Faculty Disclosure

Mikayla Spangler, PharmD, BCPS

Dr. Spangler has listed no financial interest/arrangement that would be

considered a conflict of interest.

Weight Loss in Diabetes-

It IS Possible!Mikayla Spangler, Pharm.D.,

BCPS

Objective

Identify medications used for diabetes that may aid in weight loss

Special focus on incretin mimetics and amylin analog

Overview of Diabetes Medications

Class Affect on Weight

Insulin Sulfonylureas Thiazolidinediones Dipeptidyl peptidase-4 inhibitors

Biguanides Incretin mimetics Amylin analog

New Agents with Weight Loss

Glucagon-Like Peptide-1 (GLP-1) receptor agonists

2005: exenatide (Byetta©)2010: liraglutide (Victoza©)

Amylin analog2004: pramlintide (Symlin©)

GLP-1 AGONISTS

GLP-1 Modes of Action in Humans

Data from Flint A, et al. J Clin Invest. 1998;101:515-520; Larsson H, et al. Acta Physiol Scand. 1997;160:413-422; Nauck MA, et al. Diabetologia. 1996;39:1546-1553; Drucker DJ. Diabetes. 1998;47:159-169.

Stomach: regulates gastric

emptying

Brain: promotes satiety and reduces food intake

Liver: reduces hepaticglucose output-cells: enhances

glucose-dependent insulin

secretion

-cells: reduces postprandial

glucagon secretion

GLP-1: secreted by intestinal L-cells in response to food

intake

Exenatide

Developed from the saliva of the Gila monster

50% homology with human GLP-1

Only approved with oral antidiabetic agentsWeight loss data from 3 AMIGO trials

AMIGO 1Metformin + placebo v. metformin + exenatide

AMIGO 2Sulfonylurea + placebo v. sulfonylurea + exenatide

AMIGO 3Metformin + sulfonylurea + placebo v. metformin + sulfonylurea + exenatide

AMIGO 1

-3

-2.5

-2

-1.5

-1

-0.5

0

0.5

1

Exenatide 5 mcg BIDExenatide 10 mcg BIDPlacebo

Weight change (kg) at 30 weeks

Data from DeFronzo RA, et al. Diabetes Care. 2005;28:1092-1100 ¤ P<0.05 v. placebo

¤

¤

AMIGO 2

-2

-1.5

-1

-0.5

0

0.5

1

Exenatide 5 mcg BIDExenatide 10 mcg BIDPlacebo

Weight change (kg) at 30 weeks

Data from Buse JB, et al. Diabetes Care. 2004;27:2628-2635 ¤ P<0.05 v. placebo

¤

AMIGO 3

Series1

-2

-1.5

-1

-0.5

0

0.5

1

Exenatide 5 mcg BIDExenatide 10 mcg BIDPlacebo

Weight change (kg) at 30 weeks

Data from Kendall DM, et al. Diabetes Care. 2005;28:1083-1091 ¤ P<0.05 v. placebo

¤¤

Thiazolidinedione (TZD) Trial

-2.5

-2

-1.5

-1

-0.5

0

0.5

Exenatide 10 mcg BIDPlacebo

Weight change (kg) at 16 weeks

Data from Zinman B, et al. Ann Intern Med. 2007;146:477-485 Ж P<0.001 v. placebo

Ж

Other Trials

Other studies with metformin + sulfonylurea + exenatide or insulin

Study 3- Crossover study with metformin or sulfonylurea had -2.2 kg difference in wt. with exenatide vs. titrated insulin glargine (p<0.001)

Wt. Change (kg)

P value

Study 1Exenatide 10 mcg BID -2.3 P<0.000

1Titrated insulin glargine +1.8

Study 2Exenatide 10 mcg BID -2.5 P<0.001

Titrated premix insulin analog

+2.9

Data from Heine R, et al. Ann Intern Med 2005;143:559-69; Nauck M, et al. Diabetologia 2007;50:259-67; Barnett AH, et al. Clin Ther 2007;29:2333-48.

Other Trials

Wt. Change (kg)

P value

Study 4Exenatide 10 mcg BID -2.7 P<0.001

Insulin glargine +3

Study 5Exenatide -3.6 P<0.000

1Insulin glargine +1

Data from Davies M, et al. DOM 2009;11:1153-62; Bunck M, et al. Diabetes Care 2009;32:762-8

Drug Naïve Trial

-3.5

-3

-2.5

-2

-1.5

-1

-0.5

0

0.5

1

Exenatide 5 mcg BIDExenatide 10 mcg BIDPlacebo

Weight change (kg) at 24 weeks

‡P<0.007 v. placeboData from Moretto TJ, et al. Clin Ther. 2008;30:1448-1460

‡

3 Year Open-Label Extension

Open-Label Extension of Phase 3 AMIGO trialsShowed continued weight loss at 3 yearsTotal weight loss: -5.3 kg

Liraglutide

Analog of human GLP-197% homology

Only approved with oral antidiabetic agentsWeight loss data from 6 LEAD trials

LEAD 1 glimepiride + rosiglitazone or placebo or liraglutide

LEAD 2 metformin + glimepiride or placebo or liraglutide

LEAD 3 glimepiride v. liraglutide

Liraglutide

LEAD trials (cont.)LEAD 4

metformin + rosiglitazone + placebo v. metformin + rosiglitazone + liraglutide

LEAD 5 metformin + glimepiride + placebo v. metformin + glimepiride + insulin glargine or metformin + glimepiride + liraglutide

LEAD 6Metformin or sulfonylurea or both + exenatide or liraglutide

LEAD 1

-1

0

1

2

3

4

5

Liraglutide 0.6 mgLiraglutide 1.2 mgLiraglutide 1.8 mgPlaceboRosiglitazone

¤ P<0.05 v. placebo§ P< 0.0001 v. rosiglitazone

¤ §

¤ §

¤

Weight Change (lb) at 26 weeks

Data from Marre M, et al. Diabet Med. 2009; 26:268-278.

LEAD 2

-7

-6

-5

-4

-3

-2

-1

0

1

2

3

Liraglutide 0.6 mgLiraglutide 1.2 mgLiraglutide 1.8 mgPlaceboGlimepiride

Ж P<0.001 v. placebo § P<0.0001 v. glimepiride

Ж §

§

Ж §Weight Change (lb) at 26 weeks

Data from Nauck MA, et al. Diabetes Care. 2009; 32:84-90.

LEAD 2 Open Label Extension

-8

-7

-6

-5

-4

-3

-2

-1

0

1

2

liraglutide 0.6 mgliraglutide 1.2 mgliraglutide 1.8 mgglimepiride

§ P<0.0001 v. glimepiride

Weight Change (lb) at 2 years

§

§ §

Data from Frid A, et al. Diabetologia. 2009;52(Suppl 1):8. [abstract]

LEAD 3

-6

-5

-4

-3

-2

-1

0

1

2

3

Liraglutide 1.2 mgLiraglutide 1.8 mgGlimepiride

§ §

§ P<0.0001 v. glimepiride

Weight Change (lb) at 1 year

Data from Garber A, et al. Lancet. 2009; 373:473-481.

LEAD 3 Open Label Extension

-7

-6

-5

-4

-3

-2

-1

0

1

2

3

Liraglutide 1.2 mgLiraglutide 1.8 mgGlimepiride

♦ p<0.05 v. glimepiride

Weight Change (lb) at 2 years

♦

♦

Data from Garber AJ, et al. Diabetes. 2009; 58(suppl 1):A42. [Abstract]

LEAD 4

-5

-4

-3

-2

-1

0

1

2

3

Liraglutide 1.2 mgLiraglutide 1.8 mgPlacebo

»

»

» P<0.0001 v. placebo

Weight change (lb) at 26 weeks

Data from Zinman B, et al. Diabetes Care. 2009; 32:1224-1230.

LEAD 5

-5

-4

-3

-2

-1

0

1

2

3

4

5

Liraglutide 1.8 mgPlaceboInsulin glargine

» §

» P<0.0001 v. placebo§ P< 0.0001 v. glargine

Weight change (lb) at 26 weeks

Data from Russell-Jones D, et al. Diabetologia. 2009; 52:2046-2055.

LEAD 6

-7.5

-7

-6.5

-6

-5.5

-5

-4.5

-4

Liraglutide 1.8 mgExenatide 10 mcg

Weight Change (lb) Weeks 26-40

Liraglutide → Liraglutide Exenatide → Liraglutide

-0.9 (p=0.0089) -2 (p<0.0001)

Weight Change (lb) to Week 26

Data from Buse JB, et al. Lancet. 2009; 374:39-47 and Buse J, et al. Diabetes Care. 2010;33:1300-03.

Liraglutide v. Sitagliptin

-8

-7

-6

-5

-4

-3

-2

-1

0

Liraglutide 1.2 mgLiraglutide 1.8 mgSitagliptin 100 mg

§

§

§ P< 0.0001 v. sitagliptin

Weight change (lb) at 26 weeks

Data from Pratley RE, et al. Lancet. 2010; 375:1447-56.

AMYLIN ANALOG

Amylin Analog Modes of Action

Pancreas Amylin

Stomach

Food Intake

─

Gastric Emptying

─Liver

PostprandialGlucagon

─

Glucose Production

Glucose Uptake

PlasmaGlucose

Pramlintide

Pramlintide made to overcome tendency to self-aggregate as natural amylin doesOnly approved in use with insulin4 long term diabetes type 1 trials and 4 long term diabetes type 2 trialsDiabetes Type 1

All studies with insulin

Diabetes Type 1 Study 1

-0.6

-0.4

-0.2

0

0.2

0.4

0.6

0.8

1

1.2

Pramlintide 30 or 60 mcg QIDPlacebo

P- value not reported

Weight change (kg) at 1 year

Data from Whitehouse F, et al. Diabetes Care. 2002;25:724-730

Diabetes Type 1 Study 2

-2

-1.5

-1

-0.5

0

0.5

Pramlintide 60 mcg TIDPramlintide 90 mcg BIDPramlintide 90 mcg TIDPlacebo

Weight change (kg) at 26 weeks

P- value not reported

Data from Fineman M, et al. Diabetes. 1999;48(Suppl 1): Abstract 0489.

Diabetes Type 1 Study 3

-0.6

-0.4

-0.2

0

0.2

0.4

0.6

0.8

1

Pramlintide 60 mcg TIDPramlintide 60 mcg QIDPlacebo

Data from Ratner RE, et al. Diabet Med. 2004;21:1204-1212

¥ P<0.027 v. placeboΦ P<0.04 v. placebo

¥ Φ

Weight change (kg) at 1 year

Diabetes Type 1 Study 4

-1.5

-1

-0.5

0

0.5

1

1.5

Pramlintide 30-60 mcg TIDPlacebo

Weight change (kg) at 29 weeks » P<0.0001 v.

placebo

»

Data from Edelman S, et al. Diabetes Care. 2006;29;2189-95.

Pramlintide

Diabetes Type 2Study 1

Insulin (±metformin or sulfonylurea) + placebo OR pramlintide

Study 2Insulin (±metformin or sulfonylurea) + placebo OR pramlintide

Study 3Insulin + placebo OR pramlintide

Diabetes Type 2 Study 1

-2

-1.5

-1

-0.5

0

0.5

1

Pramlintide 90 mcg BIDPramlintide 120 mcg BIDPlacebo TID

Weight change (kg) at 1 year ¤ P<0.05 v. placebo

¤

Data from Hollander PA, et al. Diabetes Care. 2003;26:784-90.

Diabetes Type 2 Study 2

-2

-1.5

-1

-0.5

0

0.5

1

1.5

Pramlintide 30 mcg TIDPramlintide 75 mcg TIDPramlintide 150 mcg TIDPlacebo

¤ P<0.05 v. placebo

¤

¤

Weight change (kg) at 1 year

¤

Data from Ratner RE, et al. Diabetes Technol Ther. 2002;4:51-61.

Diabetes Type 2 Study 3

-2

-1.5

-1

-0.5

0

0.5

1

Pramlintide 90 mcg BIDPramlintide 90 mcg TIDPramlintide 120 mcg BIDPlacebo

Weight change (kg) at 26 weeks

P- value not reported

Data from Gottlieb A, et al. Diabetologia. 1999;42(Suppl 1):A232.

Summary

Many therapies available to treat diabetes

Only few that promote weight lossNew incretin mimetics and amylin analog promote weight loss significantly more than other therapies