Faculty Disclosure Mikayla Spangler, PharmD, BCPS Dr. Spangler has listed no financial interest/arrangement that would be considered a conflict of interest.

Mikayla Spangler, Pharm.D., BCPS

Identify medications used for diabetes that may aid in weight loss Special focus on incretin mimetics and amylin analog

ClassAffect on Weight Insulin  Sulfonylureas  Thiazolidinediones  Dipeptidyl peptidase-4 inhibitors  Biguanides  Incretin mimetics  Amylin analog 

Glucagon-Like Peptide-1 (GLP-1) receptor agonists 2005: exenatide (Byetta©) 2010: liraglutide (Victoza©) Amylin analog 2004: pramlintide (Symlin©)

Data from Flint A, et al. J Clin Invest. 1998;101: ; Larsson H, et al. Acta Physiol Scand. 1997;160: ; Nauck MA, et al. Diabetologia. 1996;39: ; Drucker DJ. Diabetes. 1998;47: Stomach: regulates gastric emptying Brain: promotes satiety and reduces food intake Liver: reduces hepatic glucose output  -cells: enhances glucose-dependent insulin secretion  -cells: reduces postprandial glucagon secretion GLP-1: secreted by intestinal L-cells in response to food intake

Developed from the saliva of the Gila monster 50% homology with human GLP-1 Only approved with oral antidiabetic agents Weight loss data from 3 AMIGO trials AMIGO 1 Metformin + placebo v. metformin + exenatide AMIGO 2 Sulfonylurea + placebo v. sulfonylurea + exenatide AMIGO 3 Metformin + sulfonylurea + placebo v. metformin + sulfonylurea + exenatide

Weight change (kg) at 30 weeks Data from DeFronzo RA, et al. Diabetes Care. 2005;28: ¤ P<0.05 v. placebo ¤ ¤

Weight change (kg) at 30 weeks Data from Buse JB, et al. Diabetes Care. 2004;27: ¤ P<0.05 v. placebo ¤

Weight change (kg) at 30 weeks Data from Kendall DM, et al. Diabetes Care. 2005;28: ¤ P<0.05 v. placebo ¤¤

Weight change (kg) at 16 weeks Data from Zinman B, et al. Ann Intern Med. 2007;146: Ж P<0.001 v. placebo Ж

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 1 Exenatide 10 mcg BID-2.3P< Titrated insulin glargine+1.8 Study 2 Exenatide 10 mcg BID-2.5P<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:

Wt. Change (kg)P value Study 4 Exenatide 10 mcg BID-2.7P<0.001 Insulin glargine+3 Study 5 Exenatide-3.6P< Insulin glargine+1 Data from Davies M, et al. DOM 2009;11: ; Bunck M, et al. Diabetes Care 2009;32:762-8

Weight change (kg) at 24 weeks ‡P<0.007 v. placebo Data from Moretto TJ, et al. Clin Ther. 2008;30: ‡

Open-Label Extension of Phase 3 AMIGO trials Showed continued weight loss at 3 years Total weight loss: -5.3 kg

Analog of human GLP-1 97% homology Only approved with oral antidiabetic agents Weight 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

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 6 Metformin or sulfonylurea or both + exenatide or liraglutide

¤ P<0.05 v. placebo § P< v. rosiglitazone ¤ § ¤ Weight Change (lb) at 26 weeks Data from Marre M, et al. Diabet Med. 2009; 26:

Ж P<0.001 v. placebo § P< v. glimepiride Ж §Ж § § Ж §Ж § Weight Change (lb) at 26 weeks Data from Nauck MA, et al. Diabetes Care. 2009; 32:84-90.

§ P< v. glimepiride Weight Change (lb) at 2 years § § § Data from Frid A, et al. Diabetologia. 2009;52(Suppl 1):8. [abstract]

§ § § P< v. glimepiride Weight Change (lb) at 1 year Data from Garber A, et al. Lancet. 2009; 373:

♦ p<0.05 v. glimepiride Weight Change (lb) at 2 years ♦ ♦ Data from Garber AJ, et al. Diabetes. 2009; 58(suppl 1):A42. [Abstract]

» » » P< v. placebo Weight change (lb) at 26 weeks Data from Zinman B, et al. Diabetes Care. 2009; 32:

» § » P< v. placebo § P< v. glargine Weight change (lb) at 26 weeks Data from Russell-Jones D, et al. Diabetologia. 2009; 52:

Weight Change (lb) Weeks Liraglutide → LiraglutideExenatide → 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:

§ § § P< v. sitagliptin Weight change (lb) at 26 weeks Data from Pratley RE, et al. Lancet. 2010; 375:

Pancreas Amylin Stomach Liver

Pramlintide made to overcome tendency to self-aggregate as natural amylin does Only approved in use with insulin 4 long term diabetes type 1 trials and 4 long term diabetes type 2 trials Diabetes Type 1 All studies with insulin

P- value not reported Weight change (kg) at 1 year Data from Whitehouse F, et al. Diabetes Care. 2002;25:

Weight change (kg) at 26 weeks P- value not reported Data from Fineman M, et al. Diabetes. 1999;48(Suppl 1): Abstract 0489.

Data from Ratner RE, et al. Diabet Med. 2004;21: ¥ P<0.027 v. placebo Φ P<0.04 v. placebo ¥Φ Weight change (kg) at 1 year

Weight change (kg) at 29 weeks » P< v. placebo » Data from Edelman S, et al. Diabetes Care. 2006;29;

Diabetes Type 2 Study 1 Insulin (±metformin or sulfonylurea) + placebo OR pramlintide Study 2 Insulin (±metformin or sulfonylurea) + placebo OR pramlintide Study 3 Insulin + placebo OR pramlintide

Weight change (kg) at 1 year ¤ P<0.05 v. placebo ¤ Data from Hollander PA, et al. Diabetes Care. 2003;26:

¤ P<0.05 v. placebo ¤ ¤ Weight change (kg) at 1 year ¤ Data from Ratner RE, et al. Diabetes Technol Ther. 2002;4:51-61.

Weight change (kg) at 26 weeks P- value not reported Data from Gottlieb A, et al. Diabetologia. 1999;42(Suppl 1):A232.

Many therapies available to treat diabetes Only few that promote weight loss New incretin mimetics and amylin analog promote weight loss significantly more than other therapies