DIABETES MANAGEMENT 2006: INTEGRATING NEW MEDICINES AND NEW DEVICES Robert B. Baron MD MS Professor and Associate Dean UCSF School of Medicine Declaration.

DIABETES MANAGEMENT 2006:DIABETES MANAGEMENT 2006:INTEGRATING NEW MEDICINES INTEGRATING NEW MEDICINES

AND NEW DEVICESAND NEW DEVICES

Robert B. Baron MD MSRobert B. Baron MD MS

Professor and Associate Dean Professor and Associate Dean

UCSF School of MedicineUCSF School of Medicine

Declaration of full disclosure: No conflict of interest

Diabetes Mellitus in the US: Diabetes Mellitus in the US: Health Impact of the DiseaseHealth Impact of the Disease

DiabetesDiabetesBlindnessBlindness**

Renal Renal failure* failure*

Amputation*Amputation*

Life expectancy Life expectancy

-5-5to 10 yrto 10 yr

CardiovascularCardiovasculardisease 2x to 4xdisease 2x to 4x

**Diabetes is the no. 1 cause of renal failure, new blindness, and nontraumatic amputationsDiabetes is the no. 1 cause of renal failure, new blindness, and nontraumatic amputations

Nerve damage in Nerve damage in 60% to 70% of patients60% to 70% of patients

6th leading cause of 6th leading cause of death death

Diabetes Mellitus: U.S. Impact

DIABETES

IFG

~1 Million Type 1

~16 Million Type 2

2/3 Diagnosed

1/3 Undiagnosed(4.9 Million)

16.7 Million (8.3%) 12.3

Million

(6.3%)

29 Million

(14.4%)

TOTAL:

Screening for Diabetes

ADA: >45, especially if BMI >25. <45 if overweight and have risk factor for DM (inactive, FH, high risk ethnicity, baby >9 lb, HTN, low HDL or high TG, PCOS, vascular disease). Screen with FPG or 2-h OGTT

Diabetes Care, 2006

USPSTF: Insufficient evidence to recommend for or against. However, recommend screening in adults with hypertension and lipid disorders

Ann Intern Med, 2003

Diagnosis of Diabetes

Two measures of any of the following:

Random glucose: 200 mg/dl with symptoms (poly’s, weight loss)

Fasting glucose: 126 mg/dl

2-hr glucose: 200 mg/dl during OGTT

Diabetes Care 2006

HbA1C for Screening ?

• HbA1c 2SD above mean has sensitivity of 66 % and specificity of 98 % and compares favorably to FPG

• Different nondiabetic reference ranges due to different glycated hemoglobin fractions

• Precision and accuracy may not be sufficient in all labs

• Affected by hemoglobinopathies, anemia, transfusions, uremia, pregnancy

Diagnosis of Pre-Diabetes

Two measures of any of the following:

Fasting glucose 100 - 125 mg/dl

2-hr glucose 140 - 199 mg/dl during OGTT

DPP: % Developing DM After 3 YearsDPP: % Developing DM After 3 Years

14.4

21.7

28.9

0

5

10

15

20

25

30

35

Lifestyle Metformin Placebo

%

deve

lop

ing

Dia

bete

s

Prevention of Type 2 DM: RCTs

Trial Description Results (RR)

Da Qing1 Diet &/or exercise 31 to 46%

Finnish PreventionStudy (FPS)2 Intensive lifestyle 58 %

Diabetes Prevention Meformin 31 % Program (DPP)3 Lifestyle 58 %

STOP- NIDDM4 Acarbose 25 %

TRIPOD5 Troglitazone 55 %

ADA Diabetes Care 2006

Recommendations for Adults

Glycemic ControlA1C: <7.0Preprandial: 90-130 mg/dlPostprandial: <180 mg/dl

Blood Pressure: <130/80 mmHg

LipidsLDL: <100 mg/dlTG: <150 mg/dlHDL: >40 mg/dl

Treatment of Type 2 Diabetes

Step 1: Lifestyle Changes

Step 2: Oral Monotherapy

Step 3: Combination Oral Therapy

Step 4: Oral Therapy plus Insulin

Step 5: Insulin Alone

Step 6: Insulin plus Thiazolidinedione/Metformin

Target metabolic values need to be individualized

Attaining Glycemic Goals Using Monotherapy in Obese Patients With Type 2 Diabetes

Turner RC et al. JAMA. 1999;281:2005-2012.

0

10

20

30

40

50

60

3 Years 6 Years 9 Years

Diet Alone

Sulfonylurea

Metformin

Insulin

Pro

porti

on o

f Pat

ient

s W

ithH

bA1c

<7%

(%)

Treatment of Type 2 Diabetes

Improved Glycemic Control

DecreaseDecreaseHepatic Hepatic GlucoseGlucose OutputOutput

IncreaseIncreaseInsulinInsulin

SecretionSecretion

Metformin SFUs/Insulin

Acarbose/

Miglitol

ThiazolidinedionesDecrease Decrease

insulininsulinresistanceresistance

DelayDelay digestion ofdigestion of

carbohydratescarbohydrates

Generic Oral Hypoglycemic Slide

HgA1c

Time

Change from Drug A to B, C, or D

Add Drug A to B, or B to A

Add Drug C

Add Drug D

Adding Instead of Switching

DeFronzo, et al. N Engl J Med. 1995;333:541-549,

Ch

ang

e in

Mea

n H

bA

1c (

%)

0–3

–2

–1

0

1

Continue glyburide

Switch to metformin

Glyburide+ metformin

9 13 17Treatment (wk)

21 25 29

** * *

+0.2%

–0.4%

–1.7%

5-2

Oral Agent “Failure”Why does this occur?

Changing HbA1c goalsCompliance, side effectsWrong diagnosis (LADA--latent

autoimmune diabetes in adults 10%)Stress, diabetogenic medicationsNatural progression of the disease

Natural History of Type 2 Diabetes

050

100150200250

-10 -5 0 5 10 15 20 25 30

Years of Years of DiabetesDiabetes

Glucose(mg/dL)

Relative Function

(%)

Insulin Resistance

Insulin Level`Beta-cell failure

*IFG = impaired fasting glucose

50100150200250300350

Fasting Glucose

Post-meal Glucose

Obesity IFGObesity IFG** Diabetes Uncontrolled hyperglycemia Diabetes Uncontrolled hyperglycemia

Natural History of Type 2 Diabetes

050

100150200250

50100150200250300350

-10 -5 0 5 10 15 20 25 30Years of Diabetes

Glucose(mg/dL)

Relative Function

(%)

LifestyleLifestyle SUSU

Insulin ResistanceInsulin Resistance

Insulin LevelInsulin Level

Fasting GlucoseFasting Glucose

Beta-cell failureBeta-cell failure

Post-meal Post-meal GlucoseGlucose

InsulinInsulin

Thiazolidinedione - Biguanide Thiazolidinedione - Biguanide

Insulin Plus Oral AgentsIntroduction of insulin

– Bedtime– Intermediate/Long-acting insulins

• NPH, UL, glargine• 10 units

– Self-monitoring of blood glucose (hypoglycemia education)

Insulin plus other oral agent combinations (maintain effect on insulin sensitivity)

When to go to > 1 shot per day HgA1c >7

Glucose in AM at goal but g lucose before dinner >140

Options

Add premeal lispro/aspart

Add bid premixed insulin – 70/30, 75/25

Questions

Continue metformin

? Sulfonylurea, ? Thiazolidinedione

Function of Insulin in Regimens

Meal coverage (carbohydrates)

Basal insulin

Correction of high blood sugar

More OptionsInsulins

– Insulin Lispro (Humalog®) ‘96– Insulin Aspart (Novolog®) 9/00– Humalog ® Mix 75/25 1/00– Insulin Glargine (Lantus®) 4/00– Novolog ® Mix 70/30 5/02– Insulin Glulisine (Apidra®) 4/04– Insulin Detemir (Levemir®) 6/05– Insulin delivery devices and glucose meters

Insulin Pharmacokinetics

Type of Insulin Onset Peak Duration Appearance

Short-acting Regular Lispro/ Aspart/ Glulisine

½-1hr <15 min

2-4hr 1-2 hr

6-8hr 3-5hr

clear clear

Intermediate-acting NPH/ Lente*

1-2hr

6-10hr

12+hr

cloudy

Long-acting Ultralente* Detemir Glargine

4-6hr 1 hr 1.5hr

18hr flat flat

24+hr 12-24hr 24hr

cloudy clear clear

On July 6, 2005 Lilly announced Lente and Ultralente will no longer be available in 2006.

Short-acting Insulin Analogues: Lispro and AspartPlasma Insulin Profiles

400

350

300

250

200

150

100

MealSC injection

50

00 30 60

Time (min)90 120 180 210150 240

Lispro

Regular Human

500450400350300250

150

50

200

100

00 50 100

Time (min)150 200 300250

Aspart

Regular Human

Pla

sma

Insu

lin

(p

mol

/L)

Pla

sma

Insu

lin

(p

mol

/L)

MealSC injection

Heinemann, et al. Diabet Med. 1996;13:625-629; Mudaliar, et al. Diabetes Care. 1999;22:1501-1506.

6-28

glulisine

Rapid-Acting Insulins

Advantages• Flexibility--given immediately before or after meals

• Postprandial control-better match with glucose peak

• Limited duration so less overlap with subsequent injections

Disadvantages• Caution with adequate CHO intake (if < than predicted, susceptible to hypoglycemia

• Cost/insurance coverage

Activity Profile in Type 1 Diabetes Lepore et al. Diabetes 1999;48(suppl 1):A97. Abst 416; Study 1015

30

(Hourly Mean Values)

Time (h) after sc injection = End of observation period

0

1

2

3

4

5

6

0

Glu

cose

U

tiliz

atio

n R

ate

(mg/

kg/m

in)

Insulin Glargine

NPH insulin

2010

When should insulin be started?

What insulin should you use in Type 2? What insulin regimen is best?

Which, if any, oral agents should be continued?

Type 2 Diabetes: Unanswered Questions

Insulin tactics

Minimize weight gain – metformin

Minimize risk of hypoglycemia – insulin analogs, optimize self management skills

Minimize insulin resistance – thiazolidinediones and metformin

Use oral agents to limit number of injections

More Options

Incretin mimeticsExenatide (Byetta ®) 4/05

Amylinomimetics (amylin analog)Pramlintide (Symlin ®)

3/05

Incretins in Type 2 DM

Gut hormones released postprandially

Oral glucose elicits greater insulin response than IV glucose; “incretin effect” accounts for 50-70% of insulin response to oral glucose

2 main gut incretins

– Glucose-dependent insulinotropic polypeptide (GIP)

• Released by K cells in duodenum

– Glucagon-like peptide-1 (GLP-1)• Released by L cells in small intestines• Levels are diminished in type 2 DM post-meal

Incretins in Type 2 DM (cont)

Rapidly degraded by dipeptidyl peptidase IV (DPP-IV)

• GLP-1 analogs; “incretin mimetics”– Liraglutide (free fatty acid added to

bind to albumin; injected daily)– Exenatide

• DPP-IV inhibitors (oral)

Actions of GLP-1

Insulin secretion (Insulinotropic effects)– Potentiates glucose-induced insulin secretion– Enhances all steps of insulin biosynthesis– Upregulates insulin gene expression– Upregulates genes needed for beta-cell function (– Stimulates beta cell proliferation– Promotes differentiation of beta cells from progenitor

cells

Inhibits glucagon secretion (Glucostatic effect)

Slows gastric emptying

Inhibits appetite and food intake

Exenatide (Byetta)

Synthetic Exendin-4, or exenatide

Exendin-4 originally isolated from Gila monster’s (Heloderma suspectum) saliva; lizard in Arizona

Analog of GLP-1– 39 amino acid peptide– >50% overlap with human GLP-1

Resistant to DPP-IV degradation

Similar binding affinity at GLP-1 receptors

Exenatide (Byetta)

Indications: adults with type 2 DM who are taking metformin, sulfonylurea or combination

Peak concentration post injection achieved in 2.1 hr (injected SQ twice daily within 60 minutes of meal)

Metabolized primarily by kidneys

Not recommended in Clcr <30 ml/minOK in hepatic impairment

Exenatide: BG Effects

Lowers post-prandial BG

– Restores first-phase insulin response

– Slows gastric emptying– Lowers post-prandial glucagon ( hepatic glucose output)

food intake

Lowers A1C

Clinical Data: Exenatide

3 large, 30 week clinical trials (randomized, double-blind, placebo-controlled) in patients with type 2 DM

• On SFU: Buse et al. Diabetes Care. 2004;27:2628-35

• On SFU & metformin: Kendall DM et al. Diabetes Care. 2005;28:1083-91.

• On metformin: DeFronzo RA et al. Diabetes Care. 2005;28:1092-1100

Placebo BID 5 mcg exenatide BID 10 mcg exenatide BID

ITT 483 480 483

Age (y) 55 55 55

BMI 34 33 34

A1C 8.5 8.4 8.5

Duration of DM 8 8 7

A1C (%) Effect (change from baseline)

Placebo BID 5 mcg exenatide BID 10 mcg exenatide BID

MET 0.1 -0.4 -0.8

SFU 0.1 -0.5 -0.9

MET+SFU 0.2 -0.6 -0.8

Changes in A1C from baseline vs placebo statistically significant

Effect on FBG less pronounced: 6-9 mg/dl (5 mcg dose);10 mg/dl (10 mcg dose)PPG 60% (5 mcg dose) & 90% (10 mcg dose)

Weight (change from baseline) & Hypoglycemia

Placebo BID

5 mcg exenatide BID 10 mcg exenatide BID

Weight (kg) -1.4 -3.1 -4.2

Hypoglycemia (%)

MET

SFU

MET + SFU

5.3

3.3

1.26

4.5

14.4

19.2

5.3

35.7

27.8

Open-label extension study to 90 weeks: persistence in weight loss and A1C

Exenatide Dosing

Start 5 mcg SQ BID before morning and evening meal

When added to SFU, lower dose of SFUAfter 1 month, can increase to 10 mcg SQ BIDAvailable in prefilled penMust be continuously stored refrigerated at

36-46°FFor oral medications dependent on threshold

concentrations or rapid onset, take them 1 hour before

Side Effects

GI– Nausea (44% vs 18% with placebo); incidence

lessens over time; 3% dropout rate due to nausea

– Vomiting (13% vs 4%)– Diarrhea (13% vs 6%)

Headache (9% vs 6%)Hypoglycemia (see previous slide)

New Options for Insulin Delivery

Durable Insulin Pens

Use replaceable insulin cartridge

Use dial mechanism for dose

NovoPen® 3

– Maximum dosage: 70 units

– 1 unit increment

– metal materialNovoPen ® Junior

– Maximum dosage: 35 units– ½ unit increment

BD™ Pen and Pen Mini

– 1.5 cc cartridge– Maximum dosage: 30 or 15 units

Innovo® & InDuo™

InDuo: Integrates two daily activities combined into one device

– Blood glucose monitoring (OneTouch® Ultra® meter) and Insulin Delivery Device (Innovo)

– Supports an acceptance and understanding of the link between SMBG and insulin therapy

– Device serves as a constant reminder to test whenever the patient injects

Memory function stores the time elapsed & amount of last insulin dose

Uses 3 cc cartridge Maximum dosage: 70 units; 1 unit increments

OptiClik

FDA approved 8/04

Reusable pen for Lantus & Apidra

1-unit increments; takes only BD pen needles

Supplied to physicians; not available in pharmacies

www.opticlik.com

Disposable/Prefilled Insulin Pens

Hold 3 cc insulinDiscard when finishedUse dial mechanism for dose; need to prime

(“air shot”)

Novolin® InnoLet®

– Clock-like dial (egg timer-like) with large scale numbers; audible clicks

– large grip and ergonomic shape that allows alternative grips, easy-to-push large button and support shoulder

– Maximum dose: 50 units

– 1 unit increments

Regular, NPH and 70/30 insulin only

Disposable/Prefilled Insulin Pens, cont.

Novo Nordisk FlexPen ® (Novolog ®, Novolog ® Mix 70/30): up to 60 units; 1 unit increments

Eli Lilly pens (Humalog ®,Humalog ® Mix 75/25™, NPH, 70/30): up to 60 units; 1 unit increments

NeedlesPen NeedlesBD

– 29 G: ½” (12.7mm)– 31 G: 3/16” (5 mm) or

5/16” (8 mm)Novo Nordisk

– NovoFine® – 30 gauge x 1/3” (8mm) – 31 gauge x ¼” (6mm)

Caution with obese patients if use shorter needles

Syringes: 1/3, ½, 1 ccSeveral times enlarged NovoFine® 30[30 gauge x 1/3” (8mm)] Disposable Needle

Alternate Testing Sites

Alternative Site Testing: Cons

Lag time of 5-30 minute between forearm & finger

– blood flow to finger is 3-5 x faster than arm

– significant when BG changing rapidly

When not to use (use fingers)

– BG rapidly changing– suspect low BG– hypoglycemic unawareness– within 1-2 hours after meals

Bruising at site

Other Methods of SMBG

Continuous ambulatory blood glucose monitoring

– CGMS (Continuous Glucose Monitoring System) System Gold™

• Medtronic MiniMed • 72-hour; BG recorded q5min

– 24-hour glucose patterns– detect unrecognized hypoglycemia– Requires HCP support

Noninvasive: GlucoWatch G2 Biographer

– Cygnus– Requires a prescription

Self-Monitoring of Blood Glucose(SMBG) - ADA Recommendations

Type 1 Diabetes : 3 x daily Type 2 Diabetes: optimal frequency and timing not

known; “sufficient to facilitate reaching glucose goals”

Postprandial BG may be necessary to reach A1C goals and/or reduce risk of hypoglycemia

Self-management training: how to use the data to adjust food intake, exercise or pharmacologic therapy

Diabetes Care 2006Diabetes Care 2006

Self-Monitoring:Outcomes

Improve overall control:

Best studies:

HbA1c 0.7% lower in type 1

HbA1c 0.6% lower in type 2

Meta-analysis

HbA1c 0.25% lower

Other Emerging Therapies

Pharmacologic– PPAR/PPAR dual agonists

• Muraglitazar (Pargluva; Advisory committee met 9/9/05; recommended approval)

• Tesaglitazar (Galida)– Alternative insulin dosage forms (IH, buccal; transdermal; nasal)

• Inhaled insulin, Exubera• Islet cell transplants

– Rimonabant (Acomplia)Monitoring

– Continous blood glucose monitoring