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

Sponsored by Novartis Pharmaceuticals

Executive Committee

Trial Oversight Publications

Steering Committee

43 Members

Data Monitoring Committee Trial Operations

Novartis

Research Sites

806 centers in 40 countries

Endpoint Committees

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

Valsartan/Nateglinide (n=2316) Nateglinide/Placebo (n=2329) Valsartan/Placebo (n=2315) Placebo/Placebo (n=2346)

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

Nateglinide Comparison Valsartan Comparison

North America 2146 Asia-Pacific 692 Africa 153 Central & South America 1406 Europe 4909

NAVIGATOR Global Enrollment

9306 patients 806 centers 40 countries

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

Meal

Saloranta C et al. Diabetes Care 2002;25:2141-2146

NAVIGATOR Pilot Study

Postprandial glucose lowering with nateglinide in IGT

Baseline Patient Characteristics

Holman RR et al, N Engl J Med, 2010

Nateglinide n=4645 Placebo n=4661

Age, years 63.7 ± 6.8 63.8 ± 6.9 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) Weight, kg 83.6 ± 17.2 83.6 ± 17.2 BMI, kg/m2 30.5 ± 5.4 30.5 ± 5.4 Waist circumference, cm 101 ± 14 101 ± 14 Men 104 ± 12 104 ± 13 Women 98 ± 14 98 ± 14 Mean sitting BP, mm HG Systolic 139.8 ± 17.5 139.5 ± 17.4 Diastolic 82.6 ± 10.3 82.5 ± 10.2 History of CVD, n (%) 1140 (24.5) 1126 (24.2)

Holman RR et al, N Engl J Med, 2010

Baseline Patient Characteristics (continued)

Nateglinide n=4645 Placebo n=4661

Glycemic indices Fasting plasma glucose (mmol/L) 6.1 ± 0.45 6.1 ± 0.46 2-hour plasma glucose (mmol/L) 9.2 ± 0.93 9.2 ± 0 .94 Glycated hemoglobin (%) 5.8 ± 0.45 5.8 ± 0.48 Metabolic syndrome, n (%) 3896 (83.9) 3898 (83.6) Lipids Total cholesterol, mg/dL 210 ± 41 210 ± 43 HDL, mg/dL 50 ± 13 50 ± 13 LDL, mg/dL 126 ± 36 127 ± 38 Triglycerides, mg/dL 151 (109, 208) 150 (107, 209) Creatinine, mg/dL 0.9 ± 0.2 0.9 ± 0.2 Estimated GFR mL/min/1.73m2 80.3 ± 18.6 81.1 ± 19.0 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

Concomitant Medications

Holman RR et al, N Engl J Med, 2010

Nateglinide n=4645 n (%) Placebo n=4661 n (%) P Value

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

Concomitant Medications (continued)

Holman RR et al, N Engl J Med, 2010

Nateglinide n=4645 Placebo n=4661 P Value

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

Extended and Core CV Outcomes

Holman RR et al, N Engl J Med, 2010 Placebo 707 events (15.2%) Nateglinide 658 events (14.2%) Placebo 387 events (8.3%) Nateglinide 365 events (7.9%)

Adverse Events: Hypoglycemia*

Nateglinide n=4645 Placebo n=4661 P Value 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 adverse events, n (%) 520 (11.2) 485 (10.4) 0.23

Holman RR et al, N Engl J Med, 2010

*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

Valsartan Data

Baseline Patient Characteristics

Characteristic Valsartan n=4631 Placebo n=4675

Age, years 63.7 ± 6.8 63.8 ± 6.8 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) Weight, kg 83.5 ± 17.4 83.8 ± 17.1 BMI, kg/m2 30.4 ± 5.5 30.6 ± 5.3 Waist circumference, cm 101 ± 14 101 ± 14 Men 104 ± 13 104 ± 12 Women 98 ± 14 98 ± 14 Mean sitting BP, mm Hg Systolic 139.4 ± 17.8 139.9 ± 17.1 Diastolic 82.5 ± 10.4 82.6 ± 10.1 Any CVD, n (%) 1148 (24.8) 1118 (23.9)

McMurray JJ et al, N Engl J Med, 2010

Baseline Patient Characteristics (continued)

Characteristic Valsartan n=4631 Placebo n=4675

Glycemic indices Fasting plasma glucose (mmol/L) 6.1 ± 0.5 6.1 ± 0.5 2 hr plasma glucose (mmol/L) 9.2 ± 0.9 9.2 ± 0.9 Glycated hemoglobin (%) 5.8 ± 0.5 5.8 ± 0.5 Metabolic syndrome, n (%) 3825 (82.6) 3969 (85.0) Lipids Total cholesterol, mg/dL 209 ± 42 209 ± 42 HDL, mg/dL 50 ± 14 50 ± 13 LDL, mg/dL 127 ± 38 127 ± 37 Triglycerides, mg/dL 177 ± 104 117 ± 104 Creatinine, mg/dL 0.9 ± 0.2 0.9 ± 0.2 Estimated GFR mL/min/1.73m2 80.9 ± 18.5 80.4 ± 19.0 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 n=4631 n (%) Placebo n=4675 n (%) P Value

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 n=4631 n (%) Placebo n=4675 n (%) P Value

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

McMurray JJ et al, N Engl J Med, 2010

*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

Incidence of Diabetes

Placebo 1722 events (36.8%) Valsartan 1532 events (33.1%)

McMurray JJ et al, N Engl J Med, 2010

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

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

Adverse Events of Interest

Valsartan n=4631 n (%) Placebo n=4675 n (%) P Value Hypotension-related* 1964 (42.4) 1680 (35.9) <0.001 Hypertension 693 (15.0) 950 (20.3) <0.001 Renal dysfunction 136 (2.9) 146 (3.1) 0.55 Hyperkalemia 35 (0.8) 35 (0.7) 0.99 Hypokalemia 45 (1.0) 84 (1.8) <0.001 Hypoglycemia 731 (15.8) 707 (15.1) 0.39 Hyperglycemia 45 (1.0) 44 (0.9) 0.93 Angioedema 89 (1.9) 123 (2.6) 0.02

*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

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

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.