Effect of Nateglinide on the Incidence of Diabetes and Cardiovascular Events

N Engl J Med. 2010 Apr 22;362(16):1463-76. doi: 10.1056/NEJMoa1001122. Epub 2010 Mar 14.

Abstract

Background: The ability of short-acting insulin secretagogues to reduce the risk of diabetes or cardiovascular events in people with impaired glucose tolerance is unknown.

Methods: In 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.

Results: After 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.

Conclusions: Among 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.)

Publication types

  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin II Type 1 Receptor Blockers / therapeutic use
  • Blood Glucose / analysis
  • Blood Glucose / drug effects
  • Body Weight / drug effects
  • Cardiovascular Diseases / epidemiology
  • Cardiovascular Diseases / mortality
  • Cardiovascular Diseases / prevention & control*
  • Cyclohexanes / adverse effects
  • Cyclohexanes / therapeutic use*
  • Diabetes Mellitus, Type 2 / epidemiology
  • Diabetes Mellitus, Type 2 / prevention & control*
  • Double-Blind Method
  • Drug Therapy, Combination
  • Exercise
  • Female
  • Follow-Up Studies
  • Glucose Intolerance / diet therapy
  • Glucose Intolerance / drug therapy*
  • Glucose Intolerance / therapy
  • Humans
  • Hypoglycemic Agents / adverse effects
  • Hypoglycemic Agents / therapeutic use*
  • Incidence
  • Kaplan-Meier Estimate
  • Male
  • Middle Aged
  • Nateglinide
  • Phenylalanine / adverse effects
  • Phenylalanine / analogs & derivatives*
  • Phenylalanine / therapeutic use
  • Proportional Hazards Models
  • Risk Factors
  • Tetrazoles / therapeutic use
  • Treatment Failure
  • Valine / analogs & derivatives
  • Valine / therapeutic use
  • Valsartan

Substances

  • Angiotensin II Type 1 Receptor Blockers
  • Blood Glucose
  • Cyclohexanes
  • Hypoglycemic Agents
  • Tetrazoles
  • Nateglinide
  • Phenylalanine
  • Valsartan
  • Valine

Associated data

  • ClinicalTrials.gov/NCT00097786