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Nateglinide and Valsartan in ImpairedGlucose 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
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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
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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
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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
Nategl in
ide
Compa
rison
Valsartan Comparison
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North
America
2146
Asia-Pacific
692
Africa153
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
eitherCVD and age 50 yror 1 risk factor for CVD and age 55 yr
*Impaired glucose tolerance according to ADA definition: Nathan DM et al, Diabetes Care, 2007
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Coprimary Endpoints
Incidence of diabetes
FPG 126 mg/dL (7.0 mmol/L) and/or2 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, arterialrevascularization, or unstable angina
Core cardiovascular outcome
CV death, nonfatal MI, nonfatal stroke, orhospitalization for heart failure
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Nateglinide Data
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Meal
Saloranta C et al. Diabetes Care 2002;25:2141-2146
NAVIGATOR Pilot Study
Postprandial glucose lowering with nateglinide in IGT
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Baseline Patient Characteristics
Holman RR et al, N Engl J Med, 2010
Nategliniden=4645
Placebon=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)
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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)
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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
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Concomitant Medications
Holman RR et al, N Engl J Med, 2010
Nategliniden=4645n (%)
Placebon=4661n (%)
PValue
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
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Concomitant Medications (continued)
Holman RR et al, N Engl J Med, 2010
Nategliniden=4645
Placebon=4661
PValue
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 (
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Holman RR et al, N Engl J Med, 2010
Nateglinide Decreased FPG; Increased 2 Hr PG
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Holman RR et al, N Engl J Med, 2010
Weight and Waist Circumference Increase with Nateglinide
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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
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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%)
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Adverse Events: Hypoglycemia*
Nategliniden=4645 Placebon=4661P
Value
Overall, n (%) 911 (19.6) 527 (11.3)
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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
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Valsartan Data
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Baseline Patient CharacteristicsCharacteristic Valsartan
n=4631Placebon=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
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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 0.2Estimated 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
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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
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Concomitant MedicationsMedication Valsartan n=4631
n (%)Placebon=4675n (%)
PValue
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)
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Concomitant Medications (continued)
Medication Valsartan n=4631n (%)
Placebon=4675n (%)
PValue
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 (
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McMurray JJ et al, N Engl J Med, 2010
Valsartan Reduced Fasting and 2 Hr Glucose
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McMurray JJ et al, N Engl J Med, 2010
Extended and Core CV Outcomes
Placebo693 events (14.8%)
Valsartan672 events (14.5%)
Placebo377 events (8.1%)
Valsartan375 events (8.1%)
O C &
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McMurray JJ et al, N Engl J Med, 2010
Exploratory Outcomes: CV & Total Mortality
Placebo327 events (7.0%)Valsartan295 events (6.4%)
Placebo116 events (2.5%)
Valsartan128 events (2.8%)
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V l t C l i
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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
Th ht Aft NAVIGATOR
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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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Slides Available from
www.dtu.ox.ac.ukwww.dcri.org
http://www.dtu.ox.ac.uk/http://www.dcri.org/http://www.dcri.org/http://www.dtu.ox.ac.uk/8/14/2019 Califf Navigator
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