Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research

1. Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research Rury R. Holman, MB, ChB, FRCP Professor of Diabetic Medicine Director, Diabetes Trials Unit, Oxford Robert M. Califf, MD, MACC  Vice Chancellor for Clinical Research Donald F. Fortin Professor of Cardiology, Duke University Director, Duke Translational Medicine Institute For the NAVIGATOR Study Group

2. NAVIGATOR Trial Organization Sponsored by Novartis Pharmaceuticals Data Monitoring Committee Executive Committee Trial Oversight Publications Endpoint Committees Steering Committee43 Members Trial Operations Novartis Research Sites 806 centers in 40 countries

3. Primary Objective To evaluate whether valsartan or nateglinide, in addition to lifestyle modification, can reduce the risk of diabetes and cardiovascular events in persons with impaired glucose tolerance (IGT) and either cardiovascular disease or risk factors for cardiovascular disease

4. NAVIGATOR 2 × 2 Factorial Design • All subjects participated in a lifestyle modification program • Nateglinide 60 mg three times a day before meals • Valsartan 160 mg once a day Valsartan Comparison Nateglinide Comparison

5. NAVIGATOR Global Enrollment 9306 patients 806 centers 40 countries Europe4909 North America 2146 Asia-Pacific 692 Africa 153 Central & South America 1406 Major Inclusion Criteria IGT* plus FPG ≥95 mg/dL (≥5.3 mmol/L) and either CVD and age  50 yr or  1 risk factor for CVD and age  55 yr *Impaired glucose tolerance according to ADA definition: Nathan DM et al, Diabetes Care, 2007

6. Coprimary Endpoints • Incidence of diabetes FPG ≥126 mg/dL (≥7.0 mmol/L) and/or 2 hr PG ≥200 mg/dL (≥11.1 mmol/L), confirmed on OGTT within 12 weeks • Extended cardiovascular outcome CV death, nonfatal MI, nonfatal stroke, hospitalization for heart failure, arterial revascularization, or unstable angina • Core cardiovascular outcome CV death, nonfatal MI, nonfatal stroke, or hospitalization for heart failure

7. Nateglinide Data

8. Meal NAVIGATOR Pilot Study Postprandial glucose lowering with nateglinide in IGT Saloranta C et al. Diabetes Care 2002;25:2141-2146

9. Baseline Patient Characteristics Holman RR et al, N Engl J Med, 2010

10. Baseline Patient Characteristics (continued) Holman RR et al, N Engl J Med, 2010

11. Adherence to Protocol • Taking study drug at 5 years • Nateglinide 70% • Placebo 71% • 13% withdrew consent or lost to follow-up, mostly during extension of trial • Vital status available for 96% of the possible follow-up time • Median follow-up • 6.5 years for vital status • 5.0 years for incident diabetes Holman RR et al, N Engl J Med, 2010

12. Concomitant Medications Holman RR et al, N Engl J Med, 2010

13. Concomitant Medications (continued) *For those with diabetes: 33.3% nateglinide, 37.7% placebo Holman RR et al, N Engl J Med, 2010

14. Nateglinide Decreased FPG; Increased 2 Hr PG Holman RR et al, N Engl J Med, 2010

15. Weight and Waist Circumference Increase with Nateglinide Holman RR et al, N Engl J Med, 2010

16. Incidence of Diabetes Placebo 1580 events (33.9%) Nateglinide 1674 events (36.0%) *Not significant after adjustment for multiple testing Holman RR et al, N Engl J Med, 2010

17. Extended and Core CV Outcomes Placebo 707 events (15.2%) Nateglinide 658 events (14.2%) Placebo 387 events (8.3%) Nateglinide 365 events (7.9%) Holman RR et al, N Engl J Med, 2010

18. Adverse Events: Hypoglycemia* *Includes MedDRA preferred terms: hypoglycemia and hypoglycemic seizure Adverse events otherwise did not differ between treatment groups Holman RR et al, N Engl J Med, 2010

19. In people with IGT and CV disease or risk factors, nateglinide in addition to lifestyle modification Did not reduce the incidence of diabetes (median follow-up 5 yrs) Did not reduce the co-primary CV outcomes Nateglinide Conclusions Holman RR et al, N Engl J Med, 2010

20. Valsartan Data

21. Baseline Patient Characteristics McMurray JJ et al, N Engl J Med, 2010

22. Baseline Patient Characteristics (continued) McMurray JJ et al, N Engl J Med, 2010

23. Adherence to Protocol • Taking study drug at 5 years • Valsartan 67% • Placebo 66% • 13% withdrew consent or lost to follow-up, mostly during extension of trial • Vital status available for 96% of the possible follow-up time • Median follow-up • 6.5 years for vital status • 5.0 years for incident diabetes

24. Concomitant Medications McMurray JJ et al, N Engl J Med, 2010

25. Concomitant Medications (continued) *For those with diabetes: 33.4% valsartan, 37.2% placebo McMurray JJ et al, N Engl J Med, 2010

26. Valsartan Significantly Reduced Mean Sitting BP McMurray JJ et al, N Engl J Med, 2010

27. Valsartan Reduced Fasting and 2 Hr Glucose McMurray JJ et al, N Engl J Med, 2010

28. Incidence of Diabetes Placebo 1722 events (36.8%) Valsartan 1532 events (33.1%) McMurray JJ et al, N Engl J Med, 2010

29. Extended and Core CV Outcomes Placebo 693 events (14.8%) Valsartan 672 events (14.5%) Placebo 377 events (8.1%) Valsartan 375 events (8.1%) McMurray JJ et al, N Engl J Med, 2010

30. Exploratory Outcomes: CV & Total Mortality Placebo 327 events (7.0%) Valsartan 295 events (6.4%) Placebo 116 events (2.5%) Valsartan 128 events (2.8%) McMurray JJ et al, N Engl J Med, 2010

31. Adverse Events of Interest *MedDRA preferred terms include: hypotension, dizziness (including dizziness exertional, dizziness postural), syncope, presyncope and shock (not otherwise specified) McMurray JJ et al, N Engl J Med, 2010

32. Valsartan Conclusions In people with IGT and CV disease or risk factors, valsartan in addition to lifestyle modification • 14% relative (3.8% absolute) reduction in incident diabetes (median follow-up 5 yrs) • Did not reduce the co-primary CV outcomes McMurray JJ et al, N Engl J Med, 2010

33. Thoughts After NAVIGATOR • We are in the midst of a global epidemic of obesity, diabetes, and associated cardiovascular disease. • Many people with impaired glucose tolerance will develop diabetes in a short period of time, even with standard medical care. • Lifestyle intervention remains the cornerstone of diabetes prevention and therapy for impaired glucose tolerance. • We must continue to seek better pharmacological treatments while emphasizing the critical importance of exercise and weight control to prevent diabetes and its morbid and mortal consequences. • The effects of medications must be measured in proper clinical trials to understand their impact.