Effect of nateglinide on the incidence of diabetes and cardiovascular events.

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.)

• Authors: NAVIGATOR Study Group, Rury R Holman, Steven M Haffner, John J McMurray, M Angelyn Bethel, Björn Holzhauer, Tsushung A Hua, Yuri Belenkov, Mitradev Boolell, John B Buse, Brendan M Buckley, Antonio R Chacra, Fu-Tien Chiang, Bernard Charbonnel, Chun-Chung Chow, Melanie J Davies, Prakash Deedwania, Peter Diem, Daniel Einhorn, Vivian Fonseca, Gregory R Fulcher, Zbigniew Gaciong, Sonia Gaztambide, Thomas Giles, Edward Horton, Hasan Ilkova, Trond Jenssen, Steven E Kahn, Henry Krum, Markku Laakso, Lawrence A Leiter, Naomi S Levitt, Viacheslav Mareev, Felipe Martinez, Chantal Masson, Theodore Mazzone, Eduardo Meaney, Richard Nesto, Changyu Pan, Rudolf Prager, Sotirios A Raptis, Guy E H M Rutten, Herbert Sandstroem, Frank Schaper, Andre Scheen, Ole Schmitz, Isaac Sinay, Vladimir Soska, Steen Stender, Gyula Tamás, Gianni Tognoni, Jaako Tuomilehto, Alberto S Villamil, Juraj Vozár, Robert M Califf
• Journal: The New England journal of medicine (N Engl J Med) Vol. 362 Issue 16 Pg. 1463-76 (Apr 22 2010) ISSN: 1533-4406 [Electronic] United States
• PMID: 20228402 (Publication Type: Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: 2010 Massachusetts Medical Society

Chemical References

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

Topics

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