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

2. Mikayla Spangler, Pharm.D., BCPS

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

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

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

7. 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 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

8. 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

9. Weight change (kg) at 30 weeks Data from DeFronzo RA, et al. Diabetes Care. 2005;28:1092-1100 ¤ P<0.05 v. placebo ¤ ¤

10. Weight change (kg) at 30 weeks Data from Buse JB, et al. Diabetes Care. 2004;27:2628-2635 ¤ P<0.05 v. placebo ¤

11. Weight change (kg) at 30 weeks Data from Kendall DM, et al. Diabetes Care. 2005;28:1083-1091 ¤ P<0.05 v. placebo ¤¤

12. 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

13. 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<0.0001 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;29:2333-48.

14. Wt. Change (kg)P value Study 4 Exenatide 10 mcg BID-2.7P<0.001 Insulin glargine+3 Study 5 Exenatide-3.6P<0.0001 Insulin glargine+1 Data from Davies M, et al. DOM 2009;11:1153-62; Bunck M, et al. Diabetes Care 2009;32:762-8

15. Weight change (kg) at 24 weeks ‡P<0.007 v. placebo Data from Moretto TJ, et al. Clin Ther. 2008;30:1448-1460 ‡

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

17. 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

18. 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

19. ¤ 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.

20. Ж P<0.001 v. placebo § P<0.0001 v. glimepiride Ж §Ж § § Ж §Ж § Weight Change (lb) at 26 weeks Data from Nauck MA, et al. Diabetes Care. 2009; 32:84-90.

21. § P<0.0001 v. glimepiride Weight Change (lb) at 2 years § § § Data from Frid A, et al. Diabetologia. 2009;52(Suppl 1):8. [abstract]

22. § § § P<0.0001 v. glimepiride Weight Change (lb) at 1 year Data from Garber A, et al. Lancet. 2009; 373:473-481.

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

24. » » » P<0.0001 v. placebo Weight change (lb) at 26 weeks Data from Zinman B, et al. Diabetes Care. 2009; 32:1224-1230.

25. » § » 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.

26. Weight Change (lb) Weeks 26-40 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;33:1300-03.

27. § § § P< 0.0001 v. sitagliptin Weight change (lb) at 26 weeks Data from Pratley RE, et al. Lancet. 2010; 375:1447-56.

29. Pancreas Amylin Stomach Liver

30. 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

31. P- value not reported Weight change (kg) at 1 year Data from Whitehouse F, et al. Diabetes Care. 2002;25:724-730

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

33. Data from Ratner RE, et al. Diabet Med. 2004;21:1204-1212 ¥ P<0.027 v. placebo Φ P<0.04 v. placebo ¥Φ Weight change (kg) at 1 year

34. Weight change (kg) at 29 weeks » P<0.0001 v. placebo » Data from Edelman S, et al. Diabetes Care. 2006;29;2189-95.

35. 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

36. Weight change (kg) at 1 year ¤ P<0.05 v. placebo ¤ Data from Hollander PA, et al. Diabetes Care. 2003;26:784-90.

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

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

39. 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