Effect of Nateglinide on the Incidence of Diabetes and Cardiovascular Events

Abstract

BackgroundThe ability of short-acting insulin secretagogues to reduce the risk of diabetes or cardiovascular events in people with impaired glucose tolerance is unknown. MethodsIn a double-blind, randomized clinical trial, we assigned 9306 participants with impaired glucose tolerance and either cardiovascular disease or cardiovascular risk factors to receive nateglinide (up to 60 mg three times daily) or placebo, in a 2-by-2 factorial design with valsartan or placebo, in addition to participation in a lifestyle modification program. We followed the participants for a median of 5.0 years for incident diabetes (and a median of 6.5 years for vital status). We evaluated the effect of nateglinide on the occurrence of three coprimary outcomes: the development of diabetes; a core cardiovascular outcome that was a composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure; and an extended cardiovascular outcome that was a composite of the individual components of the core composite cardiovascular outcome, hospitalization for unstable angina, or arterial revascularization. ResultsAfter adjustment for multiple testing, nateglinide, as compared with placebo, did not significantly reduce the cumulative incidence of diabetes (36% and 34%, respectively; hazard ratio, 1.07; 95% confidence interval [CI], 1.00 to 1.15; P = 0.05), the core composite cardiovascular outcome (7.9% and 8.3%, respectively; hazard ratio, 0.94, 95% CI, 0.82 to 1.09; P = 0.43), or the extended composite cardiovascular outcome (14.2% and 15.2%, respectively; hazard ratio, 0.93, 95% CI, 0.83 to 1.03; P = 0.16). Nateglinide did, however, increase the risk of hypoglycemia. ConclusionsAmong persons with impaired glucose tolerance and established cardiovascular disease or cardiovascular risk factors, assignment to nateglinide for 5 years did not reduce the incidence of diabetes or the coprimary composite cardiovascular outcomes. (ClinicalTrials.gov number, NCT00097786.)

Effect of Valsartan on the Incidence of Diabetes and Cardiovascular Events

“…17 These calculations were revised after an updated meta-analysis of trials of renin-angiotensin blockers suggesting that the reduction in the hazard of the extended cardiovascular outcome was more likely to be 12% (providing a power of 64%) and 18% for the core cardiovascular outcome (providing a power of 74%, assuming the occurrence of 784 core events); the estimated power to show a reduction in at least one of the cardiovascular outcomes was 77%. 17,19 While accumulating 1374 extended cardiovascular events, we anticipated that more than 3000 patients would have progression to diabetes, en-suring a power of more than 99% to detect a hazard reduction of 18%. Because we examined the effects of two drugs (valsartan and nateglinide) on three primary outcomes in a factorial manner, we adjusted for the three tests that were performed for each study drug (but not across drugs).…”

“…A third coprimary core cardiovascular outcome (a composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, and hospitalization for heart failure), which was initially a secondary composite outcome, was added, as described previously. 17,19 …”

International Variation in Outcomes Among People with Cardiovascular Disease or Cardiovascular Risk Factors and Impaired Glucose Tolerance: Insights from the NAVIGATOR Trial

“…The study design, participant characteristics, and outcomes of the NAVIGATOR study have been published 12, 13, 14. Briefly, NAVIGATOR was a prospective multicenter randomized controlled trial with a 2×2 factorial design that included 9306 patients with IGT and established cardiovascular disease or cardiovascular risk factors.…”

“…The NAVIGATOR (Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research) trial assessed whether nateglinide, a short‐acting insulin secretagogue, or valsartan, an angiotensin receptor blocker, could reduce the risk of new‐onset diabetes mellitus and/or cardiovascular events among people with IGT and established cardiovascular disease or cardiovascular risk factors 12, 13. The NAVIGATOR trial recruited from 40 countries, providing an opportunity to evaluate the potential role of regional differences in outcomes.…”

Effect of Valsartan on the Incidence of Diabetes and Cardiovascular Events

“…The effects of study treatment were evaluated in prespecified subgroups. 17 We compared baseline characteristics, safety, and other trial assessments using summary statistics. …”