID=420114Accessed April 27 2010

                                                PhenTPMMid

                                                -104

                                                Phentermine and Topiramate SEQUELWeight Loss Over Time

                                                Garvey WT Ryan DH Look M Gadde KM Am J Clin Nutr 201295(2)297-308

                                                Placebo-25

                                                Plt00001 v placebo

                                                Weight Loss

                                                Week

                                                Total Population

                                                0

                                                -2

                                                -4

                                                -6

                                                -8

                                                -10

                                                -12

                                                -14

                                                -16

                                                0 12 24 36 48 60 72 84 96 108

                                                Weight Loss ITT-LOCF

                                                PhenTPMTop

                                                -114

                                                Mid = 75 mg46 mgTop = 15 mg92 mg

                                                CONQUER Significant Improvement in Cardiovascular Risk Factors

                                                (LS Mean Wt Loss)

                                                QNEXAMid(78)

                                                P valueQNEXATop

                                                (98) P value

                                                Waist Circumference (cm) ‐52 lt00001 ‐68 lt00001

                                                Systolic BP (mmHg) ‐23 00008 ‐32 lt00001

                                                Diastolic BP (mmHg) ‐07 NS ‐11 00031

                                                Triglycerides ( ∆) ‐133 lt00001 ‐153 lt00001

                                                Total Cholesterol ( ∆) ‐16 00345 ‐30 lt00001

                                                LDL ( ∆) 04 NS ‐28 00069

                                                HDL ( ∆) 40 lt00001 56 lt00001

                                                P values represent comparisons to placebo NS= non‐significant

                                                ITT‐LOCF Placebo ComparisonsTotal Study Population

                                                Davidson MH et al Am J Cardiol 2013 Jan 29 pii S0002‐9149(12)02641‐0 doi 101016jamjcard201212038

                                                Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors

                                                Risk FactorsPhenTPMMid

                                                p-valuePhenTPMTop

                                                p-value

                                                CRP lt0001 lt0001Fibrinogen lt005 lt005Adiponectin lt00001 lt00001

                                                p-values represent comparisons to placebo

                                                ITT-LOCF Placebo Comparisons

                                                Gadde KM et al Lancet 2011377(9774)1341-52

                                                Mid = 75 mg46 mgTop = 15 mg92 mg

                                                Lorcaserin

                                                bull Selective 5‐HT2C receptor agonist designed to promote weight loss

                                                bull Schedule IV ndash Expected soonbull Indication weight loss and maintenance of

                                                weight loss in patients with BMI gt30 kgm2 or BMI gt27 kgm2 + weight-related comorbidcondition(s)

                                                bull Dose - 10 mg BIDbull Most common side effects headache nausea

                                                dizziness dry mouth

                                                BLOOM Study Body Weight Over Years 1 and 2

                                                Smith SR et al N Engl J Med 2010363245-256 Study Week0 8 16 24 32 40 48 56 64 72 80 88 96 104

                                                Bod

                                                y W

                                                eigh

                                                t (kg

                                                )

                                                102

                                                100

                                                98

                                                96

                                                94

                                                92

                                                90

                                                0

                                                Year 1

                                                Placebo in year 1 and 2 (n = 684)Lorcaserin in year 1 placebo in year 2 (n = 275)Lorcaserin in year 1 and 2 (n = 564)

                                                Year 2

                                                Endpoint Lorcaserin Placebo P valueWaist circumference (cm) minus68plusmn02 minus39plusmn02 lt001BMI (kgm2) minus209plusmn006 minus078plusmn005 lt001SBPDBP (mm Hg) minus14plusmn03minus11plusmn02 minus08plusmn03minus06plusmn02 0401Cholesterol ( ∆)Total LDLHDL

                                                minus090plusmn033287plusmn056005plusmn033

                                                057plusmn034403plusmn058minus021plusmn034

                                                001

                                                049

                                                72Triglycerides minus615plusmn103 minus014plusmn099 lt001SafetyHR (beatsmin)PASP (mm Hg)Beck depression II score

                                                minus20plusmn03minus092plusmn023minus11plusmn01

                                                minus16plusmn04 minus023plusmn023 minus09plusmn01

                                                0499014026

                                                BLOOM StudyKey Secondary Endpoints

                                                Smith SR et al N Engl J Med 2010363245-256

                                                BLOOM-DMChange in Glycemic Parameters

                                                P lt001 P lt05 LS mean change plusmn SEMOrsquoNeil PM et al Obesity 201220(7)1426-36 httpwwwnaturecomdoifinder101038oby201266

                                                00

                                                -05

                                                -10

                                                -150 12 24 36 52

                                                Cha

                                                nge

                                                from

                                                bas

                                                elin

                                                e (

                                                )

                                                A1c

                                                Study week

                                                0

                                                -10

                                                -20

                                                -30

                                                -400 12 24 52

                                                Cha

                                                nge

                                                from

                                                bas

                                                elin

                                                e m

                                                gdl

                                                )

                                                Fasting plasma glucose

                                                Study week

                                                Lorcaserin 10 mg BID Lorcaserin 10 mg Placebo

                                                Lorcaserin Adverse Events Reported by 5 or More in Any Group in Year 1

                                                55

                                                N () Lorcaserin(N = 1593)

                                                Placebo(N = 1584)

                                                Headache 287 (180) 175 (110)

                                                Dizziness 130 (82) 60 (38)

                                                Nausea 119 (75) 85 (54)

                                                Constipation 106 (67) 64 (40)

                                                Fatigue 95 (60) 48 (30)

                                                Dry mouth 83 (52) 37 (23)

                                                Smith SR et al ADA 2009 Late‐Breaking Abstract 96

                                                LorcaserinNo Increase in Rate of Valvulopathy

                                                Smith SR et al N Engl J Med 2010363245-256

                                                10

                                                8

                                                6

                                                4

                                                2

                                                024 52 76 104

                                                1351714

                                                9

                                                19

                                                3421Patie

                                                nts

                                                ()

                                                Week

                                                Lorcaserin in yr 1 and 2

                                                Lorcaserin in yr 1 Placebo in yr 2

                                                Placebo in yr 1 and 2

                                                Phase III Study Outcomes Compared

                                                Buproprion SR (360 mgd) Naltrexone SR (32 mgd)

                                                Lorcaserin(20 mgd)

                                                Phentermine Topiramate CR

                                                COR1 COR-I2 COR-II3 NB3043 BLOOM4 BLOSSOM5 EQUIP CONQUER

                                                Number of patients (ITT-LOCF)

                                                793 obese 1453 obese

                                                1281 obese

                                                502 type II diabetes

                                                3182 obese 4008 obese

                                                1230 obese BMI 44

                                                2448 comorbidBMI 36

                                                Mean change compared with placebo from base

                                                93 vs5 1c

                                                61a vs13c

                                                64a vs12

                                                50 a vs12c

                                                58 vs22c

                                                48 vs28c

                                                11 Fullbvs 16

                                                104 Fullb 84 Midb

                                                vs 18

                                                51 Lowb vs16c

                                                Categorical change 5 compared with placebo from base

                                                56 vs43

                                                48a vs164

                                                563a

                                                vs 171445a vs189

                                                475b

                                                vs 203472b vs25

                                                67 Fullb 45 Lowb vs17

                                                70 Fullb 62 Midb

                                                vs 21

                                                Phenterminetopiramate doses Low 375 mg phentermine23 mg topiramate Mid 75 mg phentermine 46 mg topiramate Full 15 mg phentermine 92 mg topiramateITT-LOCF intent-to-treat last observation carried forwardData not available aP lt 001 vs placebo bP lt 0001 vs placebo

                                                Obesity Treatments in Late Development

                                                Kushner RF Expert Opin Pharmacother 200891339-1350

                                                Agents ActionBupropionNaltrexone

                                                bull Dopaminenoradrenaline reuptake inhibitorbull Opioid receptor antagonist

                                                Liraglutide bull GLP-1 agonist

                                                BupropionNaltrexone

                                                bull Mechanism of Actionndash Bupropion - Dopaminenoradrenaline reuptake inhibitorndash Naltrexone- Opioid receptor antagonist

                                                bull Was approved by FDA committee but FDA did not approve until a CV outcome study is performed 2nd concerns about BP and P in some patients

                                                bull The Light Study is now underway and reported to be enrolling well under PI Dr Nissen

                                                bull BupropionNaltrexone will have first completed CV outcome study

                                                Buproprion ndash Naltrexone

                                                Greenway FL et al Lancet 2010376(9741)595-605

                                                0

                                                -2

                                                -4

                                                -6

                                                -8

                                                -100 4 8 12 16 20 24 28 32 36 40 44 48 52 56

                                                Weeks

                                                Wei

                                                ght c

                                                hang

                                                e fro

                                                m b

                                                asel

                                                ine

                                                ()

                                                Placebo

                                                Naltrexone 16 mg plus bupropion

                                                Naltrexone 32 mg plus bupropion

                                                Liraglutide for Weight Loss in Patients with Type 2 Diabetes

                                                bull GLP-1 analog approved for treatment of type 2 diabetes

                                                bull Anorectic effect mediated both by the activation of GLP-1 receptor expressed on vagal afferents and by the GLP-1R activation in CNS

                                                bull Affects visceral fat adiposity appetite food preference and cardiovascular biomarkers in patients with type 2 diabetes

                                                Inoue K et al Cardiovasc Diabetol 2011 10109 doi1011861475-2840-10-109

                                                Liraglutide Weight Loss Over 2 Years ITT Observed Means

                                                Astrup A et al Int J Obes (Lond) 201236(6)843-54

                                                FromScreening

                                                -94 kg

                                                -67 kg-88 kg

                                                -99 kg-94 kg

                                                -103 kg

                                                ITT intention to treat

                                                Phase III Study Outcomes Compared

                                                Buproprion SR (360 mgd) Naltrexone SR (32 mgd)

                                                Lorcaserin(20 mgd)

                                                Phentermine Topiramate CR

                                                COR1 COR-I2 COR-II3 NB3043 BLOOM4 BLOSSOM5 EQUIP CONQUER

                                                Number of patients (ITT-LOCF)

                                                793 obese 1453 obese

                                                1281 obese

                                                502 type II diabetes

                                                3182 obese 4008 obese

                                                1230 obese BMI 44

                                                2448 comorbidBMI 36

                                                Mean change compared with placebo from base

                                                93 vs5 1c

                                                61a vs13c

                                                64a vs12

                                                50 a vs12c

                                                58 vs22c

                                                48 vs28c

                                                11 Fullbvs 16

                                                104 Fullb 84 Midb

                                                vs 18

                                                51 Lowb vs16c

                                                Categorical change 5 compared with placebo from base

                                                56 vs43

                                                48a vs164

                                                563a

                                                vs 171445a vs189

                                                475b

                                                vs 203472b vs25

                                                67 Fullb 45 Lowb vs17

                                                70 Fullb 62 Midb

                                                vs 21

                                                Phenterminetopiramate doses Low 375 mg phentermine23 mg topiramate Mid 75 mg phentermine 46 mg topiramate Full 15 mg phentermine 92 mg topiramateITT-LOCF intent-to-treat last observation carried forwardData not available aP lt 001 vs placebo bP lt 0001 vs placebo

                                                Treatment Gap in theManagement of Obesity

                                                Physicians Need Effective Pharmacotherapies That Will Reduce Weight Significantly and Reduce Weight-related Comorbidities

                                                0 5 10 15 20 25 30 35

                                                Diet and Lifestyle Lap Band Gastric Bypass

                                                TreatmentGap

                                                What will fill the gap

                                                Too risky for many peopleNot effective enoughfor many people

                                                Treatment Gap in theManagement of Obesity

                                                0 5 10 15 20 25 30 35

                                                Diet and Lifestyle Lap Band Gastric Bypass

                                                TreatmentGap

                                                Too risky for many peopleNot effective enoughfor many people Pharmacotherapy

                                                Less invasive procedures

                                                Physicians Need Effective Pharmacotherapies That Will Reduce Weight Significantly and Reduce Weight-related Comorbidities

                                                What will fill the gap

                                                • Slide Number 1
                                                • Slide Number 2
                                                • Weight Management is Moving into the Workplace and Mainstream of Healthcare
                                                • US Preventative Services Task Force
                                                • A Proposal from CMS about Coverage for Intensive Behavioral Therapy for Obesity
                                                • Slide Number 6
                                                • Biggest Increases in Clinically Severe Obesity US 1987-2005
                                                • Relationship Between BMI and Risk of Type 2 Diabetes
                                                • Slide Number 9
                                                • Medical Complications of Obesity Almost every organ system is affected
                                                • Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and disease
                                                • Current Therapies Often Address Individual Risk Factors Cardiometabolic risk
                                                • Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and disease
                                                • Are You Treating These Drivers of Cardiometabolic Risk Should You Treat The Underlying Cause
                                                • Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors
                                                • In My Opinion The Winds of Change are Blowing in the Treatment of Chronic Diseases
                                                • Bariatric Surgery Reduces Overall Mortality Diabetes Mortality by 88
                                                • Health Care Costs Attributable to ObesityEstimates of what various conditions add to health-care service costs over a 12-month period
                                                • What-if scenarios (The Lancet forthcoming)
                                                • How Much Weight Loss Is Needed to Prevent T2DMndashNot Very Much The DPP Experience
                                                • In the Da Qing Study 6-year Intervention Led to Lower Incidence of Type 2 Diabetes 14 Years Later
                                                • Slide Number 22
                                                • Slide Number 23
                                                • New Compounds andCombination Interventions
                                                • Phentermine and Topiramate Extended-Release
                                                • Phentermine and Topiramate Extended-Release
                                                • EQUIP amp CONQUER Discontinuation RateDue to AEs in All Doses Studied
                                                • Phentermine and Topiramate SEQUELWeight Loss Over Time
                                                • CONQUER Significant Improvement in Cardiovascular Risk Factors
                                                • Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors
                                                • Lorcaserin
                                                • BLOOM Study Body Weight Over Years 1 and 2
                                                • BLOOM StudyKey Secondary Endpoints
                                                • BLOOM-DMChange in Glycemic Parameters
                                                • Lorcaserin Adverse Events Reported by 5 or More in Any Group in Year 1
                                                • LorcaserinNo Increase in Rate of Valvulopathy
                                                • Phase III Study Outcomes Compared
                                                • Obesity Treatments in Late Development
                                                • BupropionNaltrexone
                                                • Buproprion ndash Naltrexone
                                                • Liraglutide for Weight Loss in Patients with Type 2 Diabetes
                                                • Liraglutide Weight Loss Over 2 Years ITT Observed Means
                                                • Phase III Study Outcomes Compared
                                                • Treatment Gap in theManagement of Obesity
                                                • Treatment Gap in theManagement of Obesity

                                                  Phentermine and TopiramateExtended-Release

                                                  bull Dose titrationndash Once dailyndash Start treatment with phentermine 375 mgtopiramate

                                                  23 mg extended-release daily for 14 daysndash After 14 days increase to the recommended dose of

                                                  phentermine 75 mgtopiramate 46 mg extended-release once daily

                                                  ndash May titrate upwards if needed to phen 15 top 92 mg strength

                                                  EQUIP amp CONQUER Discontinuation RateDue to AEs in All Doses Studied

                                                  Placebo Low Mid Full

                                                  Number of patients 1508 241 498 1507Discontinuation due to AEs 9 12 12 18Blurred vision 05 21 08 07Headache 07 17 02 09Insomnia 04 00 04 17Depression 02 00 08 14Tingling 00 04 10 12Irritability 01 08 08 12Anxiety 03 00 02 11Dizziness 02 04 12 08

                                                  Includes adverse events (AEs) by dose for EQUIP amp CONQUER which lead to discontinuation in gt 1 of patientsPress release Sept 9 2009 Available at httpirvivuscomreleasedetailcfmReleaseID=420114Accessed April 27 2010

                                                  PhenTPMMid

                                                  -104

                                                  Phentermine and Topiramate SEQUELWeight Loss Over Time

                                                  Garvey WT Ryan DH Look M Gadde KM Am J Clin Nutr 201295(2)297-308

                                                  Placebo-25

                                                  Plt00001 v placebo

                                                  Weight Loss

                                                  Week

                                                  Total Population

                                                  0

                                                  -2

                                                  -4

                                                  -6

                                                  -8

                                                  -10

                                                  -12

                                                  -14

                                                  -16

                                                  0 12 24 36 48 60 72 84 96 108

                                                  Weight Loss ITT-LOCF

                                                  PhenTPMTop

                                                  -114

                                                  Mid = 75 mg46 mgTop = 15 mg92 mg

                                                  CONQUER Significant Improvement in Cardiovascular Risk Factors

                                                  (LS Mean Wt Loss)

                                                  QNEXAMid(78)

                                                  P valueQNEXATop

                                                  (98) P value

                                                  Waist Circumference (cm) ‐52 lt00001 ‐68 lt00001

                                                  Systolic BP (mmHg) ‐23 00008 ‐32 lt00001

                                                  Diastolic BP (mmHg) ‐07 NS ‐11 00031

                                                  Triglycerides ( ∆) ‐133 lt00001 ‐153 lt00001

                                                  Total Cholesterol ( ∆) ‐16 00345 ‐30 lt00001

                                                  LDL ( ∆) 04 NS ‐28 00069

                                                  HDL ( ∆) 40 lt00001 56 lt00001

                                                  P values represent comparisons to placebo NS= non‐significant

                                                  ITT‐LOCF Placebo ComparisonsTotal Study Population

                                                  Davidson MH et al Am J Cardiol 2013 Jan 29 pii S0002‐9149(12)02641‐0 doi 101016jamjcard201212038

                                                  Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors

                                                  Risk FactorsPhenTPMMid

                                                  p-valuePhenTPMTop

                                                  p-value

                                                  CRP lt0001 lt0001Fibrinogen lt005 lt005Adiponectin lt00001 lt00001

                                                  p-values represent comparisons to placebo

                                                  ITT-LOCF Placebo Comparisons

                                                  Gadde KM et al Lancet 2011377(9774)1341-52

                                                  Mid = 75 mg46 mgTop = 15 mg92 mg

                                                  Lorcaserin

                                                  bull Selective 5‐HT2C receptor agonist designed to promote weight loss

                                                  bull Schedule IV ndash Expected soonbull Indication weight loss and maintenance of

                                                  weight loss in patients with BMI gt30 kgm2 or BMI gt27 kgm2 + weight-related comorbidcondition(s)

                                                  bull Dose - 10 mg BIDbull Most common side effects headache nausea

                                                  dizziness dry mouth

                                                  BLOOM Study Body Weight Over Years 1 and 2

                                                  Smith SR et al N Engl J Med 2010363245-256 Study Week0 8 16 24 32 40 48 56 64 72 80 88 96 104

                                                  Bod

                                                  y W

                                                  eigh

                                                  t (kg

                                                  )

                                                  102

                                                  100

                                                  98

                                                  96

                                                  94

                                                  92

                                                  90

                                                  0

                                                  Year 1

                                                  Placebo in year 1 and 2 (n = 684)Lorcaserin in year 1 placebo in year 2 (n = 275)Lorcaserin in year 1 and 2 (n = 564)

                                                  Year 2

                                                  Endpoint Lorcaserin Placebo P valueWaist circumference (cm) minus68plusmn02 minus39plusmn02 lt001BMI (kgm2) minus209plusmn006 minus078plusmn005 lt001SBPDBP (mm Hg) minus14plusmn03minus11plusmn02 minus08plusmn03minus06plusmn02 0401Cholesterol ( ∆)Total LDLHDL

                                                  minus090plusmn033287plusmn056005plusmn033

                                                  057plusmn034403plusmn058minus021plusmn034

                                                  001

                                                  049

                                                  72Triglycerides minus615plusmn103 minus014plusmn099 lt001SafetyHR (beatsmin)PASP (mm Hg)Beck depression II score

                                                  minus20plusmn03minus092plusmn023minus11plusmn01

                                                  minus16plusmn04 minus023plusmn023 minus09plusmn01

                                                  0499014026

                                                  BLOOM StudyKey Secondary Endpoints

                                                  Smith SR et al N Engl J Med 2010363245-256

                                                  BLOOM-DMChange in Glycemic Parameters

                                                  P lt001 P lt05 LS mean change plusmn SEMOrsquoNeil PM et al Obesity 201220(7)1426-36 httpwwwnaturecomdoifinder101038oby201266

                                                  00

                                                  -05

                                                  -10

                                                  -150 12 24 36 52

                                                  Cha

                                                  nge

                                                  from

                                                  bas

                                                  elin

                                                  e (

                                                  )

                                                  A1c

                                                  Study week

                                                  0

                                                  -10

                                                  -20

                                                  -30

                                                  -400 12 24 52

                                                  Cha

                                                  nge

                                                  from

                                                  bas

                                                  elin

                                                  e m

                                                  gdl

                                                  )

                                                  Fasting plasma glucose

                                                  Study week

                                                  Lorcaserin 10 mg BID Lorcaserin 10 mg Placebo

                                                  Lorcaserin Adverse Events Reported by 5 or More in Any Group in Year 1

                                                  55

                                                  N () Lorcaserin(N = 1593)

                                                  Placebo(N = 1584)

                                                  Headache 287 (180) 175 (110)

                                                  Dizziness 130 (82) 60 (38)

                                                  Nausea 119 (75) 85 (54)

                                                  Constipation 106 (67) 64 (40)

                                                  Fatigue 95 (60) 48 (30)

                                                  Dry mouth 83 (52) 37 (23)

                                                  Smith SR et al ADA 2009 Late‐Breaking Abstract 96

                                                  LorcaserinNo Increase in Rate of Valvulopathy

                                                  Smith SR et al N Engl J Med 2010363245-256

                                                  10

                                                  8

                                                  6

                                                  4

                                                  2

                                                  024 52 76 104

                                                  1351714

                                                  9

                                                  19

                                                  3421Patie

                                                  nts

                                                  ()

                                                  Week

                                                  Lorcaserin in yr 1 and 2

                                                  Lorcaserin in yr 1 Placebo in yr 2

                                                  Placebo in yr 1 and 2

                                                  Phase III Study Outcomes Compared

                                                  Buproprion SR (360 mgd) Naltrexone SR (32 mgd)

                                                  Lorcaserin(20 mgd)

                                                  Phentermine Topiramate CR

                                                  COR1 COR-I2 COR-II3 NB3043 BLOOM4 BLOSSOM5 EQUIP CONQUER

                                                  Number of patients (ITT-LOCF)

                                                  793 obese 1453 obese

                                                  1281 obese

                                                  502 type II diabetes

                                                  3182 obese 4008 obese

                                                  1230 obese BMI 44

                                                  2448 comorbidBMI 36

                                                  Mean change compared with placebo from base

                                                  93 vs5 1c

                                                  61a vs13c

                                                  64a vs12

                                                  50 a vs12c

                                                  58 vs22c

                                                  48 vs28c

                                                  11 Fullbvs 16

                                                  104 Fullb 84 Midb

                                                  vs 18

                                                  51 Lowb vs16c

                                                  Categorical change 5 compared with placebo from base

                                                  56 vs43

                                                  48a vs164

                                                  563a

                                                  vs 171445a vs189

                                                  475b

                                                  vs 203472b vs25

                                                  67 Fullb 45 Lowb vs17

                                                  70 Fullb 62 Midb

                                                  vs 21

                                                  Phenterminetopiramate doses Low 375 mg phentermine23 mg topiramate Mid 75 mg phentermine 46 mg topiramate Full 15 mg phentermine 92 mg topiramateITT-LOCF intent-to-treat last observation carried forwardData not available aP lt 001 vs placebo bP lt 0001 vs placebo

                                                  Obesity Treatments in Late Development

                                                  Kushner RF Expert Opin Pharmacother 200891339-1350

                                                  Agents ActionBupropionNaltrexone

                                                  bull Dopaminenoradrenaline reuptake inhibitorbull Opioid receptor antagonist

                                                  Liraglutide bull GLP-1 agonist

                                                  BupropionNaltrexone

                                                  bull Mechanism of Actionndash Bupropion - Dopaminenoradrenaline reuptake inhibitorndash Naltrexone- Opioid receptor antagonist

                                                  bull Was approved by FDA committee but FDA did not approve until a CV outcome study is performed 2nd concerns about BP and P in some patients

                                                  bull The Light Study is now underway and reported to be enrolling well under PI Dr Nissen

                                                  bull BupropionNaltrexone will have first completed CV outcome study

                                                  Buproprion ndash Naltrexone

                                                  Greenway FL et al Lancet 2010376(9741)595-605

                                                  0

                                                  -2

                                                  -4

                                                  -6

                                                  -8

                                                  -100 4 8 12 16 20 24 28 32 36 40 44 48 52 56

                                                  Weeks

                                                  Wei

                                                  ght c

                                                  hang

                                                  e fro

                                                  m b

                                                  asel

                                                  ine

                                                  ()

                                                  Placebo

                                                  Naltrexone 16 mg plus bupropion

                                                  Naltrexone 32 mg plus bupropion

                                                  Liraglutide for Weight Loss in Patients with Type 2 Diabetes

                                                  bull GLP-1 analog approved for treatment of type 2 diabetes

                                                  bull Anorectic effect mediated both by the activation of GLP-1 receptor expressed on vagal afferents and by the GLP-1R activation in CNS

                                                  bull Affects visceral fat adiposity appetite food preference and cardiovascular biomarkers in patients with type 2 diabetes

                                                  Inoue K et al Cardiovasc Diabetol 2011 10109 doi1011861475-2840-10-109

                                                  Liraglutide Weight Loss Over 2 Years ITT Observed Means

                                                  Astrup A et al Int J Obes (Lond) 201236(6)843-54

                                                  FromScreening

                                                  -94 kg

                                                  -67 kg-88 kg

                                                  -99 kg-94 kg

                                                  -103 kg

                                                  ITT intention to treat

                                                  Phase III Study Outcomes Compared

                                                  Buproprion SR (360 mgd) Naltrexone SR (32 mgd)

                                                  Lorcaserin(20 mgd)

                                                  Phentermine Topiramate CR

                                                  COR1 COR-I2 COR-II3 NB3043 BLOOM4 BLOSSOM5 EQUIP CONQUER

                                                  Number of patients (ITT-LOCF)

                                                  793 obese 1453 obese

                                                  1281 obese

                                                  502 type II diabetes

                                                  3182 obese 4008 obese

                                                  1230 obese BMI 44

                                                  2448 comorbidBMI 36

                                                  Mean change compared with placebo from base

                                                  93 vs5 1c

                                                  61a vs13c

                                                  64a vs12

                                                  50 a vs12c

                                                  58 vs22c

                                                  48 vs28c

                                                  11 Fullbvs 16

                                                  104 Fullb 84 Midb

                                                  vs 18

                                                  51 Lowb vs16c

                                                  Categorical change 5 compared with placebo from base

                                                  56 vs43

                                                  48a vs164

                                                  563a

                                                  vs 171445a vs189

                                                  475b

                                                  vs 203472b vs25

                                                  67 Fullb 45 Lowb vs17

                                                  70 Fullb 62 Midb

                                                  vs 21

                                                  Phenterminetopiramate doses Low 375 mg phentermine23 mg topiramate Mid 75 mg phentermine 46 mg topiramate Full 15 mg phentermine 92 mg topiramateITT-LOCF intent-to-treat last observation carried forwardData not available aP lt 001 vs placebo bP lt 0001 vs placebo

                                                  Treatment Gap in theManagement of Obesity

                                                  Physicians Need Effective Pharmacotherapies That Will Reduce Weight Significantly and Reduce Weight-related Comorbidities

                                                  0 5 10 15 20 25 30 35

                                                  Diet and Lifestyle Lap Band Gastric Bypass

                                                  TreatmentGap

                                                  What will fill the gap

                                                  Too risky for many peopleNot effective enoughfor many people

                                                  Treatment Gap in theManagement of Obesity

                                                  0 5 10 15 20 25 30 35

                                                  Diet and Lifestyle Lap Band Gastric Bypass

                                                  TreatmentGap

                                                  Too risky for many peopleNot effective enoughfor many people Pharmacotherapy

                                                  Less invasive procedures

                                                  Physicians Need Effective Pharmacotherapies That Will Reduce Weight Significantly and Reduce Weight-related Comorbidities

                                                  What will fill the gap

                                                  • Slide Number 1
                                                  • Slide Number 2
                                                  • Weight Management is Moving into the Workplace and Mainstream of Healthcare
                                                  • US Preventative Services Task Force
                                                  • A Proposal from CMS about Coverage for Intensive Behavioral Therapy for Obesity
                                                  • Slide Number 6
                                                  • Biggest Increases in Clinically Severe Obesity US 1987-2005
                                                  • Relationship Between BMI and Risk of Type 2 Diabetes
                                                  • Slide Number 9
                                                  • Medical Complications of Obesity Almost every organ system is affected
                                                  • Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and disease
                                                  • Current Therapies Often Address Individual Risk Factors Cardiometabolic risk
                                                  • Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and disease
                                                  • Are You Treating These Drivers of Cardiometabolic Risk Should You Treat The Underlying Cause
                                                  • Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors
                                                  • In My Opinion The Winds of Change are Blowing in the Treatment of Chronic Diseases
                                                  • Bariatric Surgery Reduces Overall Mortality Diabetes Mortality by 88
                                                  • Health Care Costs Attributable to ObesityEstimates of what various conditions add to health-care service costs over a 12-month period
                                                  • What-if scenarios (The Lancet forthcoming)
                                                  • How Much Weight Loss Is Needed to Prevent T2DMndashNot Very Much The DPP Experience
                                                  • In the Da Qing Study 6-year Intervention Led to Lower Incidence of Type 2 Diabetes 14 Years Later
                                                  • Slide Number 22
                                                  • Slide Number 23
                                                  • New Compounds andCombination Interventions
                                                  • Phentermine and Topiramate Extended-Release
                                                  • Phentermine and Topiramate Extended-Release
                                                  • EQUIP amp CONQUER Discontinuation RateDue to AEs in All Doses Studied
                                                  • Phentermine and Topiramate SEQUELWeight Loss Over Time
                                                  • CONQUER Significant Improvement in Cardiovascular Risk Factors
                                                  • Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors
                                                  • Lorcaserin
                                                  • BLOOM Study Body Weight Over Years 1 and 2
                                                  • BLOOM StudyKey Secondary Endpoints
                                                  • BLOOM-DMChange in Glycemic Parameters
                                                  • Lorcaserin Adverse Events Reported by 5 or More in Any Group in Year 1
                                                  • LorcaserinNo Increase in Rate of Valvulopathy
                                                  • Phase III Study Outcomes Compared
                                                  • Obesity Treatments in Late Development
                                                  • BupropionNaltrexone
                                                  • Buproprion ndash Naltrexone
                                                  • Liraglutide for Weight Loss in Patients with Type 2 Diabetes
                                                  • Liraglutide Weight Loss Over 2 Years ITT Observed Means
                                                  • Phase III Study Outcomes Compared
                                                  • Treatment Gap in theManagement of Obesity
                                                  • Treatment Gap in theManagement of Obesity

                                                    EQUIP amp CONQUER Discontinuation RateDue to AEs in All Doses Studied

                                                    Placebo Low Mid Full

                                                    Number of patients 1508 241 498 1507Discontinuation due to AEs 9 12 12 18Blurred vision 05 21 08 07Headache 07 17 02 09Insomnia 04 00 04 17Depression 02 00 08 14Tingling 00 04 10 12Irritability 01 08 08 12Anxiety 03 00 02 11Dizziness 02 04 12 08

                                                    Includes adverse events (AEs) by dose for EQUIP amp CONQUER which lead to discontinuation in gt 1 of patientsPress release Sept 9 2009 Available at httpirvivuscomreleasedetailcfmReleaseID=420114Accessed April 27 2010

                                                    PhenTPMMid

                                                    -104

                                                    Phentermine and Topiramate SEQUELWeight Loss Over Time

                                                    Garvey WT Ryan DH Look M Gadde KM Am J Clin Nutr 201295(2)297-308

                                                    Placebo-25

                                                    Plt00001 v placebo

                                                    Weight Loss

                                                    Week

                                                    Total Population

                                                    0

                                                    -2

                                                    -4

                                                    -6

                                                    -8

                                                    -10

                                                    -12

                                                    -14

                                                    -16

                                                    0 12 24 36 48 60 72 84 96 108

                                                    Weight Loss ITT-LOCF

                                                    PhenTPMTop

                                                    -114

                                                    Mid = 75 mg46 mgTop = 15 mg92 mg

                                                    CONQUER Significant Improvement in Cardiovascular Risk Factors

                                                    (LS Mean Wt Loss)

                                                    QNEXAMid(78)

                                                    P valueQNEXATop

                                                    (98) P value

                                                    Waist Circumference (cm) ‐52 lt00001 ‐68 lt00001

                                                    Systolic BP (mmHg) ‐23 00008 ‐32 lt00001

                                                    Diastolic BP (mmHg) ‐07 NS ‐11 00031

                                                    Triglycerides ( ∆) ‐133 lt00001 ‐153 lt00001

                                                    Total Cholesterol ( ∆) ‐16 00345 ‐30 lt00001

                                                    LDL ( ∆) 04 NS ‐28 00069

                                                    HDL ( ∆) 40 lt00001 56 lt00001

                                                    P values represent comparisons to placebo NS= non‐significant

                                                    ITT‐LOCF Placebo ComparisonsTotal Study Population

                                                    Davidson MH et al Am J Cardiol 2013 Jan 29 pii S0002‐9149(12)02641‐0 doi 101016jamjcard201212038

                                                    Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors

                                                    Risk FactorsPhenTPMMid

                                                    p-valuePhenTPMTop

                                                    p-value

                                                    CRP lt0001 lt0001Fibrinogen lt005 lt005Adiponectin lt00001 lt00001

                                                    p-values represent comparisons to placebo

                                                    ITT-LOCF Placebo Comparisons

                                                    Gadde KM et al Lancet 2011377(9774)1341-52

                                                    Mid = 75 mg46 mgTop = 15 mg92 mg

                                                    Lorcaserin

                                                    bull Selective 5‐HT2C receptor agonist designed to promote weight loss

                                                    bull Schedule IV ndash Expected soonbull Indication weight loss and maintenance of

                                                    weight loss in patients with BMI gt30 kgm2 or BMI gt27 kgm2 + weight-related comorbidcondition(s)

                                                    bull Dose - 10 mg BIDbull Most common side effects headache nausea

                                                    dizziness dry mouth

                                                    BLOOM Study Body Weight Over Years 1 and 2

                                                    Smith SR et al N Engl J Med 2010363245-256 Study Week0 8 16 24 32 40 48 56 64 72 80 88 96 104

                                                    Bod

                                                    y W

                                                    eigh

                                                    t (kg

                                                    )

                                                    102

                                                    100

                                                    98

                                                    96

                                                    94

                                                    92

                                                    90

                                                    0

                                                    Year 1

                                                    Placebo in year 1 and 2 (n = 684)Lorcaserin in year 1 placebo in year 2 (n = 275)Lorcaserin in year 1 and 2 (n = 564)

                                                    Year 2

                                                    Endpoint Lorcaserin Placebo P valueWaist circumference (cm) minus68plusmn02 minus39plusmn02 lt001BMI (kgm2) minus209plusmn006 minus078plusmn005 lt001SBPDBP (mm Hg) minus14plusmn03minus11plusmn02 minus08plusmn03minus06plusmn02 0401Cholesterol ( ∆)Total LDLHDL

                                                    minus090plusmn033287plusmn056005plusmn033

                                                    057plusmn034403plusmn058minus021plusmn034

                                                    001

                                                    049

                                                    72Triglycerides minus615plusmn103 minus014plusmn099 lt001SafetyHR (beatsmin)PASP (mm Hg)Beck depression II score

                                                    minus20plusmn03minus092plusmn023minus11plusmn01

                                                    minus16plusmn04 minus023plusmn023 minus09plusmn01

                                                    0499014026

                                                    BLOOM StudyKey Secondary Endpoints

                                                    Smith SR et al N Engl J Med 2010363245-256

                                                    BLOOM-DMChange in Glycemic Parameters

                                                    P lt001 P lt05 LS mean change plusmn SEMOrsquoNeil PM et al Obesity 201220(7)1426-36 httpwwwnaturecomdoifinder101038oby201266

                                                    00

                                                    -05

                                                    -10

                                                    -150 12 24 36 52

                                                    Cha

                                                    nge

                                                    from

                                                    bas

                                                    elin

                                                    e (

                                                    )

                                                    A1c

                                                    Study week

                                                    0

                                                    -10

                                                    -20

                                                    -30

                                                    -400 12 24 52

                                                    Cha

                                                    nge

                                                    from

                                                    bas

                                                    elin

                                                    e m

                                                    gdl

                                                    )

                                                    Fasting plasma glucose

                                                    Study week

                                                    Lorcaserin 10 mg BID Lorcaserin 10 mg Placebo

                                                    Lorcaserin Adverse Events Reported by 5 or More in Any Group in Year 1

                                                    55

                                                    N () Lorcaserin(N = 1593)

                                                    Placebo(N = 1584)

                                                    Headache 287 (180) 175 (110)

                                                    Dizziness 130 (82) 60 (38)

                                                    Nausea 119 (75) 85 (54)

                                                    Constipation 106 (67) 64 (40)

                                                    Fatigue 95 (60) 48 (30)

                                                    Dry mouth 83 (52) 37 (23)

                                                    Smith SR et al ADA 2009 Late‐Breaking Abstract 96

                                                    LorcaserinNo Increase in Rate of Valvulopathy

                                                    Smith SR et al N Engl J Med 2010363245-256

                                                    10

                                                    8

                                                    6

                                                    4

                                                    2

                                                    024 52 76 104

                                                    1351714

                                                    9

                                                    19

                                                    3421Patie

                                                    nts

                                                    ()

                                                    Week

                                                    Lorcaserin in yr 1 and 2

                                                    Lorcaserin in yr 1 Placebo in yr 2

                                                    Placebo in yr 1 and 2

                                                    Phase III Study Outcomes Compared

                                                    Buproprion SR (360 mgd) Naltrexone SR (32 mgd)

                                                    Lorcaserin(20 mgd)

                                                    Phentermine Topiramate CR

                                                    COR1 COR-I2 COR-II3 NB3043 BLOOM4 BLOSSOM5 EQUIP CONQUER

                                                    Number of patients (ITT-LOCF)

                                                    793 obese 1453 obese

                                                    1281 obese

                                                    502 type II diabetes

                                                    3182 obese 4008 obese

                                                    1230 obese BMI 44

                                                    2448 comorbidBMI 36

                                                    Mean change compared with placebo from base

                                                    93 vs5 1c

                                                    61a vs13c

                                                    64a vs12

                                                    50 a vs12c

                                                    58 vs22c

                                                    48 vs28c

                                                    11 Fullbvs 16

                                                    104 Fullb 84 Midb

                                                    vs 18

                                                    51 Lowb vs16c

                                                    Categorical change 5 compared with placebo from base

                                                    56 vs43

                                                    48a vs164

                                                    563a

                                                    vs 171445a vs189

                                                    475b

                                                    vs 203472b vs25

                                                    67 Fullb 45 Lowb vs17

                                                    70 Fullb 62 Midb

                                                    vs 21

                                                    Phenterminetopiramate doses Low 375 mg phentermine23 mg topiramate Mid 75 mg phentermine 46 mg topiramate Full 15 mg phentermine 92 mg topiramateITT-LOCF intent-to-treat last observation carried forwardData not available aP lt 001 vs placebo bP lt 0001 vs placebo

                                                    Obesity Treatments in Late Development

                                                    Kushner RF Expert Opin Pharmacother 200891339-1350

                                                    Agents ActionBupropionNaltrexone

                                                    bull Dopaminenoradrenaline reuptake inhibitorbull Opioid receptor antagonist

                                                    Liraglutide bull GLP-1 agonist

                                                    BupropionNaltrexone

                                                    bull Mechanism of Actionndash Bupropion - Dopaminenoradrenaline reuptake inhibitorndash Naltrexone- Opioid receptor antagonist

                                                    bull Was approved by FDA committee but FDA did not approve until a CV outcome study is performed 2nd concerns about BP and P in some patients

                                                    bull The Light Study is now underway and reported to be enrolling well under PI Dr Nissen

                                                    bull BupropionNaltrexone will have first completed CV outcome study

                                                    Buproprion ndash Naltrexone

                                                    Greenway FL et al Lancet 2010376(9741)595-605

                                                    0

                                                    -2

                                                    -4

                                                    -6

                                                    -8

                                                    -100 4 8 12 16 20 24 28 32 36 40 44 48 52 56

                                                    Weeks

                                                    Wei

                                                    ght c

                                                    hang

                                                    e fro

                                                    m b

                                                    asel

                                                    ine

                                                    ()

                                                    Placebo

                                                    Naltrexone 16 mg plus bupropion

                                                    Naltrexone 32 mg plus bupropion

                                                    Liraglutide for Weight Loss in Patients with Type 2 Diabetes

                                                    bull GLP-1 analog approved for treatment of type 2 diabetes

                                                    bull Anorectic effect mediated both by the activation of GLP-1 receptor expressed on vagal afferents and by the GLP-1R activation in CNS

                                                    bull Affects visceral fat adiposity appetite food preference and cardiovascular biomarkers in patients with type 2 diabetes

                                                    Inoue K et al Cardiovasc Diabetol 2011 10109 doi1011861475-2840-10-109

                                                    Liraglutide Weight Loss Over 2 Years ITT Observed Means

                                                    Astrup A et al Int J Obes (Lond) 201236(6)843-54

                                                    FromScreening

                                                    -94 kg

                                                    -67 kg-88 kg

                                                    -99 kg-94 kg

                                                    -103 kg

                                                    ITT intention to treat

                                                    Phase III Study Outcomes Compared

                                                    Buproprion SR (360 mgd) Naltrexone SR (32 mgd)

                                                    Lorcaserin(20 mgd)

                                                    Phentermine Topiramate CR

                                                    COR1 COR-I2 COR-II3 NB3043 BLOOM4 BLOSSOM5 EQUIP CONQUER

                                                    Number of patients (ITT-LOCF)

                                                    793 obese 1453 obese

                                                    1281 obese

                                                    502 type II diabetes

                                                    3182 obese 4008 obese

                                                    1230 obese BMI 44

                                                    2448 comorbidBMI 36

                                                    Mean change compared with placebo from base

                                                    93 vs5 1c

                                                    61a vs13c

                                                    64a vs12

                                                    50 a vs12c

                                                    58 vs22c

                                                    48 vs28c

                                                    11 Fullbvs 16

                                                    104 Fullb 84 Midb

                                                    vs 18

                                                    51 Lowb vs16c

                                                    Categorical change 5 compared with placebo from base

                                                    56 vs43

                                                    48a vs164

                                                    563a

                                                    vs 171445a vs189

                                                    475b

                                                    vs 203472b vs25

                                                    67 Fullb 45 Lowb vs17

                                                    70 Fullb 62 Midb

                                                    vs 21

                                                    Phenterminetopiramate doses Low 375 mg phentermine23 mg topiramate Mid 75 mg phentermine 46 mg topiramate Full 15 mg phentermine 92 mg topiramateITT-LOCF intent-to-treat last observation carried forwardData not available aP lt 001 vs placebo bP lt 0001 vs placebo

                                                    Treatment Gap in theManagement of Obesity

                                                    Physicians Need Effective Pharmacotherapies That Will Reduce Weight Significantly and Reduce Weight-related Comorbidities

                                                    0 5 10 15 20 25 30 35

                                                    Diet and Lifestyle Lap Band Gastric Bypass

                                                    TreatmentGap

                                                    What will fill the gap

                                                    Too risky for many peopleNot effective enoughfor many people

                                                    Treatment Gap in theManagement of Obesity

                                                    0 5 10 15 20 25 30 35

                                                    Diet and Lifestyle Lap Band Gastric Bypass

                                                    TreatmentGap

                                                    Too risky for many peopleNot effective enoughfor many people Pharmacotherapy

                                                    Less invasive procedures

                                                    Physicians Need Effective Pharmacotherapies That Will Reduce Weight Significantly and Reduce Weight-related Comorbidities

                                                    What will fill the gap

                                                    • Slide Number 1
                                                    • Slide Number 2
                                                    • Weight Management is Moving into the Workplace and Mainstream of Healthcare
                                                    • US Preventative Services Task Force
                                                    • A Proposal from CMS about Coverage for Intensive Behavioral Therapy for Obesity
                                                    • Slide Number 6
                                                    • Biggest Increases in Clinically Severe Obesity US 1987-2005
                                                    • Relationship Between BMI and Risk of Type 2 Diabetes
                                                    • Slide Number 9
                                                    • Medical Complications of Obesity Almost every organ system is affected
                                                    • Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and disease
                                                    • Current Therapies Often Address Individual Risk Factors Cardiometabolic risk
                                                    • Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and disease
                                                    • Are You Treating These Drivers of Cardiometabolic Risk Should You Treat The Underlying Cause
                                                    • Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors
                                                    • In My Opinion The Winds of Change are Blowing in the Treatment of Chronic Diseases
                                                    • Bariatric Surgery Reduces Overall Mortality Diabetes Mortality by 88
                                                    • Health Care Costs Attributable to ObesityEstimates of what various conditions add to health-care service costs over a 12-month period
                                                    • What-if scenarios (The Lancet forthcoming)
                                                    • How Much Weight Loss Is Needed to Prevent T2DMndashNot Very Much The DPP Experience
                                                    • In the Da Qing Study 6-year Intervention Led to Lower Incidence of Type 2 Diabetes 14 Years Later
                                                    • Slide Number 22
                                                    • Slide Number 23
                                                    • New Compounds andCombination Interventions
                                                    • Phentermine and Topiramate Extended-Release
                                                    • Phentermine and Topiramate Extended-Release
                                                    • EQUIP amp CONQUER Discontinuation RateDue to AEs in All Doses Studied
                                                    • Phentermine and Topiramate SEQUELWeight Loss Over Time
                                                    • CONQUER Significant Improvement in Cardiovascular Risk Factors
                                                    • Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors
                                                    • Lorcaserin
                                                    • BLOOM Study Body Weight Over Years 1 and 2
                                                    • BLOOM StudyKey Secondary Endpoints
                                                    • BLOOM-DMChange in Glycemic Parameters
                                                    • Lorcaserin Adverse Events Reported by 5 or More in Any Group in Year 1
                                                    • LorcaserinNo Increase in Rate of Valvulopathy
                                                    • Phase III Study Outcomes Compared
                                                    • Obesity Treatments in Late Development
                                                    • BupropionNaltrexone
                                                    • Buproprion ndash Naltrexone
                                                    • Liraglutide for Weight Loss in Patients with Type 2 Diabetes
                                                    • Liraglutide Weight Loss Over 2 Years ITT Observed Means
                                                    • Phase III Study Outcomes Compared
                                                    • Treatment Gap in theManagement of Obesity
                                                    • Treatment Gap in theManagement of Obesity

                                                      PhenTPMMid

                                                      -104

                                                      Phentermine and Topiramate SEQUELWeight Loss Over Time

                                                      Garvey WT Ryan DH Look M Gadde KM Am J Clin Nutr 201295(2)297-308

                                                      Placebo-25

                                                      Plt00001 v placebo

                                                      Weight Loss

                                                      Week

                                                      Total Population

                                                      0

                                                      -2

                                                      -4

                                                      -6

                                                      -8

                                                      -10

                                                      -12

                                                      -14

                                                      -16

                                                      0 12 24 36 48 60 72 84 96 108

                                                      Weight Loss ITT-LOCF

                                                      PhenTPMTop

                                                      -114

                                                      Mid = 75 mg46 mgTop = 15 mg92 mg

                                                      CONQUER Significant Improvement in Cardiovascular Risk Factors

                                                      (LS Mean Wt Loss)

                                                      QNEXAMid(78)

                                                      P valueQNEXATop

                                                      (98) P value

                                                      Waist Circumference (cm) ‐52 lt00001 ‐68 lt00001

                                                      Systolic BP (mmHg) ‐23 00008 ‐32 lt00001

                                                      Diastolic BP (mmHg) ‐07 NS ‐11 00031

                                                      Triglycerides ( ∆) ‐133 lt00001 ‐153 lt00001

                                                      Total Cholesterol ( ∆) ‐16 00345 ‐30 lt00001

                                                      LDL ( ∆) 04 NS ‐28 00069

                                                      HDL ( ∆) 40 lt00001 56 lt00001

                                                      P values represent comparisons to placebo NS= non‐significant

                                                      ITT‐LOCF Placebo ComparisonsTotal Study Population

                                                      Davidson MH et al Am J Cardiol 2013 Jan 29 pii S0002‐9149(12)02641‐0 doi 101016jamjcard201212038

                                                      Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors

                                                      Risk FactorsPhenTPMMid

                                                      p-valuePhenTPMTop

                                                      p-value

                                                      CRP lt0001 lt0001Fibrinogen lt005 lt005Adiponectin lt00001 lt00001

                                                      p-values represent comparisons to placebo

                                                      ITT-LOCF Placebo Comparisons

                                                      Gadde KM et al Lancet 2011377(9774)1341-52

                                                      Mid = 75 mg46 mgTop = 15 mg92 mg

                                                      Lorcaserin

                                                      bull Selective 5‐HT2C receptor agonist designed to promote weight loss

                                                      bull Schedule IV ndash Expected soonbull Indication weight loss and maintenance of

                                                      weight loss in patients with BMI gt30 kgm2 or BMI gt27 kgm2 + weight-related comorbidcondition(s)

                                                      bull Dose - 10 mg BIDbull Most common side effects headache nausea

                                                      dizziness dry mouth

                                                      BLOOM Study Body Weight Over Years 1 and 2

                                                      Smith SR et al N Engl J Med 2010363245-256 Study Week0 8 16 24 32 40 48 56 64 72 80 88 96 104

                                                      Bod

                                                      y W

                                                      eigh

                                                      t (kg

                                                      )

                                                      102

                                                      100

                                                      98

                                                      96

                                                      94

                                                      92

                                                      90

                                                      0

                                                      Year 1

                                                      Placebo in year 1 and 2 (n = 684)Lorcaserin in year 1 placebo in year 2 (n = 275)Lorcaserin in year 1 and 2 (n = 564)

                                                      Year 2

                                                      Endpoint Lorcaserin Placebo P valueWaist circumference (cm) minus68plusmn02 minus39plusmn02 lt001BMI (kgm2) minus209plusmn006 minus078plusmn005 lt001SBPDBP (mm Hg) minus14plusmn03minus11plusmn02 minus08plusmn03minus06plusmn02 0401Cholesterol ( ∆)Total LDLHDL

                                                      minus090plusmn033287plusmn056005plusmn033

                                                      057plusmn034403plusmn058minus021plusmn034

                                                      001

                                                      049

                                                      72Triglycerides minus615plusmn103 minus014plusmn099 lt001SafetyHR (beatsmin)PASP (mm Hg)Beck depression II score

                                                      minus20plusmn03minus092plusmn023minus11plusmn01

                                                      minus16plusmn04 minus023plusmn023 minus09plusmn01

                                                      0499014026

                                                      BLOOM StudyKey Secondary Endpoints

                                                      Smith SR et al N Engl J Med 2010363245-256

                                                      BLOOM-DMChange in Glycemic Parameters

                                                      P lt001 P lt05 LS mean change plusmn SEMOrsquoNeil PM et al Obesity 201220(7)1426-36 httpwwwnaturecomdoifinder101038oby201266

                                                      00

                                                      -05

                                                      -10

                                                      -150 12 24 36 52

                                                      Cha

                                                      nge

                                                      from

                                                      bas

                                                      elin

                                                      e (

                                                      )

                                                      A1c

                                                      Study week

                                                      0

                                                      -10

                                                      -20

                                                      -30

                                                      -400 12 24 52

                                                      Cha

                                                      nge

                                                      from

                                                      bas

                                                      elin

                                                      e m

                                                      gdl

                                                      )

                                                      Fasting plasma glucose

                                                      Study week

                                                      Lorcaserin 10 mg BID Lorcaserin 10 mg Placebo

                                                      Lorcaserin Adverse Events Reported by 5 or More in Any Group in Year 1

                                                      55

                                                      N () Lorcaserin(N = 1593)

                                                      Placebo(N = 1584)

                                                      Headache 287 (180) 175 (110)

                                                      Dizziness 130 (82) 60 (38)

                                                      Nausea 119 (75) 85 (54)

                                                      Constipation 106 (67) 64 (40)

                                                      Fatigue 95 (60) 48 (30)

                                                      Dry mouth 83 (52) 37 (23)

                                                      Smith SR et al ADA 2009 Late‐Breaking Abstract 96

                                                      LorcaserinNo Increase in Rate of Valvulopathy

                                                      Smith SR et al N Engl J Med 2010363245-256

                                                      10

                                                      8

                                                      6

                                                      4

                                                      2

                                                      024 52 76 104

                                                      1351714

                                                      9

                                                      19

                                                      3421Patie

                                                      nts

                                                      ()

                                                      Week

                                                      Lorcaserin in yr 1 and 2

                                                      Lorcaserin in yr 1 Placebo in yr 2

                                                      Placebo in yr 1 and 2

                                                      Phase III Study Outcomes Compared

                                                      Buproprion SR (360 mgd) Naltrexone SR (32 mgd)

                                                      Lorcaserin(20 mgd)

                                                      Phentermine Topiramate CR

                                                      COR1 COR-I2 COR-II3 NB3043 BLOOM4 BLOSSOM5 EQUIP CONQUER

                                                      Number of patients (ITT-LOCF)

                                                      793 obese 1453 obese

                                                      1281 obese

                                                      502 type II diabetes

                                                      3182 obese 4008 obese

                                                      1230 obese BMI 44

                                                      2448 comorbidBMI 36

                                                      Mean change compared with placebo from base

                                                      93 vs5 1c

                                                      61a vs13c

                                                      64a vs12

                                                      50 a vs12c

                                                      58 vs22c

                                                      48 vs28c

                                                      11 Fullbvs 16

                                                      104 Fullb 84 Midb

                                                      vs 18

                                                      51 Lowb vs16c

                                                      Categorical change 5 compared with placebo from base

                                                      56 vs43

                                                      48a vs164

                                                      563a

                                                      vs 171445a vs189

                                                      475b

                                                      vs 203472b vs25

                                                      67 Fullb 45 Lowb vs17

                                                      70 Fullb 62 Midb

                                                      vs 21

                                                      Phenterminetopiramate doses Low 375 mg phentermine23 mg topiramate Mid 75 mg phentermine 46 mg topiramate Full 15 mg phentermine 92 mg topiramateITT-LOCF intent-to-treat last observation carried forwardData not available aP lt 001 vs placebo bP lt 0001 vs placebo

                                                      Obesity Treatments in Late Development

                                                      Kushner RF Expert Opin Pharmacother 200891339-1350

                                                      Agents ActionBupropionNaltrexone

                                                      bull Dopaminenoradrenaline reuptake inhibitorbull Opioid receptor antagonist

                                                      Liraglutide bull GLP-1 agonist

                                                      BupropionNaltrexone

                                                      bull Mechanism of Actionndash Bupropion - Dopaminenoradrenaline reuptake inhibitorndash Naltrexone- Opioid receptor antagonist

                                                      bull Was approved by FDA committee but FDA did not approve until a CV outcome study is performed 2nd concerns about BP and P in some patients

                                                      bull The Light Study is now underway and reported to be enrolling well under PI Dr Nissen

                                                      bull BupropionNaltrexone will have first completed CV outcome study

                                                      Buproprion ndash Naltrexone

                                                      Greenway FL et al Lancet 2010376(9741)595-605

                                                      0

                                                      -2

                                                      -4

                                                      -6

                                                      -8

                                                      -100 4 8 12 16 20 24 28 32 36 40 44 48 52 56

                                                      Weeks

                                                      Wei

                                                      ght c

                                                      hang

                                                      e fro

                                                      m b

                                                      asel

                                                      ine

                                                      ()

                                                      Placebo

                                                      Naltrexone 16 mg plus bupropion

                                                      Naltrexone 32 mg plus bupropion

                                                      Liraglutide for Weight Loss in Patients with Type 2 Diabetes

                                                      bull GLP-1 analog approved for treatment of type 2 diabetes

                                                      bull Anorectic effect mediated both by the activation of GLP-1 receptor expressed on vagal afferents and by the GLP-1R activation in CNS

                                                      bull Affects visceral fat adiposity appetite food preference and cardiovascular biomarkers in patients with type 2 diabetes

                                                      Inoue K et al Cardiovasc Diabetol 2011 10109 doi1011861475-2840-10-109

                                                      Liraglutide Weight Loss Over 2 Years ITT Observed Means

                                                      Astrup A et al Int J Obes (Lond) 201236(6)843-54

                                                      FromScreening

                                                      -94 kg

                                                      -67 kg-88 kg

                                                      -99 kg-94 kg

                                                      -103 kg

                                                      ITT intention to treat

                                                      Phase III Study Outcomes Compared

                                                      Buproprion SR (360 mgd) Naltrexone SR (32 mgd)

                                                      Lorcaserin(20 mgd)

                                                      Phentermine Topiramate CR

                                                      COR1 COR-I2 COR-II3 NB3043 BLOOM4 BLOSSOM5 EQUIP CONQUER

                                                      Number of patients (ITT-LOCF)

                                                      793 obese 1453 obese

                                                      1281 obese

                                                      502 type II diabetes

                                                      3182 obese 4008 obese

                                                      1230 obese BMI 44

                                                      2448 comorbidBMI 36

                                                      Mean change compared with placebo from base

                                                      93 vs5 1c

                                                      61a vs13c

                                                      64a vs12

                                                      50 a vs12c

                                                      58 vs22c

                                                      48 vs28c

                                                      11 Fullbvs 16

                                                      104 Fullb 84 Midb

                                                      vs 18

                                                      51 Lowb vs16c

                                                      Categorical change 5 compared with placebo from base

                                                      56 vs43

                                                      48a vs164

                                                      563a

                                                      vs 171445a vs189

                                                      475b

                                                      vs 203472b vs25

                                                      67 Fullb 45 Lowb vs17

                                                      70 Fullb 62 Midb

                                                      vs 21

                                                      Phenterminetopiramate doses Low 375 mg phentermine23 mg topiramate Mid 75 mg phentermine 46 mg topiramate Full 15 mg phentermine 92 mg topiramateITT-LOCF intent-to-treat last observation carried forwardData not available aP lt 001 vs placebo bP lt 0001 vs placebo

                                                      Treatment Gap in theManagement of Obesity

                                                      Physicians Need Effective Pharmacotherapies That Will Reduce Weight Significantly and Reduce Weight-related Comorbidities

                                                      0 5 10 15 20 25 30 35

                                                      Diet and Lifestyle Lap Band Gastric Bypass

                                                      TreatmentGap

                                                      What will fill the gap

                                                      Too risky for many peopleNot effective enoughfor many people

                                                      Treatment Gap in theManagement of Obesity

                                                      0 5 10 15 20 25 30 35

                                                      Diet and Lifestyle Lap Band Gastric Bypass

                                                      TreatmentGap

                                                      Too risky for many peopleNot effective enoughfor many people Pharmacotherapy

                                                      Less invasive procedures

                                                      Physicians Need Effective Pharmacotherapies That Will Reduce Weight Significantly and Reduce Weight-related Comorbidities

                                                      What will fill the gap

                                                      • Slide Number 1
                                                      • Slide Number 2
                                                      • Weight Management is Moving into the Workplace and Mainstream of Healthcare
                                                      • US Preventative Services Task Force
                                                      • A Proposal from CMS about Coverage for Intensive Behavioral Therapy for Obesity
                                                      • Slide Number 6
                                                      • Biggest Increases in Clinically Severe Obesity US 1987-2005
                                                      • Relationship Between BMI and Risk of Type 2 Diabetes
                                                      • Slide Number 9
                                                      • Medical Complications of Obesity Almost every organ system is affected
                                                      • Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and disease
                                                      • Current Therapies Often Address Individual Risk Factors Cardiometabolic risk
                                                      • Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and disease
                                                      • Are You Treating These Drivers of Cardiometabolic Risk Should You Treat The Underlying Cause
                                                      • Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors
                                                      • In My Opinion The Winds of Change are Blowing in the Treatment of Chronic Diseases
                                                      • Bariatric Surgery Reduces Overall Mortality Diabetes Mortality by 88
                                                      • Health Care Costs Attributable to ObesityEstimates of what various conditions add to health-care service costs over a 12-month period
                                                      • What-if scenarios (The Lancet forthcoming)
                                                      • How Much Weight Loss Is Needed to Prevent T2DMndashNot Very Much The DPP Experience
                                                      • In the Da Qing Study 6-year Intervention Led to Lower Incidence of Type 2 Diabetes 14 Years Later
                                                      • Slide Number 22
                                                      • Slide Number 23
                                                      • New Compounds andCombination Interventions
                                                      • Phentermine and Topiramate Extended-Release
                                                      • Phentermine and Topiramate Extended-Release
                                                      • EQUIP amp CONQUER Discontinuation RateDue to AEs in All Doses Studied
                                                      • Phentermine and Topiramate SEQUELWeight Loss Over Time
                                                      • CONQUER Significant Improvement in Cardiovascular Risk Factors
                                                      • Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors
                                                      • Lorcaserin
                                                      • BLOOM Study Body Weight Over Years 1 and 2
                                                      • BLOOM StudyKey Secondary Endpoints
                                                      • BLOOM-DMChange in Glycemic Parameters
                                                      • Lorcaserin Adverse Events Reported by 5 or More in Any Group in Year 1
                                                      • LorcaserinNo Increase in Rate of Valvulopathy
                                                      • Phase III Study Outcomes Compared
                                                      • Obesity Treatments in Late Development
                                                      • BupropionNaltrexone
                                                      • Buproprion ndash Naltrexone
                                                      • Liraglutide for Weight Loss in Patients with Type 2 Diabetes
                                                      • Liraglutide Weight Loss Over 2 Years ITT Observed Means
                                                      • Phase III Study Outcomes Compared
                                                      • Treatment Gap in theManagement of Obesity
                                                      • Treatment Gap in theManagement of Obesity

                                                        CONQUER Significant Improvement in Cardiovascular Risk Factors

                                                        (LS Mean Wt Loss)

                                                        QNEXAMid(78)

                                                        P valueQNEXATop

                                                        (98) P value

                                                        Waist Circumference (cm) ‐52 lt00001 ‐68 lt00001

                                                        Systolic BP (mmHg) ‐23 00008 ‐32 lt00001

                                                        Diastolic BP (mmHg) ‐07 NS ‐11 00031

                                                        Triglycerides ( ∆) ‐133 lt00001 ‐153 lt00001

                                                        Total Cholesterol ( ∆) ‐16 00345 ‐30 lt00001

                                                        LDL ( ∆) 04 NS ‐28 00069

                                                        HDL ( ∆) 40 lt00001 56 lt00001

                                                        P values represent comparisons to placebo NS= non‐significant

                                                        ITT‐LOCF Placebo ComparisonsTotal Study Population

                                                        Davidson MH et al Am J Cardiol 2013 Jan 29 pii S0002‐9149(12)02641‐0 doi 101016jamjcard201212038

                                                        Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors

                                                        Risk FactorsPhenTPMMid

                                                        p-valuePhenTPMTop

                                                        p-value

                                                        CRP lt0001 lt0001Fibrinogen lt005 lt005Adiponectin lt00001 lt00001

                                                        p-values represent comparisons to placebo

                                                        ITT-LOCF Placebo Comparisons

                                                        Gadde KM et al Lancet 2011377(9774)1341-52

                                                        Mid = 75 mg46 mgTop = 15 mg92 mg

                                                        Lorcaserin

                                                        bull Selective 5‐HT2C receptor agonist designed to promote weight loss

                                                        bull Schedule IV ndash Expected soonbull Indication weight loss and maintenance of

                                                        weight loss in patients with BMI gt30 kgm2 or BMI gt27 kgm2 + weight-related comorbidcondition(s)

                                                        bull Dose - 10 mg BIDbull Most common side effects headache nausea

                                                        dizziness dry mouth

                                                        BLOOM Study Body Weight Over Years 1 and 2

                                                        Smith SR et al N Engl J Med 2010363245-256 Study Week0 8 16 24 32 40 48 56 64 72 80 88 96 104

                                                        Bod

                                                        y W

                                                        eigh

                                                        t (kg

                                                        )

                                                        102

                                                        100

                                                        98

                                                        96

                                                        94

                                                        92

                                                        90

                                                        0

                                                        Year 1

                                                        Placebo in year 1 and 2 (n = 684)Lorcaserin in year 1 placebo in year 2 (n = 275)Lorcaserin in year 1 and 2 (n = 564)

                                                        Year 2

                                                        Endpoint Lorcaserin Placebo P valueWaist circumference (cm) minus68plusmn02 minus39plusmn02 lt001BMI (kgm2) minus209plusmn006 minus078plusmn005 lt001SBPDBP (mm Hg) minus14plusmn03minus11plusmn02 minus08plusmn03minus06plusmn02 0401Cholesterol ( ∆)Total LDLHDL

                                                        minus090plusmn033287plusmn056005plusmn033

                                                        057plusmn034403plusmn058minus021plusmn034

                                                        001

                                                        049

                                                        72Triglycerides minus615plusmn103 minus014plusmn099 lt001SafetyHR (beatsmin)PASP (mm Hg)Beck depression II score

                                                        minus20plusmn03minus092plusmn023minus11plusmn01

                                                        minus16plusmn04 minus023plusmn023 minus09plusmn01

                                                        0499014026

                                                        BLOOM StudyKey Secondary Endpoints

                                                        Smith SR et al N Engl J Med 2010363245-256

                                                        BLOOM-DMChange in Glycemic Parameters

                                                        P lt001 P lt05 LS mean change plusmn SEMOrsquoNeil PM et al Obesity 201220(7)1426-36 httpwwwnaturecomdoifinder101038oby201266

                                                        00

                                                        -05

                                                        -10

                                                        -150 12 24 36 52

                                                        Cha

                                                        nge

                                                        from

                                                        bas

                                                        elin

                                                        e (

                                                        )

                                                        A1c

                                                        Study week

                                                        0

                                                        -10

                                                        -20

                                                        -30

                                                        -400 12 24 52

                                                        Cha

                                                        nge

                                                        from

                                                        bas

                                                        elin

                                                        e m

                                                        gdl

                                                        )

                                                        Fasting plasma glucose

                                                        Study week

                                                        Lorcaserin 10 mg BID Lorcaserin 10 mg Placebo

                                                        Lorcaserin Adverse Events Reported by 5 or More in Any Group in Year 1

                                                        55

                                                        N () Lorcaserin(N = 1593)

                                                        Placebo(N = 1584)

                                                        Headache 287 (180) 175 (110)

                                                        Dizziness 130 (82) 60 (38)

                                                        Nausea 119 (75) 85 (54)

                                                        Constipation 106 (67) 64 (40)

                                                        Fatigue 95 (60) 48 (30)

                                                        Dry mouth 83 (52) 37 (23)

                                                        Smith SR et al ADA 2009 Late‐Breaking Abstract 96

                                                        LorcaserinNo Increase in Rate of Valvulopathy

                                                        Smith SR et al N Engl J Med 2010363245-256

                                                        10

                                                        8

                                                        6

                                                        4

                                                        2

                                                        024 52 76 104

                                                        1351714

                                                        9

                                                        19

                                                        3421Patie

                                                        nts

                                                        ()

                                                        Week

                                                        Lorcaserin in yr 1 and 2

                                                        Lorcaserin in yr 1 Placebo in yr 2

                                                        Placebo in yr 1 and 2

                                                        Phase III Study Outcomes Compared

                                                        Buproprion SR (360 mgd) Naltrexone SR (32 mgd)

                                                        Lorcaserin(20 mgd)

                                                        Phentermine Topiramate CR

                                                        COR1 COR-I2 COR-II3 NB3043 BLOOM4 BLOSSOM5 EQUIP CONQUER

                                                        Number of patients (ITT-LOCF)

                                                        793 obese 1453 obese

                                                        1281 obese

                                                        502 type II diabetes

                                                        3182 obese 4008 obese

                                                        1230 obese BMI 44

                                                        2448 comorbidBMI 36

                                                        Mean change compared with placebo from base

                                                        93 vs5 1c

                                                        61a vs13c

                                                        64a vs12

                                                        50 a vs12c

                                                        58 vs22c

                                                        48 vs28c

                                                        11 Fullbvs 16

                                                        104 Fullb 84 Midb

                                                        vs 18

                                                        51 Lowb vs16c

                                                        Categorical change 5 compared with placebo from base

                                                        56 vs43

                                                        48a vs164

                                                        563a

                                                        vs 171445a vs189

                                                        475b

                                                        vs 203472b vs25

                                                        67 Fullb 45 Lowb vs17

                                                        70 Fullb 62 Midb

                                                        vs 21

                                                        Phenterminetopiramate doses Low 375 mg phentermine23 mg topiramate Mid 75 mg phentermine 46 mg topiramate Full 15 mg phentermine 92 mg topiramateITT-LOCF intent-to-treat last observation carried forwardData not available aP lt 001 vs placebo bP lt 0001 vs placebo

                                                        Obesity Treatments in Late Development

                                                        Kushner RF Expert Opin Pharmacother 200891339-1350

                                                        Agents ActionBupropionNaltrexone

                                                        bull Dopaminenoradrenaline reuptake inhibitorbull Opioid receptor antagonist

                                                        Liraglutide bull GLP-1 agonist

                                                        BupropionNaltrexone

                                                        bull Mechanism of Actionndash Bupropion - Dopaminenoradrenaline reuptake inhibitorndash Naltrexone- Opioid receptor antagonist

                                                        bull Was approved by FDA committee but FDA did not approve until a CV outcome study is performed 2nd concerns about BP and P in some patients

                                                        bull The Light Study is now underway and reported to be enrolling well under PI Dr Nissen

                                                        bull BupropionNaltrexone will have first completed CV outcome study

                                                        Buproprion ndash Naltrexone

                                                        Greenway FL et al Lancet 2010376(9741)595-605

                                                        0

                                                        -2

                                                        -4

                                                        -6

                                                        -8

                                                        -100 4 8 12 16 20 24 28 32 36 40 44 48 52 56

                                                        Weeks

                                                        Wei

                                                        ght c

                                                        hang

                                                        e fro

                                                        m b

                                                        asel

                                                        ine

                                                        ()

                                                        Placebo

                                                        Naltrexone 16 mg plus bupropion

                                                        Naltrexone 32 mg plus bupropion

                                                        Liraglutide for Weight Loss in Patients with Type 2 Diabetes

                                                        bull GLP-1 analog approved for treatment of type 2 diabetes

                                                        bull Anorectic effect mediated both by the activation of GLP-1 receptor expressed on vagal afferents and by the GLP-1R activation in CNS

                                                        bull Affects visceral fat adiposity appetite food preference and cardiovascular biomarkers in patients with type 2 diabetes

                                                        Inoue K et al Cardiovasc Diabetol 2011 10109 doi1011861475-2840-10-109

                                                        Liraglutide Weight Loss Over 2 Years ITT Observed Means

                                                        Astrup A et al Int J Obes (Lond) 201236(6)843-54

                                                        FromScreening

                                                        -94 kg

                                                        -67 kg-88 kg

                                                        -99 kg-94 kg

                                                        -103 kg

                                                        ITT intention to treat

                                                        Phase III Study Outcomes Compared

                                                        Buproprion SR (360 mgd) Naltrexone SR (32 mgd)

                                                        Lorcaserin(20 mgd)

                                                        Phentermine Topiramate CR

                                                        COR1 COR-I2 COR-II3 NB3043 BLOOM4 BLOSSOM5 EQUIP CONQUER

                                                        Number of patients (ITT-LOCF)

                                                        793 obese 1453 obese

                                                        1281 obese

                                                        502 type II diabetes

                                                        3182 obese 4008 obese

                                                        1230 obese BMI 44

                                                        2448 comorbidBMI 36

                                                        Mean change compared with placebo from base

                                                        93 vs5 1c

                                                        61a vs13c

                                                        64a vs12

                                                        50 a vs12c

                                                        58 vs22c

                                                        48 vs28c

                                                        11 Fullbvs 16

                                                        104 Fullb 84 Midb

                                                        vs 18

                                                        51 Lowb vs16c

                                                        Categorical change 5 compared with placebo from base

                                                        56 vs43

                                                        48a vs164

                                                        563a

                                                        vs 171445a vs189

                                                        475b

                                                        vs 203472b vs25

                                                        67 Fullb 45 Lowb vs17

                                                        70 Fullb 62 Midb

                                                        vs 21

                                                        Phenterminetopiramate doses Low 375 mg phentermine23 mg topiramate Mid 75 mg phentermine 46 mg topiramate Full 15 mg phentermine 92 mg topiramateITT-LOCF intent-to-treat last observation carried forwardData not available aP lt 001 vs placebo bP lt 0001 vs placebo

                                                        Treatment Gap in theManagement of Obesity

                                                        Physicians Need Effective Pharmacotherapies That Will Reduce Weight Significantly and Reduce Weight-related Comorbidities

                                                        0 5 10 15 20 25 30 35

                                                        Diet and Lifestyle Lap Band Gastric Bypass

                                                        TreatmentGap

                                                        What will fill the gap

                                                        Too risky for many peopleNot effective enoughfor many people

                                                        Treatment Gap in theManagement of Obesity

                                                        0 5 10 15 20 25 30 35

                                                        Diet and Lifestyle Lap Band Gastric Bypass

                                                        TreatmentGap

                                                        Too risky for many peopleNot effective enoughfor many people Pharmacotherapy

                                                        Less invasive procedures

                                                        Physicians Need Effective Pharmacotherapies That Will Reduce Weight Significantly and Reduce Weight-related Comorbidities

                                                        What will fill the gap

                                                        • Slide Number 1
                                                        • Slide Number 2
                                                        • Weight Management is Moving into the Workplace and Mainstream of Healthcare
                                                        • US Preventative Services Task Force
                                                        • A Proposal from CMS about Coverage for Intensive Behavioral Therapy for Obesity
                                                        • Slide Number 6
                                                        • Biggest Increases in Clinically Severe Obesity US 1987-2005
                                                        • Relationship Between BMI and Risk of Type 2 Diabetes
                                                        • Slide Number 9
                                                        • Medical Complications of Obesity Almost every organ system is affected
                                                        • Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and disease
                                                        • Current Therapies Often Address Individual Risk Factors Cardiometabolic risk
                                                        • Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and disease
                                                        • Are You Treating These Drivers of Cardiometabolic Risk Should You Treat The Underlying Cause
                                                        • Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors
                                                        • In My Opinion The Winds of Change are Blowing in the Treatment of Chronic Diseases
                                                        • Bariatric Surgery Reduces Overall Mortality Diabetes Mortality by 88
                                                        • Health Care Costs Attributable to ObesityEstimates of what various conditions add to health-care service costs over a 12-month period
                                                        • What-if scenarios (The Lancet forthcoming)
                                                        • How Much Weight Loss Is Needed to Prevent T2DMndashNot Very Much The DPP Experience
                                                        • In the Da Qing Study 6-year Intervention Led to Lower Incidence of Type 2 Diabetes 14 Years Later
                                                        • Slide Number 22
                                                        • Slide Number 23
                                                        • New Compounds andCombination Interventions
                                                        • Phentermine and Topiramate Extended-Release
                                                        • Phentermine and Topiramate Extended-Release
                                                        • EQUIP amp CONQUER Discontinuation RateDue to AEs in All Doses Studied
                                                        • Phentermine and Topiramate SEQUELWeight Loss Over Time
                                                        • CONQUER Significant Improvement in Cardiovascular Risk Factors
                                                        • Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors
                                                        • Lorcaserin
                                                        • BLOOM Study Body Weight Over Years 1 and 2
                                                        • BLOOM StudyKey Secondary Endpoints
                                                        • BLOOM-DMChange in Glycemic Parameters
                                                        • Lorcaserin Adverse Events Reported by 5 or More in Any Group in Year 1
                                                        • LorcaserinNo Increase in Rate of Valvulopathy
                                                        • Phase III Study Outcomes Compared
                                                        • Obesity Treatments in Late Development
                                                        • BupropionNaltrexone
                                                        • Buproprion ndash Naltrexone
                                                        • Liraglutide for Weight Loss in Patients with Type 2 Diabetes
                                                        • Liraglutide Weight Loss Over 2 Years ITT Observed Means
                                                        • Phase III Study Outcomes Compared
                                                        • Treatment Gap in theManagement of Obesity
                                                        • Treatment Gap in theManagement of Obesity

                                                          Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors

                                                          Risk FactorsPhenTPMMid

                                                          p-valuePhenTPMTop

                                                          p-value

                                                          CRP lt0001 lt0001Fibrinogen lt005 lt005Adiponectin lt00001 lt00001

                                                          p-values represent comparisons to placebo

                                                          ITT-LOCF Placebo Comparisons

                                                          Gadde KM et al Lancet 2011377(9774)1341-52

                                                          Mid = 75 mg46 mgTop = 15 mg92 mg

                                                          Lorcaserin

                                                          bull Selective 5‐HT2C receptor agonist designed to promote weight loss

                                                          bull Schedule IV ndash Expected soonbull Indication weight loss and maintenance of

                                                          weight loss in patients with BMI gt30 kgm2 or BMI gt27 kgm2 + weight-related comorbidcondition(s)

                                                          bull Dose - 10 mg BIDbull Most common side effects headache nausea

                                                          dizziness dry mouth

                                                          BLOOM Study Body Weight Over Years 1 and 2

                                                          Smith SR et al N Engl J Med 2010363245-256 Study Week0 8 16 24 32 40 48 56 64 72 80 88 96 104

                                                          Bod

                                                          y W

                                                          eigh

                                                          t (kg

                                                          )

                                                          102

                                                          100

                                                          98

                                                          96

                                                          94

                                                          92

                                                          90

                                                          0

                                                          Year 1

                                                          Placebo in year 1 and 2 (n = 684)Lorcaserin in year 1 placebo in year 2 (n = 275)Lorcaserin in year 1 and 2 (n = 564)

                                                          Year 2

                                                          Endpoint Lorcaserin Placebo P valueWaist circumference (cm) minus68plusmn02 minus39plusmn02 lt001BMI (kgm2) minus209plusmn006 minus078plusmn005 lt001SBPDBP (mm Hg) minus14plusmn03minus11plusmn02 minus08plusmn03minus06plusmn02 0401Cholesterol ( ∆)Total LDLHDL

                                                          minus090plusmn033287plusmn056005plusmn033

                                                          057plusmn034403plusmn058minus021plusmn034

                                                          001

                                                          049

                                                          72Triglycerides minus615plusmn103 minus014plusmn099 lt001SafetyHR (beatsmin)PASP (mm Hg)Beck depression II score

                                                          minus20plusmn03minus092plusmn023minus11plusmn01

                                                          minus16plusmn04 minus023plusmn023 minus09plusmn01

                                                          0499014026

                                                          BLOOM StudyKey Secondary Endpoints

                                                          Smith SR et al N Engl J Med 2010363245-256

                                                          BLOOM-DMChange in Glycemic Parameters

                                                          P lt001 P lt05 LS mean change plusmn SEMOrsquoNeil PM et al Obesity 201220(7)1426-36 httpwwwnaturecomdoifinder101038oby201266

                                                          00

                                                          -05

                                                          -10

                                                          -150 12 24 36 52

                                                          Cha

                                                          nge

                                                          from

                                                          bas

                                                          elin

                                                          e (

                                                          )

                                                          A1c

                                                          Study week

                                                          0

                                                          -10

                                                          -20

                                                          -30

                                                          -400 12 24 52

                                                          Cha

                                                          nge

                                                          from

                                                          bas

                                                          elin

                                                          e m

                                                          gdl

                                                          )

                                                          Fasting plasma glucose

                                                          Study week

                                                          Lorcaserin 10 mg BID Lorcaserin 10 mg Placebo

                                                          Lorcaserin Adverse Events Reported by 5 or More in Any Group in Year 1

                                                          55

                                                          N () Lorcaserin(N = 1593)

                                                          Placebo(N = 1584)

                                                          Headache 287 (180) 175 (110)

                                                          Dizziness 130 (82) 60 (38)

                                                          Nausea 119 (75) 85 (54)

                                                          Constipation 106 (67) 64 (40)

                                                          Fatigue 95 (60) 48 (30)

                                                          Dry mouth 83 (52) 37 (23)

                                                          Smith SR et al ADA 2009 Late‐Breaking Abstract 96

                                                          LorcaserinNo Increase in Rate of Valvulopathy

                                                          Smith SR et al N Engl J Med 2010363245-256

                                                          10

                                                          8

                                                          6

                                                          4

                                                          2

                                                          024 52 76 104

                                                          1351714

                                                          9

                                                          19

                                                          3421Patie

                                                          nts

                                                          ()

                                                          Week

                                                          Lorcaserin in yr 1 and 2

                                                          Lorcaserin in yr 1 Placebo in yr 2

                                                          Placebo in yr 1 and 2

                                                          Phase III Study Outcomes Compared

                                                          Buproprion SR (360 mgd) Naltrexone SR (32 mgd)

                                                          Lorcaserin(20 mgd)

                                                          Phentermine Topiramate CR

                                                          COR1 COR-I2 COR-II3 NB3043 BLOOM4 BLOSSOM5 EQUIP CONQUER

                                                          Number of patients (ITT-LOCF)

                                                          793 obese 1453 obese

                                                          1281 obese

                                                          502 type II diabetes

                                                          3182 obese 4008 obese

                                                          1230 obese BMI 44

                                                          2448 comorbidBMI 36

                                                          Mean change compared with placebo from base

                                                          93 vs5 1c

                                                          61a vs13c

                                                          64a vs12

                                                          50 a vs12c

                                                          58 vs22c

                                                          48 vs28c

                                                          11 Fullbvs 16

                                                          104 Fullb 84 Midb

                                                          vs 18

                                                          51 Lowb vs16c

                                                          Categorical change 5 compared with placebo from base

                                                          56 vs43

                                                          48a vs164

                                                          563a

                                                          vs 171445a vs189

                                                          475b

                                                          vs 203472b vs25

                                                          67 Fullb 45 Lowb vs17

                                                          70 Fullb 62 Midb

                                                          vs 21

                                                          Phenterminetopiramate doses Low 375 mg phentermine23 mg topiramate Mid 75 mg phentermine 46 mg topiramate Full 15 mg phentermine 92 mg topiramateITT-LOCF intent-to-treat last observation carried forwardData not available aP lt 001 vs placebo bP lt 0001 vs placebo

                                                          Obesity Treatments in Late Development

                                                          Kushner RF Expert Opin Pharmacother 200891339-1350

                                                          Agents ActionBupropionNaltrexone

                                                          bull Dopaminenoradrenaline reuptake inhibitorbull Opioid receptor antagonist

                                                          Liraglutide bull GLP-1 agonist

                                                          BupropionNaltrexone

                                                          bull Mechanism of Actionndash Bupropion - Dopaminenoradrenaline reuptake inhibitorndash Naltrexone- Opioid receptor antagonist

                                                          bull Was approved by FDA committee but FDA did not approve until a CV outcome study is performed 2nd concerns about BP and P in some patients

                                                          bull The Light Study is now underway and reported to be enrolling well under PI Dr Nissen

                                                          bull BupropionNaltrexone will have first completed CV outcome study

                                                          Buproprion ndash Naltrexone

                                                          Greenway FL et al Lancet 2010376(9741)595-605

                                                          0

                                                          -2

                                                          -4

                                                          -6

                                                          -8

                                                          -100 4 8 12 16 20 24 28 32 36 40 44 48 52 56

                                                          Weeks

                                                          Wei

                                                          ght c

                                                          hang

                                                          e fro

                                                          m b

                                                          asel

                                                          ine

                                                          ()

                                                          Placebo

                                                          Naltrexone 16 mg plus bupropion

                                                          Naltrexone 32 mg plus bupropion

                                                          Liraglutide for Weight Loss in Patients with Type 2 Diabetes

                                                          bull GLP-1 analog approved for treatment of type 2 diabetes

                                                          bull Anorectic effect mediated both by the activation of GLP-1 receptor expressed on vagal afferents and by the GLP-1R activation in CNS

                                                          bull Affects visceral fat adiposity appetite food preference and cardiovascular biomarkers in patients with type 2 diabetes

                                                          Inoue K et al Cardiovasc Diabetol 2011 10109 doi1011861475-2840-10-109

                                                          Liraglutide Weight Loss Over 2 Years ITT Observed Means

                                                          Astrup A et al Int J Obes (Lond) 201236(6)843-54

                                                          FromScreening

                                                          -94 kg

                                                          -67 kg-88 kg

                                                          -99 kg-94 kg

                                                          -103 kg

                                                          ITT intention to treat

                                                          Phase III Study Outcomes Compared

                                                          Buproprion SR (360 mgd) Naltrexone SR (32 mgd)

                                                          Lorcaserin(20 mgd)

                                                          Phentermine Topiramate CR

                                                          COR1 COR-I2 COR-II3 NB3043 BLOOM4 BLOSSOM5 EQUIP CONQUER

                                                          Number of patients (ITT-LOCF)

                                                          793 obese 1453 obese

                                                          1281 obese

                                                          502 type II diabetes

                                                          3182 obese 4008 obese

                                                          1230 obese BMI 44

                                                          2448 comorbidBMI 36

                                                          Mean change compared with placebo from base

                                                          93 vs5 1c

                                                          61a vs13c

                                                          64a vs12

                                                          50 a vs12c

                                                          58 vs22c

                                                          48 vs28c

                                                          11 Fullbvs 16

                                                          104 Fullb 84 Midb

                                                          vs 18

                                                          51 Lowb vs16c

                                                          Categorical change 5 compared with placebo from base

                                                          56 vs43

                                                          48a vs164

                                                          563a

                                                          vs 171445a vs189

                                                          475b

                                                          vs 203472b vs25

                                                          67 Fullb 45 Lowb vs17

                                                          70 Fullb 62 Midb

                                                          vs 21

                                                          Phenterminetopiramate doses Low 375 mg phentermine23 mg topiramate Mid 75 mg phentermine 46 mg topiramate Full 15 mg phentermine 92 mg topiramateITT-LOCF intent-to-treat last observation carried forwardData not available aP lt 001 vs placebo bP lt 0001 vs placebo

                                                          Treatment Gap in theManagement of Obesity

                                                          Physicians Need Effective Pharmacotherapies That Will Reduce Weight Significantly and Reduce Weight-related Comorbidities

                                                          0 5 10 15 20 25 30 35

                                                          Diet and Lifestyle Lap Band Gastric Bypass

                                                          TreatmentGap

                                                          What will fill the gap

                                                          Too risky for many peopleNot effective enoughfor many people

                                                          Treatment Gap in theManagement of Obesity

                                                          0 5 10 15 20 25 30 35

                                                          Diet and Lifestyle Lap Band Gastric Bypass

                                                          TreatmentGap

                                                          Too risky for many peopleNot effective enoughfor many people Pharmacotherapy

                                                          Less invasive procedures

                                                          Physicians Need Effective Pharmacotherapies That Will Reduce Weight Significantly and Reduce Weight-related Comorbidities

                                                          What will fill the gap

                                                          • Slide Number 1
                                                          • Slide Number 2
                                                          • Weight Management is Moving into the Workplace and Mainstream of Healthcare
                                                          • US Preventative Services Task Force
                                                          • A Proposal from CMS about Coverage for Intensive Behavioral Therapy for Obesity
                                                          • Slide Number 6
                                                          • Biggest Increases in Clinically Severe Obesity US 1987-2005
                                                          • Relationship Between BMI and Risk of Type 2 Diabetes
                                                          • Slide Number 9
                                                          • Medical Complications of Obesity Almost every organ system is affected
                                                          • Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and disease
                                                          • Current Therapies Often Address Individual Risk Factors Cardiometabolic risk
                                                          • Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and disease
                                                          • Are You Treating These Drivers of Cardiometabolic Risk Should You Treat The Underlying Cause
                                                          • Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors
                                                          • In My Opinion The Winds of Change are Blowing in the Treatment of Chronic Diseases
                                                          • Bariatric Surgery Reduces Overall Mortality Diabetes Mortality by 88
                                                          • Health Care Costs Attributable to ObesityEstimates of what various conditions add to health-care service costs over a 12-month period
                                                          • What-if scenarios (The Lancet forthcoming)
                                                          • How Much Weight Loss Is Needed to Prevent T2DMndashNot Very Much The DPP Experience
                                                          • In the Da Qing Study 6-year Intervention Led to Lower Incidence of Type 2 Diabetes 14 Years Later
                                                          • Slide Number 22
                                                          • Slide Number 23
                                                          • New Compounds andCombination Interventions
                                                          • Phentermine and Topiramate Extended-Release
                                                          • Phentermine and Topiramate Extended-Release
                                                          • EQUIP amp CONQUER Discontinuation RateDue to AEs in All Doses Studied
                                                          • Phentermine and Topiramate SEQUELWeight Loss Over Time
                                                          • CONQUER Significant Improvement in Cardiovascular Risk Factors
                                                          • Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors
                                                          • Lorcaserin
                                                          • BLOOM Study Body Weight Over Years 1 and 2
                                                          • BLOOM StudyKey Secondary Endpoints
                                                          • BLOOM-DMChange in Glycemic Parameters
                                                          • Lorcaserin Adverse Events Reported by 5 or More in Any Group in Year 1
                                                          • LorcaserinNo Increase in Rate of Valvulopathy
                                                          • Phase III Study Outcomes Compared
                                                          • Obesity Treatments in Late Development
                                                          • BupropionNaltrexone
                                                          • Buproprion ndash Naltrexone
                                                          • Liraglutide for Weight Loss in Patients with Type 2 Diabetes
                                                          • Liraglutide Weight Loss Over 2 Years ITT Observed Means
                                                          • Phase III Study Outcomes Compared
                                                          • Treatment Gap in theManagement of Obesity
                                                          • Treatment Gap in theManagement of Obesity

                                                            Lorcaserin

                                                            bull Selective 5‐HT2C receptor agonist designed to promote weight loss

                                                            bull Schedule IV ndash Expected soonbull Indication weight loss and maintenance of

                                                            weight loss in patients with BMI gt30 kgm2 or BMI gt27 kgm2 + weight-related comorbidcondition(s)

                                                            bull Dose - 10 mg BIDbull Most common side effects headache nausea

                                                            dizziness dry mouth

                                                            BLOOM Study Body Weight Over Years 1 and 2

                                                            Smith SR et al N Engl J Med 2010363245-256 Study Week0 8 16 24 32 40 48 56 64 72 80 88 96 104

                                                            Bod

                                                            y W

                                                            eigh

                                                            t (kg

                                                            )

                                                            102

                                                            100

                                                            98

                                                            96

                                                            94

                                                            92

                                                            90

                                                            0

                                                            Year 1

                                                            Placebo in year 1 and 2 (n = 684)Lorcaserin in year 1 placebo in year 2 (n = 275)Lorcaserin in year 1 and 2 (n = 564)

                                                            Year 2

                                                            Endpoint Lorcaserin Placebo P valueWaist circumference (cm) minus68plusmn02 minus39plusmn02 lt001BMI (kgm2) minus209plusmn006 minus078plusmn005 lt001SBPDBP (mm Hg) minus14plusmn03minus11plusmn02 minus08plusmn03minus06plusmn02 0401Cholesterol ( ∆)Total LDLHDL

                                                            minus090plusmn033287plusmn056005plusmn033

                                                            057plusmn034403plusmn058minus021plusmn034

                                                            001

                                                            049

                                                            72Triglycerides minus615plusmn103 minus014plusmn099 lt001SafetyHR (beatsmin)PASP (mm Hg)Beck depression II score

                                                            minus20plusmn03minus092plusmn023minus11plusmn01

                                                            minus16plusmn04 minus023plusmn023 minus09plusmn01

                                                            0499014026

                                                            BLOOM StudyKey Secondary Endpoints

                                                            Smith SR et al N Engl J Med 2010363245-256

                                                            BLOOM-DMChange in Glycemic Parameters

                                                            P lt001 P lt05 LS mean change plusmn SEMOrsquoNeil PM et al Obesity 201220(7)1426-36 httpwwwnaturecomdoifinder101038oby201266

                                                            00

                                                            -05

                                                            -10

                                                            -150 12 24 36 52

                                                            Cha

                                                            nge

                                                            from

                                                            bas

                                                            elin

                                                            e (

                                                            )

                                                            A1c

                                                            Study week

                                                            0

                                                            -10

                                                            -20

                                                            -30

                                                            -400 12 24 52

                                                            Cha

                                                            nge

                                                            from

                                                            bas

                                                            elin

                                                            e m

                                                            gdl

                                                            )

                                                            Fasting plasma glucose

                                                            Study week

                                                            Lorcaserin 10 mg BID Lorcaserin 10 mg Placebo

                                                            Lorcaserin Adverse Events Reported by 5 or More in Any Group in Year 1

                                                            55

                                                            N () Lorcaserin(N = 1593)

                                                            Placebo(N = 1584)

                                                            Headache 287 (180) 175 (110)

                                                            Dizziness 130 (82) 60 (38)

                                                            Nausea 119 (75) 85 (54)

                                                            Constipation 106 (67) 64 (40)

                                                            Fatigue 95 (60) 48 (30)

                                                            Dry mouth 83 (52) 37 (23)

                                                            Smith SR et al ADA 2009 Late‐Breaking Abstract 96

                                                            LorcaserinNo Increase in Rate of Valvulopathy

                                                            Smith SR et al N Engl J Med 2010363245-256

                                                            10

                                                            8

                                                            6

                                                            4

                                                            2

                                                            024 52 76 104

                                                            1351714

                                                            9

                                                            19

                                                            3421Patie

                                                            nts

                                                            ()

                                                            Week

                                                            Lorcaserin in yr 1 and 2

                                                            Lorcaserin in yr 1 Placebo in yr 2

                                                            Placebo in yr 1 and 2

                                                            Phase III Study Outcomes Compared

                                                            Buproprion SR (360 mgd) Naltrexone SR (32 mgd)

                                                            Lorcaserin(20 mgd)

                                                            Phentermine Topiramate CR

                                                            COR1 COR-I2 COR-II3 NB3043 BLOOM4 BLOSSOM5 EQUIP CONQUER

                                                            Number of patients (ITT-LOCF)

                                                            793 obese 1453 obese

                                                            1281 obese

                                                            502 type II diabetes

                                                            3182 obese 4008 obese

                                                            1230 obese BMI 44

                                                            2448 comorbidBMI 36

                                                            Mean change compared with placebo from base

                                                            93 vs5 1c

                                                            61a vs13c

                                                            64a vs12

                                                            50 a vs12c

                                                            58 vs22c

                                                            48 vs28c

                                                            11 Fullbvs 16

                                                            104 Fullb 84 Midb

                                                            vs 18

                                                            51 Lowb vs16c

                                                            Categorical change 5 compared with placebo from base

                                                            56 vs43

                                                            48a vs164

                                                            563a

                                                            vs 171445a vs189

                                                            475b

                                                            vs 203472b vs25

                                                            67 Fullb 45 Lowb vs17

                                                            70 Fullb 62 Midb

                                                            vs 21

                                                            Phenterminetopiramate doses Low 375 mg phentermine23 mg topiramate Mid 75 mg phentermine 46 mg topiramate Full 15 mg phentermine 92 mg topiramateITT-LOCF intent-to-treat last observation carried forwardData not available aP lt 001 vs placebo bP lt 0001 vs placebo

                                                            Obesity Treatments in Late Development

                                                            Kushner RF Expert Opin Pharmacother 200891339-1350

                                                            Agents ActionBupropionNaltrexone

                                                            bull Dopaminenoradrenaline reuptake inhibitorbull Opioid receptor antagonist

                                                            Liraglutide bull GLP-1 agonist

                                                            BupropionNaltrexone

                                                            bull Mechanism of Actionndash Bupropion - Dopaminenoradrenaline reuptake inhibitorndash Naltrexone- Opioid receptor antagonist

                                                            bull Was approved by FDA committee but FDA did not approve until a CV outcome study is performed 2nd concerns about BP and P in some patients

                                                            bull The Light Study is now underway and reported to be enrolling well under PI Dr Nissen

                                                            bull BupropionNaltrexone will have first completed CV outcome study

                                                            Buproprion ndash Naltrexone

                                                            Greenway FL et al Lancet 2010376(9741)595-605

                                                            0

                                                            -2

                                                            -4

                                                            -6

                                                            -8

                                                            -100 4 8 12 16 20 24 28 32 36 40 44 48 52 56

                                                            Weeks

                                                            Wei

                                                            ght c

                                                            hang

                                                            e fro

                                                            m b

                                                            asel

                                                            ine

                                                            ()

                                                            Placebo

                                                            Naltrexone 16 mg plus bupropion

                                                            Naltrexone 32 mg plus bupropion

                                                            Liraglutide for Weight Loss in Patients with Type 2 Diabetes

                                                            bull GLP-1 analog approved for treatment of type 2 diabetes

                                                            bull Anorectic effect mediated both by the activation of GLP-1 receptor expressed on vagal afferents and by the GLP-1R activation in CNS

                                                            bull Affects visceral fat adiposity appetite food preference and cardiovascular biomarkers in patients with type 2 diabetes

                                                            Inoue K et al Cardiovasc Diabetol 2011 10109 doi1011861475-2840-10-109

                                                            Liraglutide Weight Loss Over 2 Years ITT Observed Means

                                                            Astrup A et al Int J Obes (Lond) 201236(6)843-54

                                                            FromScreening

                                                            -94 kg

                                                            -67 kg-88 kg

                                                            -99 kg-94 kg

                                                            -103 kg

                                                            ITT intention to treat

                                                            Phase III Study Outcomes Compared

                                                            Buproprion SR (360 mgd) Naltrexone SR (32 mgd)

                                                            Lorcaserin(20 mgd)

                                                            Phentermine Topiramate CR

                                                            COR1 COR-I2 COR-II3 NB3043 BLOOM4 BLOSSOM5 EQUIP CONQUER

                                                            Number of patients (ITT-LOCF)

                                                            793 obese 1453 obese

                                                            1281 obese

                                                            502 type II diabetes

                                                            3182 obese 4008 obese

                                                            1230 obese BMI 44

                                                            2448 comorbidBMI 36

                                                            Mean change compared with placebo from base

                                                            93 vs5 1c

                                                            61a vs13c

                                                            64a vs12

                                                            50 a vs12c

                                                            58 vs22c

                                                            48 vs28c

                                                            11 Fullbvs 16

                                                            104 Fullb 84 Midb

                                                            vs 18

                                                            51 Lowb vs16c

                                                            Categorical change 5 compared with placebo from base

                                                            56 vs43

                                                            48a vs164

                                                            563a

                                                            vs 171445a vs189

                                                            475b

                                                            vs 203472b vs25

                                                            67 Fullb 45 Lowb vs17

                                                            70 Fullb 62 Midb

                                                            vs 21

                                                            Phenterminetopiramate doses Low 375 mg phentermine23 mg topiramate Mid 75 mg phentermine 46 mg topiramate Full 15 mg phentermine 92 mg topiramateITT-LOCF intent-to-treat last observation carried forwardData not available aP lt 001 vs placebo bP lt 0001 vs placebo

                                                            Treatment Gap in theManagement of Obesity

                                                            Physicians Need Effective Pharmacotherapies That Will Reduce Weight Significantly and Reduce Weight-related Comorbidities

                                                            0 5 10 15 20 25 30 35

                                                            Diet and Lifestyle Lap Band Gastric Bypass

                                                            TreatmentGap

                                                            What will fill the gap

                                                            Too risky for many peopleNot effective enoughfor many people

                                                            Treatment Gap in theManagement of Obesity

                                                            0 5 10 15 20 25 30 35

                                                            Diet and Lifestyle Lap Band Gastric Bypass

                                                            TreatmentGap

                                                            Too risky for many peopleNot effective enoughfor many people Pharmacotherapy

                                                            Less invasive procedures

                                                            Physicians Need Effective Pharmacotherapies That Will Reduce Weight Significantly and Reduce Weight-related Comorbidities

                                                            What will fill the gap

                                                            • Slide Number 1
                                                            • Slide Number 2
                                                            • Weight Management is Moving into the Workplace and Mainstream of Healthcare
                                                            • US Preventative Services Task Force
                                                            • A Proposal from CMS about Coverage for Intensive Behavioral Therapy for Obesity
                                                            • Slide Number 6
                                                            • Biggest Increases in Clinically Severe Obesity US 1987-2005
                                                            • Relationship Between BMI and Risk of Type 2 Diabetes
                                                            • Slide Number 9
                                                            • Medical Complications of Obesity Almost every organ system is affected
                                                            • Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and disease
                                                            • Current Therapies Often Address Individual Risk Factors Cardiometabolic risk
                                                            • Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and disease
                                                            • Are You Treating These Drivers of Cardiometabolic Risk Should You Treat The Underlying Cause
                                                            • Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors
                                                            • In My Opinion The Winds of Change are Blowing in the Treatment of Chronic Diseases
                                                            • Bariatric Surgery Reduces Overall Mortality Diabetes Mortality by 88
                                                            • Health Care Costs Attributable to ObesityEstimates of what various conditions add to health-care service costs over a 12-month period
                                                            • What-if scenarios (The Lancet forthcoming)
                                                            • How Much Weight Loss Is Needed to Prevent T2DMndashNot Very Much The DPP Experience
                                                            • In the Da Qing Study 6-year Intervention Led to Lower Incidence of Type 2 Diabetes 14 Years Later
                                                            • Slide Number 22
                                                            • Slide Number 23
                                                            • New Compounds andCombination Interventions
                                                            • Phentermine and Topiramate Extended-Release
                                                            • Phentermine and Topiramate Extended-Release
                                                            • EQUIP amp CONQUER Discontinuation RateDue to AEs in All Doses Studied
                                                            • Phentermine and Topiramate SEQUELWeight Loss Over Time
                                                            • CONQUER Significant Improvement in Cardiovascular Risk Factors
                                                            • Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors
                                                            • Lorcaserin
                                                            • BLOOM Study Body Weight Over Years 1 and 2
                                                            • BLOOM StudyKey Secondary Endpoints
                                                            • BLOOM-DMChange in Glycemic Parameters
                                                            • Lorcaserin Adverse Events Reported by 5 or More in Any Group in Year 1
                                                            • LorcaserinNo Increase in Rate of Valvulopathy
                                                            • Phase III Study Outcomes Compared
                                                            • Obesity Treatments in Late Development
                                                            • BupropionNaltrexone
                                                            • Buproprion ndash Naltrexone
                                                            • Liraglutide for Weight Loss in Patients with Type 2 Diabetes
                                                            • Liraglutide Weight Loss Over 2 Years ITT Observed Means
                                                            • Phase III Study Outcomes Compared
                                                            • Treatment Gap in theManagement of Obesity
                                                            • Treatment Gap in theManagement of Obesity

                                                              BLOOM Study Body Weight Over Years 1 and 2

                                                              Smith SR et al N Engl J Med 2010363245-256 Study Week0 8 16 24 32 40 48 56 64 72 80 88 96 104

                                                              Bod

                                                              y W

                                                              eigh

                                                              t (kg

                                                              )

                                                              102

                                                              100

                                                              98

                                                              96

                                                              94

                                                              92

                                                              90

                                                              0

                                                              Year 1

                                                              Placebo in year 1 and 2 (n = 684)Lorcaserin in year 1 placebo in year 2 (n = 275)Lorcaserin in year 1 and 2 (n = 564)

                                                              Year 2

                                                              Endpoint Lorcaserin Placebo P valueWaist circumference (cm) minus68plusmn02 minus39plusmn02 lt001BMI (kgm2) minus209plusmn006 minus078plusmn005 lt001SBPDBP (mm Hg) minus14plusmn03minus11plusmn02 minus08plusmn03minus06plusmn02 0401Cholesterol ( ∆)Total LDLHDL

                                                              minus090plusmn033287plusmn056005plusmn033

                                                              057plusmn034403plusmn058minus021plusmn034

                                                              001

                                                              049

                                                              72Triglycerides minus615plusmn103 minus014plusmn099 lt001SafetyHR (beatsmin)PASP (mm Hg)Beck depression II score

                                                              minus20plusmn03minus092plusmn023minus11plusmn01

                                                              minus16plusmn04 minus023plusmn023 minus09plusmn01

                                                              0499014026

                                                              BLOOM StudyKey Secondary Endpoints

                                                              Smith SR et al N Engl J Med 2010363245-256

                                                              BLOOM-DMChange in Glycemic Parameters

                                                              P lt001 P lt05 LS mean change plusmn SEMOrsquoNeil PM et al Obesity 201220(7)1426-36 httpwwwnaturecomdoifinder101038oby201266

                                                              00

                                                              -05

                                                              -10

                                                              -150 12 24 36 52

                                                              Cha

                                                              nge

                                                              from

                                                              bas

                                                              elin

                                                              e (

                                                              )

                                                              A1c

                                                              Study week

                                                              0

                                                              -10

                                                              -20

                                                              -30

                                                              -400 12 24 52

                                                              Cha

                                                              nge

                                                              from

                                                              bas

                                                              elin

                                                              e m

                                                              gdl

                                                              )

                                                              Fasting plasma glucose

                                                              Study week

                                                              Lorcaserin 10 mg BID Lorcaserin 10 mg Placebo

                                                              Lorcaserin Adverse Events Reported by 5 or More in Any Group in Year 1

                                                              55

                                                              N () Lorcaserin(N = 1593)

                                                              Placebo(N = 1584)

                                                              Headache 287 (180) 175 (110)

                                                              Dizziness 130 (82) 60 (38)

                                                              Nausea 119 (75) 85 (54)

                                                              Constipation 106 (67) 64 (40)

                                                              Fatigue 95 (60) 48 (30)

                                                              Dry mouth 83 (52) 37 (23)

                                                              Smith SR et al ADA 2009 Late‐Breaking Abstract 96

                                                              LorcaserinNo Increase in Rate of Valvulopathy

                                                              Smith SR et al N Engl J Med 2010363245-256

                                                              10

                                                              8

                                                              6

                                                              4

                                                              2

                                                              024 52 76 104

                                                              1351714

                                                              9

                                                              19

                                                              3421Patie

                                                              nts

                                                              ()

                                                              Week

                                                              Lorcaserin in yr 1 and 2

                                                              Lorcaserin in yr 1 Placebo in yr 2

                                                              Placebo in yr 1 and 2

                                                              Phase III Study Outcomes Compared

                                                              Buproprion SR (360 mgd) Naltrexone SR (32 mgd)

                                                              Lorcaserin(20 mgd)

                                                              Phentermine Topiramate CR

                                                              COR1 COR-I2 COR-II3 NB3043 BLOOM4 BLOSSOM5 EQUIP CONQUER

                                                              Number of patients (ITT-LOCF)

                                                              793 obese 1453 obese

                                                              1281 obese

                                                              502 type II diabetes

                                                              3182 obese 4008 obese

                                                              1230 obese BMI 44

                                                              2448 comorbidBMI 36

                                                              Mean change compared with placebo from base

                                                              93 vs5 1c

                                                              61a vs13c

                                                              64a vs12

                                                              50 a vs12c

                                                              58 vs22c

                                                              48 vs28c

                                                              11 Fullbvs 16

                                                              104 Fullb 84 Midb

                                                              vs 18

                                                              51 Lowb vs16c

                                                              Categorical change 5 compared with placebo from base

                                                              56 vs43

                                                              48a vs164

                                                              563a

                                                              vs 171445a vs189

                                                              475b

                                                              vs 203472b vs25

                                                              67 Fullb 45 Lowb vs17

                                                              70 Fullb 62 Midb

                                                              vs 21

                                                              Phenterminetopiramate doses Low 375 mg phentermine23 mg topiramate Mid 75 mg phentermine 46 mg topiramate Full 15 mg phentermine 92 mg topiramateITT-LOCF intent-to-treat last observation carried forwardData not available aP lt 001 vs placebo bP lt 0001 vs placebo

                                                              Obesity Treatments in Late Development

                                                              Kushner RF Expert Opin Pharmacother 200891339-1350

                                                              Agents ActionBupropionNaltrexone

                                                              bull Dopaminenoradrenaline reuptake inhibitorbull Opioid receptor antagonist

                                                              Liraglutide bull GLP-1 agonist

                                                              BupropionNaltrexone

                                                              bull Mechanism of Actionndash Bupropion - Dopaminenoradrenaline reuptake inhibitorndash Naltrexone- Opioid receptor antagonist

                                                              bull Was approved by FDA committee but FDA did not approve until a CV outcome study is performed 2nd concerns about BP and P in some patients

                                                              bull The Light Study is now underway and reported to be enrolling well under PI Dr Nissen

                                                              bull BupropionNaltrexone will have first completed CV outcome study

                                                              Buproprion ndash Naltrexone

                                                              Greenway FL et al Lancet 2010376(9741)595-605

                                                              0

                                                              -2

                                                              -4

                                                              -6

                                                              -8

                                                              -100 4 8 12 16 20 24 28 32 36 40 44 48 52 56

                                                              Weeks

                                                              Wei

                                                              ght c

                                                              hang

                                                              e fro

                                                              m b

                                                              asel

                                                              ine

                                                              ()

                                                              Placebo

                                                              Naltrexone 16 mg plus bupropion

                                                              Naltrexone 32 mg plus bupropion

                                                              Liraglutide for Weight Loss in Patients with Type 2 Diabetes

                                                              bull GLP-1 analog approved for treatment of type 2 diabetes

                                                              bull Anorectic effect mediated both by the activation of GLP-1 receptor expressed on vagal afferents and by the GLP-1R activation in CNS

                                                              bull Affects visceral fat adiposity appetite food preference and cardiovascular biomarkers in patients with type 2 diabetes

                                                              Inoue K et al Cardiovasc Diabetol 2011 10109 doi1011861475-2840-10-109

                                                              Liraglutide Weight Loss Over 2 Years ITT Observed Means

                                                              Astrup A et al Int J Obes (Lond) 201236(6)843-54

                                                              FromScreening

                                                              -94 kg

                                                              -67 kg-88 kg

                                                              -99 kg-94 kg

                                                              -103 kg

                                                              ITT intention to treat

                                                              Phase III Study Outcomes Compared

                                                              Buproprion SR (360 mgd) Naltrexone SR (32 mgd)

                                                              Lorcaserin(20 mgd)

                                                              Phentermine Topiramate CR

                                                              COR1 COR-I2 COR-II3 NB3043 BLOOM4 BLOSSOM5 EQUIP CONQUER

                                                              Number of patients (ITT-LOCF)

                                                              793 obese 1453 obese

                                                              1281 obese

                                                              502 type II diabetes

                                                              3182 obese 4008 obese

                                                              1230 obese BMI 44

                                                              2448 comorbidBMI 36

                                                              Mean change compared with placebo from base

                                                              93 vs5 1c

                                                              61a vs13c

                                                              64a vs12

                                                              50 a vs12c

                                                              58 vs22c

                                                              48 vs28c

                                                              11 Fullbvs 16

                                                              104 Fullb 84 Midb

                                                              vs 18

                                                              51 Lowb vs16c

                                                              Categorical change 5 compared with placebo from base

                                                              56 vs43

                                                              48a vs164

                                                              563a

                                                              vs 171445a vs189

                                                              475b

                                                              vs 203472b vs25

                                                              67 Fullb 45 Lowb vs17

                                                              70 Fullb 62 Midb

                                                              vs 21

                                                              Phenterminetopiramate doses Low 375 mg phentermine23 mg topiramate Mid 75 mg phentermine 46 mg topiramate Full 15 mg phentermine 92 mg topiramateITT-LOCF intent-to-treat last observation carried forwardData not available aP lt 001 vs placebo bP lt 0001 vs placebo

                                                              Treatment Gap in theManagement of Obesity

                                                              Physicians Need Effective Pharmacotherapies That Will Reduce Weight Significantly and Reduce Weight-related Comorbidities

                                                              0 5 10 15 20 25 30 35

                                                              Diet and Lifestyle Lap Band Gastric Bypass

                                                              TreatmentGap

                                                              What will fill the gap

                                                              Too risky for many peopleNot effective enoughfor many people

                                                              Treatment Gap in theManagement of Obesity

                                                              0 5 10 15 20 25 30 35

                                                              Diet and Lifestyle Lap Band Gastric Bypass

                                                              TreatmentGap

                                                              Too risky for many peopleNot effective enoughfor many people Pharmacotherapy

                                                              Less invasive procedures

                                                              Physicians Need Effective Pharmacotherapies That Will Reduce Weight Significantly and Reduce Weight-related Comorbidities

                                                              What will fill the gap

                                                              • Slide Number 1
                                                              • Slide Number 2
                                                              • Weight Management is Moving into the Workplace and Mainstream of Healthcare
                                                              • US Preventative Services Task Force
                                                              • A Proposal from CMS about Coverage for Intensive Behavioral Therapy for Obesity
                                                              • Slide Number 6
                                                              • Biggest Increases in Clinically Severe Obesity US 1987-2005
                                                              • Relationship Between BMI and Risk of Type 2 Diabetes
                                                              • Slide Number 9
                                                              • Medical Complications of Obesity Almost every organ system is affected
                                                              • Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and disease
                                                              • Current Therapies Often Address Individual Risk Factors Cardiometabolic risk
                                                              • Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and disease
                                                              • Are You Treating These Drivers of Cardiometabolic Risk Should You Treat The Underlying Cause
                                                              • Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors
                                                              • In My Opinion The Winds of Change are Blowing in the Treatment of Chronic Diseases
                                                              • Bariatric Surgery Reduces Overall Mortality Diabetes Mortality by 88
                                                              • Health Care Costs Attributable to ObesityEstimates of what various conditions add to health-care service costs over a 12-month period
                                                              • What-if scenarios (The Lancet forthcoming)
                                                              • How Much Weight Loss Is Needed to Prevent T2DMndashNot Very Much The DPP Experience
                                                              • In the Da Qing Study 6-year Intervention Led to Lower Incidence of Type 2 Diabetes 14 Years Later
                                                              • Slide Number 22
                                                              • Slide Number 23
                                                              • New Compounds andCombination Interventions
                                                              • Phentermine and Topiramate Extended-Release
                                                              • Phentermine and Topiramate Extended-Release
                                                              • EQUIP amp CONQUER Discontinuation RateDue to AEs in All Doses Studied
                                                              • Phentermine and Topiramate SEQUELWeight Loss Over Time
                                                              • CONQUER Significant Improvement in Cardiovascular Risk Factors
                                                              • Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors
                                                              • Lorcaserin
                                                              • BLOOM Study Body Weight Over Years 1 and 2
                                                              • BLOOM StudyKey Secondary Endpoints
                                                              • BLOOM-DMChange in Glycemic Parameters
                                                              • Lorcaserin Adverse Events Reported by 5 or More in Any Group in Year 1
                                                              • LorcaserinNo Increase in Rate of Valvulopathy
                                                              • Phase III Study Outcomes Compared
                                                              • Obesity Treatments in Late Development
                                                              • BupropionNaltrexone
                                                              • Buproprion ndash Naltrexone
                                                              • Liraglutide for Weight Loss in Patients with Type 2 Diabetes
                                                              • Liraglutide Weight Loss Over 2 Years ITT Observed Means
                                                              • Phase III Study Outcomes Compared
                                                              • Treatment Gap in theManagement of Obesity
                                                              • Treatment Gap in theManagement of Obesity

                                                                Endpoint Lorcaserin Placebo P valueWaist circumference (cm) minus68plusmn02 minus39plusmn02 lt001BMI (kgm2) minus209plusmn006 minus078plusmn005 lt001SBPDBP (mm Hg) minus14plusmn03minus11plusmn02 minus08plusmn03minus06plusmn02 0401Cholesterol ( ∆)Total LDLHDL

                                                                minus090plusmn033287plusmn056005plusmn033

                                                                057plusmn034403plusmn058minus021plusmn034

                                                                001

                                                                049

                                                                72Triglycerides minus615plusmn103 minus014plusmn099 lt001SafetyHR (beatsmin)PASP (mm Hg)Beck depression II score

                                                                minus20plusmn03minus092plusmn023minus11plusmn01

                                                                minus16plusmn04 minus023plusmn023 minus09plusmn01

                                                                0499014026

                                                                BLOOM StudyKey Secondary Endpoints

                                                                Smith SR et al N Engl J Med 2010363245-256

                                                                BLOOM-DMChange in Glycemic Parameters

                                                                P lt001 P lt05 LS mean change plusmn SEMOrsquoNeil PM et al Obesity 201220(7)1426-36 httpwwwnaturecomdoifinder101038oby201266

                                                                00

                                                                -05

                                                                -10

                                                                -150 12 24 36 52

                                                                Cha

                                                                nge

                                                                from

                                                                bas

                                                                elin

                                                                e (

                                                                )

                                                                A1c

                                                                Study week

                                                                0

                                                                -10

                                                                -20

                                                                -30

                                                                -400 12 24 52

                                                                Cha

                                                                nge

                                                                from

                                                                bas

                                                                elin

                                                                e m

                                                                gdl

                                                                )

                                                                Fasting plasma glucose

                                                                Study week

                                                                Lorcaserin 10 mg BID Lorcaserin 10 mg Placebo

                                                                Lorcaserin Adverse Events Reported by 5 or More in Any Group in Year 1

                                                                55

                                                                N () Lorcaserin(N = 1593)

                                                                Placebo(N = 1584)

                                                                Headache 287 (180) 175 (110)

                                                                Dizziness 130 (82) 60 (38)

                                                                Nausea 119 (75) 85 (54)

                                                                Constipation 106 (67) 64 (40)

                                                                Fatigue 95 (60) 48 (30)

                                                                Dry mouth 83 (52) 37 (23)

                                                                Smith SR et al ADA 2009 Late‐Breaking Abstract 96

                                                                LorcaserinNo Increase in Rate of Valvulopathy

                                                                Smith SR et al N Engl J Med 2010363245-256

                                                                10

                                                                8

                                                                6

                                                                4

                                                                2

                                                                024 52 76 104

                                                                1351714

                                                                9

                                                                19

                                                                3421Patie

                                                                nts

                                                                ()

                                                                Week

                                                                Lorcaserin in yr 1 and 2

                                                                Lorcaserin in yr 1 Placebo in yr 2

                                                                Placebo in yr 1 and 2

                                                                Phase III Study Outcomes Compared

                                                                Buproprion SR (360 mgd) Naltrexone SR (32 mgd)

                                                                Lorcaserin(20 mgd)

                                                                Phentermine Topiramate CR

                                                                COR1 COR-I2 COR-II3 NB3043 BLOOM4 BLOSSOM5 EQUIP CONQUER

                                                                Number of patients (ITT-LOCF)

                                                                793 obese 1453 obese

                                                                1281 obese

                                                                502 type II diabetes

                                                                3182 obese 4008 obese

                                                                1230 obese BMI 44

                                                                2448 comorbidBMI 36

                                                                Mean change compared with placebo from base

                                                                93 vs5 1c

                                                                61a vs13c

                                                                64a vs12

                                                                50 a vs12c

                                                                58 vs22c

                                                                48 vs28c

                                                                11 Fullbvs 16

                                                                104 Fullb 84 Midb

                                                                vs 18

                                                                51 Lowb vs16c

                                                                Categorical change 5 compared with placebo from base

                                                                56 vs43

                                                                48a vs164

                                                                563a

                                                                vs 171445a vs189

                                                                475b

                                                                vs 203472b vs25

                                                                67 Fullb 45 Lowb vs17

                                                                70 Fullb 62 Midb

                                                                vs 21

                                                                Phenterminetopiramate doses Low 375 mg phentermine23 mg topiramate Mid 75 mg phentermine 46 mg topiramate Full 15 mg phentermine 92 mg topiramateITT-LOCF intent-to-treat last observation carried forwardData not available aP lt 001 vs placebo bP lt 0001 vs placebo

                                                                Obesity Treatments in Late Development

                                                                Kushner RF Expert Opin Pharmacother 200891339-1350

                                                                Agents ActionBupropionNaltrexone

                                                                bull Dopaminenoradrenaline reuptake inhibitorbull Opioid receptor antagonist

                                                                Liraglutide bull GLP-1 agonist

                                                                BupropionNaltrexone

                                                                bull Mechanism of Actionndash Bupropion - Dopaminenoradrenaline reuptake inhibitorndash Naltrexone- Opioid receptor antagonist

                                                                bull Was approved by FDA committee but FDA did not approve until a CV outcome study is performed 2nd concerns about BP and P in some patients

                                                                bull The Light Study is now underway and reported to be enrolling well under PI Dr Nissen

                                                                bull BupropionNaltrexone will have first completed CV outcome study

                                                                Buproprion ndash Naltrexone

                                                                Greenway FL et al Lancet 2010376(9741)595-605

                                                                0

                                                                -2

                                                                -4

                                                                -6

                                                                -8

                                                                -100 4 8 12 16 20 24 28 32 36 40 44 48 52 56

                                                                Weeks

                                                                Wei

                                                                ght c

                                                                hang

                                                                e fro

                                                                m b

                                                                asel

                                                                ine

                                                                ()

                                                                Placebo

                                                                Naltrexone 16 mg plus bupropion

                                                                Naltrexone 32 mg plus bupropion

                                                                Liraglutide for Weight Loss in Patients with Type 2 Diabetes

                                                                bull GLP-1 analog approved for treatment of type 2 diabetes

                                                                bull Anorectic effect mediated both by the activation of GLP-1 receptor expressed on vagal afferents and by the GLP-1R activation in CNS

                                                                bull Affects visceral fat adiposity appetite food preference and cardiovascular biomarkers in patients with type 2 diabetes

                                                                Inoue K et al Cardiovasc Diabetol 2011 10109 doi1011861475-2840-10-109

                                                                Liraglutide Weight Loss Over 2 Years ITT Observed Means

                                                                Astrup A et al Int J Obes (Lond) 201236(6)843-54

                                                                FromScreening

                                                                -94 kg

                                                                -67 kg-88 kg

                                                                -99 kg-94 kg

                                                                -103 kg

                                                                ITT intention to treat

                                                                Phase III Study Outcomes Compared

                                                                Buproprion SR (360 mgd) Naltrexone SR (32 mgd)

                                                                Lorcaserin(20 mgd)

                                                                Phentermine Topiramate CR

                                                                COR1 COR-I2 COR-II3 NB3043 BLOOM4 BLOSSOM5 EQUIP CONQUER

                                                                Number of patients (ITT-LOCF)

                                                                793 obese 1453 obese

                                                                1281 obese

                                                                502 type II diabetes

                                                                3182 obese 4008 obese

                                                                1230 obese BMI 44

                                                                2448 comorbidBMI 36

                                                                Mean change compared with placebo from base

                                                                93 vs5 1c

                                                                61a vs13c

                                                                64a vs12

                                                                50 a vs12c

                                                                58 vs22c

                                                                48 vs28c

                                                                11 Fullbvs 16

                                                                104 Fullb 84 Midb

                                                                vs 18

                                                                51 Lowb vs16c

                                                                Categorical change 5 compared with placebo from base

                                                                56 vs43

                                                                48a vs164

                                                                563a

                                                                vs 171445a vs189

                                                                475b

                                                                vs 203472b vs25

                                                                67 Fullb 45 Lowb vs17

                                                                70 Fullb 62 Midb

                                                                vs 21

                                                                Phenterminetopiramate doses Low 375 mg phentermine23 mg topiramate Mid 75 mg phentermine 46 mg topiramate Full 15 mg phentermine 92 mg topiramateITT-LOCF intent-to-treat last observation carried forwardData not available aP lt 001 vs placebo bP lt 0001 vs placebo

                                                                Treatment Gap in theManagement of Obesity

                                                                Physicians Need Effective Pharmacotherapies That Will Reduce Weight Significantly and Reduce Weight-related Comorbidities

                                                                0 5 10 15 20 25 30 35

                                                                Diet and Lifestyle Lap Band Gastric Bypass

                                                                TreatmentGap

                                                                What will fill the gap

                                                                Too risky for many peopleNot effective enoughfor many people

                                                                Treatment Gap in theManagement of Obesity

                                                                0 5 10 15 20 25 30 35

                                                                Diet and Lifestyle Lap Band Gastric Bypass

                                                                TreatmentGap

                                                                Too risky for many peopleNot effective enoughfor many people Pharmacotherapy

                                                                Less invasive procedures

                                                                Physicians Need Effective Pharmacotherapies That Will Reduce Weight Significantly and Reduce Weight-related Comorbidities

                                                                What will fill the gap

                                                                • Slide Number 1
                                                                • Slide Number 2
                                                                • Weight Management is Moving into the Workplace and Mainstream of Healthcare
                                                                • US Preventative Services Task Force
                                                                • A Proposal from CMS about Coverage for Intensive Behavioral Therapy for Obesity
                                                                • Slide Number 6
                                                                • Biggest Increases in Clinically Severe Obesity US 1987-2005
                                                                • Relationship Between BMI and Risk of Type 2 Diabetes
                                                                • Slide Number 9
                                                                • Medical Complications of Obesity Almost every organ system is affected
                                                                • Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and disease
                                                                • Current Therapies Often Address Individual Risk Factors Cardiometabolic risk
                                                                • Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and disease
                                                                • Are You Treating These Drivers of Cardiometabolic Risk Should You Treat The Underlying Cause
                                                                • Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors
                                                                • In My Opinion The Winds of Change are Blowing in the Treatment of Chronic Diseases
                                                                • Bariatric Surgery Reduces Overall Mortality Diabetes Mortality by 88
                                                                • Health Care Costs Attributable to ObesityEstimates of what various conditions add to health-care service costs over a 12-month period
                                                                • What-if scenarios (The Lancet forthcoming)
                                                                • How Much Weight Loss Is Needed to Prevent T2DMndashNot Very Much The DPP Experience
                                                                • In the Da Qing Study 6-year Intervention Led to Lower Incidence of Type 2 Diabetes 14 Years Later
                                                                • Slide Number 22
                                                                • Slide Number 23
                                                                • New Compounds andCombination Interventions
                                                                • Phentermine and Topiramate Extended-Release
                                                                • Phentermine and Topiramate Extended-Release
                                                                • EQUIP amp CONQUER Discontinuation RateDue to AEs in All Doses Studied
                                                                • Phentermine and Topiramate SEQUELWeight Loss Over Time
                                                                • CONQUER Significant Improvement in Cardiovascular Risk Factors
                                                                • Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors
                                                                • Lorcaserin
                                                                • BLOOM Study Body Weight Over Years 1 and 2
                                                                • BLOOM StudyKey Secondary Endpoints
                                                                • BLOOM-DMChange in Glycemic Parameters
                                                                • Lorcaserin Adverse Events Reported by 5 or More in Any Group in Year 1
                                                                • LorcaserinNo Increase in Rate of Valvulopathy
                                                                • Phase III Study Outcomes Compared
                                                                • Obesity Treatments in Late Development
                                                                • BupropionNaltrexone
                                                                • Buproprion ndash Naltrexone
                                                                • Liraglutide for Weight Loss in Patients with Type 2 Diabetes
                                                                • Liraglutide Weight Loss Over 2 Years ITT Observed Means
                                                                • Phase III Study Outcomes Compared
                                                                • Treatment Gap in theManagement of Obesity
                                                                • Treatment Gap in theManagement of Obesity

                                                                  BLOOM-DMChange in Glycemic Parameters

                                                                  P lt001 P lt05 LS mean change plusmn SEMOrsquoNeil PM et al Obesity 201220(7)1426-36 httpwwwnaturecomdoifinder101038oby201266

                                                                  00

                                                                  -05

                                                                  -10

                                                                  -150 12 24 36 52

                                                                  Cha

                                                                  nge

                                                                  from

                                                                  bas

                                                                  elin

                                                                  e (

                                                                  )

                                                                  A1c

                                                                  Study week

                                                                  0

                                                                  -10

                                                                  -20

                                                                  -30

                                                                  -400 12 24 52

                                                                  Cha

                                                                  nge

                                                                  from

                                                                  bas

                                                                  elin

                                                                  e m

                                                                  gdl

                                                                  )

                                                                  Fasting plasma glucose

                                                                  Study week

                                                                  Lorcaserin 10 mg BID Lorcaserin 10 mg Placebo

                                                                  Lorcaserin Adverse Events Reported by 5 or More in Any Group in Year 1

                                                                  55

                                                                  N () Lorcaserin(N = 1593)

                                                                  Placebo(N = 1584)

                                                                  Headache 287 (180) 175 (110)

                                                                  Dizziness 130 (82) 60 (38)

                                                                  Nausea 119 (75) 85 (54)

                                                                  Constipation 106 (67) 64 (40)

                                                                  Fatigue 95 (60) 48 (30)

                                                                  Dry mouth 83 (52) 37 (23)

                                                                  Smith SR et al ADA 2009 Late‐Breaking Abstract 96

                                                                  LorcaserinNo Increase in Rate of Valvulopathy

                                                                  Smith SR et al N Engl J Med 2010363245-256

                                                                  10

                                                                  8

                                                                  6

                                                                  4

                                                                  2

                                                                  024 52 76 104

                                                                  1351714

                                                                  9

                                                                  19

                                                                  3421Patie

                                                                  nts

                                                                  ()

                                                                  Week

                                                                  Lorcaserin in yr 1 and 2

                                                                  Lorcaserin in yr 1 Placebo in yr 2

                                                                  Placebo in yr 1 and 2

                                                                  Phase III Study Outcomes Compared

                                                                  Buproprion SR (360 mgd) Naltrexone SR (32 mgd)

                                                                  Lorcaserin(20 mgd)

                                                                  Phentermine Topiramate CR

                                                                  COR1 COR-I2 COR-II3 NB3043 BLOOM4 BLOSSOM5 EQUIP CONQUER

                                                                  Number of patients (ITT-LOCF)

                                                                  793 obese 1453 obese

                                                                  1281 obese

                                                                  502 type II diabetes

                                                                  3182 obese 4008 obese

                                                                  1230 obese BMI 44

                                                                  2448 comorbidBMI 36

                                                                  Mean change compared with placebo from base

                                                                  93 vs5 1c

                                                                  61a vs13c

                                                                  64a vs12

                                                                  50 a vs12c

                                                                  58 vs22c

                                                                  48 vs28c

                                                                  11 Fullbvs 16

                                                                  104 Fullb 84 Midb

                                                                  vs 18

                                                                  51 Lowb vs16c

                                                                  Categorical change 5 compared with placebo from base

                                                                  56 vs43

                                                                  48a vs164

                                                                  563a

                                                                  vs 171445a vs189

                                                                  475b

                                                                  vs 203472b vs25

                                                                  67 Fullb 45 Lowb vs17

                                                                  70 Fullb 62 Midb

                                                                  vs 21

                                                                  Phenterminetopiramate doses Low 375 mg phentermine23 mg topiramate Mid 75 mg phentermine 46 mg topiramate Full 15 mg phentermine 92 mg topiramateITT-LOCF intent-to-treat last observation carried forwardData not available aP lt 001 vs placebo bP lt 0001 vs placebo

                                                                  Obesity Treatments in Late Development

                                                                  Kushner RF Expert Opin Pharmacother 200891339-1350

                                                                  Agents ActionBupropionNaltrexone

                                                                  bull Dopaminenoradrenaline reuptake inhibitorbull Opioid receptor antagonist

                                                                  Liraglutide bull GLP-1 agonist

                                                                  BupropionNaltrexone

                                                                  bull Mechanism of Actionndash Bupropion - Dopaminenoradrenaline reuptake inhibitorndash Naltrexone- Opioid receptor antagonist

                                                                  bull Was approved by FDA committee but FDA did not approve until a CV outcome study is performed 2nd concerns about BP and P in some patients

                                                                  bull The Light Study is now underway and reported to be enrolling well under PI Dr Nissen

                                                                  bull BupropionNaltrexone will have first completed CV outcome study

                                                                  Buproprion ndash Naltrexone

                                                                  Greenway FL et al Lancet 2010376(9741)595-605

                                                                  0

                                                                  -2

                                                                  -4

                                                                  -6

                                                                  -8

                                                                  -100 4 8 12 16 20 24 28 32 36 40 44 48 52 56

                                                                  Weeks

                                                                  Wei

                                                                  ght c

                                                                  hang

                                                                  e fro

                                                                  m b

                                                                  asel

                                                                  ine

                                                                  ()

                                                                  Placebo

                                                                  Naltrexone 16 mg plus bupropion

                                                                  Naltrexone 32 mg plus bupropion

                                                                  Liraglutide for Weight Loss in Patients with Type 2 Diabetes

                                                                  bull GLP-1 analog approved for treatment of type 2 diabetes

                                                                  bull Anorectic effect mediated both by the activation of GLP-1 receptor expressed on vagal afferents and by the GLP-1R activation in CNS

                                                                  bull Affects visceral fat adiposity appetite food preference and cardiovascular biomarkers in patients with type 2 diabetes

                                                                  Inoue K et al Cardiovasc Diabetol 2011 10109 doi1011861475-2840-10-109

                                                                  Liraglutide Weight Loss Over 2 Years ITT Observed Means

                                                                  Astrup A et al Int J Obes (Lond) 201236(6)843-54

                                                                  FromScreening

                                                                  -94 kg

                                                                  -67 kg-88 kg

                                                                  -99 kg-94 kg

                                                                  -103 kg

                                                                  ITT intention to treat

                                                                  Phase III Study Outcomes Compared

                                                                  Buproprion SR (360 mgd) Naltrexone SR (32 mgd)

                                                                  Lorcaserin(20 mgd)

                                                                  Phentermine Topiramate CR

                                                                  COR1 COR-I2 COR-II3 NB3043 BLOOM4 BLOSSOM5 EQUIP CONQUER

                                                                  Number of patients (ITT-LOCF)

                                                                  793 obese 1453 obese

                                                                  1281 obese

                                                                  502 type II diabetes

                                                                  3182 obese 4008 obese

                                                                  1230 obese BMI 44

                                                                  2448 comorbidBMI 36

                                                                  Mean change compared with placebo from base

                                                                  93 vs5 1c

                                                                  61a vs13c

                                                                  64a vs12

                                                                  50 a vs12c

                                                                  58 vs22c

                                                                  48 vs28c

                                                                  11 Fullbvs 16

                                                                  104 Fullb 84 Midb

                                                                  vs 18

                                                                  51 Lowb vs16c

                                                                  Categorical change 5 compared with placebo from base

                                                                  56 vs43

                                                                  48a vs164

                                                                  563a

                                                                  vs 171445a vs189

                                                                  475b

                                                                  vs 203472b vs25

                                                                  67 Fullb 45 Lowb vs17

                                                                  70 Fullb 62 Midb

                                                                  vs 21

                                                                  Phenterminetopiramate doses Low 375 mg phentermine23 mg topiramate Mid 75 mg phentermine 46 mg topiramate Full 15 mg phentermine 92 mg topiramateITT-LOCF intent-to-treat last observation carried forwardData not available aP lt 001 vs placebo bP lt 0001 vs placebo

                                                                  Treatment Gap in theManagement of Obesity

                                                                  Physicians Need Effective Pharmacotherapies That Will Reduce Weight Significantly and Reduce Weight-related Comorbidities

                                                                  0 5 10 15 20 25 30 35

                                                                  Diet and Lifestyle Lap Band Gastric Bypass

                                                                  TreatmentGap

                                                                  What will fill the gap

                                                                  Too risky for many peopleNot effective enoughfor many people

                                                                  Treatment Gap in theManagement of Obesity

                                                                  0 5 10 15 20 25 30 35

                                                                  Diet and Lifestyle Lap Band Gastric Bypass

                                                                  TreatmentGap

                                                                  Too risky for many peopleNot effective enoughfor many people Pharmacotherapy

                                                                  Less invasive procedures

                                                                  Physicians Need Effective Pharmacotherapies That Will Reduce Weight Significantly and Reduce Weight-related Comorbidities

                                                                  What will fill the gap

                                                                  • Slide Number 1
                                                                  • Slide Number 2
                                                                  • Weight Management is Moving into the Workplace and Mainstream of Healthcare
                                                                  • US Preventative Services Task Force
                                                                  • A Proposal from CMS about Coverage for Intensive Behavioral Therapy for Obesity
                                                                  • Slide Number 6
                                                                  • Biggest Increases in Clinically Severe Obesity US 1987-2005
                                                                  • Relationship Between BMI and Risk of Type 2 Diabetes
                                                                  • Slide Number 9
                                                                  • Medical Complications of Obesity Almost every organ system is affected
                                                                  • Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and disease
                                                                  • Current Therapies Often Address Individual Risk Factors Cardiometabolic risk
                                                                  • Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and disease
                                                                  • Are You Treating These Drivers of Cardiometabolic Risk Should You Treat The Underlying Cause
                                                                  • Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors
                                                                  • In My Opinion The Winds of Change are Blowing in the Treatment of Chronic Diseases
                                                                  • Bariatric Surgery Reduces Overall Mortality Diabetes Mortality by 88
                                                                  • Health Care Costs Attributable to ObesityEstimates of what various conditions add to health-care service costs over a 12-month period
                                                                  • What-if scenarios (The Lancet forthcoming)
                                                                  • How Much Weight Loss Is Needed to Prevent T2DMndashNot Very Much The DPP Experience
                                                                  • In the Da Qing Study 6-year Intervention Led to Lower Incidence of Type 2 Diabetes 14 Years Later
                                                                  • Slide Number 22
                                                                  • Slide Number 23
                                                                  • New Compounds andCombination Interventions
                                                                  • Phentermine and Topiramate Extended-Release
                                                                  • Phentermine and Topiramate Extended-Release
                                                                  • EQUIP amp CONQUER Discontinuation RateDue to AEs in All Doses Studied
                                                                  • Phentermine and Topiramate SEQUELWeight Loss Over Time
                                                                  • CONQUER Significant Improvement in Cardiovascular Risk Factors
                                                                  • Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors
                                                                  • Lorcaserin
                                                                  • BLOOM Study Body Weight Over Years 1 and 2
                                                                  • BLOOM StudyKey Secondary Endpoints
                                                                  • BLOOM-DMChange in Glycemic Parameters
                                                                  • Lorcaserin Adverse Events Reported by 5 or More in Any Group in Year 1
                                                                  • LorcaserinNo Increase in Rate of Valvulopathy
                                                                  • Phase III Study Outcomes Compared
                                                                  • Obesity Treatments in Late Development
                                                                  • BupropionNaltrexone
                                                                  • Buproprion ndash Naltrexone
                                                                  • Liraglutide for Weight Loss in Patients with Type 2 Diabetes
                                                                  • Liraglutide Weight Loss Over 2 Years ITT Observed Means
                                                                  • Phase III Study Outcomes Compared
                                                                  • Treatment Gap in theManagement of Obesity
                                                                  • Treatment Gap in theManagement of Obesity

                                                                    Lorcaserin Adverse Events Reported by 5 or More in Any Group in Year 1

                                                                    55

                                                                    N () Lorcaserin(N = 1593)

                                                                    Placebo(N = 1584)

                                                                    Headache 287 (180) 175 (110)

                                                                    Dizziness 130 (82) 60 (38)

                                                                    Nausea 119 (75) 85 (54)

                                                                    Constipation 106 (67) 64 (40)

                                                                    Fatigue 95 (60) 48 (30)

                                                                    Dry mouth 83 (52) 37 (23)

                                                                    Smith SR et al ADA 2009 Late‐Breaking Abstract 96

                                                                    LorcaserinNo Increase in Rate of Valvulopathy

                                                                    Smith SR et al N Engl J Med 2010363245-256

                                                                    10

                                                                    8

                                                                    6

                                                                    4

                                                                    2

                                                                    024 52 76 104

                                                                    1351714

                                                                    9

                                                                    19

                                                                    3421Patie

                                                                    nts

                                                                    ()

                                                                    Week

                                                                    Lorcaserin in yr 1 and 2

                                                                    Lorcaserin in yr 1 Placebo in yr 2

                                                                    Placebo in yr 1 and 2

                                                                    Phase III Study Outcomes Compared

                                                                    Buproprion SR (360 mgd) Naltrexone SR (32 mgd)

                                                                    Lorcaserin(20 mgd)

                                                                    Phentermine Topiramate CR

                                                                    COR1 COR-I2 COR-II3 NB3043 BLOOM4 BLOSSOM5 EQUIP CONQUER

                                                                    Number of patients (ITT-LOCF)

                                                                    793 obese 1453 obese

                                                                    1281 obese

                                                                    502 type II diabetes

                                                                    3182 obese 4008 obese

                                                                    1230 obese BMI 44

                                                                    2448 comorbidBMI 36

                                                                    Mean change compared with placebo from base

                                                                    93 vs5 1c

                                                                    61a vs13c

                                                                    64a vs12

                                                                    50 a vs12c

                                                                    58 vs22c

                                                                    48 vs28c

                                                                    11 Fullbvs 16

                                                                    104 Fullb 84 Midb

                                                                    vs 18

                                                                    51 Lowb vs16c

                                                                    Categorical change 5 compared with placebo from base

                                                                    56 vs43

                                                                    48a vs164

                                                                    563a

                                                                    vs 171445a vs189

                                                                    475b

                                                                    vs 203472b vs25

                                                                    67 Fullb 45 Lowb vs17

                                                                    70 Fullb 62 Midb

                                                                    vs 21

                                                                    Phenterminetopiramate doses Low 375 mg phentermine23 mg topiramate Mid 75 mg phentermine 46 mg topiramate Full 15 mg phentermine 92 mg topiramateITT-LOCF intent-to-treat last observation carried forwardData not available aP lt 001 vs placebo bP lt 0001 vs placebo

                                                                    Obesity Treatments in Late Development

                                                                    Kushner RF Expert Opin Pharmacother 200891339-1350

                                                                    Agents ActionBupropionNaltrexone

                                                                    bull Dopaminenoradrenaline reuptake inhibitorbull Opioid receptor antagonist

                                                                    Liraglutide bull GLP-1 agonist

                                                                    BupropionNaltrexone

                                                                    bull Mechanism of Actionndash Bupropion - Dopaminenoradrenaline reuptake inhibitorndash Naltrexone- Opioid receptor antagonist

                                                                    bull Was approved by FDA committee but FDA did not approve until a CV outcome study is performed 2nd concerns about BP and P in some patients

                                                                    bull The Light Study is now underway and reported to be enrolling well under PI Dr Nissen

                                                                    bull BupropionNaltrexone will have first completed CV outcome study

                                                                    Buproprion ndash Naltrexone

                                                                    Greenway FL et al Lancet 2010376(9741)595-605

                                                                    0

                                                                    -2

                                                                    -4

                                                                    -6

                                                                    -8

                                                                    -100 4 8 12 16 20 24 28 32 36 40 44 48 52 56

                                                                    Weeks

                                                                    Wei

                                                                    ght c

                                                                    hang

                                                                    e fro

                                                                    m b

                                                                    asel

                                                                    ine

                                                                    ()

                                                                    Placebo

                                                                    Naltrexone 16 mg plus bupropion

                                                                    Naltrexone 32 mg plus bupropion

                                                                    Liraglutide for Weight Loss in Patients with Type 2 Diabetes

                                                                    bull GLP-1 analog approved for treatment of type 2 diabetes

                                                                    bull Anorectic effect mediated both by the activation of GLP-1 receptor expressed on vagal afferents and by the GLP-1R activation in CNS

                                                                    bull Affects visceral fat adiposity appetite food preference and cardiovascular biomarkers in patients with type 2 diabetes

                                                                    Inoue K et al Cardiovasc Diabetol 2011 10109 doi1011861475-2840-10-109

                                                                    Liraglutide Weight Loss Over 2 Years ITT Observed Means

                                                                    Astrup A et al Int J Obes (Lond) 201236(6)843-54

                                                                    FromScreening

                                                                    -94 kg

                                                                    -67 kg-88 kg

                                                                    -99 kg-94 kg

                                                                    -103 kg

                                                                    ITT intention to treat

                                                                    Phase III Study Outcomes Compared

                                                                    Buproprion SR (360 mgd) Naltrexone SR (32 mgd)

                                                                    Lorcaserin(20 mgd)

                                                                    Phentermine Topiramate CR

                                                                    COR1 COR-I2 COR-II3 NB3043 BLOOM4 BLOSSOM5 EQUIP CONQUER

                                                                    Number of patients (ITT-LOCF)

                                                                    793 obese 1453 obese

                                                                    1281 obese

                                                                    502 type II diabetes

                                                                    3182 obese 4008 obese

                                                                    1230 obese BMI 44

                                                                    2448 comorbidBMI 36

                                                                    Mean change compared with placebo from base

                                                                    93 vs5 1c

                                                                    61a vs13c

                                                                    64a vs12

                                                                    50 a vs12c

                                                                    58 vs22c

                                                                    48 vs28c

                                                                    11 Fullbvs 16

                                                                    104 Fullb 84 Midb

                                                                    vs 18

                                                                    51 Lowb vs16c

                                                                    Categorical change 5 compared with placebo from base

                                                                    56 vs43

                                                                    48a vs164

                                                                    563a

                                                                    vs 171445a vs189

                                                                    475b

                                                                    vs 203472b vs25

                                                                    67 Fullb 45 Lowb vs17

                                                                    70 Fullb 62 Midb

                                                                    vs 21

                                                                    Phenterminetopiramate doses Low 375 mg phentermine23 mg topiramate Mid 75 mg phentermine 46 mg topiramate Full 15 mg phentermine 92 mg topiramateITT-LOCF intent-to-treat last observation carried forwardData not available aP lt 001 vs placebo bP lt 0001 vs placebo

                                                                    Treatment Gap in theManagement of Obesity

                                                                    Physicians Need Effective Pharmacotherapies That Will Reduce Weight Significantly and Reduce Weight-related Comorbidities

                                                                    0 5 10 15 20 25 30 35

                                                                    Diet and Lifestyle Lap Band Gastric Bypass

                                                                    TreatmentGap

                                                                    What will fill the gap

                                                                    Too risky for many peopleNot effective enoughfor many people

                                                                    Treatment Gap in theManagement of Obesity

                                                                    0 5 10 15 20 25 30 35

                                                                    Diet and Lifestyle Lap Band Gastric Bypass

                                                                    TreatmentGap

                                                                    Too risky for many peopleNot effective enoughfor many people Pharmacotherapy

                                                                    Less invasive procedures

                                                                    Physicians Need Effective Pharmacotherapies That Will Reduce Weight Significantly and Reduce Weight-related Comorbidities

                                                                    What will fill the gap

                                                                    • Slide Number 1
                                                                    • Slide Number 2
                                                                    • Weight Management is Moving into the Workplace and Mainstream of Healthcare
                                                                    • US Preventative Services Task Force
                                                                    • A Proposal from CMS about Coverage for Intensive Behavioral Therapy for Obesity
                                                                    • Slide Number 6
                                                                    • Biggest Increases in Clinically Severe Obesity US 1987-2005
                                                                    • Relationship Between BMI and Risk of Type 2 Diabetes
                                                                    • Slide Number 9
                                                                    • Medical Complications of Obesity Almost every organ system is affected
                                                                    • Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and disease
                                                                    • Current Therapies Often Address Individual Risk Factors Cardiometabolic risk
                                                                    • Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and disease
                                                                    • Are You Treating These Drivers of Cardiometabolic Risk Should You Treat The Underlying Cause
                                                                    • Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors
                                                                    • In My Opinion The Winds of Change are Blowing in the Treatment of Chronic Diseases
                                                                    • Bariatric Surgery Reduces Overall Mortality Diabetes Mortality by 88
                                                                    • Health Care Costs Attributable to ObesityEstimates of what various conditions add to health-care service costs over a 12-month period
                                                                    • What-if scenarios (The Lancet forthcoming)
                                                                    • How Much Weight Loss Is Needed to Prevent T2DMndashNot Very Much The DPP Experience
                                                                    • In the Da Qing Study 6-year Intervention Led to Lower Incidence of Type 2 Diabetes 14 Years Later
                                                                    • Slide Number 22
                                                                    • Slide Number 23
                                                                    • New Compounds andCombination Interventions
                                                                    • Phentermine and Topiramate Extended-Release
                                                                    • Phentermine and Topiramate Extended-Release
                                                                    • EQUIP amp CONQUER Discontinuation RateDue to AEs in All Doses Studied
                                                                    • Phentermine and Topiramate SEQUELWeight Loss Over Time
                                                                    • CONQUER Significant Improvement in Cardiovascular Risk Factors
                                                                    • Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors
                                                                    • Lorcaserin
                                                                    • BLOOM Study Body Weight Over Years 1 and 2
                                                                    • BLOOM StudyKey Secondary Endpoints
                                                                    • BLOOM-DMChange in Glycemic Parameters
                                                                    • Lorcaserin Adverse Events Reported by 5 or More in Any Group in Year 1
                                                                    • LorcaserinNo Increase in Rate of Valvulopathy
                                                                    • Phase III Study Outcomes Compared
                                                                    • Obesity Treatments in Late Development
                                                                    • BupropionNaltrexone
                                                                    • Buproprion ndash Naltrexone
                                                                    • Liraglutide for Weight Loss in Patients with Type 2 Diabetes
                                                                    • Liraglutide Weight Loss Over 2 Years ITT Observed Means
                                                                    • Phase III Study Outcomes Compared
                                                                    • Treatment Gap in theManagement of Obesity
                                                                    • Treatment Gap in theManagement of Obesity

                                                                      LorcaserinNo Increase in Rate of Valvulopathy

                                                                      Smith SR et al N Engl J Med 2010363245-256

                                                                      10

                                                                      8

                                                                      6

                                                                      4

                                                                      2

                                                                      024 52 76 104

                                                                      1351714

                                                                      9

                                                                      19

                                                                      3421Patie

                                                                      nts

                                                                      ()

                                                                      Week

                                                                      Lorcaserin in yr 1 and 2

                                                                      Lorcaserin in yr 1 Placebo in yr 2

                                                                      Placebo in yr 1 and 2

                                                                      Phase III Study Outcomes Compared

                                                                      Buproprion SR (360 mgd) Naltrexone SR (32 mgd)

                                                                      Lorcaserin(20 mgd)

                                                                      Phentermine Topiramate CR

                                                                      COR1 COR-I2 COR-II3 NB3043 BLOOM4 BLOSSOM5 EQUIP CONQUER

                                                                      Number of patients (ITT-LOCF)

                                                                      793 obese 1453 obese

                                                                      1281 obese

                                                                      502 type II diabetes

                                                                      3182 obese 4008 obese

                                                                      1230 obese BMI 44

                                                                      2448 comorbidBMI 36

                                                                      Mean change compared with placebo from base

                                                                      93 vs5 1c

                                                                      61a vs13c

                                                                      64a vs12

                                                                      50 a vs12c

                                                                      58 vs22c

                                                                      48 vs28c

                                                                      11 Fullbvs 16

                                                                      104 Fullb 84 Midb

                                                                      vs 18

                                                                      51 Lowb vs16c

                                                                      Categorical change 5 compared with placebo from base

                                                                      56 vs43

                                                                      48a vs164

                                                                      563a

                                                                      vs 171445a vs189

                                                                      475b

                                                                      vs 203472b vs25

                                                                      67 Fullb 45 Lowb vs17

                                                                      70 Fullb 62 Midb

                                                                      vs 21

                                                                      Phenterminetopiramate doses Low 375 mg phentermine23 mg topiramate Mid 75 mg phentermine 46 mg topiramate Full 15 mg phentermine 92 mg topiramateITT-LOCF intent-to-treat last observation carried forwardData not available aP lt 001 vs placebo bP lt 0001 vs placebo

                                                                      Obesity Treatments in Late Development

                                                                      Kushner RF Expert Opin Pharmacother 200891339-1350

                                                                      Agents ActionBupropionNaltrexone

                                                                      bull Dopaminenoradrenaline reuptake inhibitorbull Opioid receptor antagonist

                                                                      Liraglutide bull GLP-1 agonist

                                                                      BupropionNaltrexone

                                                                      bull Mechanism of Actionndash Bupropion - Dopaminenoradrenaline reuptake inhibitorndash Naltrexone- Opioid receptor antagonist

                                                                      bull Was approved by FDA committee but FDA did not approve until a CV outcome study is performed 2nd concerns about BP and P in some patients

                                                                      bull The Light Study is now underway and reported to be enrolling well under PI Dr Nissen

                                                                      bull BupropionNaltrexone will have first completed CV outcome study

                                                                      Buproprion ndash Naltrexone

                                                                      Greenway FL et al Lancet 2010376(9741)595-605

                                                                      0

                                                                      -2

                                                                      -4

                                                                      -6

                                                                      -8

                                                                      -100 4 8 12 16 20 24 28 32 36 40 44 48 52 56

                                                                      Weeks

                                                                      Wei

                                                                      ght c

                                                                      hang

                                                                      e fro

                                                                      m b

                                                                      asel

                                                                      ine

                                                                      ()

                                                                      Placebo

                                                                      Naltrexone 16 mg plus bupropion

                                                                      Naltrexone 32 mg plus bupropion

                                                                      Liraglutide for Weight Loss in Patients with Type 2 Diabetes

                                                                      bull GLP-1 analog approved for treatment of type 2 diabetes

                                                                      bull Anorectic effect mediated both by the activation of GLP-1 receptor expressed on vagal afferents and by the GLP-1R activation in CNS

                                                                      bull Affects visceral fat adiposity appetite food preference and cardiovascular biomarkers in patients with type 2 diabetes

                                                                      Inoue K et al Cardiovasc Diabetol 2011 10109 doi1011861475-2840-10-109

                                                                      Liraglutide Weight Loss Over 2 Years ITT Observed Means

                                                                      Astrup A et al Int J Obes (Lond) 201236(6)843-54

                                                                      FromScreening

                                                                      -94 kg

                                                                      -67 kg-88 kg

                                                                      -99 kg-94 kg

                                                                      -103 kg

                                                                      ITT intention to treat

                                                                      Phase III Study Outcomes Compared

                                                                      Buproprion SR (360 mgd) Naltrexone SR (32 mgd)

                                                                      Lorcaserin(20 mgd)

                                                                      Phentermine Topiramate CR

                                                                      COR1 COR-I2 COR-II3 NB3043 BLOOM4 BLOSSOM5 EQUIP CONQUER

                                                                      Number of patients (ITT-LOCF)

                                                                      793 obese 1453 obese

                                                                      1281 obese

                                                                      502 type II diabetes

                                                                      3182 obese 4008 obese

                                                                      1230 obese BMI 44

                                                                      2448 comorbidBMI 36

                                                                      Mean change compared with placebo from base

                                                                      93 vs5 1c

                                                                      61a vs13c

                                                                      64a vs12

                                                                      50 a vs12c

                                                                      58 vs22c

                                                                      48 vs28c

                                                                      11 Fullbvs 16

                                                                      104 Fullb 84 Midb

                                                                      vs 18

                                                                      51 Lowb vs16c

                                                                      Categorical change 5 compared with placebo from base

                                                                      56 vs43

                                                                      48a vs164

                                                                      563a

                                                                      vs 171445a vs189

                                                                      475b

                                                                      vs 203472b vs25

                                                                      67 Fullb 45 Lowb vs17

                                                                      70 Fullb 62 Midb

                                                                      vs 21

                                                                      Phenterminetopiramate doses Low 375 mg phentermine23 mg topiramate Mid 75 mg phentermine 46 mg topiramate Full 15 mg phentermine 92 mg topiramateITT-LOCF intent-to-treat last observation carried forwardData not available aP lt 001 vs placebo bP lt 0001 vs placebo

                                                                      Treatment Gap in theManagement of Obesity

                                                                      Physicians Need Effective Pharmacotherapies That Will Reduce Weight Significantly and Reduce Weight-related Comorbidities

                                                                      0 5 10 15 20 25 30 35

                                                                      Diet and Lifestyle Lap Band Gastric Bypass

                                                                      TreatmentGap

                                                                      What will fill the gap

                                                                      Too risky for many peopleNot effective enoughfor many people

                                                                      Treatment Gap in theManagement of Obesity

                                                                      0 5 10 15 20 25 30 35

                                                                      Diet and Lifestyle Lap Band Gastric Bypass

                                                                      TreatmentGap

                                                                      Too risky for many peopleNot effective enoughfor many people Pharmacotherapy

                                                                      Less invasive procedures

                                                                      Physicians Need Effective Pharmacotherapies That Will Reduce Weight Significantly and Reduce Weight-related Comorbidities

                                                                      What will fill the gap

                                                                      • Slide Number 1
                                                                      • Slide Number 2
                                                                      • Weight Management is Moving into the Workplace and Mainstream of Healthcare
                                                                      • US Preventative Services Task Force
                                                                      • A Proposal from CMS about Coverage for Intensive Behavioral Therapy for Obesity
                                                                      • Slide Number 6
                                                                      • Biggest Increases in Clinically Severe Obesity US 1987-2005
                                                                      • Relationship Between BMI and Risk of Type 2 Diabetes
                                                                      • Slide Number 9
                                                                      • Medical Complications of Obesity Almost every organ system is affected
                                                                      • Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and disease
                                                                      • Current Therapies Often Address Individual Risk Factors Cardiometabolic risk
                                                                      • Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and disease
                                                                      • Are You Treating These Drivers of Cardiometabolic Risk Should You Treat The Underlying Cause
                                                                      • Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors
                                                                      • In My Opinion The Winds of Change are Blowing in the Treatment of Chronic Diseases
                                                                      • Bariatric Surgery Reduces Overall Mortality Diabetes Mortality by 88
                                                                      • Health Care Costs Attributable to ObesityEstimates of what various conditions add to health-care service costs over a 12-month period
                                                                      • What-if scenarios (The Lancet forthcoming)
                                                                      • How Much Weight Loss Is Needed to Prevent T2DMndashNot Very Much The DPP Experience
                                                                      • In the Da Qing Study 6-year Intervention Led to Lower Incidence of Type 2 Diabetes 14 Years Later
                                                                      • Slide Number 22
                                                                      • Slide Number 23
                                                                      • New Compounds andCombination Interventions
                                                                      • Phentermine and Topiramate Extended-Release
                                                                      • Phentermine and Topiramate Extended-Release
                                                                      • EQUIP amp CONQUER Discontinuation RateDue to AEs in All Doses Studied
                                                                      • Phentermine and Topiramate SEQUELWeight Loss Over Time
                                                                      • CONQUER Significant Improvement in Cardiovascular Risk Factors
                                                                      • Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors
                                                                      • Lorcaserin
                                                                      • BLOOM Study Body Weight Over Years 1 and 2
                                                                      • BLOOM StudyKey Secondary Endpoints
                                                                      • BLOOM-DMChange in Glycemic Parameters
                                                                      • Lorcaserin Adverse Events Reported by 5 or More in Any Group in Year 1
                                                                      • LorcaserinNo Increase in Rate of Valvulopathy
                                                                      • Phase III Study Outcomes Compared
                                                                      • Obesity Treatments in Late Development
                                                                      • BupropionNaltrexone
                                                                      • Buproprion ndash Naltrexone
                                                                      • Liraglutide for Weight Loss in Patients with Type 2 Diabetes
                                                                      • Liraglutide Weight Loss Over 2 Years ITT Observed Means
                                                                      • Phase III Study Outcomes Compared
                                                                      • Treatment Gap in theManagement of Obesity
                                                                      • Treatment Gap in theManagement of Obesity

                                                                        Phase III Study Outcomes Compared

                                                                        Buproprion SR (360 mgd) Naltrexone SR (32 mgd)

                                                                        Lorcaserin(20 mgd)

                                                                        Phentermine Topiramate CR

                                                                        COR1 COR-I2 COR-II3 NB3043 BLOOM4 BLOSSOM5 EQUIP CONQUER

                                                                        Number of patients (ITT-LOCF)

                                                                        793 obese 1453 obese

                                                                        1281 obese

                                                                        502 type II diabetes

                                                                        3182 obese 4008 obese

                                                                        1230 obese BMI 44

                                                                        2448 comorbidBMI 36

                                                                        Mean change compared with placebo from base

                                                                        93 vs5 1c

                                                                        61a vs13c

                                                                        64a vs12

                                                                        50 a vs12c

                                                                        58 vs22c

                                                                        48 vs28c

                                                                        11 Fullbvs 16

                                                                        104 Fullb 84 Midb

                                                                        vs 18

                                                                        51 Lowb vs16c

                                                                        Categorical change 5 compared with placebo from base

                                                                        56 vs43

                                                                        48a vs164

                                                                        563a

                                                                        vs 171445a vs189

                                                                        475b

                                                                        vs 203472b vs25

                                                                        67 Fullb 45 Lowb vs17

                                                                        70 Fullb 62 Midb

                                                                        vs 21

                                                                        Phenterminetopiramate doses Low 375 mg phentermine23 mg topiramate Mid 75 mg phentermine 46 mg topiramate Full 15 mg phentermine 92 mg topiramateITT-LOCF intent-to-treat last observation carried forwardData not available aP lt 001 vs placebo bP lt 0001 vs placebo

                                                                        Obesity Treatments in Late Development

                                                                        Kushner RF Expert Opin Pharmacother 200891339-1350

                                                                        Agents ActionBupropionNaltrexone

                                                                        bull Dopaminenoradrenaline reuptake inhibitorbull Opioid receptor antagonist

                                                                        Liraglutide bull GLP-1 agonist

                                                                        BupropionNaltrexone

                                                                        bull Mechanism of Actionndash Bupropion - Dopaminenoradrenaline reuptake inhibitorndash Naltrexone- Opioid receptor antagonist

                                                                        bull Was approved by FDA committee but FDA did not approve until a CV outcome study is performed 2nd concerns about BP and P in some patients

                                                                        bull The Light Study is now underway and reported to be enrolling well under PI Dr Nissen

                                                                        bull BupropionNaltrexone will have first completed CV outcome study

                                                                        Buproprion ndash Naltrexone

                                                                        Greenway FL et al Lancet 2010376(9741)595-605

                                                                        0

                                                                        -2

                                                                        -4

                                                                        -6

                                                                        -8

                                                                        -100 4 8 12 16 20 24 28 32 36 40 44 48 52 56

                                                                        Weeks

                                                                        Wei

                                                                        ght c

                                                                        hang

                                                                        e fro

                                                                        m b

                                                                        asel

                                                                        ine

                                                                        ()

                                                                        Placebo

                                                                        Naltrexone 16 mg plus bupropion

                                                                        Naltrexone 32 mg plus bupropion

                                                                        Liraglutide for Weight Loss in Patients with Type 2 Diabetes

                                                                        bull GLP-1 analog approved for treatment of type 2 diabetes

                                                                        bull Anorectic effect mediated both by the activation of GLP-1 receptor expressed on vagal afferents and by the GLP-1R activation in CNS

                                                                        bull Affects visceral fat adiposity appetite food preference and cardiovascular biomarkers in patients with type 2 diabetes

                                                                        Inoue K et al Cardiovasc Diabetol 2011 10109 doi1011861475-2840-10-109

                                                                        Liraglutide Weight Loss Over 2 Years ITT Observed Means

                                                                        Astrup A et al Int J Obes (Lond) 201236(6)843-54

                                                                        FromScreening

                                                                        -94 kg

                                                                        -67 kg-88 kg

                                                                        -99 kg-94 kg

                                                                        -103 kg

                                                                        ITT intention to treat

                                                                        Phase III Study Outcomes Compared

                                                                        Buproprion SR (360 mgd) Naltrexone SR (32 mgd)

                                                                        Lorcaserin(20 mgd)

                                                                        Phentermine Topiramate CR

                                                                        COR1 COR-I2 COR-II3 NB3043 BLOOM4 BLOSSOM5 EQUIP CONQUER

                                                                        Number of patients (ITT-LOCF)

                                                                        793 obese 1453 obese

                                                                        1281 obese

                                                                        502 type II diabetes

                                                                        3182 obese 4008 obese

                                                                        1230 obese BMI 44

                                                                        2448 comorbidBMI 36

                                                                        Mean change compared with placebo from base

                                                                        93 vs5 1c

                                                                        61a vs13c

                                                                        64a vs12

                                                                        50 a vs12c

                                                                        58 vs22c

                                                                        48 vs28c

                                                                        11 Fullbvs 16

                                                                        104 Fullb 84 Midb

                                                                        vs 18

                                                                        51 Lowb vs16c

                                                                        Categorical change 5 compared with placebo from base

                                                                        56 vs43

                                                                        48a vs164

                                                                        563a

                                                                        vs 171445a vs189

                                                                        475b

                                                                        vs 203472b vs25

                                                                        67 Fullb 45 Lowb vs17

                                                                        70 Fullb 62 Midb

                                                                        vs 21

                                                                        Phenterminetopiramate doses Low 375 mg phentermine23 mg topiramate Mid 75 mg phentermine 46 mg topiramate Full 15 mg phentermine 92 mg topiramateITT-LOCF intent-to-treat last observation carried forwardData not available aP lt 001 vs placebo bP lt 0001 vs placebo

                                                                        Treatment Gap in theManagement of Obesity

                                                                        Physicians Need Effective Pharmacotherapies That Will Reduce Weight Significantly and Reduce Weight-related Comorbidities

                                                                        0 5 10 15 20 25 30 35

                                                                        Diet and Lifestyle Lap Band Gastric Bypass

                                                                        TreatmentGap

                                                                        What will fill the gap

                                                                        Too risky for many peopleNot effective enoughfor many people

                                                                        Treatment Gap in theManagement of Obesity

                                                                        0 5 10 15 20 25 30 35

                                                                        Diet and Lifestyle Lap Band Gastric Bypass

                                                                        TreatmentGap

                                                                        Too risky for many peopleNot effective enoughfor many people Pharmacotherapy

                                                                        Less invasive procedures

                                                                        Physicians Need Effective Pharmacotherapies That Will Reduce Weight Significantly and Reduce Weight-related Comorbidities

                                                                        What will fill the gap

                                                                        • Slide Number 1
                                                                        • Slide Number 2
                                                                        • Weight Management is Moving into the Workplace and Mainstream of Healthcare
                                                                        • US Preventative Services Task Force
                                                                        • A Proposal from CMS about Coverage for Intensive Behavioral Therapy for Obesity
                                                                        • Slide Number 6
                                                                        • Biggest Increases in Clinically Severe Obesity US 1987-2005
                                                                        • Relationship Between BMI and Risk of Type 2 Diabetes
                                                                        • Slide Number 9
                                                                        • Medical Complications of Obesity Almost every organ system is affected
                                                                        • Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and disease
                                                                        • Current Therapies Often Address Individual Risk Factors Cardiometabolic risk
                                                                        • Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and disease
                                                                        • Are You Treating These Drivers of Cardiometabolic Risk Should You Treat The Underlying Cause
                                                                        • Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors
                                                                        • In My Opinion The Winds of Change are Blowing in the Treatment of Chronic Diseases
                                                                        • Bariatric Surgery Reduces Overall Mortality Diabetes Mortality by 88
                                                                        • Health Care Costs Attributable to ObesityEstimates of what various conditions add to health-care service costs over a 12-month period
                                                                        • What-if scenarios (The Lancet forthcoming)
                                                                        • How Much Weight Loss Is Needed to Prevent T2DMndashNot Very Much The DPP Experience
                                                                        • In the Da Qing Study 6-year Intervention Led to Lower Incidence of Type 2 Diabetes 14 Years Later
                                                                        • Slide Number 22
                                                                        • Slide Number 23
                                                                        • New Compounds andCombination Interventions
                                                                        • Phentermine and Topiramate Extended-Release
                                                                        • Phentermine and Topiramate Extended-Release
                                                                        • EQUIP amp CONQUER Discontinuation RateDue to AEs in All Doses Studied
                                                                        • Phentermine and Topiramate SEQUELWeight Loss Over Time
                                                                        • CONQUER Significant Improvement in Cardiovascular Risk Factors
                                                                        • Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors
                                                                        • Lorcaserin
                                                                        • BLOOM Study Body Weight Over Years 1 and 2
                                                                        • BLOOM StudyKey Secondary Endpoints
                                                                        • BLOOM-DMChange in Glycemic Parameters
                                                                        • Lorcaserin Adverse Events Reported by 5 or More in Any Group in Year 1
                                                                        • LorcaserinNo Increase in Rate of Valvulopathy
                                                                        • Phase III Study Outcomes Compared
                                                                        • Obesity Treatments in Late Development
                                                                        • BupropionNaltrexone
                                                                        • Buproprion ndash Naltrexone
                                                                        • Liraglutide for Weight Loss in Patients with Type 2 Diabetes
                                                                        • Liraglutide Weight Loss Over 2 Years ITT Observed Means
                                                                        • Phase III Study Outcomes Compared
                                                                        • Treatment Gap in theManagement of Obesity
                                                                        • Treatment Gap in theManagement of Obesity

                                                                          Obesity Treatments in Late Development

                                                                          Kushner RF Expert Opin Pharmacother 200891339-1350

                                                                          Agents ActionBupropionNaltrexone

                                                                          bull Dopaminenoradrenaline reuptake inhibitorbull Opioid receptor antagonist

                                                                          Liraglutide bull GLP-1 agonist

                                                                          BupropionNaltrexone

                                                                          bull Mechanism of Actionndash Bupropion - Dopaminenoradrenaline reuptake inhibitorndash Naltrexone- Opioid receptor antagonist

                                                                          bull Was approved by FDA committee but FDA did not approve until a CV outcome study is performed 2nd concerns about BP and P in some patients

                                                                          bull The Light Study is now underway and reported to be enrolling well under PI Dr Nissen

                                                                          bull BupropionNaltrexone will have first completed CV outcome study

                                                                          Buproprion ndash Naltrexone

                                                                          Greenway FL et al Lancet 2010376(9741)595-605

                                                                          0

                                                                          -2

                                                                          -4

                                                                          -6

                                                                          -8

                                                                          -100 4 8 12 16 20 24 28 32 36 40 44 48 52 56

                                                                          Weeks

                                                                          Wei

                                                                          ght c

                                                                          hang

                                                                          e fro

                                                                          m b

                                                                          asel

                                                                          ine

                                                                          ()

                                                                          Placebo

                                                                          Naltrexone 16 mg plus bupropion

                                                                          Naltrexone 32 mg plus bupropion

                                                                          Liraglutide for Weight Loss in Patients with Type 2 Diabetes

                                                                          bull GLP-1 analog approved for treatment of type 2 diabetes

                                                                          bull Anorectic effect mediated both by the activation of GLP-1 receptor expressed on vagal afferents and by the GLP-1R activation in CNS

                                                                          bull Affects visceral fat adiposity appetite food preference and cardiovascular biomarkers in patients with type 2 diabetes

                                                                          Inoue K et al Cardiovasc Diabetol 2011 10109 doi1011861475-2840-10-109

                                                                          Liraglutide Weight Loss Over 2 Years ITT Observed Means

                                                                          Astrup A et al Int J Obes (Lond) 201236(6)843-54

                                                                          FromScreening

                                                                          -94 kg

                                                                          -67 kg-88 kg

                                                                          -99 kg-94 kg

                                                                          -103 kg

                                                                          ITT intention to treat

                                                                          Phase III Study Outcomes Compared

                                                                          Buproprion SR (360 mgd) Naltrexone SR (32 mgd)

                                                                          Lorcaserin(20 mgd)

                                                                          Phentermine Topiramate CR

                                                                          COR1 COR-I2 COR-II3 NB3043 BLOOM4 BLOSSOM5 EQUIP CONQUER

                                                                          Number of patients (ITT-LOCF)

                                                                          793 obese 1453 obese

                                                                          1281 obese

                                                                          502 type II diabetes

                                                                          3182 obese 4008 obese

                                                                          1230 obese BMI 44

                                                                          2448 comorbidBMI 36

                                                                          Mean change compared with placebo from base

                                                                          93 vs5 1c

                                                                          61a vs13c

                                                                          64a vs12

                                                                          50 a vs12c

                                                                          58 vs22c

                                                                          48 vs28c

                                                                          11 Fullbvs 16

                                                                          104 Fullb 84 Midb

                                                                          vs 18

                                                                          51 Lowb vs16c

                                                                          Categorical change 5 compared with placebo from base

                                                                          56 vs43

                                                                          48a vs164

                                                                          563a

                                                                          vs 171445a vs189

                                                                          475b

                                                                          vs 203472b vs25

                                                                          67 Fullb 45 Lowb vs17

                                                                          70 Fullb 62 Midb

                                                                          vs 21

                                                                          Phenterminetopiramate doses Low 375 mg phentermine23 mg topiramate Mid 75 mg phentermine 46 mg topiramate Full 15 mg phentermine 92 mg topiramateITT-LOCF intent-to-treat last observation carried forwardData not available aP lt 001 vs placebo bP lt 0001 vs placebo

                                                                          Treatment Gap in theManagement of Obesity

                                                                          Physicians Need Effective Pharmacotherapies That Will Reduce Weight Significantly and Reduce Weight-related Comorbidities

                                                                          0 5 10 15 20 25 30 35

                                                                          Diet and Lifestyle Lap Band Gastric Bypass

                                                                          TreatmentGap

                                                                          What will fill the gap

                                                                          Too risky for many peopleNot effective enoughfor many people

                                                                          Treatment Gap in theManagement of Obesity

                                                                          0 5 10 15 20 25 30 35

                                                                          Diet and Lifestyle Lap Band Gastric Bypass

                                                                          TreatmentGap

                                                                          Too risky for many peopleNot effective enoughfor many people Pharmacotherapy

                                                                          Less invasive procedures

                                                                          Physicians Need Effective Pharmacotherapies That Will Reduce Weight Significantly and Reduce Weight-related Comorbidities

                                                                          What will fill the gap

                                                                          • Slide Number 1
                                                                          • Slide Number 2
                                                                          • Weight Management is Moving into the Workplace and Mainstream of Healthcare
                                                                          • US Preventative Services Task Force
                                                                          • A Proposal from CMS about Coverage for Intensive Behavioral Therapy for Obesity
                                                                          • Slide Number 6
                                                                          • Biggest Increases in Clinically Severe Obesity US 1987-2005
                                                                          • Relationship Between BMI and Risk of Type 2 Diabetes
                                                                          • Slide Number 9
                                                                          • Medical Complications of Obesity Almost every organ system is affected
                                                                          • Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and disease
                                                                          • Current Therapies Often Address Individual Risk Factors Cardiometabolic risk
                                                                          • Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and disease
                                                                          • Are You Treating These Drivers of Cardiometabolic Risk Should You Treat The Underlying Cause
                                                                          • Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors
                                                                          • In My Opinion The Winds of Change are Blowing in the Treatment of Chronic Diseases
                                                                          • Bariatric Surgery Reduces Overall Mortality Diabetes Mortality by 88
                                                                          • Health Care Costs Attributable to ObesityEstimates of what various conditions add to health-care service costs over a 12-month period
                                                                          • What-if scenarios (The Lancet forthcoming)
                                                                          • How Much Weight Loss Is Needed to Prevent T2DMndashNot Very Much The DPP Experience
                                                                          • In the Da Qing Study 6-year Intervention Led to Lower Incidence of Type 2 Diabetes 14 Years Later
                                                                          • Slide Number 22
                                                                          • Slide Number 23
                                                                          • New Compounds andCombination Interventions
                                                                          • Phentermine and Topiramate Extended-Release
                                                                          • Phentermine and Topiramate Extended-Release
                                                                          • EQUIP amp CONQUER Discontinuation RateDue to AEs in All Doses Studied
                                                                          • Phentermine and Topiramate SEQUELWeight Loss Over Time
                                                                          • CONQUER Significant Improvement in Cardiovascular Risk Factors
                                                                          • Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors
                                                                          • Lorcaserin
                                                                          • BLOOM Study Body Weight Over Years 1 and 2
                                                                          • BLOOM StudyKey Secondary Endpoints
                                                                          • BLOOM-DMChange in Glycemic Parameters
                                                                          • Lorcaserin Adverse Events Reported by 5 or More in Any Group in Year 1
                                                                          • LorcaserinNo Increase in Rate of Valvulopathy
                                                                          • Phase III Study Outcomes Compared
                                                                          • Obesity Treatments in Late Development
                                                                          • BupropionNaltrexone
                                                                          • Buproprion ndash Naltrexone
                                                                          • Liraglutide for Weight Loss in Patients with Type 2 Diabetes
                                                                          • Liraglutide Weight Loss Over 2 Years ITT Observed Means
                                                                          • Phase III Study Outcomes Compared
                                                                          • Treatment Gap in theManagement of Obesity
                                                                          • Treatment Gap in theManagement of Obesity

                                                                            BupropionNaltrexone

                                                                            bull Mechanism of Actionndash Bupropion - Dopaminenoradrenaline reuptake inhibitorndash Naltrexone- Opioid receptor antagonist

                                                                            bull Was approved by FDA committee but FDA did not approve until a CV outcome study is performed 2nd concerns about BP and P in some patients

                                                                            bull The Light Study is now underway and reported to be enrolling well under PI Dr Nissen

                                                                            bull BupropionNaltrexone will have first completed CV outcome study

                                                                            Buproprion ndash Naltrexone

                                                                            Greenway FL et al Lancet 2010376(9741)595-605

                                                                            0

                                                                            -2

                                                                            -4

                                                                            -6

                                                                            -8

                                                                            -100 4 8 12 16 20 24 28 32 36 40 44 48 52 56

                                                                            Weeks

                                                                            Wei

                                                                            ght c

                                                                            hang

                                                                            e fro

                                                                            m b

                                                                            asel

                                                                            ine

                                                                            ()

                                                                            Placebo

                                                                            Naltrexone 16 mg plus bupropion

                                                                            Naltrexone 32 mg plus bupropion

                                                                            Liraglutide for Weight Loss in Patients with Type 2 Diabetes

                                                                            bull GLP-1 analog approved for treatment of type 2 diabetes

                                                                            bull Anorectic effect mediated both by the activation of GLP-1 receptor expressed on vagal afferents and by the GLP-1R activation in CNS

                                                                            bull Affects visceral fat adiposity appetite food preference and cardiovascular biomarkers in patients with type 2 diabetes

                                                                            Inoue K et al Cardiovasc Diabetol 2011 10109 doi1011861475-2840-10-109

                                                                            Liraglutide Weight Loss Over 2 Years ITT Observed Means

                                                                            Astrup A et al Int J Obes (Lond) 201236(6)843-54

                                                                            FromScreening

                                                                            -94 kg

                                                                            -67 kg-88 kg

                                                                            -99 kg-94 kg

                                                                            -103 kg

                                                                            ITT intention to treat

                                                                            Phase III Study Outcomes Compared

                                                                            Buproprion SR (360 mgd) Naltrexone SR (32 mgd)

                                                                            Lorcaserin(20 mgd)

                                                                            Phentermine Topiramate CR

                                                                            COR1 COR-I2 COR-II3 NB3043 BLOOM4 BLOSSOM5 EQUIP CONQUER

                                                                            Number of patients (ITT-LOCF)

                                                                            793 obese 1453 obese

                                                                            1281 obese

                                                                            502 type II diabetes

                                                                            3182 obese 4008 obese

                                                                            1230 obese BMI 44

                                                                            2448 comorbidBMI 36

                                                                            Mean change compared with placebo from base

                                                                            93 vs5 1c

                                                                            61a vs13c

                                                                            64a vs12

                                                                            50 a vs12c

                                                                            58 vs22c

                                                                            48 vs28c

                                                                            11 Fullbvs 16

                                                                            104 Fullb 84 Midb

                                                                            vs 18

                                                                            51 Lowb vs16c

                                                                            Categorical change 5 compared with placebo from base

                                                                            56 vs43

                                                                            48a vs164

                                                                            563a

                                                                            vs 171445a vs189

                                                                            475b

                                                                            vs 203472b vs25

                                                                            67 Fullb 45 Lowb vs17

                                                                            70 Fullb 62 Midb

                                                                            vs 21

                                                                            Phenterminetopiramate doses Low 375 mg phentermine23 mg topiramate Mid 75 mg phentermine 46 mg topiramate Full 15 mg phentermine 92 mg topiramateITT-LOCF intent-to-treat last observation carried forwardData not available aP lt 001 vs placebo bP lt 0001 vs placebo

                                                                            Treatment Gap in theManagement of Obesity

                                                                            Physicians Need Effective Pharmacotherapies That Will Reduce Weight Significantly and Reduce Weight-related Comorbidities

                                                                            0 5 10 15 20 25 30 35

                                                                            Diet and Lifestyle Lap Band Gastric Bypass

                                                                            TreatmentGap

                                                                            What will fill the gap

                                                                            Too risky for many peopleNot effective enoughfor many people

                                                                            Treatment Gap in theManagement of Obesity

                                                                            0 5 10 15 20 25 30 35

                                                                            Diet and Lifestyle Lap Band Gastric Bypass

                                                                            TreatmentGap

                                                                            Too risky for many peopleNot effective enoughfor many people Pharmacotherapy

                                                                            Less invasive procedures

                                                                            Physicians Need Effective Pharmacotherapies That Will Reduce Weight Significantly and Reduce Weight-related Comorbidities

                                                                            What will fill the gap

                                                                            • Slide Number 1
                                                                            • Slide Number 2
                                                                            • Weight Management is Moving into the Workplace and Mainstream of Healthcare
                                                                            • US Preventative Services Task Force
                                                                            • A Proposal from CMS about Coverage for Intensive Behavioral Therapy for Obesity
                                                                            • Slide Number 6
                                                                            • Biggest Increases in Clinically Severe Obesity US 1987-2005
                                                                            • Relationship Between BMI and Risk of Type 2 Diabetes
                                                                            • Slide Number 9
                                                                            • Medical Complications of Obesity Almost every organ system is affected
                                                                            • Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and disease
                                                                            • Current Therapies Often Address Individual Risk Factors Cardiometabolic risk
                                                                            • Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and disease
                                                                            • Are You Treating These Drivers of Cardiometabolic Risk Should You Treat The Underlying Cause
                                                                            • Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors
                                                                            • In My Opinion The Winds of Change are Blowing in the Treatment of Chronic Diseases
                                                                            • Bariatric Surgery Reduces Overall Mortality Diabetes Mortality by 88
                                                                            • Health Care Costs Attributable to ObesityEstimates of what various conditions add to health-care service costs over a 12-month period
                                                                            • What-if scenarios (The Lancet forthcoming)
                                                                            • How Much Weight Loss Is Needed to Prevent T2DMndashNot Very Much The DPP Experience
                                                                            • In the Da Qing Study 6-year Intervention Led to Lower Incidence of Type 2 Diabetes 14 Years Later
                                                                            • Slide Number 22
                                                                            • Slide Number 23
                                                                            • New Compounds andCombination Interventions
                                                                            • Phentermine and Topiramate Extended-Release
                                                                            • Phentermine and Topiramate Extended-Release
                                                                            • EQUIP amp CONQUER Discontinuation RateDue to AEs in All Doses Studied
                                                                            • Phentermine and Topiramate SEQUELWeight Loss Over Time
                                                                            • CONQUER Significant Improvement in Cardiovascular Risk Factors
                                                                            • Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors
                                                                            • Lorcaserin
                                                                            • BLOOM Study Body Weight Over Years 1 and 2
                                                                            • BLOOM StudyKey Secondary Endpoints
                                                                            • BLOOM-DMChange in Glycemic Parameters
                                                                            • Lorcaserin Adverse Events Reported by 5 or More in Any Group in Year 1
                                                                            • LorcaserinNo Increase in Rate of Valvulopathy
                                                                            • Phase III Study Outcomes Compared
                                                                            • Obesity Treatments in Late Development
                                                                            • BupropionNaltrexone
                                                                            • Buproprion ndash Naltrexone
                                                                            • Liraglutide for Weight Loss in Patients with Type 2 Diabetes
                                                                            • Liraglutide Weight Loss Over 2 Years ITT Observed Means
                                                                            • Phase III Study Outcomes Compared
                                                                            • Treatment Gap in theManagement of Obesity
                                                                            • Treatment Gap in theManagement of Obesity

                                                                              Buproprion ndash Naltrexone

                                                                              Greenway FL et al Lancet 2010376(9741)595-605

                                                                              0

                                                                              -2

                                                                              -4

                                                                              -6

                                                                              -8

                                                                              -100 4 8 12 16 20 24 28 32 36 40 44 48 52 56

                                                                              Weeks

                                                                              Wei

                                                                              ght c

                                                                              hang

                                                                              e fro

                                                                              m b

                                                                              asel

                                                                              ine

                                                                              ()

                                                                              Placebo

                                                                              Naltrexone 16 mg plus bupropion

                                                                              Naltrexone 32 mg plus bupropion

                                                                              Liraglutide for Weight Loss in Patients with Type 2 Diabetes

                                                                              bull GLP-1 analog approved for treatment of type 2 diabetes

                                                                              bull Anorectic effect mediated both by the activation of GLP-1 receptor expressed on vagal afferents and by the GLP-1R activation in CNS

                                                                              bull Affects visceral fat adiposity appetite food preference and cardiovascular biomarkers in patients with type 2 diabetes

                                                                              Inoue K et al Cardiovasc Diabetol 2011 10109 doi1011861475-2840-10-109

                                                                              Liraglutide Weight Loss Over 2 Years ITT Observed Means

                                                                              Astrup A et al Int J Obes (Lond) 201236(6)843-54

                                                                              FromScreening

                                                                              -94 kg

                                                                              -67 kg-88 kg

                                                                              -99 kg-94 kg

                                                                              -103 kg

                                                                              ITT intention to treat

                                                                              Phase III Study Outcomes Compared

                                                                              Buproprion SR (360 mgd) Naltrexone SR (32 mgd)

                                                                              Lorcaserin(20 mgd)

                                                                              Phentermine Topiramate CR

                                                                              COR1 COR-I2 COR-II3 NB3043 BLOOM4 BLOSSOM5 EQUIP CONQUER

                                                                              Number of patients (ITT-LOCF)

                                                                              793 obese 1453 obese

                                                                              1281 obese

                                                                              502 type II diabetes

                                                                              3182 obese 4008 obese

                                                                              1230 obese BMI 44

                                                                              2448 comorbidBMI 36

                                                                              Mean change compared with placebo from base

                                                                              93 vs5 1c

                                                                              61a vs13c

                                                                              64a vs12

                                                                              50 a vs12c

                                                                              58 vs22c

                                                                              48 vs28c

                                                                              11 Fullbvs 16

                                                                              104 Fullb 84 Midb

                                                                              vs 18

                                                                              51 Lowb vs16c

                                                                              Categorical change 5 compared with placebo from base

                                                                              56 vs43

                                                                              48a vs164

                                                                              563a

                                                                              vs 171445a vs189

                                                                              475b

                                                                              vs 203472b vs25

                                                                              67 Fullb 45 Lowb vs17

                                                                              70 Fullb 62 Midb

                                                                              vs 21

                                                                              Phenterminetopiramate doses Low 375 mg phentermine23 mg topiramate Mid 75 mg phentermine 46 mg topiramate Full 15 mg phentermine 92 mg topiramateITT-LOCF intent-to-treat last observation carried forwardData not available aP lt 001 vs placebo bP lt 0001 vs placebo

                                                                              Treatment Gap in theManagement of Obesity

                                                                              Physicians Need Effective Pharmacotherapies That Will Reduce Weight Significantly and Reduce Weight-related Comorbidities

                                                                              0 5 10 15 20 25 30 35

                                                                              Diet and Lifestyle Lap Band Gastric Bypass

                                                                              TreatmentGap

                                                                              What will fill the gap

                                                                              Too risky for many peopleNot effective enoughfor many people

                                                                              Treatment Gap in theManagement of Obesity

                                                                              0 5 10 15 20 25 30 35

                                                                              Diet and Lifestyle Lap Band Gastric Bypass

                                                                              TreatmentGap

                                                                              Too risky for many peopleNot effective enoughfor many people Pharmacotherapy

                                                                              Less invasive procedures

                                                                              Physicians Need Effective Pharmacotherapies That Will Reduce Weight Significantly and Reduce Weight-related Comorbidities

                                                                              What will fill the gap

                                                                              • Slide Number 1
                                                                              • Slide Number 2
                                                                              • Weight Management is Moving into the Workplace and Mainstream of Healthcare
                                                                              • US Preventative Services Task Force
                                                                              • A Proposal from CMS about Coverage for Intensive Behavioral Therapy for Obesity
                                                                              • Slide Number 6
                                                                              • Biggest Increases in Clinically Severe Obesity US 1987-2005
                                                                              • Relationship Between BMI and Risk of Type 2 Diabetes
                                                                              • Slide Number 9
                                                                              • Medical Complications of Obesity Almost every organ system is affected
                                                                              • Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and disease
                                                                              • Current Therapies Often Address Individual Risk Factors Cardiometabolic risk
                                                                              • Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and disease
                                                                              • Are You Treating These Drivers of Cardiometabolic Risk Should You Treat The Underlying Cause
                                                                              • Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors
                                                                              • In My Opinion The Winds of Change are Blowing in the Treatment of Chronic Diseases
                                                                              • Bariatric Surgery Reduces Overall Mortality Diabetes Mortality by 88
                                                                              • Health Care Costs Attributable to ObesityEstimates of what various conditions add to health-care service costs over a 12-month period
                                                                              • What-if scenarios (The Lancet forthcoming)
                                                                              • How Much Weight Loss Is Needed to Prevent T2DMndashNot Very Much The DPP Experience
                                                                              • In the Da Qing Study 6-year Intervention Led to Lower Incidence of Type 2 Diabetes 14 Years Later
                                                                              • Slide Number 22
                                                                              • Slide Number 23
                                                                              • New Compounds andCombination Interventions
                                                                              • Phentermine and Topiramate Extended-Release
                                                                              • Phentermine and Topiramate Extended-Release
                                                                              • EQUIP amp CONQUER Discontinuation RateDue to AEs in All Doses Studied
                                                                              • Phentermine and Topiramate SEQUELWeight Loss Over Time
                                                                              • CONQUER Significant Improvement in Cardiovascular Risk Factors
                                                                              • Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors
                                                                              • Lorcaserin
                                                                              • BLOOM Study Body Weight Over Years 1 and 2
                                                                              • BLOOM StudyKey Secondary Endpoints
                                                                              • BLOOM-DMChange in Glycemic Parameters
                                                                              • Lorcaserin Adverse Events Reported by 5 or More in Any Group in Year 1
                                                                              • LorcaserinNo Increase in Rate of Valvulopathy
                                                                              • Phase III Study Outcomes Compared
                                                                              • Obesity Treatments in Late Development
                                                                              • BupropionNaltrexone
                                                                              • Buproprion ndash Naltrexone
                                                                              • Liraglutide for Weight Loss in Patients with Type 2 Diabetes
                                                                              • Liraglutide Weight Loss Over 2 Years ITT Observed Means
                                                                              • Phase III Study Outcomes Compared
                                                                              • Treatment Gap in theManagement of Obesity
                                                                              • Treatment Gap in theManagement of Obesity

                                                                                Liraglutide for Weight Loss in Patients with Type 2 Diabetes

                                                                                bull GLP-1 analog approved for treatment of type 2 diabetes

                                                                                bull Anorectic effect mediated both by the activation of GLP-1 receptor expressed on vagal afferents and by the GLP-1R activation in CNS

                                                                                bull Affects visceral fat adiposity appetite food preference and cardiovascular biomarkers in patients with type 2 diabetes

                                                                                Inoue K et al Cardiovasc Diabetol 2011 10109 doi1011861475-2840-10-109

                                                                                Liraglutide Weight Loss Over 2 Years ITT Observed Means

                                                                                Astrup A et al Int J Obes (Lond) 201236(6)843-54

                                                                                FromScreening

                                                                                -94 kg

                                                                                -67 kg-88 kg

                                                                                -99 kg-94 kg

                                                                                -103 kg

                                                                                ITT intention to treat

                                                                                Phase III Study Outcomes Compared

                                                                                Buproprion SR (360 mgd) Naltrexone SR (32 mgd)

                                                                                Lorcaserin(20 mgd)

                                                                                Phentermine Topiramate CR

                                                                                COR1 COR-I2 COR-II3 NB3043 BLOOM4 BLOSSOM5 EQUIP CONQUER

                                                                                Number of patients (ITT-LOCF)

                                                                                793 obese 1453 obese

                                                                                1281 obese

                                                                                502 type II diabetes

                                                                                3182 obese 4008 obese

                                                                                1230 obese BMI 44

                                                                                2448 comorbidBMI 36

                                                                                Mean change compared with placebo from base

                                                                                93 vs5 1c

                                                                                61a vs13c

                                                                                64a vs12

                                                                                50 a vs12c

                                                                                58 vs22c

                                                                                48 vs28c

                                                                                11 Fullbvs 16

                                                                                104 Fullb 84 Midb

                                                                                vs 18

                                                                                51 Lowb vs16c

                                                                                Categorical change 5 compared with placebo from base

                                                                                56 vs43

                                                                                48a vs164

                                                                                563a

                                                                                vs 171445a vs189

                                                                                475b

                                                                                vs 203472b vs25

                                                                                67 Fullb 45 Lowb vs17

                                                                                70 Fullb 62 Midb

                                                                                vs 21

                                                                                Phenterminetopiramate doses Low 375 mg phentermine23 mg topiramate Mid 75 mg phentermine 46 mg topiramate Full 15 mg phentermine 92 mg topiramateITT-LOCF intent-to-treat last observation carried forwardData not available aP lt 001 vs placebo bP lt 0001 vs placebo

                                                                                Treatment Gap in theManagement of Obesity

                                                                                Physicians Need Effective Pharmacotherapies That Will Reduce Weight Significantly and Reduce Weight-related Comorbidities

                                                                                0 5 10 15 20 25 30 35

                                                                                Diet and Lifestyle Lap Band Gastric Bypass

                                                                                TreatmentGap

                                                                                What will fill the gap

                                                                                Too risky for many peopleNot effective enoughfor many people

                                                                                Treatment Gap in theManagement of Obesity

                                                                                0 5 10 15 20 25 30 35

                                                                                Diet and Lifestyle Lap Band Gastric Bypass

                                                                                TreatmentGap

                                                                                Too risky for many peopleNot effective enoughfor many people Pharmacotherapy

                                                                                Less invasive procedures

                                                                                Physicians Need Effective Pharmacotherapies That Will Reduce Weight Significantly and Reduce Weight-related Comorbidities

                                                                                What will fill the gap

                                                                                • Slide Number 1
                                                                                • Slide Number 2
                                                                                • Weight Management is Moving into the Workplace and Mainstream of Healthcare
                                                                                • US Preventative Services Task Force
                                                                                • A Proposal from CMS about Coverage for Intensive Behavioral Therapy for Obesity
                                                                                • Slide Number 6
                                                                                • Biggest Increases in Clinically Severe Obesity US 1987-2005
                                                                                • Relationship Between BMI and Risk of Type 2 Diabetes
                                                                                • Slide Number 9
                                                                                • Medical Complications of Obesity Almost every organ system is affected
                                                                                • Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and disease
                                                                                • Current Therapies Often Address Individual Risk Factors Cardiometabolic risk
                                                                                • Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and disease
                                                                                • Are You Treating These Drivers of Cardiometabolic Risk Should You Treat The Underlying Cause
                                                                                • Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors
                                                                                • In My Opinion The Winds of Change are Blowing in the Treatment of Chronic Diseases
                                                                                • Bariatric Surgery Reduces Overall Mortality Diabetes Mortality by 88
                                                                                • Health Care Costs Attributable to ObesityEstimates of what various conditions add to health-care service costs over a 12-month period
                                                                                • What-if scenarios (The Lancet forthcoming)
                                                                                • How Much Weight Loss Is Needed to Prevent T2DMndashNot Very Much The DPP Experience
                                                                                • In the Da Qing Study 6-year Intervention Led to Lower Incidence of Type 2 Diabetes 14 Years Later
                                                                                • Slide Number 22
                                                                                • Slide Number 23
                                                                                • New Compounds andCombination Interventions
                                                                                • Phentermine and Topiramate Extended-Release
                                                                                • Phentermine and Topiramate Extended-Release
                                                                                • EQUIP amp CONQUER Discontinuation RateDue to AEs in All Doses Studied
                                                                                • Phentermine and Topiramate SEQUELWeight Loss Over Time
                                                                                • CONQUER Significant Improvement in Cardiovascular Risk Factors
                                                                                • Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors
                                                                                • Lorcaserin
                                                                                • BLOOM Study Body Weight Over Years 1 and 2
                                                                                • BLOOM StudyKey Secondary Endpoints
                                                                                • BLOOM-DMChange in Glycemic Parameters
                                                                                • Lorcaserin Adverse Events Reported by 5 or More in Any Group in Year 1
                                                                                • LorcaserinNo Increase in Rate of Valvulopathy
                                                                                • Phase III Study Outcomes Compared
                                                                                • Obesity Treatments in Late Development
                                                                                • BupropionNaltrexone
                                                                                • Buproprion ndash Naltrexone
                                                                                • Liraglutide for Weight Loss in Patients with Type 2 Diabetes
                                                                                • Liraglutide Weight Loss Over 2 Years ITT Observed Means
                                                                                • Phase III Study Outcomes Compared
                                                                                • Treatment Gap in theManagement of Obesity
                                                                                • Treatment Gap in theManagement of Obesity

                                                                                  Liraglutide Weight Loss Over 2 Years ITT Observed Means

                                                                                  Astrup A et al Int J Obes (Lond) 201236(6)843-54

                                                                                  FromScreening

                                                                                  -94 kg

                                                                                  -67 kg-88 kg

                                                                                  -99 kg-94 kg

                                                                                  -103 kg

                                                                                  ITT intention to treat

                                                                                  Phase III Study Outcomes Compared

                                                                                  Buproprion SR (360 mgd) Naltrexone SR (32 mgd)

                                                                                  Lorcaserin(20 mgd)

                                                                                  Phentermine Topiramate CR

                                                                                  COR1 COR-I2 COR-II3 NB3043 BLOOM4 BLOSSOM5 EQUIP CONQUER

                                                                                  Number of patients (ITT-LOCF)

                                                                                  793 obese 1453 obese

                                                                                  1281 obese

                                                                                  502 type II diabetes

                                                                                  3182 obese 4008 obese

                                                                                  1230 obese BMI 44

                                                                                  2448 comorbidBMI 36

                                                                                  Mean change compared with placebo from base

                                                                                  93 vs5 1c

                                                                                  61a vs13c

                                                                                  64a vs12

                                                                                  50 a vs12c

                                                                                  58 vs22c

                                                                                  48 vs28c

                                                                                  11 Fullbvs 16

                                                                                  104 Fullb 84 Midb

                                                                                  vs 18

                                                                                  51 Lowb vs16c

                                                                                  Categorical change 5 compared with placebo from base

                                                                                  56 vs43

                                                                                  48a vs164

                                                                                  563a

                                                                                  vs 171445a vs189

                                                                                  475b

                                                                                  vs 203472b vs25

                                                                                  67 Fullb 45 Lowb vs17

                                                                                  70 Fullb 62 Midb

                                                                                  vs 21

                                                                                  Phenterminetopiramate doses Low 375 mg phentermine23 mg topiramate Mid 75 mg phentermine 46 mg topiramate Full 15 mg phentermine 92 mg topiramateITT-LOCF intent-to-treat last observation carried forwardData not available aP lt 001 vs placebo bP lt 0001 vs placebo

                                                                                  Treatment Gap in theManagement of Obesity

                                                                                  Physicians Need Effective Pharmacotherapies That Will Reduce Weight Significantly and Reduce Weight-related Comorbidities

                                                                                  0 5 10 15 20 25 30 35

                                                                                  Diet and Lifestyle Lap Band Gastric Bypass

                                                                                  TreatmentGap

                                                                                  What will fill the gap

                                                                                  Too risky for many peopleNot effective enoughfor many people

                                                                                  Treatment Gap in theManagement of Obesity

                                                                                  0 5 10 15 20 25 30 35

                                                                                  Diet and Lifestyle Lap Band Gastric Bypass

                                                                                  TreatmentGap

                                                                                  Too risky for many peopleNot effective enoughfor many people Pharmacotherapy

                                                                                  Less invasive procedures

                                                                                  Physicians Need Effective Pharmacotherapies That Will Reduce Weight Significantly and Reduce Weight-related Comorbidities

                                                                                  What will fill the gap

                                                                                  • Slide Number 1
                                                                                  • Slide Number 2
                                                                                  • Weight Management is Moving into the Workplace and Mainstream of Healthcare
                                                                                  • US Preventative Services Task Force
                                                                                  • A Proposal from CMS about Coverage for Intensive Behavioral Therapy for Obesity
                                                                                  • Slide Number 6
                                                                                  • Biggest Increases in Clinically Severe Obesity US 1987-2005
                                                                                  • Relationship Between BMI and Risk of Type 2 Diabetes
                                                                                  • Slide Number 9
                                                                                  • Medical Complications of Obesity Almost every organ system is affected
                                                                                  • Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and disease
                                                                                  • Current Therapies Often Address Individual Risk Factors Cardiometabolic risk
                                                                                  • Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and disease
                                                                                  • Are You Treating These Drivers of Cardiometabolic Risk Should You Treat The Underlying Cause
                                                                                  • Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors
                                                                                  • In My Opinion The Winds of Change are Blowing in the Treatment of Chronic Diseases
                                                                                  • Bariatric Surgery Reduces Overall Mortality Diabetes Mortality by 88
                                                                                  • Health Care Costs Attributable to ObesityEstimates of what various conditions add to health-care service costs over a 12-month period
                                                                                  • What-if scenarios (The Lancet forthcoming)
                                                                                  • How Much Weight Loss Is Needed to Prevent T2DMndashNot Very Much The DPP Experience
                                                                                  • In the Da Qing Study 6-year Intervention Led to Lower Incidence of Type 2 Diabetes 14 Years Later
                                                                                  • Slide Number 22
                                                                                  • Slide Number 23
                                                                                  • New Compounds andCombination Interventions
                                                                                  • Phentermine and Topiramate Extended-Release
                                                                                  • Phentermine and Topiramate Extended-Release
                                                                                  • EQUIP amp CONQUER Discontinuation RateDue to AEs in All Doses Studied
                                                                                  • Phentermine and Topiramate SEQUELWeight Loss Over Time
                                                                                  • CONQUER Significant Improvement in Cardiovascular Risk Factors
                                                                                  • Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors
                                                                                  • Lorcaserin
                                                                                  • BLOOM Study Body Weight Over Years 1 and 2
                                                                                  • BLOOM StudyKey Secondary Endpoints
                                                                                  • BLOOM-DMChange in Glycemic Parameters
                                                                                  • Lorcaserin Adverse Events Reported by 5 or More in Any Group in Year 1
                                                                                  • LorcaserinNo Increase in Rate of Valvulopathy
                                                                                  • Phase III Study Outcomes Compared
                                                                                  • Obesity Treatments in Late Development
                                                                                  • BupropionNaltrexone
                                                                                  • Buproprion ndash Naltrexone
                                                                                  • Liraglutide for Weight Loss in Patients with Type 2 Diabetes
                                                                                  • Liraglutide Weight Loss Over 2 Years ITT Observed Means
                                                                                  • Phase III Study Outcomes Compared
                                                                                  • Treatment Gap in theManagement of Obesity
                                                                                  • Treatment Gap in theManagement of Obesity

                                                                                    Phase III Study Outcomes Compared

                                                                                    Buproprion SR (360 mgd) Naltrexone SR (32 mgd)

                                                                                    Lorcaserin(20 mgd)

                                                                                    Phentermine Topiramate CR

                                                                                    COR1 COR-I2 COR-II3 NB3043 BLOOM4 BLOSSOM5 EQUIP CONQUER

                                                                                    Number of patients (ITT-LOCF)

                                                                                    793 obese 1453 obese

                                                                                    1281 obese

                                                                                    502 type II diabetes

                                                                                    3182 obese 4008 obese

                                                                                    1230 obese BMI 44

                                                                                    2448 comorbidBMI 36

                                                                                    Mean change compared with placebo from base

                                                                                    93 vs5 1c

                                                                                    61a vs13c

                                                                                    64a vs12

                                                                                    50 a vs12c

                                                                                    58 vs22c

                                                                                    48 vs28c

                                                                                    11 Fullbvs 16

                                                                                    104 Fullb 84 Midb

                                                                                    vs 18

                                                                                    51 Lowb vs16c

                                                                                    Categorical change 5 compared with placebo from base

                                                                                    56 vs43

                                                                                    48a vs164

                                                                                    563a

                                                                                    vs 171445a vs189

                                                                                    475b

                                                                                    vs 203472b vs25

                                                                                    67 Fullb 45 Lowb vs17

                                                                                    70 Fullb 62 Midb

                                                                                    vs 21

                                                                                    Phenterminetopiramate doses Low 375 mg phentermine23 mg topiramate Mid 75 mg phentermine 46 mg topiramate Full 15 mg phentermine 92 mg topiramateITT-LOCF intent-to-treat last observation carried forwardData not available aP lt 001 vs placebo bP lt 0001 vs placebo

                                                                                    Treatment Gap in theManagement of Obesity

                                                                                    Physicians Need Effective Pharmacotherapies That Will Reduce Weight Significantly and Reduce Weight-related Comorbidities

                                                                                    0 5 10 15 20 25 30 35

                                                                                    Diet and Lifestyle Lap Band Gastric Bypass

                                                                                    TreatmentGap

                                                                                    What will fill the gap

                                                                                    Too risky for many peopleNot effective enoughfor many people

                                                                                    Treatment Gap in theManagement of Obesity

                                                                                    0 5 10 15 20 25 30 35

                                                                                    Diet and Lifestyle Lap Band Gastric Bypass

                                                                                    TreatmentGap

                                                                                    Too risky for many peopleNot effective enoughfor many people Pharmacotherapy

                                                                                    Less invasive procedures

                                                                                    Physicians Need Effective Pharmacotherapies That Will Reduce Weight Significantly and Reduce Weight-related Comorbidities

                                                                                    What will fill the gap

                                                                                    • Slide Number 1
                                                                                    • Slide Number 2
                                                                                    • Weight Management is Moving into the Workplace and Mainstream of Healthcare
                                                                                    • US Preventative Services Task Force
                                                                                    • A Proposal from CMS about Coverage for Intensive Behavioral Therapy for Obesity
                                                                                    • Slide Number 6
                                                                                    • Biggest Increases in Clinically Severe Obesity US 1987-2005
                                                                                    • Relationship Between BMI and Risk of Type 2 Diabetes
                                                                                    • Slide Number 9
                                                                                    • Medical Complications of Obesity Almost every organ system is affected
                                                                                    • Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and disease
                                                                                    • Current Therapies Often Address Individual Risk Factors Cardiometabolic risk
                                                                                    • Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and disease
                                                                                    • Are You Treating These Drivers of Cardiometabolic Risk Should You Treat The Underlying Cause
                                                                                    • Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors
                                                                                    • In My Opinion The Winds of Change are Blowing in the Treatment of Chronic Diseases
                                                                                    • Bariatric Surgery Reduces Overall Mortality Diabetes Mortality by 88
                                                                                    • Health Care Costs Attributable to ObesityEstimates of what various conditions add to health-care service costs over a 12-month period
                                                                                    • What-if scenarios (The Lancet forthcoming)
                                                                                    • How Much Weight Loss Is Needed to Prevent T2DMndashNot Very Much The DPP Experience
                                                                                    • In the Da Qing Study 6-year Intervention Led to Lower Incidence of Type 2 Diabetes 14 Years Later
                                                                                    • Slide Number 22
                                                                                    • Slide Number 23
                                                                                    • New Compounds andCombination Interventions
                                                                                    • Phentermine and Topiramate Extended-Release
                                                                                    • Phentermine and Topiramate Extended-Release
                                                                                    • EQUIP amp CONQUER Discontinuation RateDue to AEs in All Doses Studied
                                                                                    • Phentermine and Topiramate SEQUELWeight Loss Over Time
                                                                                    • CONQUER Significant Improvement in Cardiovascular Risk Factors
                                                                                    • Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors
                                                                                    • Lorcaserin
                                                                                    • BLOOM Study Body Weight Over Years 1 and 2
                                                                                    • BLOOM StudyKey Secondary Endpoints
                                                                                    • BLOOM-DMChange in Glycemic Parameters
                                                                                    • Lorcaserin Adverse Events Reported by 5 or More in Any Group in Year 1
                                                                                    • LorcaserinNo Increase in Rate of Valvulopathy
                                                                                    • Phase III Study Outcomes Compared
                                                                                    • Obesity Treatments in Late Development
                                                                                    • BupropionNaltrexone
                                                                                    • Buproprion ndash Naltrexone
                                                                                    • Liraglutide for Weight Loss in Patients with Type 2 Diabetes
                                                                                    • Liraglutide Weight Loss Over 2 Years ITT Observed Means
                                                                                    • Phase III Study Outcomes Compared
                                                                                    • Treatment Gap in theManagement of Obesity
                                                                                    • Treatment Gap in theManagement of Obesity

                                                                                      Treatment Gap in theManagement of Obesity

                                                                                      Physicians Need Effective Pharmacotherapies That Will Reduce Weight Significantly and Reduce Weight-related Comorbidities

                                                                                      0 5 10 15 20 25 30 35

                                                                                      Diet and Lifestyle Lap Band Gastric Bypass

                                                                                      TreatmentGap

                                                                                      What will fill the gap

                                                                                      Too risky for many peopleNot effective enoughfor many people

                                                                                      Treatment Gap in theManagement of Obesity

                                                                                      0 5 10 15 20 25 30 35

                                                                                      Diet and Lifestyle Lap Band Gastric Bypass

                                                                                      TreatmentGap

                                                                                      Too risky for many peopleNot effective enoughfor many people Pharmacotherapy

                                                                                      Less invasive procedures

                                                                                      Physicians Need Effective Pharmacotherapies That Will Reduce Weight Significantly and Reduce Weight-related Comorbidities

                                                                                      What will fill the gap

                                                                                      • Slide Number 1
                                                                                      • Slide Number 2
                                                                                      • Weight Management is Moving into the Workplace and Mainstream of Healthcare
                                                                                      • US Preventative Services Task Force
                                                                                      • A Proposal from CMS about Coverage for Intensive Behavioral Therapy for Obesity
                                                                                      • Slide Number 6
                                                                                      • Biggest Increases in Clinically Severe Obesity US 1987-2005
                                                                                      • Relationship Between BMI and Risk of Type 2 Diabetes
                                                                                      • Slide Number 9
                                                                                      • Medical Complications of Obesity Almost every organ system is affected
                                                                                      • Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and disease
                                                                                      • Current Therapies Often Address Individual Risk Factors Cardiometabolic risk
                                                                                      • Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and disease
                                                                                      • Are You Treating These Drivers of Cardiometabolic Risk Should You Treat The Underlying Cause
                                                                                      • Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors
                                                                                      • In My Opinion The Winds of Change are Blowing in the Treatment of Chronic Diseases
                                                                                      • Bariatric Surgery Reduces Overall Mortality Diabetes Mortality by 88
                                                                                      • Health Care Costs Attributable to ObesityEstimates of what various conditions add to health-care service costs over a 12-month period
                                                                                      • What-if scenarios (The Lancet forthcoming)
                                                                                      • How Much Weight Loss Is Needed to Prevent T2DMndashNot Very Much The DPP Experience
                                                                                      • In the Da Qing Study 6-year Intervention Led to Lower Incidence of Type 2 Diabetes 14 Years Later
                                                                                      • Slide Number 22
                                                                                      • Slide Number 23
                                                                                      • New Compounds andCombination Interventions
                                                                                      • Phentermine and Topiramate Extended-Release
                                                                                      • Phentermine and Topiramate Extended-Release
                                                                                      • EQUIP amp CONQUER Discontinuation RateDue to AEs in All Doses Studied
                                                                                      • Phentermine and Topiramate SEQUELWeight Loss Over Time
                                                                                      • CONQUER Significant Improvement in Cardiovascular Risk Factors
                                                                                      • Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors
                                                                                      • Lorcaserin
                                                                                      • BLOOM Study Body Weight Over Years 1 and 2
                                                                                      • BLOOM StudyKey Secondary Endpoints
                                                                                      • BLOOM-DMChange in Glycemic Parameters
                                                                                      • Lorcaserin Adverse Events Reported by 5 or More in Any Group in Year 1
                                                                                      • LorcaserinNo Increase in Rate of Valvulopathy
                                                                                      • Phase III Study Outcomes Compared
                                                                                      • Obesity Treatments in Late Development
                                                                                      • BupropionNaltrexone
                                                                                      • Buproprion ndash Naltrexone
                                                                                      • Liraglutide for Weight Loss in Patients with Type 2 Diabetes
                                                                                      • Liraglutide Weight Loss Over 2 Years ITT Observed Means
                                                                                      • Phase III Study Outcomes Compared
                                                                                      • Treatment Gap in theManagement of Obesity
                                                                                      • Treatment Gap in theManagement of Obesity

                                                                                        Treatment Gap in theManagement of Obesity

                                                                                        0 5 10 15 20 25 30 35

                                                                                        Diet and Lifestyle Lap Band Gastric Bypass

                                                                                        TreatmentGap

                                                                                        Too risky for many peopleNot effective enoughfor many people Pharmacotherapy

                                                                                        Less invasive procedures

                                                                                        Physicians Need Effective Pharmacotherapies That Will Reduce Weight Significantly and Reduce Weight-related Comorbidities

                                                                                        What will fill the gap

                                                                                        • Slide Number 1
                                                                                        • Slide Number 2
                                                                                        • Weight Management is Moving into the Workplace and Mainstream of Healthcare
                                                                                        • US Preventative Services Task Force
                                                                                        • A Proposal from CMS about Coverage for Intensive Behavioral Therapy for Obesity
                                                                                        • Slide Number 6
                                                                                        • Biggest Increases in Clinically Severe Obesity US 1987-2005
                                                                                        • Relationship Between BMI and Risk of Type 2 Diabetes
                                                                                        • Slide Number 9
                                                                                        • Medical Complications of Obesity Almost every organ system is affected
                                                                                        • Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and disease
                                                                                        • Current Therapies Often Address Individual Risk Factors Cardiometabolic risk
                                                                                        • Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and disease
                                                                                        • Are You Treating These Drivers of Cardiometabolic Risk Should You Treat The Underlying Cause
                                                                                        • Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors
                                                                                        • In My Opinion The Winds of Change are Blowing in the Treatment of Chronic Diseases
                                                                                        • Bariatric Surgery Reduces Overall Mortality Diabetes Mortality by 88
                                                                                        • Health Care Costs Attributable to ObesityEstimates of what various conditions add to health-care service costs over a 12-month period
                                                                                        • What-if scenarios (The Lancet forthcoming)
                                                                                        • How Much Weight Loss Is Needed to Prevent T2DMndashNot Very Much The DPP Experience
                                                                                        • In the Da Qing Study 6-year Intervention Led to Lower Incidence of Type 2 Diabetes 14 Years Later
                                                                                        • Slide Number 22
                                                                                        • Slide Number 23
                                                                                        • New Compounds andCombination Interventions
                                                                                        • Phentermine and Topiramate Extended-Release
                                                                                        • Phentermine and Topiramate Extended-Release
                                                                                        • EQUIP amp CONQUER Discontinuation RateDue to AEs in All Doses Studied
                                                                                        • Phentermine and Topiramate SEQUELWeight Loss Over Time
                                                                                        • CONQUER Significant Improvement in Cardiovascular Risk Factors
                                                                                        • Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors
                                                                                        • Lorcaserin
                                                                                        • BLOOM Study Body Weight Over Years 1 and 2
                                                                                        • BLOOM StudyKey Secondary Endpoints
                                                                                        • BLOOM-DMChange in Glycemic Parameters
                                                                                        • Lorcaserin Adverse Events Reported by 5 or More in Any Group in Year 1
                                                                                        • LorcaserinNo Increase in Rate of Valvulopathy
                                                                                        • Phase III Study Outcomes Compared
                                                                                        • Obesity Treatments in Late Development
                                                                                        • BupropionNaltrexone
                                                                                        • Buproprion ndash Naltrexone
                                                                                        • Liraglutide for Weight Loss in Patients with Type 2 Diabetes
                                                                                        • Liraglutide Weight Loss Over 2 Years ITT Observed Means
                                                                                        • Phase III Study Outcomes Compared
                                                                                        • Treatment Gap in theManagement of Obesity
                                                                                        • Treatment Gap in theManagement of Obesity

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