1 Core Defects of Type 2 Diabetes Targeting Mechanisms for a Comprehensive Approach Part 1 1

2 Objectives Discuss challenges in treating type 2 diabetes and rationale for earlier and more aggressive treatment approaches Review the physiologic regulation of glucose homeostasis, the role of incretins, and core defects of type 2 diabetes Describe the complementary MOAs of agents used in the treatment of type 2 diabetes to address the 3 core defects Provide a clinical overview of JANUVIA™ (sitagliptin) Provide an overview of the prescribing information for JANUMET™ (sitagliptin/metformin HCl)

3 Reaven GM. Physiol Rev. 1995;75: Clauser, et al. Horm Res. 1992;38:5-12. Medications Aging INSULIN RESISTANCE Atherosclerosis Genetic abnormalities Obesity and inactivity Rare disorders PCOS Dyslipidemia Hypertension Type 2 diabetes Reaven GM. Physiol Rev. 1995;75: Clauser, et al. Horm Res. 1992;38:5-12. Insulin Resistance: An Underlying Cause of Type 2 Diabetes

4 Development and Progression of Type 2 Diabetes (Conceptual Representation) Metabolic Activity Glucose Regulation Years From Diabetes Diagnosis –10– –10– NGT=normal glucose tolerance; IGT=impaired glucose tolerance; IFG=impaired fasting glucose. Kendall DM, Bergenstal RM. ©2005 International Diabetes Center, Minneapolis, MN. All rights reserved. Adapted from Ferrannini E. Presentation at 65th ADA in Washington, DC, NGT  Insulin  IGT/ IFG  Type 2 Diabetes Resistance Postprandial glucose Fasting glucose Insulin resistance— hepatic and peripheral Insulin level Beta-cell function

5  -Cell Function (%) * Postprandial Hyperglycemia IGT † Type 2 Diabetes Phase I Type 2 Diabetes Phase II Type 2 Diabetes Phase III Years From Diagnosis Patients treated with insulin, metformin, sulfonylureas ‡ * Dashed line shows extrapolation forward and backward from years 0 to 6 from diagnosis based on Homeostasis Model Assessment (HOMA) data from UKPDS. † IGT=impaired glucose testing ‡ The data points for the time of diagnosis (0) and the subsequent 6 years are taken from a subset of the UPKDS population and were determined by the HOMA model. Lebovitz HE. Diabetes Rev. 1999;7: UKPDS:  -Cell Loss Over Time

6 Median HbA 1c (%) Conventional Insulin Chlorpropamide Glibenclamide (glyburide) Metformin Time From Randomization (years) Upper limit of normal range (6.2%) ADA goal ADA action United Kingdom Prospective Diabetes Study (UKPDS) UK Prospective Diabetes Study (UKPDS 34) Group. Lancet. 1998;352: Intensive Treatments and Increase in HbA 1c Over Time

7 Guideline Recommendations Are Becoming More Aggressive 2007 ADA standards 1 –“The A1C goal for patients in general is an A1C goal of <7%.” –“The A1C goal for the individual patient is an A1C as close to normal (<6%) as possible without significant hypoglycemia.” [boldface added] ADA=American Diabetes Association; EASD=European Association for the Study of Diabetes. 1. American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S Nathan DM et al. Diabetes Care. 2006;29:1963–1972. ADA/EASD consensus statement 2 –“If lifestyle intervention and maximal tolerated dose of metformin fail to achieve or sustain glycemic goals, another medication should be added within 2–3 months of the initiation of therapy or at any time when A1C goal is not achieved.” [boldface added]

Most Patients With Type 2 Diabetes May Fail to Attain A1C Goal With Conventional Treatment Paradigm OAD monotherapy Diet and exercise OAD combination OAD up-titration OAD + multiple daily insulin injections OAD + basal insulin OAD=oral antihyperglycemic drug. Adapted from Del Prato S et al. Int J Clin Pract. 2005;59:1345–1355. A1C, % Mean A1C of patients Duration of Diabetes Published Conceptual Approach

Mean A1C of patients Adapted from Del Prato S et al. Int J Clin Pract. 2005;59:1345–1355. A1C, % Duration of Diabetes OAD monotherapy Diet and exercise OAD combination OAD up-titration OAD + multiple daily insulin injections OAD + basal insulin Published Conceptual Approach Earlier and More Aggressive Intervention May Improve Treating to Target Compared With Conventional Therapy

10 Challenges in Achieving Glycemic Goals in Diabetes Less aggressive treat-to-target approach by some clinicians 1 Suboptimal use of available therapies 1 Inability of any single agent’s MOA to address all core defects of type 2 diabetes 2 Potential for increased side effects with use of multiple agents 3 Suboptimal adherence to lifestyle measures 1 Underuse of medications as a result of –Cost 4 –Complexity of therapy 5 1. Blonde L. Clin Cornerstone. 2005;7(suppl 3):S6–S Van Gaal LF et al. Diabetologia. 2003;46(suppl 1):M44–M McDonald HP et al. JAMA. 2002;288:2868– Piette JD et al. Diabetes Care. 2004;27:384– Donnan PT et al. Diabet Med. 2002;19:279–284.

11 Hepatic glucose output Insulin resistance Glucose uptake in muscle and fat Glucagon (alpha cell) Insulin (beta cell) Hyperglycemia Islet-cell dysfunction Major Pathophysiologic Defects in Type 2 Diabetes Adapted with permission from Kahn CR, Saltiel AR. Joslin’s Diabetes Mellitus. 14th ed. Lippincott Williams & Wilkins; 2005:145–168. Del Prato S, Marchetti P. Horm Metab Res. 2004;36:775–781. Porte D Jr, Kahn SE. Clin Invest Med. 1995;18:247–254. Pancreas Liver Adipose tissue Liver Muscle

12 Glucose absorption Hepatic glucose overproduction Beta-cell dysfunction Insulin resistance Major Targeted Sites of Oral Drug Classes DPP-4=dipeptidyl peptidase-4; TZDs=thiazolidinediones. DeFronzo RA. Ann Intern Med. 1999;131:281–303. Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483. Pancreas ↓Glucose level Muscle and fat Liver Biguanides TZDsBiguanides Sulfonylureas Meglitinides TZDs Alpha- glucosidase inhibitors Gut The glucose-dependent mechanism of DPP-4 inhibitors targets 2 key defects: insulin release and unsuppressed hepatic glucose production. DPP-4 inhibitors GLP-1 DPP-4 inhibitors Biguanides