1. 1 Core Defects of Type 2 Diabetes Targeting Mechanisms for a Comprehensive Approach 1 Part 3 of 4

2. 2 JANUVIA™ (sitagliptin): Adverse Reactions Overall: Adverse reactions and discontinuation rates were similar to placebo (both as monotherapy and as combination therapy) Incidence of hypoglycemia with JANUVIA was similar to placebo (1.2% vs 0.9%) The adverse reactions, reported regardless of investigator assessment of causality in ≥5% of patients treated with JANUVIA 100 mg daily as monotherapy or in combination with pioglitazone and more commonly than in patients treated with placebo, were upper respiratory tract infection, nasopharyngitis, and headache. Incidence of selected GI adverse reactions in patients treated with JANUVIA vs placebo was as follows: –Abdominal pain (2.3%, 2.1%) –Nausea (1.4%, 0.6%) –Diarrhea (3.0%, 2.3%)

3. 3 Usual Dosing for JANUVIA* Patients With Renal Insufficiency*,† A dosage adjustment is recommended in patients with moderate or severe renal insufficiency and in patients with end-stage renal disease requiring hemodialysis or peritoneal dialysis. 50 mg once daily25 mg once daily Moderate CrCl  30 to <50 mL/min (~Serum Cr levels [mg/dL] Men: >1.7–≤3.0; Women: >1.5–≤2.5) Severe and ESRD ‡ CrCl <30 mL/min (~Serum Cr levels [mg/dL] Men: >3.0; Women: >2.5) The recommended dose of JANUVIA is 100 mg once daily as monotherapy or as combination therapy with metformin or a PPAR  agonist. Assessment of renal function is recommended prior to JANUVIA initiation and periodically thereafter. JANUVIA™ (sitagliptin): Once-Daily Dosing— Proven 24-Hour Glycemic Control *JANUVIA can be taken with or without food. † Patients with mild renal insufficiency—100 mg once daily. ‡ ESRD=end-stage renal disease requiring hemodialysis or peritoneal dialysis.

4. 4 Contraindications –None Warnings and Precautions –Use in patients with renal insufficiency: A dosage adjustment is recommended in patients with moderate or severe renal insufficiency and in patients with ESRD requiring hemodialysis or peritoneal dialysis. –Use with medications known to cause hypoglycemia: As monotherapy and as part of combination therapy with metformin or pioglitazone, rates of hypoglycemia were similar to rates in patients taking placebo. The use of JANUVIA in combination with medications known to cause hypoglycemia, such as sulfonylureas or insulin, has not been adequately studied. JANUVIA™ (sitagliptin): Contraindications/Warnings and Precautions

5. 5 Summary of JANUVIA™ (sitagliptin) JANUVIA is an oral, selective inhibitor of the DPP-4 enzyme Indication: –Indicated as monotherapy and in combination with metformin or TZDs –Usual recommended dose is 100 mg once daily In clinical studies: –JANUVIA significantly improved A1C, FPG, and PPG –Mean A1C response with JANUVIA appears to be related to baseline A1C level Overall: –Incidence of adverse reactions was similar to that with placebo  Overall incidence of hypoglycemia similar to that with placebo  A neutral effect on weight relative to that with placebo Before prescribing JANUVIA, please read the full Prescribing Information, available at this presentation.

6. 6 Complementary Mechanisms of Action Combining Sitagliptin and Metformin

7. 7 Metformin Lowers Plasma Glucose by Lowering Hepatic Glucose Production and by Improving Insulin Sensitivity Metformin Blood glucose ↑Glucose uptake in muscle and fat by increasing insulin sensitivity 5 1. Kirpichnikov D et al. Ann Intern Med. 2002;137:25–33. 2. Setter SM et al. Clin Ther. 2003;25:2991–3026. 3. Hundal RS et al. Diabetes. 2000;49:2063–2069. 4. Chu CA et al. Metabolism. 2000;49:1619–1626. 5. Bailey CJ et al. N Engl J Med. 1996;334:574–579. Muscle Adipose tissue Liver ↓ Gluconeogenesis ↓ Glycogenolysis ↑ Glycogen synthesis ↓Glucose production reduced by 1–4 : Liver

8. 8 Sitagliptin improves beta-cell function and increases insulin synthesis and release. Sitagliptin reduces HGO through suppression of glucagon from alpha cells. Metformin decreases HGO by targeting the liver to decrease gluconeogenesis and glycogenolysis. Metformin has insulin- sensitizing properties. Beta-Cell Dysfunction Hepatic Glucose Overproduction (HGO) Sitagliptin Reduces Hyperglycemia Metformin Reduces Hyperglycemia The Combination of Sitagliptin and Metformin Addresses the 3 Core Defects of Type 2 Diabetes in a Complementary Manner Insulin Resistance *Please see corresponding speaker note for references.

9. 9 JANUMET™ (sitagliptin/metformin HCl): Indications and Usage Indication –JANUMET is indicated as an adjunct to diet and exercise to improve glycemic control in adult patients with type 2 diabetes mellitus who are not adequately controlled on metformin or sitagliptin alone or in patients already being treated with the combination of sitagliptin and metformin. Important limitations of use –JANUMET should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.

10. 10 The labeling for JANUMET contains a boxed warning for lactic acidosis, a rare,* but serious, metabolic complication that can occur due to metformin accumulation during treatment with JANUMET. The risk of lactic acidosis increases with conditions such as sepsis, dehydration, excess alcohol intake, hepatic insufficiency, renal impairment, and acute congestive heart failure. The onset is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress. Laboratory abnormalities include low pH, increased anion gap, and elevated blood lactate. If acidosis is suspected, JANUMET should be discontinued and the patient hospitalized immediately. See the full Prescribing Information for the complete Boxed Warning. JANUMET™ (sitagliptin/metformin HCl): Boxed Warning: Lactic Acidosis *The reported incidence of lactic acidosis in patients receiving metformin hydrochloride is very low (approximately 0.03 cases/1,000 patient-years, with approximately 0.015 fatal cases/1,000 patient-years). When lactic acidosis occurs, it is fatal in approximately 50% of cases.

11. 11 JANUMET™ (sitagliptin/metformin HCl): Pharmacokinetics Bioequivalence: A clinical bioequivalence study has demonstrated that JANUMET is bioequivalent to corresponding doses of sitagliptin plus metformin as individual tablets Bioavailability: –Sitagliptin ~87% –Metformin ~50–60% Metabolism: both sitagliptin and metformin are predominantly excreted unchanged in the urine Pharmacokinetics: no meaningful changes in either sitagliptin or metformin with co-administration