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
Monitoring
Committee
Executive Committee
Trial Oversight
Publications
Endpoint
Committees
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/Placebo
(n=2329)
Valsartan/Placebo
(n=2315)
Placebo/Placebo
(n=2346)
Nateglinide Comparison
Valsartan/Nateglinide
(n=2316)
• 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
4909
North
America
2146
9306 patients
806 centers
40 countries
Asia-Pacific
692
Africa
153
Central & South
America
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
n=4645
Placebo
n=4661
Age, years
63.7 ± 6.8
63.8 ± 6.9
Female sex, n (%)
2368 (51.0)
2343 (50.3)
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
Systolic
139.8 ± 17.5
139.5 ± 17.4
Diastolic
82.6 ± 10.3
82.5 ± 10.2
1140 (24.5)
1126 (24.2)
Race, n (%)
Mean sitting BP, mm HG
History of CVD, n (%)
Holman RR et al, N Engl J Med, 2010
Baseline Patient Characteristics (continued)
Nateglinide
n=4645
Placebo
n=4661
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)
Total cholesterol, mg/dL
210 ± 41
210 ± 43
HDL, mg/dL
50 ± 13
50 ± 13
LDL, mg/dL
126 ± 36
127 ± 38
151 (109, 208)
150 (107, 209)
0.9 ± 0.2
0.9 ± 0.2
80.3 ± 18.6
81.1 ± 19.0
7.1 (4.5, 14.1)
7.1 (4.5, 14.8)
Glycemic indices
Lipids
Triglycerides, mg/dL
Creatinine, mg/dL
Estimated GFR mL/min/1.73m2
Urinary albumin:creatinine (mg/g)
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
n=4645
n (%)
Placebo
n=4661
n (%)
Baseline
330 (7.1)
346 (7.4)
Last study visit
729 (15.7)
745 (16.0)
Baseline
12 (0.3)
18 (0.4)
Last study visit
249 (5.4)
229 (4.9)
Baseline
1872 (40.3)
1794 (38.5)
Last study visit
1913 (41.2)
1927 (41.3)
Baseline
1519 (32.7)
1493 (32.0)
Last study visit
1674 (36.0)
1720 (36.9)
Baseline
1461 (31.5)
1499 (32.2)
Last study visit
1664 (35.8)
1755 (37.7)
P Value
ACE inhibitor
0.64
Angiotensin-receptor blocker
0.32
Beta blocker
0.82
Calcium channel blocker
0.39
Diuretic
Holman RR et al, N Engl J Med, 2010
0.07
Concomitant Medications (continued)
Nateglinide
n=4645
Placebo
n=4661
n (%)
n (%)
Baseline
1797 (38.7)
1780 (38.2)
Last study visit
2301 (49.5)
2358 (50.6)
Baseline
1712 (36.9)
1713 (36.8)
Last study visit
2119 (45.6)
2114 (45.4)
2 (<0.1)
5 (0.1)
651 (14.0)
670 (14.4)
P Value
Lipid-lowering drug
0.25
Aspirin/other antiplatelet drug
0.91
Antidiabetic drug
Baseline
Last study visit—all subjects*
*For those with diabetes: 33.3% nateglinide, 37.7% placebo
Holman RR et al, N Engl J Med, 2010
0.61
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
Nateglinide
*Not significant after adjustment for multiple testing
Holman RR et al, N Engl J Med, 2010
1580 events (33.9%)
1674 events (36.0%)
Extended and Core CV Outcomes
Holman RR et al, N Engl J Med, 2010
Placebo
Nateglinide
707 events (15.2%)
658 events (14.2%)
Placebo
Nateglinide
387 events (8.3%)
365 events (7.9%)
Adverse Events: Hypoglycemia*
Overall, n (%)
Mild (maximum severity)
Moderate (maximum severity)
Severe (maximum severity)
Discontinuation for
adverse events, n (%)
Nateglinide
n=4645
Placebo
n=4661
P Value
911 (19.6)
676
527 (11.3)
411
<0.001
214
21
104
12
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
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
n=4631
Placebo
n=4675
Age, years
63.7 ± 6.8
63.8 ± 6.8
Female sex, n (%)
2317 (50.0)
2278 (51.3)
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
Systolic
139.4 ± 17.8
139.9 ± 17.1
Diastolic
82.5 ± 10.4
82.6 ± 10.1
1148 (24.8)
1118 (23.9)
Race, n (%)
Mean sitting BP, mm Hg
Any CVD, n (%)
McMurray JJ et al, N Engl J Med, 2010
Baseline Patient Characteristics (continued)
Characteristic
Valsartan
n=4631
Placebo
n=4675
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
3825 (82.6)
3969 (85.0)
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
0.9 ± 0.2
0.9 ± 0.2
80.9 ± 18.5
80.4 ± 19.0
0.8
0.8
Glycemic indices
Metabolic syndrome, n (%)
Lipids
Creatinine, mg/dL
Estimated GFR mL/min/1.73m2
Urinary albumin:creatinine (mg/g)
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 (%)
Baseline
351 (7.6)
325 (7.0)
Last study visit
688 (14.9)
786 (16.8)
Baseline
10 (0.2)
20 (0.4)
Last study visit
212 (4.6)
266 (5.7)
Baseline
1863 (40.2)
1803 (38.6)
Last study visit
1840 (39.7)
2000 (42.8)
Baseline
1483 (32.0)
1529 (32.7)
Last study visit
1537 (33.2)
1857 (39.7)
Baseline
1451 (31.3)
1509 (32.3)
Last study visit
1578 (34.1)
1841 (39.4)
P Value
ACE inhibitor
0.005
Angiotensin-receptor blocker
0.02
Beta blocker
<0.001
Calcium channel blocker
<0.001
Diuretic, n (%)
McMurray JJ et al, N Engl J Med, 2010
<0.001
Concomitant Medications (continued)
Medication
Valsartan
n=4631
n (%)
Placebo
n=4675
n (%)
Baseline
1782 (38.5)
1795 (38.4)
Last study visit
2298 (49.6)
2361 (50.5)
Baseline
1729 (37.3)
1696 (36.3)
Last study visit
2103 (45.4)
2130 (45.6)
1 (<0.1)
6 (0.1)
588 (12.7)
733 (15.7)
P Value
Lipid-lowering drug, n (%)
0.27
Aspirin/other antiplatelet drug, n (%)
0.64
Antidiabetic drug, n (%)
Baseline
Last study visit—all subjects*
*For those with diabetes: 33.4% valsartan, 37.2% placebo
McMurray JJ et al, N Engl J Med, 2010
<0.001
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
Valsartan
McMurray JJ et al, N Engl J Med, 2010
1722 events (36.8%)
1532 events (33.1%)
Extended and Core CV Outcomes
Placebo 693 events (14.8%)
Valsartan 672 events (14.5%)
Placebo
Valsartan
McMurray JJ et al, N Engl J Med, 2010
377 events (8.1%)
375 events (8.1%)
Exploratory Outcomes: CV & Total Mortality
McMurray JJ et al, N Engl J Med, 2010
Placebo
Valsartan
327 events (7.0%)
295 events (6.4%)
Placebo
Valsartan
116 events (2.5%)
128 events (2.8%)
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 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
Slides Available from
www.dtu.ox.ac.uk
www.dcri.org
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.