Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research`

1
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

2
NAVIGATOR Trial Organization
Data Monitoring Committee
Executive Committee Trial Oversight Publications
Endpoint Committees
Steering Committee43 Members
Trial Operations Novartis
Research Sites 806 centers in 40 countries

• Sponsored by Novartis Pharmaceuticals

3
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

4
NAVIGATOR 2 2 Factorial Design
Valsartan Comparison
Valsartan/Nateglinide (n2316) Nateglinide/Placebo (n2329)
Valsartan/Placebo (n2315) Placebo/Placebo (n2346)
Nateglinide Comparison

• All subjects participated in a lifestyle
  modification program
• Nateglinide 60 mg three times a day before meals
• Valsartan 160 mg once a day

5
NAVIGATOR Global Enrollment
Europe4909
North America 2146
Asia-Pacific 692
Africa 153

• 9306 patients
• 806 centers
• 40 countries

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
6
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

7
Nateglinide Data
8
NAVIGATOR Pilot Study
Postprandial glucose lowering with nateglinide in
IGT
Saloranta C et al. Diabetes Care 2002252141-2146
9
Baseline Patient Characteristics
Nateglinide n4645 Placebo n4661
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
10
Baseline Patient Characteristics (continued)
Nategliniden4645 Placebon4661
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 albumincreatinine (mg/g) 7.1 (4.5, 14.1) 7.1 (4.5, 14.8)
Holman RR et al, N Engl J Med, 2010
11
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
12
Concomitant Medications
Nategliniden4645n () Placebon4661 n () 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
Holman RR et al, N Engl J Med, 2010
13
Concomitant Medications (continued)
Nategliniden4645 Placebon4661 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 (lt0.1) 5 (0.1)
Last study visitall 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
14
Nateglinide Decreased FPG Increased 2 Hr PG
Holman RR et al, N Engl J Med, 2010
15
Weight and Waist Circumference Increase with
Nateglinide
Holman RR et al, N Engl J Med, 2010
16
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
17
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
18
Adverse Events Hypoglycemia
Nategliniden4645 Placebon4661 P Value
Overall, n () 911 (19.6) 527 (11.3) lt0.001
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
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
19
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
20
Valsartan Data
21
Baseline Patient Characteristics
Characteristic Valsartan n4631 Placebo n4675
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
22
Baseline Patient Characteristics (continued)
Characteristic Valsartan n4631 Placebon4675
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 albumincreatinine (mg/g) 0.8 0.8
McMurray JJ et al, N Engl J Med, 2010
23
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

24
Concomitant Medications
Medication Valsartan n4631 n () Placebon4675 n () 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) lt0.001
Calcium channel blocker
Baseline 1483 (32.0) 1529 (32.7)
Last study visit 1537 (33.2) 1857 (39.7) lt0.001
Diuretic, n ()
Baseline 1451 (31.3) 1509 (32.3)
Last study visit 1578 (34.1) 1841 (39.4) lt0.001
McMurray JJ et al, N Engl J Med, 2010
25
Concomitant Medications (continued)
Medication Valsartan n4631 n () Placebon4675 n () 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 (lt0.1) 6 (0.1)
Last study visitall subjects 588 (12.7) 733 (15.7) lt0.001
For those with diabetes 33.4 valsartan, 37.2
placebo
McMurray JJ et al, N Engl J Med, 2010
26
Valsartan Significantly Reduced Mean Sitting BP
McMurray JJ et al, N Engl J Med, 2010
27
Valsartan Reduced Fasting and 2 Hr Glucose
McMurray JJ et al, N Engl J Med, 2010
28
Incidence of Diabetes
Placebo 1722 events (36.8) Valsartan 1532 events
(33.1)
McMurray JJ et al, N Engl J Med, 2010
29
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
30
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
31
Adverse Events of Interest
Valsartan n4631n () Placebo n4675n () P Value
Hypotension-related 1964 (42.4) 1680 (35.9) lt0.001
Hypertension 693 (15.0) 950 (20.3) lt0.001
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) lt0.001
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
32
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
33
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

34
Slides Available from

• www.dtu.ox.ac.uk
• www.dcri.org

35
(No Transcript)
36
Disclosures

• Robert M. Califf, MD reports receiving research
  grant support from Novartis Pharmaceuticals, Johns
  on 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.

37
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.