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 Committee Endpoint

Monitoring Trial Oversight
Publications
Committees
Committee

Steering Committee Trial Operations

43 Members Novartis

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

North Europe
4909 Asia-Pacific
America
692
2146

Africa
9306 patients 153
806 centers Central & South
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
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 Placebo
n=4645 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
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
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 Placebo
n=4631 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 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

 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 Placebo P Value
n=4631 n=4675
n (%) n (%)
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 leads to:
– 14% relative (3.8% absolute) reduction in
the incidence of diabetes (median follow-up
5 yrs)
– Did not reduce the co-primary CV outcomes

McMurray JJ et al, N Engl J Med, 2010

 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 exercise and weight control to prevent
diabetes and its morbid and mortal consequences.
• NAVIGATOR demonstrates once again that the risks and
benefits of therapies cannot be predicted accurately based on
biology and intermediate measures, so they must be
empirically demonstrated with proper RCTs
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