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)
Holman RR et al, N Engl J Med, 2010
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)
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
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)
Holman RR et al, N Engl J Med, 2010
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
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*
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
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 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
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 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
McMurray JJ et al, N Engl J Med, 2010
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
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
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)
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
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
Disclosures
Robert M. Califf, MD reports receiving research grant support from Novartis Pharmaceuticals, Johnson & Johnson/Scios, Lilly, Merck, and Schering Plough, and consulting fees from Annenberg, Aterovax, Bayer/Ortho McNeil, BMS, Boehringer Ingelheim, GSK, WebMd/theheart.org, Johnson and Johnson/Scios, Kowa Research Institute, McKinsey & Company, Medtronic, Merck, Novartis Pharmaceuticals, Sanofi Aventis, and Schering Plough, and an equity position with NITROX, LLC. All personal income from industry relations is donated to non-profit entities. Dr. Califf's industry relations are kept up to date quarterly at www.dcri.org/coi.jsp.
Disclosures
Rury R. Holman MD, reports receiving grant support from Asahi Kasei Pharma, Bayer Healthcare, Bayer Schering Pharma, Bristol-Myers Squibb, GlaxoSmithKline, Merck, Merck Serono, Novartis, Novo Nordisk, Pfizer, and Sanofi-Aventis, consulting fees from Amylin, Eli Lilly, GlaxoSmithKline, Merck, and Novartis, and lecture fees from Astella, Bayer, GlaxoSmithKline, King Pharmaceuticals, Eli Lilly, Merck, Merck Serono, Novo Nordisk, Takeda and Sanofi-Aventis.