1. Leveraging Weight Loss in the Treatment of Type 2 Diabetes Part 4 of 4

2. Amylin Insulin Amylin the Hormone 37-amino acid peptide Colocated and cosecreted with insulin from pancreatic  cells Deficient in diabetes Unger RH, et al. Williams Textbook of Endocrinology. 8th ed. 1992;1273-1275. Photographs reprinted with permission of Elsevier.

3. Pramlintide Synthetic analog of the  -cell hormone, amylin Pramlintide limits postprandial glucose excursions through at least 3 mechanisms of action – Slows gastric emptying – Decreases postprandial hypersecretion of glucagon – Increases satiety, leading to decreased caloric intake and potential weight loss Chapman I, et al. Diabetologia. 2005;48:838-848. Fineman M, et al. Horm Metab Res. 2002;34:504-508. Kong M-F, et al. Diabetologia. 1998;41:577-583. Kruger DF, et al. Drugs. 2004;64:1419-1432.

4. Effect of Pramlintide Adjunctive Therapy on Weight in Individuals With Type 2 Diabetes 0395226 -2.0 13 -1.5 -1.5 1.5 1.0 0.5 0.0 Placebo Weeks Change in Weight From Baseline (kg) * P<.05 vs placebo. Hollander PA, et al. Diabetes Care. 2003;26:784-790. Pramlintide [prescribing information]. http://www.fda.gov/cdev/foi/label/2005/021332lbl.pdf. Symlin® [package insert]. San Diego, CA: Amlyn Pharmaceuticals; 2007.

5. * * -0.3% ± 0.1 ∆ A1C (%) Time (weeks) 0481216 -2.0 -1.5 -1.0 -0.5 0.0 0.5 1.0 † † † † † -2.3 ± 0. 4 kg ∆ Body Weight (kg) Placebo + Insulin Glargine Pramlintide + Insulin Glargine Baseline A1C 8.5 ± 0.1% Baseline Weight. 103 ± 1.8 kg 103 ± 1.7 kg Mean±SE; ITT LOCF: Placebo (n=106); Pramlintide (n=105); *P<.05 vs placebo; † P<.001 vs placebo. Riddle M, et al. Diabetes Care. 2007;30:2794-2799. 0481216 -0.8 -0.6 -0.4 -0.2 -0.0 Pramlintide Lowers A1C and Weight in Individuals With T2DM on Basal Insulin

6. Multihormonal Control of Body Weight: Role of Fat-, Gut-, and Islet-Derived Signals Leptin (r-met human) (AC164594) Pramlintide (AC137) PYY3-36 (synthetic) (AC162352) Clinical-Stage Compounds Adapted from Badman MK, et al. Science. 2005;307:1909-1914.

7. Weeks Leptin -20 -15 -10 -5 0 % ∆ Body Weight (vehicle corrected) -25 0123 Fen/phen 1 Roux-en-Y 2 Vehicle Amylin Amylin+Leptin ½ Dose: Amylin+Leptin+PYY 3-36 DIO = diet-induced obese; Continuous infusion of peptides at full doses (osmotic minipump). 1. Weintraub M, et al. Clin Pharmacol Ther. 1992;51(5):602-601. 2. Stylopoulos N, et al. Surg Endosc. 2005;19:942-946. 3. Roth JD, et al. Proc Natl Acad Sci U S A. 2008;105:7257-7262. 4. Roth J, et al. Obesity. 2006;14(suppl 9):A57-A58. Abstract 177-P. Means of Achieving Greater Weight Loss: Integrated Therapy With 3 Neurohormones in DIO Rats

8. Bariatric Surgery: Gastrorestrictive Procedures Vertical-Banded Gastroplasty Gastric Bypass (Roux-en-Y) Gastric Banding Out of FavorGold StandardCommonly Used American Society for Bariatric Surgery. http://www.asbs.org. Accessed May 30, 2003. Mun EC, et al. Gastroenterology. 2001;120:669-681. Philadelphia, PA. Elsevier; 2003:275-298. Pratt JSA, et al. In: Office Management of Obesity.

9. Diabetes Remits After Adjustable Gastric Banding Unblinded, randomized, controlled trial of 60 individuals with type 2 diabetes diagnosed within preceding 2 years Diabetes remission defined by A1C <6.2%, taking no diabetes medications SurgeryControl P V alue Weight (kg) -21.1  10.5-1.5  5.4 <.001 A1C (%) -1.81  1.240.38  1.26 <.001 TG (mg/dL) -71.7  92.9-2.1  120.6.02 HDL-C (mg/dL) 12.6  9.82.6  6.1 <.001 % Achieving Remission of Diabetes Dixon JB, et al. JAMA. 2008;299:316-323. 73 13 0 20 40 60 80 100 SurgeryConventional

10. Bariatric Surgery: Diabetes Compared to 2 year data, about half of those in remission after surgery will need treatment for diabetes at 10-year follow-up 1 In a 10-year follow-up study of all individuals 2 – gastric bypass associated with 40% lower mortality – 56% reduction in death from coronary artery disease – 92% lower death rate from “diabetes” 1. Sjostrom L, et al. N Engl J Med. 2004;351:2683-2693. 2. Adams TD, et al. N Engl J Med. 2007;357:753-761.

11. National Survey Cites Need for New Medical Options for Controlling Type 2 Diabetes Survey of 636 patients with diabetes and 409 primary care physicians in United States Both groups said they lack the tools to successfully manage diabetes over time – 88% of patients and 92% of physicians expressed need for better treatment options 60% of patients are at least somewhat dissatisfied with the weight gain due to their current diabetes medication Both physicians and patients desire new antihyperglycemic therapies that minimize side effects of hypoglycemia and weight gain Physicians may overestimate patients’ fear of needles – 87% of physicians report patients fear needles – 36% of patients expressed such fear http://www.devicespace.com/news_story.aspx?NewsEntitld=2264. Accessed April 9, 2008.

12. Body Weight (lb) 200 220 240 260 280 300 320 Adapted from Kendall DM, et al. © 2004 International Diabetes Center, Minneapolis, MN. All rights reserved. Years Diabetes Diagnosis Onset Prediabetes (IFG, IGT) Metabolic Syndrome Fasting Glucose Postmeal Glucose Glucose (mg/dL) 50 100 150 200 250 300 350 Obesity, Inactivity, Genetics Relative Function -10-5051015202530 Insulin Resistance Insulin Response 0 50 100 150 200 250 -15 Progressive  -Cell Defect (glucose specific) Amylin Response Oral Agents/Incretin Enhancers Basal Insulin Basal/Bolus Insulin Amylin Replacement Natural History of Type 2 Diabetes and Obesity

13. Weight gain from diabetes medications – Worsens cardiovascular risk factors Especially blood pressure – Is unacceptable for patients Will not choose therapy known to cause weight gain May discourage patients from taking medications Is avoidable with several antihyperglycemic therapies – Metformin – Sitagliptin – Exenatide – Pramlintide Data from bariatric surgery is promising Summary