Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes - PowerPoint PPT Presentation

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

NAVIGATOR Trial Organization Data Executive Endpoint Monitoring Committee Committees Committee Trial Oversight Publications Steering Trial Operations Novartis Committee 43 Members Research Sites 806 centers in 40 countries Sponsored by Novartis Pharmaceuticals

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

NAVIGATOR 2 × 2 Factorial Design Valsartan Comparison Nateglinide Comparison Valsartan/Nateglinide Nateglinide/Placebo (n=2316) (n=2329) Valsartan/Placebo Placebo/Placebo (n=2315) (n=2346) • All subjects participated in a lifestyle modification program • Nateglinide 60 mg three times a day before meals • Valsartan 160 mg once a day

NAVIGATOR Global Enrollment Europe North Asia-Pacific 4909 America 692 2146 Africa 153 9306 patients Central & South 806 centers America 40 countries 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

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

Nateglinide Data

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

Baseline Patient Characteristics Nateglinide Placebo n=4645 n=4661 63.7 ± 6.8 63.8 ± 6.9 Age, years Female sex, n (%) 2368 (51.0) 2343 (50.3) Race, n (%) White 3854 (83.0) 3880 (83.2) Black 120 (2.6) 116 (2.5) Asian 310 (6.7) 303 (6.5) Other 361 (7.8) 362 (7.8) 83.6 ± 17.2 83.6 ± 17.2 Weight, kg 30.5 ± 5.4 30.5 ± 5.4 BMI, kg/m 2 101 ± 14 101 ± 14 Waist circumference, cm 104 ± 12 104 ± 13 Men 98 ± 14 98 ± 14 Women Mean sitting BP, mm HG 139.8 ± 17.5 139.5 ± 17.4 Systolic 82.6 ± 10.3 82.5 ± 10.2 Diastolic History of CVD, n (%) 1140 (24.5) 1126 (24.2) Holman RR et al, N Engl J Med, 2010

Baseline Patient Characteristics (continued) Nateglinide Placebo n=4645 n=4661 Glycemic indices 6.1 ± 0.45 6.1 ± 0.46 Fasting plasma glucose (mmol/L) 9.2 ± 0.93 9.2 ± 0 .94 2-hour plasma glucose (mmol/L) 5.8 ± 0.45 5.8 ± 0.48 Glycated hemoglobin (%) Metabolic syndrome, n (%) 3896 (83.9) 3898 (83.6) Lipids 210 ± 41 210 ± 43 Total cholesterol, mg/dL 50 ± 13 50 ± 13 HDL, mg/dL 126 ± 36 127 ± 38 LDL, mg/dL Triglycerides, mg/dL 151 (109, 208) 150 (107, 209) 0.9 ± 0.2 0.9 ± 0.2 Creatinine, mg/dL 80.3 ± 18.6 81.1 ± 19.0 Estimated GFR mL/min/1.73m 2 Urinary albumin:creatinine (mg/g) 7.1 (4.5, 14.1) 7.1 (4.5, 14.8) Holman RR et al, N Engl J Med, 2010

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

Concomitant Medications Nateglinide Placebo P Value n=4645 n=4661 n (%) n (%) ACE inhibitor Baseline 330 (7.1) 346 (7.4) Last study visit 729 (15.7) 745 (16.0) 0.64 Angiotensin-receptor blocker Baseline 12 (0.3) 18 (0.4) Last study visit 249 (5.4) 229 (4.9) 0.32 Beta blocker Baseline 1872 (40.3) 1794 (38.5) Last study visit 1913 (41.2) 1927 (41.3) 0.82 Calcium channel blocker Baseline 1519 (32.7) 1493 (32.0) Last study visit 1674 (36.0) 1720 (36.9) 0.39 Diuretic Baseline 1461 (31.5) 1499 (32.2) Last study visit 1664 (35.8) 1755 (37.7) 0.07 Holman RR et al, N Engl J Med, 2010

Concomitant Medications (continued) Nateglinide Placebo P Value n=4645 n=4661 n (%) n (%) Lipid-lowering drug Baseline 1797 (38.7) 1780 (38.2) Last study visit 2301 (49.5) 2358 (50.6) 0.25 Aspirin/other antiplatelet drug Baseline 1712 (36.9) 1713 (36.8) Last study visit 2119 (45.6) 2114 (45.4) 0.91 Antidiabetic drug Baseline 2 (<0.1) 5 (0.1) Last study visit—all subjects* 651 (14.0) 670 (14.4) 0.61 *For those with diabetes: 33.3% nateglinide, 37.7% placebo Holman RR et al, N Engl J Med, 2010

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

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

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

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

Adverse Events: Hypoglycemia* Nateglinide Placebo P Value n=4645 n=4661 Overall, n (%) 911 (19.6) 527 (11.3) <0.001 Mild (maximum severity) 676 411 Moderate (maximum severity) 214 104 Severe (maximum severity) 21 12 Discontinuation for 520 (11.2) 485 (10.4) 0.23 adverse events, n (%) * 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

Nateglinide Conclusions 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 Holman RR et al, N Engl J Med, 2010

Valsartan Data

Baseline Patient Characteristics Characteristic Valsartan Placebo n=4631 n=4675 63.7 ± 6.8 63.8 ± 6.8 Age, years Female sex, n (%) 2317 (50.0) 2278 (51.3) Race, n (%) White 3849 (83.1) 3885 (83.1) Black 113 (2.4) 123 (2.6) Asian 298 (6.4) 315 (6.7) Other 371 (8.0) 352 (7.5) 83.5 ± 17.4 83.8 ± 17.1 Weight, kg 30.4 ± 5.5 30.6 ± 5.3 BMI, kg/m 2 101 ± 14 101 ± 14 Waist circumference, cm 104 ± 13 104 ± 12 Men 98 ± 14 98 ± 14 Women Mean sitting BP, mm Hg 139.4 ± 17.8 139.9 ± 17.1 Systolic 82.5 ± 10.4 82.6 ± 10.1 Diastolic Any CVD, n (%) 1148 (24.8) 1118 (23.9) McMurray JJ et al, N Engl J Med, 2010

Baseline Patient Characteristics (continued) Characteristic Valsartan Placebo n=4631 n=4675 Glycemic indices 6.1 ± 0.5 6.1 ± 0.5 Fasting plasma glucose (mmol/L) 9.2 ± 0.9 9.2 ± 0.9 2 hr plasma glucose (mmol/L) 5.8 ± 0.5 5.8 ± 0.5 Glycated hemoglobin (%) Metabolic syndrome, n (%) 3825 (82.6) 3969 (85.0) Lipids 209 ± 42 209 ± 42 Total cholesterol, mg/dL 50 ± 14 50 ± 13 HDL, mg/dL 127 ± 38 127 ± 37 LDL, mg/dL 177 ± 104 117 ± 104 Triglycerides, mg/dL 0.9 ± 0.2 0.9 ± 0.2 Creatinine, mg/dL 80.9 ± 18.5 80.4 ± 19.0 Estimated GFR mL/min/1.73m 2 Urinary albumin:creatinine (mg/g) 0.8 0.8 McMurray JJ et al, N Engl J Med, 2010

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

Concomitant Medications Medication Valsartan Placebo P Value n=4631 n=4675 n (%) n (%) ACE inhibitor Baseline 351 (7.6) 325 (7.0) Last study visit 688 (14.9) 786 (16.8) 0.005 Angiotensin-receptor blocker Baseline 10 (0.2) 20 (0.4) Last study visit 212 (4.6) 266 (5.7) 0.02 Beta blocker Baseline 1863 (40.2) 1803 (38.6) Last study visit 1840 (39.7) 2000 (42.8) <0.001 Calcium channel blocker Baseline 1483 (32.0) 1529 (32.7) Last study visit 1537 (33.2) 1857 (39.7) <0.001 Diuretic, n (%) Baseline 1451 (31.3) 1509 (32.3) Last study visit 1578 (34.1) 1841 (39.4) <0.001 McMurray JJ et al, N Engl J Med, 2010

Concomitant Medications (continued) Medication Valsartan Placebo P Value n=4631 n=4675 n (%) n (%) Lipid-lowering drug, n (%) Baseline 1782 (38.5) 1795 (38.4) Last study visit 2298 (49.6) 2361 (50.5) 0.27 Aspirin/other antiplatelet drug, n (%) Baseline 1729 (37.3) 1696 (36.3) Last study visit 2103 (45.4) 2130 (45.6) 0.64 Antidiabetic drug, n (%) Baseline 1 (<0.1) 6 (0.1) Last study visit—all subjects* 588 (12.7) 733 (15.7) <0.001 *For those with diabetes: 33.4% valsartan, 37.2% placebo McMurray JJ et al, N Engl J Med, 2010

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

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