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

2. Intentional Weight Loss Reduces Mortality *Mortality rates are directly age-standardized to the age distribution of the cohort and expressed per 1000 person-years. † Adjusted for age, sex, initial BMI. Williamson DF, et al. Diabetes Care. 2000;23:1499-1504. Intentional loss resulted in a Relative Risk Reduction † of: 22% ↓ all-cause death 24% ↓ death from CVD + diabetes Age-Adjusted Death Rate* 45.6 40.3 31.8 26.1 31.4 33.6 0 10 20 30 40 50 No ChangeUnintended Gain Intentional Loss All CausesCVD + Diabetes

3. Obese Individuals With Diabetes Have Difficulty Losing Weight Compared With Obese Nondiabetic Individuals Wing RR, et al. Diabetes Care. 1987;10:563-566. Diabetic Individuals Nondiabetic Individuals Week Change of Ideal Weight (%) 0 Baseline 5101520 P<.01 -25 -20 -15 -10 -5 With Behavioral Weight Control Program

4. Body Weight Over 2 Years of Lifestyle Intervention Wing RR, et al. Diabetes Care. 1998;21:350-359. 84 88 92 96 100 061224 Months Weight (kg) Control Diet + Exercise 18

5. Look AHEAD: Study Objective and Design Objective: Examine the long-term effects of an Intensive Lifestyle Intervention (ILI) on the incidence of major cardiovascular disease events Intensive Lifestyle Intervention (ILI) Toolbox approach – Diet modification and caloric restriction – Increased physical activity – Weekly followed by bimonthly group meetings – Monthly one-on-one counseling sessions 2-Week Prerandomization Self-monitoring of diet and physical activity 1 diabetes education session Diabetes Support and Education (DSE) Access to 3 additional group education sessions No weigh-in at meetings and no behavioral strategy counseling N=5145 Age 45-74 Years with type 2 diabetes and BMI >25 kg/m 2 The Look AHEAD Research Group. Diabetes Care. 2007;30:1374-1383.

6. Look AHEAD: Changes in Weight and A1C -10 -8 -6 -4 -2 0 ILI DSE -0.7 *P<.001. † P=.002. Data % Mean ± SD. The Look AHEAD Research Group. Diabetes Care. 2007;30:1374-1383. A1C -8.6* Change (%) Weight -0.64* -0.14 Insulin Users -10 -8 -6 -4 -2 0 -7.6 Percent Weight Change (%) Non-Users -8.7 †

7. Look AHEAD: Changes in Risk Factors -25 -20 -15 -10 -5 0 ILI DSE *P<.001. † P=.49. Data % Mean ± SD. The Look AHEAD Research Group. Diabetes Care. 2007;30:1374-1383. 5 Change (%) LDL -5.2 -6.8* -5.7 † -2.8 3.4* 1.4 -30.3* -14.6 Systolic BP HDL Triglycerides -30

8. Look AHEAD: Change in Percent Reaching Goal 0 5 10 15 20 25 ILI DSE 5.4 30 A1C (<7%) 26.4* Change (%) BP (<130/80 mm Hg) LDL (<100 mg/dL) All 3 Goals 15.1* 12.8* 6.7 † 6.5 8.0 7.0 *P<.001; † P=.34; Data % Mean ± SD. The Look AHEAD Research Group. Diabetes Care. 2007;30:1374-1383.

9. Moderate weight loss improves glycemic control and reduces cardiovascular disease risk in individuals with type 2 diabetes 1 12-Year American Cancer Society Mortality Study: Prospective 12-year ACS mortality and weight loss substudy of 4970 diabetic individuals 2 – Intentional weight loss ► 25% reduced mortality risk – 10% to 15% or 20 to 29 lb loss ► 33% reduced mortality risk Meta-analysis: Multiple weight loss and mortality studies in ~2800 diabetic individuals 3 – Intentional weight loss ► 25% reduced mortality risk 1. Klein S. Am J Clin Nutr. 2004;80:257-263. 2. Williamson DF, et al. Diabetes Care. 2000;23:1499-1504. 3. Poobalan AS, et al. Obes Rev. 2007;8(6):503-513. Weight Loss Is Important in the Management of Type 2 Diabetes

10. Sulfonylureas 1-4 Weight Change (kg) Side Effects of Oral Agents: Weight Gain - Thiazolidinedimes 4-6 Metformin + Thiazolidinedimes 4-6 Metformin + Sulfonylurea 1-3 Meglitinides 4,7,8 Metformin 1-3 Oral Antidiabetic Agent* Sitagliptin 10 -5-4-3-2-1012345 No increase from baseline -0.2 - 4.3 0.9 - 4.6 0.3 - 3.0 -0.3 - 1.9 -3.8 - 0.5 0.8 - 2.1 *Data are not from head-to-head studies. 1. Bristol-Myers Squibb. Metformin HCI Full Prescribing Information. 2006. 2. Bristol-Myers Squibb. Glyburide/Metformin HCI Full Prescribing Information. 2006. 3. Bristol-Myers Squibb. Glipizide/Metformin HCI Full Prescribing Information. 2007. 4. Malone M. Ann Pharmacother. 2005;39:2046-2055. 5. Takeda. Pioglitazone HCI Full Prescribing Information. 2007. 6. GlaxoSmithKline. Rosiglitazone maleate Full Prescribing Information. 2008. 7. Novartis. Nateglinide Full Prescribing Information. 2006. 8. Novo Nordisk. Repaglinide Full Prescribing Information. 2006. 9. GlaxoSmithKline. Rosiglitazone maleate/Metformin HCI Full Prescribing Information. 2007. 10. Merck & Co., Inc. Sitagliptin Full Prescribing Information. 2007.

11. All Insulin Regimens Improve Glycemic Control, but Often With Weight Gain A1C (%) 1. Riddle MC, et al. Diabetes Care. 2003;26:3080-3086. 2. Yki-Jarvinen H, et al. Ann Intern Med. 1999;130:389-396. 3. Holman RR. N Engl J Med. 2007;357:1716-1730. 4. Henry RR, et al. Diabetes Care. 1993;16:21-31. BASAL Insulin ∆ Weight (lb) 0 20 12 16 8 4 BID Insulin Intensive Insulin Prandial Insulin Biphasic Insulin Riddle et al 1 Yki-Jarvinen et al 2 Yki-Jarvinen et al 2 Henry et al 4 Riddle et al 1 Holman et al 3 Holman et al 3 +6.6 lb +8.6 lb +10.1 lb +19.2 lb +6.2 lb +4.2 lb +10.4 lb +12.6 lb Holman et al 3 -2.6% -2.1% -1.3% -1.4%-0.8% -2.1% -2.2% Landmark Insulin Studies in Which Exenatide Was Not a Comparator ADA GOAL 6 7 8 9 10 11 5

12. Combination Therapy With Insulin: Weight Gain GLIT = glitazone; MET = metformin; SU = sulfonylurea. Yki-Jarvinen H. Diabetes Care. 2001;24:758-767. MET SU SU+MET GLIT SU Weight Gain (kg/1% decrease in A1C) 4 5 3 1 2 0 Previously insulin-treated Insulin-naive

13. Potential Causes of Weight Gain With Treatment of Type 2 Diabetes Improved glycemic control Fear of, or treatment for, hypoglycemia Increased appetite Catch-up from weight-loss pretreatment Weight gain with insulin treatment – Correlates with insulin dose – Mean weight gain 3.2 - 4.4 kg per 1% reduction in A1C – About ⅔ adipose tissue and ⅓ lean body mass Westphal SA, et al. Insulin. 2007;2:31-36.