type 2 dm Mx

8/8/2019 type 2 dm Mx

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Meeting the Challenges of Type 2 Diabetes with

New & Emerging Therapies

Herbert Schuster M.D., Ph.D.

Professor of Medicine

Humboldt University Berlin, Berlin, Germany

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2

The challenges in future medicine

1. Genomics and biotech allow development of theories and

models in life sciences

2. To recognize health and disease as a process and not asa condition

3. Molecular medicine will cause a shift from intervention to

prevention

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3

Palliative care

healthy sick

healthy sick

sick years gainedhealthy

Interventional care

Preventive care

Historical development of healthcare systems

Birth Death

lower pain

increase life time

shorten disease period

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4

Attributes

Health

Disease

Environment

Genes

Dynamic network model of processes

The future disease model

Drugs

Life style

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5

Network model of cardiovascular disease mechanisms

MI

Stroke

Heart failure

ClinicalPhenotypes

Kidney failure

Hypertension

Hyperlipidemia

Diabetes

Obesity

Atherosclerosis

Thrombosis

MedicalPhenotypes

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6


MI

Stroke

Heart failure

ClinicalPhenotypes

Genotypes

Gene 1

Gene 2

Gene 3

MolecularPhenotypes

Receptors

Enzymes

Hormones

Kidney failure

Hypertension

Hyperlipidemia

Diabetes

Obesity

Atherosclerosis

Thrombosis

MedicalPhenotypes

Blood pressure

Lipoproteines

Glucose

Clotting

Body weight

Endothelial cells

BiologicalPhenotypes

Muscle cells

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MI

Stroke

Heart failure

ClinicalPhenotypes

Genotypes

Gene 1

Gene 2

Gene 3

MolecularPhenotypes

Receptors

Enzymes

Hormones

Biology Medicine

Kidney failure

Hypertension

Hyperlipidemia

Diabetes

Obesity

Atherosclerosis

Thrombosis

MedicalPhenotypes

Blood pressure

Lipoproteines

Glucose

Clotting

Body weight

Endothelial cells

BiologicalPhenotypes

Muscle cells

Threshold of signsand symptoms

healthy subclinial symptomatic

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Different cause-effect relationship models

a) Linear response to change of conditions

Condition

O u t c o m e

a

Condition

b

b) Dramatic increase of response after reaching a critical condition

c) “Catastrophic shift of complex biological systems”

with point of no return after reaching a critical condition

Condition

Networks

c

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subclinical clinical

Modified according to Ross R. N Engl J Med 1999;362:115 –126

Threshold of signs & symptoms

healthy

Decades Decades/Years Minutes Months/Years

EndothelialDysfunction

StablePlaque

Instable PlaquePlaque Rupture

Acute CoronarySyndrome

Thrombosis

Infarction

Normal Artery

Atherosclerosis - Disease (ICD 10 I170.9) Complications

PrimaryPrevention

SecondaryPrevention

TertiaryPrevention

Current understanding of atherosclerosis

(staging and grading)

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“Molecular” therapy of atherosclerosis

NO Adhesion moleculesProliferation factorsOxidationProteasisCytokinesClotting

ß-Blocker

ACE-Inhibitor AT 1 Blocker Statins Aspirin

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Angiotensinogen Angiotensinogen

ReninRenin

AT1 AT2

ACE ACE ChymaseChymase

Atherogenesis and the renin system

Angiotensin I Angiotensin I

Angiotensin II Angiotensin II

Vasoconstriction

Aldosterone secretionSympathic activiation

Cardiac contractility

Renal blood flow

Vascular hypertrophy

Myocardial hypertrophy

Cell proliferation

Cell differentiationZellregeneration

Vasodilatation

Bradykinine secretion

t-PA

ARB

ACEI

BradykininBradykinin

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0 1 2 3 years

5

10

15

20

25

30%

0

CV death

Non-CV death

Placebo

Candesartan

Placebo

Candesartan

HR 0.88 (95% CI 0.79-0.97), p=0.012 Adjusted HR 0.87, p=0.006

p=0.45

3.5Number at risk

Candesartan 3803 3563 3271 2215 761

Placebo 3796 3464 3170 2157 743

Pfeffer et al., Lancet 2003 362: 759 –66

Reduction in CVD mortality with Candesartan (CHARM)

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0 1.0 2.0 3.0 3.5

0

2

4

6

8

10

Plazebo

77 (7%)

47 (4%)

Candesartan

HR 0.60 (0.41-0.86)

Years

N u m b e r o f P a t i e

n t s i n %

Relative Risk Reduction - 40%, p=0.005

Reduction in new onset of type 2 diabetes

with Candesartan (CHARM)

Pfeffer et al., Lancet 2003 362: 759 –66

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GLP-1,GLP-2

Identification of gastrointestinal peptides

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How DPP4 inhibitors work

FoodFood

IntakeIntake

StomachStomach

GI TractGI Tract

IntestineIntestine

Increases and Prolongs GLPIncreases and Prolongs GLP--11

Effect on AlphaEffect on Alpha--cells:cells:AlphaAlpha--cells:cells:

PancreasPancreas

Insulin ReleaseInsulin Release

Net Effect:Net Effect:

Blood GlucoseBlood Glucose

BetaBeta--cells:cells:

Increases and Prolongs GLPIncreases and Prolongs GLP--11

And GIP Effects on BetaAnd GIP Effects on Beta--cells:cells:DPP4DPP4

Inhibitor Inhibitor

Glucagon secretionGlucagon secretion

Adapted from Drucker and Nauck, 2006; Idris and Donnelly, 2007; Barnett, 2006

IncretinsIncretins

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16

•Drawbacks of Key Classes

– Metformin

• GI Effects

– Sulfonylureas

• Weight Gain

• Hypoglycemia

• Cardiac Effects

– TZDs

• Weight Gain

• Edema

• CHF Contra-Indication

Note: U.S. and EU percentage come from different studies and thus may not be entirely consistent —

EU data from physician chart review; U.S. data from NHANES 1999-2000Source: BMS Market Research; BMS Outcomes Research

64

69

58

51

62

57

0

20

40

60

80

100

U.S. U.K. France Ger. Italy Spain

Percentage of patients not controlled(relative to A1C Target of 7.0%)

P a t i e n t s ( %

)

Patients often not at goal and suffer many

safety / tolerability Issues

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17

Glycemic Control in an Illustrative Patient

A 1 C

Goal*Goal*A1C=<7A1C=<7

Normal**Normal**A1C=5%A1C=5%

TimeTime

PotentialPotential

treatmenttreatment

changechangeFirstAgent

Sources: ADOPT, UKPDSSources: ADOPT, UKPDS

(*) According to the ADA; (**) according to the NIH(*) According to the ADA; (**) according to the NIH

MonotherapyMonotherapy CombinationCombinationTherapyTherapy

The progressive nature of type 2 diabetes ultimately

overwhelms medications

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OGTT=oral glucose tolerance test; IV=intravenous.

Nauck MA et al. J Clin Endocrinol Metab 1986;63:492 –498. Copyright ©1986. The Endocrine Society.

200

Time (min)

400Glucose (mg/dL) Insulin (pmol/L)

0

50

100

150

-30 0 30 60 90 120 150 180 210 210

Time (min)

0

100

200

300

-30 0 30 60 90 120 150 180

Oral

IV

The effect of incretin, OGTT and iv infusion

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0

20

40

60

80

0 30 60 90 120 150 180

** * *

**

*

Oral glucose

IV glucose

0

20

40

60

80

0 30 60 90 120 150 180

I n s u l i n ( m U / L

)

I n s u l i n ( m U / L )

Controls Type 2 Diabetes

Time (min)Time (min)

Oral glucose

IV glucose

Reduced effect of incretins in type 2 diabetes

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GIP

0

40

80

120

160

-30 0 30 60 90 120 150 180 210

Time (min)

T

o t a l G I P ( p m o

l / L )

kcal 260

kcal 520

GLP-1

0

10

20

30

40

50

-30 0 30 60 90 120 150 180 210

Time (min)

T o

t a l G L P - 1 ( p m

o l / L )

kcal 260

kcal 520

Vilsbøll T et al. J Clin Endocrinol Metab 2003;88:2706 –2713. Copyright © 2003. The Endocrine Society.

Meal size dependent effect of incretins

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Vilsbøll T et al. J Clin Endocrinol Metab. 2001;50:609 –613.

Total GLP-1, controls

Total GLP-1, patients

Intact GLP-1, controls

Intact GLP-1, patients G L P - 1 ( p m

o l / L )

Time (min)

30

25

20

15

10

5

0

0 50 100 150

Impaired post prandial GLP-1 response in T2D

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500

400

300

200

100

0 G a s t r i c v o l u

m e ( m L )

*

GLP-1 [7-36 amide] sc

Liquid meal

p <0.0001

-30 0 30 60 90 120 150 180 210 240

Time (min)

*

*

*

*

Placebo

GLP-1

Nauck MA et al. Diabetologia 1996;39:1546 –1553. Copyright ©1996 Springer. Reprinted with permission.

Exogenes GLP-1 and decreased stomach emptying

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0

2000

4000

6000

8000

Time (min)

C - p e p t i d e ( p m

o l / L )

GLP-1

GIP

Saline

Hyperglycemic Clamp

Saline or GIP or GLP-1

-15 -10 0 5 10 15 20 30 45 60 75 90 105 120 150

Adapted from Vilsbøll T et al. Diabetologia 2002;45:1111 –1119.

Effect of GLP-1 and GIP on insulin

secretion in type 2 diabetic patients

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00

22

44

66

88

1010

1212

1414

1616

00:0000:00 04:0004:00 08:0008:00 12:0012:00 16:0016:00

SnackSnackLunchLunchBreakfastBreakfast

DiabeticDiabetic--salinesaline

DiabeticDiabetic--GLPGLP--11

NondiabeticNondiabetic

G l u c o s

e

G l u c o s

e

( m m o l / L )

( m m o l / L )

Time of dayTime of day

Rachman J et al. Diabetologia 1997;40:205 –211.

Normal blood glucose levels after GLP-1 infusion in type

2 diabetic patients

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*

* ** * *

* * *

*** *

**

* * *

Minutes

Insulin

Glucagon

Fasting

glucose

250

150

5

250200

10050

40

30

20

0

mU/L

2015

10

0 60 120 180 240

15.012.510.07.55.0

200

150

100

50Infusion

*

mmol/L

mg/dL

pmol/L

pmol/L

Placebo

GLP-1

*P <0.05

n = 10

10

Nauck NA et al. Diabetologia 1993;36:741 –744.

Glucose dependent response of GLP-1 in

type 2 diabetic patients

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Intestinal

GLP-1

Release

GLP-1 (9-36)

Inactive

(> 80% of pool)

GLP-1 (7-36)

Active

Mixed

Meal

DPP-4

t1/2

= 1 to 2 min

Increased insulin secretion

Enhanced beta-cell proliferation

Reduced beta-cell apoptosis

Reduced glucagon secretion (GLP-1)

Intestinal

GIP

Release

GIP (1-42)

Active

Decreased gastric emptying, food intake,

and glucagon secretion

DPP-4iDrucker DJ. Diabetes Care 2003;26:2929 –2940.

Incretine secretion and DPP-4-induced inactivation

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--3030 00 3030 6060 120120 18018000

55

1010

1515

B l o o d g l u c o s e ( m

M )

B l o o d g l u c o s e ( m

M )

‡‡

††

+/++/+--//--

Lower glucose in DPPLower glucose in DPP--44--//-- micemice

+/++/+ --/ /--00

1010

2020

**

P l a s m a g l u c o s e ( m M )

P l a s m a g l u c o s e ( m M )

+/++/+ --/ /--00

5050

100100

150150

**

P l a s m a i n s u l i n ( p M )

P l a s m a i n s u l i n ( p M )

+/++/+ --/ /--00

11

22

33**

P l a s m a G

L P

P l a s m a G

L P - - 1 ( p M )

1 ( p M )

*p <0.05*p <0.05††p <0.01p <0.01‡‡p <0.001p <0.001

Increased levels of insulin and intact GLP-1 in DPP-4 -/- mice

Marguet D et al. Proc Natl Acad Sci USA 2000;97:6874 –6879.

Genetic inactivation of DPP-4 increases incretine

response and glucose clearance in vivo

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0 20 40 60 80 100 120 140 160 180 200 220

Time (min)

0

100

200

300

400

500

G L P - 1 ( p m o l / L )

GLP-1 infusion

Glucose

GLP-1 infusion

Glucose

DPP-4 Inhibition

Val-pyr=valine-pyrrolidine.

Deacon CF et al. Diabetes 1998;47:764 –769.

Pharmacological DPP-4 inhibition decreases N-terminal

degradation of GLP-1 in pigs

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Insulin secretion

Glucagon secretion

Gastric emptying

Appetite

Cardioprotection

Cardiac output

Insulin biosynthesis

Beta-cell proliferationBeta-cell apoptosis

Neuroprotection

Glucose production

Insulin sensitivity

Brain

Heart

GI tract

Liver

Muscle

Stomach

GLP-1

Adapted from Drucker DJ. Cell Metab. 2006;3:153 –165.

“Pleiotropic effects” of incretins

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GLP-1R Agonists DPP-4 Inhibitors

Administration Injection Orally Available

GLP-1 concentrations Pharmacological Physiological

Mechanisms of action

Activation of portal glucose

sensor

GLP-1

No

GLP-1 + GIP

Yes

Insulin secretion +++ +

Glucagon secretion ++ ++

Gastric emptying Inhibited +/-

Weight loss Yes No

Expansion of beta-cell mass

In preclinical studies Yes Yes

Nausea and vomiting Yes No

Potential immunogenicity Yes No

Adapted from Drucker DJ. Cell Metab 2006;3:153 –165.

GLP-1 receptor agonists vs. DPP-4 inhibitors

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*,†,# indicate significant differences vs the vehicle treated group, the metformin treated group, and the valine-pyrrolidide treated group, respectively.

One, two and three symbols indicated p<0.05, p<0.01, and p<0.001 respectively.

Yasuda N et al. Biochem Biophys Res Commun 2002;298:779 –784.

P l a s m

a a c t i v e G L P - 1 ( % o

f v a l u e s a t 0 h )

Time (h)

0 1 2 3 4 5

250

200

150

100

50

0

Vehicle

Metformin (300 mg/kg)

Val-pyr (30 mg/kg)

Metformin (300 mg/kg) and valine-pyrrolidide (30 mg/kg)

**,††,#

**,†,#

***,†††,###

Combination of metformin und DPP-4 inhibitor increases

GLP-1 levels in rats

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32

– Highly potent, competitive inhibitor of DPP4 – 2 orders of magnitude or greater selectivity for DPP4 versus

other proteases

– Major active mono-hydroxy metabolite (BMS-510849) is 2-foldless potent than saxagliptin

– Pharmacodynamic properties of 5 mg dose consistent with once-

daily dosing

– Rapidly and extensively absorbed after oral dosing; may be takenwithout regard to meals

– Predictable and dose-proportional pharmacokinetics similar inhealthy and diabetic patients with minimal accumulation withonce-daily dosing

– Clearance of saxagliptin and/or its metabolites via metabolism,renal, and non-renal routes

H2N N

O CN

HO

BMS-477118

N

OCN

HO

OH

BMS-510849

H2N

Properties of Saxagliptin

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33

Saxagliptin – approved indications

• Indications

– Saxagliptin is indicated as an adjunct to diet and exercise to improve

glycemic control in adults with type 2 diabetes

• Treatment Settings

– Monotherapy

– Add-on combination to MET, SU, TZD

– Initial Combination with MET

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34

Saxagliptin clinical development program

MET = metformin; OL = open-label; SU = sulfonylurea;T2DM = type 2 diabetes mellitus; TZD = thiazolidinedione

All SubjectsAll Subjects

N = 5346N = 5346

Phase 2bPhase 2bN = 423N = 423

Study 008Study 008

Phase 3Phase 3N = 4250N = 4250

ClinicalClinicalPharmacologyPharmacology

N = 673N = 673

Patients w/ T2DMPatients w/ T2DMN = 40N = 40

Study 002Study 002

Patients w/ HepaticPatients w/ Hepatic

ImpairmentImpairmentN = 18N = 18Study 020Study 020

Patients w/ RenalPatients w/ RenalImpairmentImpairment

N = 32N = 32Study 019Study 019

MechanismMechanismof Actionof ActionN = 36N = 36

Study 041Study 041

MonotherapyMonotherapyN = 832N = 832

AddAdd--ononCombinationCombination

N = 2076N = 2076

N = 401N = 401+ 66 OL+ 66 OL

Study 011Study 011

N = 365N = 365Study 038Study 038

AddAdd--on to METon to METN = 743N = 743

Study 014Study 014

AddAdd--on to SUon to SUN = 768N = 768

Study 040Study 040

AddAdd--on to TZDon to TZDN = 565N = 565

Study 013Study 013

Initial Comb.Initial Comb.with METwith METN = 1306N = 1306

Study 039Study 039

Healthy SubjectsHealthy Subjects

N = 583N = 58321 Studies21 Studies

M th St diM th St di

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35

Change from baseline in A1C at week 24

Monotherapy StudiesMonotherapy Studies

-0,43 -0,46-0,54

0,19

-1,0

-0,8

-0,6

-0,4

-0,2

0,0

0,2

0,4

0,6

A1C (A1C (%)%)

withwith

95% CI95% CI

SAXA (mg)SAXA (mg)Dose 2.5 5 10 PBO

n = 100 103 95 92

Bsl Mean (%) 7.91 7.98 7.85 7.88

* p < .0001 vs. PBO

** ****

-0,71 -0,66-0,63

-0,26

-0,61

-1,0

-0,8

-0,6

-0,4

-0,2

0,0

0,2

0,4

0,6

SAXA (mg)

QAM QAM QAM QPM2.5 5 2.5 / 5 5 PBO

67 69 69 70 68

8.04 7.93 8.02 7.88 7.79

* p < .01 vs. PBO ** p < .02 vs. PBO** ** **** ****

Combination Studies: MET TZD SUCombination Studies: MET TZD SU

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36


Combination Studies: MET, TZD, SUCombination Studies: MET, TZD, SU

-0,59

-0,69

-0,58

0,13

-1,2

-1,0

-0,8

-0,6

-0,4

-0,2

0,0

0,2

0,4

A 1 C (

A 1 C ( % ) w i t h 9 5 % C

I

% ) w i t h 9 5 % C

I

******

* p < .0001 vs. PBO + MET

Dose 2.5 5 10

PBO +

METn = 186 186 180 175

Bsl Mean (%) 8.08 8.07 7.98 8.06

2.5 5

PBO

+TZD

192 183 180

8.25 8.35 8.19

2.5 5

PBO

+GLY

246 250 264

8.36 8.48 8.44

-0,66

-0,94

-0,3

-1,2

-1,0

-0,8

-0,6

-0,4

-0,2

0,0

0,2

0,4

**

*p < .0001 vs. PBO + TZD

** p = .0007 vs. PBO + TZD

-0,54 -0,64

0,08

-1,2

-1,0

-0,8

-0,6

-0,4

-0,2

0,0

0,2

0,4

** **

* p < .0001 vs. PBO + GLY

****

SAXA + MET SAXA + TZD SAXA + GLY

I iti l C bi ti St d ith METI iti l C bi ti St d ith MET

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37


Initial Combination Study with METInitial Combination Study with MET

-2,53 -2,49

-1,69

-1,99

-3,0

-2,5

-2,0

-1,5

-1,0

-0,5

0,0

A1C (A1C (%)%)withwith

95% CI95% CI

SAXA (mg) + METSAXA (mg) + MET

Dose 5 10 10 MET

n = 306 315 317 313

Baseline Mean (%) 9.41 9.53 9.61 9.43

SAXA (mg)SAXA (mg)

* p < .0001 vs. MET

** **

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38

-0,51

-0,61

-1,2

-1,0

-0,8

-0,6

-0,4

-0,2

0,0

A 1 C

(

A 1 C

( % ) w i t h 9 5 % C

I

% ) w i t h 9 5 % C

I

Difference from placebo in adjusted mean change from

baseline in A1C

Phase 2b/3 Monotherapy StudiesPhase 2b/3 Monotherapy Studies

PostPost--hoc Pooled Analysis (Wk 12)hoc Pooled Analysis (Wk 12)

PooledPooledSAXASAXA2.5 mg2.5 mg

PooledPooledSAXASAXA5 mg5 mg

SAXA + METSAXA + MET(014)(014)

2.5 mg2.5 mg 5 mg5 mg

-0,62

-0,36

-0,73 -0,72

-0,63

-0,83

-1,2

-1,0

-0,8

-0,6

-0,4

-0,2

0,0

Phase 3 AddPhase 3 Add--on Combination Studieson Combination Studies

ST Period (Wk 24)ST Period (Wk 24)

SAXA + TZDSAXA + TZD(013)(013)

2.5 mg2.5 mg 5 mg5 mg

SAXA + SUSAXA + SU(040)(040)

2.5 mg2.5 mg 5 mg5 mg

AddAdd--on Combination Study with METon Combination Study with MET

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39

Difference from Control in Change from Baseline in A1C at Week 24(LOCF) for Saxagliptin 5 mg by Subgroup

yy

SubsetSAXA

nPBO

n

Gender Male 100 95

Female 86 80

Race White 154 146

Non-White 32 29

Age (yrs) < 65 156 149

65 30 26

Baseline A1C (%) < 8 88 84

8 – < 9 68 60

9 30 31

Duration of disease (yrs) 1.5 13 20

3 46 49

3 –

<5 39 36

5 101 90

10 36 47

Creatinine Clearance(ml/min)

80 31 24

80 155 151

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40

General Safety Profile

– Well-tolerated at all doses studied in Phase 3

– Low risk for hypoglycemia

– No adverse effects in lipid parameters, blood pressure or heart rate

– Associated with no or minimal differences in weight changecompared with control

– No identified hepatic, pancreatic, skeletal myopathy, or renal safety

signals

– No evidence for clinically meaningful effects on hematology or

chemistry parameters

Controlled Phase 2b/3 Pooled PopulationControlled Phase 2b/3 Pooled Population

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41

Cardiovascular Risk Factors (in addition to T2DM)

1 Includes mixed dyslipidemia

2 Prior CV Disease defined as previous myocardial infarction, congestive heart failure, hospitalization for unstable angina, stable angina, percutaneous coronary intervention, coronary artery bypass graft, coronary

artery disease, cerebrovascular disease, peripheral vascular disease3 Includes contribution from 20 –100 mg saxagliptin in Phase 2b Study (-008).

Number (%) of Patients

SAXA2.5 mgN = 937

SAXA5 mg

N = 1269

SAXA10 mg

N = 1000All SAXA3

N = 3356Control

N = 1251

Patients with at least one

CV Risk Factor

in addition to T2DM

777 (83) 1015 (80) 803 (80) 2724 (81) 1035 (83)

Hypertension 519 (55) 655 (52) 510 (51) 1750 (52) 688 (55)

Hypercholesterolemia1 471 (50) 565 (45) 353 (35) 1475 (44) 566 (45)

Smoking History 383 (41) 449 (35) 393 (39) 1301 (39) 471 (38)

First degree family

member with

Premature CoronaryHeart Disease

190 (20) 248 (20) 186 (19) 677 (20) 265 (21)

Patients with

Prior CV Disease2 118 (13) 150 (12) 118 (12) 404 (12) 165 (13)


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42

Time to Onset of First Primary MACE

24 37 50 63 76 89 102 115 128BL0

1

2

3

4

5

Weeks

Patients at Risk

Control 1251 935 860 774 545 288 144 123 102 57

All SAXA 3356 2615 2419 2209 1638 994 498 436 373 197

All SAXA

Control


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43

Pooled Phase 2b/3

Phase 2 Dose-Ranging (-008)

Monotherapy (-011)

Monotherapy (-038)

MOA (-041)

+ MET (-014)

+ SU (-040)

+ TZD (-013)

Initial Combination with MET (-039)

Incidence Rate Ratio of Primary MACE by Therapy

1,52

0,83

4,09

0,18

0,25

0,07

0,12

0,24

0,01

0,07

0,003

31,02

1,30

0,95

9,90

0,02

1,36

11,55

0,001 0,01 0,1 1 10 100

Ratio of Saxagliptin to Control

Control Better Control Better Saxagliptin Better Saxagliptin Better

0,45

0,30

0,47

0,11

0,80

0,37

0,28

1,25

0,50

Data represent point estimate and 95% CI.Size of point estimate is relative to number of events.


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44

9,9

22,5

13,2

22,5

18,4

15,8

46,3

0

5

10

15

20

25

30

35

40

45

50

55

60

65

11,4

7,78,08,89,17,0

9,2

0

5

10

15

20

25

30

35

40

45

50

55

60

65

Incidence Rate for Primary MACE by Subgroups

History of

CV Disease

At Least One

CV Risk Factor

(in addition to

T2DM)

At Least Two

CV Risk Factors

(in addition to

T2DM)

History of

Hypertension

History of

Hyper-

cholesterolemia

Male

Gender Age ≥65

n = 569 n = 3759 n = 2286 n = 2438 n = 2041 n = 2279 n = 699

Error bars represent SEM

Saxa Control

E v e n t s p e r 1 0 0 0 p

a t i e n t - y e a r s


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45

SAXA 2.5 mg SAXA 5 mg SAXA 10 mg All SAXA* Control

N (total patients) 937 1269 1000 3356 1251

Total Pt-years 1149 1462 1119 3758 1293

Mean Duration of

Follow Up (yrs)1.23 1.15 1.12 1.12 1.03

Number (%)

FDA-defined

SMQ MACE 28 (3.0) 37 (2.9) 30 (3.0) 100 (3.0) 41 (3.3)

Custom MACE 6 (0.6) 6 (0.5) 11 (1.1) 23 (0.7) 17 (1.4)

Investigator-defined

Primary MACE 6 (0.6) 6 (0.5) 11 (1.1) 23 (0.7) 18 (1.4)

Acute CV Events 14 (1.5) 10 (0.8) 14 (1.4) 38 (1.1) 23 (1.8)

Frequency of Major CV Endpoints by Definition

* Includes contribution from 20 –100 mg saxagliptin in Phase 2b Study (-008).

pp


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SAXA 2.5 mg SAXA 5 mg SAXA 10 mg All SAXA* Control

N (total patients) 937 1269 1000 3356 1251

Total Pt-years 1149 1462 1119 3758 1293

Mean Duration of

Follow Up (yrs)1.23 1.15 1.12 1.12 1.03

Number (%)

Patients with Any

Cardiac Disorder AE 53 (5.7) 63 (5.0) 48 (4.8) 164 (4.9) 71 (5.7)

FDA-defined

Ischemic Heart Disease 14 (1.5) 17 (1.3) 12 (1.2) 43 (1.3) 24 (1.9)

Cardiac Failure 8 (0.9) 7 (0.6) 5 (0.5) 20 (0.6) 7 (0.6)

Cardiac Arrhythmias 32 (3.4) 36 (2.8) 31 (3.1) 99 (2.9) 37 (3.0)

Other 9 (1.0) 8 (0.6) 6 (0.6) 23 (0.7) 7 (0.6)

Investigator-defined

Secondary MACE 8 (0.9) 7 (0.6) 11 (1.1) 26 (0.8) 20 (1.6)

All Death 3 (0.3) 3 (0.2) 4 (0.4) 10 (0.3) 12 (1.0)

CV Death 1 (0.1) 2 (0.2) 4 (0.4) 7 (0.2) 10 (0.8)

Frequency of Additional CV Endpoints by Definition

pp

* Includes contribution from 20 –100 mg saxagliptin in Phase 2b Study (-008).

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Saxagliptin – Demonstrated Benefits

• Clinically meaningful reductions in A1C, FPG, and PPG

– Demonstrated in wide-range of treatment contexts (monotherapy,

add-on and initial combination)

– Consistent effect across subgroups

– Complementary mechanism of action to currently existing

therapies

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Saxagliptin – Favorable Safety Profile

– Studied in extensive clinical program at exposuresup to 80x proposed usual clinical dose

– Well-tolerated at all doses studied in Phase 3

– Low risk for hypoglycemia

– No or minimal differences in body weight change compared with control

– No identified hepatic, pancreatic, renal safety signals

– No human clinical correlate to monkey skin-findings

– Small decrease in mean, absolute lymphocyte count

• Not associated with effect on infectious-related AEs

• Changes stable, non-progressive over long-term dosing

– No identified CV safety signal

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Conclusion

• Saxagliptin provides meaningful benefits in

glycemic control

• Saxagliptin provides a favorable safety and

tolerability profile

• Saxagliptin offers a new treatment option with a

favorable benefit / risk profile for patients with

type 2 diabetes

type 2 dm Mx

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