Core Defects of Type 2 Diabetes Targeting Mechanisms

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

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) 2

Insulin Resistance: An Underlying Cause of Type 2 Diabetes Obesity and inactivity Genetic abnormalities Type 2 diabetes Aging Medications INSULIN RESISTANCE Rare disorders PCOS Hypertension Atherosclerosis Dyslipidemia Reaven GM. Physiol Rev. 1995; 75: 473 -486 Clauser, et al. Horm Res. 1992; 38: 5 -12. 3

Development and Progression of Type 2 Diabetes (Conceptual Representation) NGT ® Insulin ® IGT/ IFG ® Type 2 Diabetes Resistance Postprandial glucose Glucose Regulation Fasting glucose – 10 Metabolic Activity – 5 0 5 Insulin level 10 15 20 25 30 Insulin resistance— hepatic and peripheral Beta-cell function – 10 – 5 0 5 10 15 20 Years From Diabetes Diagnosis 25 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 65 th ADA in Washington, DC, 2006. 30 4

UKPDS: -Cell Loss Over Time -Cell Function (%)* 100 75 Patients treated with insulin, metformin, sulfonylureas‡ 50 25 IGT† 0 -12 -10 Type 2 Postprandial Diabetes Hyperglycemia Phase I -6 -2 0 Type 2 Diabetes Phase II 2 6 Type 2 Diabetes Phase III 10 14 Years From Diagnosis *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: 139 -153. 5

Intensive Treatments and Increase in Hb. A 1 c Over Time United Kingdom Prospective Diabetes Study (UKPDS) Median Hb. A 1 c (%) 9 8 ADA action 7 ADA goal 6 0 Conventional Insulin Chlorpropamide Glibenclamide (glyburide) Metformin Upper limit of normal range (6. 2%) 0 3 6 9 10 Time From Randomization (years) UK Prospective Diabetes Study (UKPDS 34) Group. Lancet. 1998; 352: 854 -65. 6

Guideline Recommendations Are Becoming More Aggressive • 2007 ADA standards 1 – “The A 1 C goal for patients in general is an A 1 C goal of <7%. ” – “The A 1 C goal for the individual patient is an A 1 C as close to normal (<6%) as possible without significant hypoglycemia. ” [boldface added] • 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 A 1 C goal is not achieved. ” [boldface added] ADA=American Diabetes Association; EASD=European Association for the Study of Diabetes. 1. American Diabetes Association. Diabetes Care. 2007; 30(suppl 1): S 4–S 41. 2. Nathan DM et al. Diabetes Care. 2006; 29: 1963– 1972. 7

Most Patients With Type 2 Diabetes May Fail to Attain A 1 C Goal With Conventional Treatment Paradigm Published Conceptual Approach Mean A 1 C of patients Diet and OAD exercise monotherapy OAD up-titration combination OAD + basal insulin OAD + multiple daily insulin injections 10 A 1 C, 9 % 8 7 6 Duration of Diabetes OAD=oral antihyperglycemic drug. Adapted from Del Prato S et al. Int J Clin Pract. 2005; 59: 1345– 1355. 8

Earlier and More Aggressive Intervention May Improve Treating to Target Compared With Conventional Therapy Published Conceptual Approach Diet and OAD exercise monotherapy OAD up-titration combination OAD + basal insulin OAD + multiple daily insulin injections 10 A 1 C, 9 % Mean A 1 C of patients 8 7 6 Duration of Diabetes Adapted from Del Prato S et al. Int J Clin Pract. 2005; 59: 1345– 1355. 9

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): S 6–S 17. 2. Van Gaal LF et al. Diabetologia. 2003; 46(suppl 1): M 44–M 50. 3. Mc. Donald HP et al. JAMA. 2002; 288: 2868– 2879. 4. Piette JD et al. Diabetes Care. 2004; 27: 384– 391. 5. Donnan PT et al. Diabet Med. 2002; 19: 279– 284. 10

Major Pathophysiologic Defects in Type 2 Diabetes Islet-cell dysfunction Glucagon (alpha cell) Pancreas Hepatic glucose output Insulin (beta cell) Insulin resistance Glucose uptake in muscle and fat Hyperglycemia Liver Muscle Liver Adapted with permission from Kahn CR, Saltiel AR. Joslin’s Diabetes Mellitus. 14 th 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. Adipose tissue 11

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