(a) Califf RM, Boolell M, Haffner SM, Bethel MA, McMurray J, Duggal A, Holman RR
(b) NAVIGATOR Study Group
(c) NAVIGATOR Study Group

(a) Prevention of diabetes and cardiovascular disease in patients with impaired glucose tolerance: rationale and design of the Nateglinide And Valsartan in Impaired
Glucose Tolerance Outcomes Research (NAVIGATOR) Trial
(b) Effect of nateglinide on the incidence of diabetes and cardiovascular events
(c) Effect of valsartan on the incidence of diabetes and cardiovascular events

(a) Am Heart J 2008;156:623–32
(b) N Engl J Med 2010;362:1463–76
(c) N Engl J Med 2010;362:1477–90

Cardiovascular disease, diabetes mellitus

To investigate whether treatment with nateglinide or valsartan can reduce progression to diabetes and new cardiovascular events in patients with or at high risk of cardiovascular disease and impaired glucose tolerance

Randomised, double-blind, placebo-controlled, 2 x 2 factorial

Median 5.0, 6.3 and 6.4 years for data on the diabetes, extended cardiovascular and core cardiovascular outcomes, respectively

9518 patients, with impaired glucose tolerance, aged ≥ 50 years, if with diagnosed cardiovascular disease, or ≥ 55 years, if at risk of cardiovascular disease

Nateglinide, 30–60 mg tid, valsartan, 80–160 mg/day, their combination, or placebo

Lifestyle intervention programme

9306 patients (nateglinide vs placebo analysis: 4645 nateglinide, 4661 placebo; valsartan vs placebo analysis: 4631 valsartan, 4675 placebo) were included in the analyses. In the nateglinide vs placebo analysis, diabetes developed in 36.0% of patients in the nateglinide group and 33.9% in the placebo group (hazard ratio 1.07, 95% CI 1.00–1.15; p = 0.05). The extended composite cardiovascular outcome of death from a cardiovascular cause, nonfatal MI, nonfatal stroke, hospitalisation for heart failure, arterial revascularisation or hospitalisation for unstable angina pectoris occurred in 14.2% of patients receiving nateglinide and 15.2% of those receiving placebo (hazard ratio 0.93, 95% CI 0.83–1.03; p = 0.16). The core composite cardiovascular outcome of death from a cardiovascular cause, nonfatal MI, nonfatal stroke or hospitalisation for heart failure was reached in 7.9% of patients with nateglinide and in 8.3% with placebo (hazard ratio 0.94, 95% CI 0.82–1.09; p = 0.43). In the valsartan vs placebo analysis, diabetes developed in significantly fewer patients in the valsartan group than in the placebo group (33.1% vs 36.8%, hazard ratio 0.86, 95% CI 0.80–0.92; p < 0.001). Compared to placebo, valsartan did not reduce the incidence of either the extended cardiovascular outcome (14.5% vs 14.8%, hazard ratio 0.96, 95% CI, 0.86–1.07; p = 0.43) or the core cardiovascular outcome (8.1% vs 8.1%, hazard ratio 0.99, 95% CI 0.86–1.14; p = 0.85)

Data on alanine aminotransferase levels and the metabolic syndrome in the NAVIGATOR population have been published in Diabet Med 2009;26:1204–11