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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/
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