nateglinide and valsartan in impaired glucose tolerance outcomes research

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 CommitteeTrial Oversight

Publications

Steering Committee43 Members

Data Monitoring Committee

Trial OperationsNovartis

Research Sites806 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

Na

teg

linid

e C

om

pa

rison

Valsartan Comparison

North America

2146

Asia-Pacific692

Africa153

Central & South America

1406

Europe4909

NAVIGATOR Global Enrollment

9306 patients

806 centers

40 countries

Major Inclusion CriteriaIGT* 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 diabetesFPG ≥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 outcomeCV death, nonfatal MI, nonfatal stroke, hospitalization for heart failure, arterial revascularization, or unstable angina

• Core cardiovascular outcomeCV 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

Nategliniden=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)


Baseline Patient Characteristics (continued)

Nategliniden=4645

Placebon=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)


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


Nategliniden=4645n (%)

Placebon=4661n (%)

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)


Nategliniden=4645

Placebon=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


Nateglinide Decreased FPG; Increased 2 Hr PG


Weight and Waist Circumference Increase with Nateglinide


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




Adverse Events: Hypoglycemia*

Nategliniden=4645

Placebon=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


*Includes MedDRA preferred terms: hypoglycemia and hypoglycemic seizure

Adverse events otherwise did not differ between treatment groups


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 CharacteristicsCharacteristic Valsartan

n=4631Placebo 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

Placebon=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


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 MedicationsMedication Valsartan

n=4631n (%)

Placebon=4675n (%)

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


Concomitant Medications (continued)

Medication Valsartan n=4631n (%)

Placebon=4675n (%)

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


*For those with diabetes: 33.4% valsartan, 37.2% placebo


Valsartan Significantly Reduced Mean Sitting BP


Valsartan Reduced Fasting and 2 Hr Glucose


Incidence of Diabetes

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


Extended and Core CV Outcomes




Exploratory Outcomes: CV & Total Mortality




Adverse Events of Interest

Valsartann=4631n (%)

Placebon=4675n (%)

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)


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.

nateglinide and valsartan in impaired glucose tolerance outcomes research

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