Effect of nateglinide on the incidence of diabetes and cardiovascular events

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; NAVIGATOR Study Group

doi:10.1056/NEJMoa1001122

Effect of nateglinide on the incidence of diabetes and cardiovascular events

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 FulcherZbigniew 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, NAVIGATOR Study Group

384 Citations (Scopus)

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.)

Original language	English
Journal	Briefings from the New England Journal of Medicine
Volume	362
Issue number	16
Pages (from-to)	1463-76
Number of pages	14
ISSN	1531-7242
DOIs	https://doi.org/10.1056/NEJMoa1001122
Publication status	Published - 22 Apr 2010

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Holman, R. R., Haffner, S. M., McMurray, J. J., Bethel, M. A., Holzhauer, B., Hua, T. A., Belenkov, Y., Boolell, M., Buse, J. B., Buckley, B. M., Chacra, A. R., Chiang, F.-T., Charbonnel, B., Chow, C.-C., Davies, M. J., Deedwania, P., Diem, P., Einhorn, D., Fonseca, V., ... NAVIGATOR Study Group (2010). Effect of nateglinide on the incidence of diabetes and cardiovascular events. Briefings from the New England Journal of Medicine, 362(16), 1463-76. https://doi.org/10.1056/NEJMoa1001122

Holman, RR, Haffner, SM, McMurray, JJ, Bethel, MA, Holzhauer, B, Hua, TA, Belenkov, Y, Boolell, M, Buse, JB, Buckley, BM, Chacra, AR, Chiang, F-T, Charbonnel, B, Chow, C-C, Davies, MJ, Deedwania, P, Diem, P, Einhorn, D, Fonseca, V, Fulcher, GR, Gaciong, Z, Gaztambide, S, Giles, T, Horton, E, Ilkova, H, Jenssen, T, Kahn, SE, Krum, H, Laakso, M, Leiter, LA, Levitt, NS, Mareev, V, Martinez, F, Masson, C, Mazzone, T, Meaney, E, Nesto, R, Pan, C, Prager, R, Raptis, SA, Rutten, GEHM, Sandstroem, H, Schaper, F, Scheen, A, Schmitz, O, Sinay, I, Soska, V, Stender, S, Tamás, G, Tognoni, G & NAVIGATOR Study Group 2010, 'Effect of nateglinide on the incidence of diabetes and cardiovascular events', Briefings from the New England Journal of Medicine, vol. 362, no. 16, pp. 1463-76. https://doi.org/10.1056/NEJMoa1001122

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title = "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.)",

author = "Holman, {Rury R} and Haffner, {Steven M} and McMurray, {John J} and Bethel, {M Angelyn} and Bj{\"o}rn Holzhauer and Hua, {Tsushung A} and Yuri Belenkov and Mitradev Boolell and Buse, {John B} and Buckley, {Brendan M} and Chacra, {Antonio R} and Fu-Tien Chiang and Bernard Charbonnel and Chun-Chung Chow and Davies, {Melanie J} and Prakash Deedwania and Peter Diem and Daniel Einhorn and Vivian Fonseca and Fulcher, {Gregory R} and Zbigniew Gaciong and Sonia Gaztambide and Thomas Giles and Edward Horton and Hasan Ilkova and Trond Jenssen and Kahn, {Steven E} and Henry Krum and Markku Laakso and Leiter, {Lawrence A} and Levitt, {Naomi S} and Viacheslav Mareev and Felipe Martinez and Chantal Masson and Theodore Mazzone and Eduardo Meaney and Richard Nesto and Changyu Pan and Rudolf Prager and Raptis, {Sotirios A} and Rutten, {Guy E H M} and Herbert Sandstroem and Frank Schaper and Andre Scheen and Ole Schmitz and Isaac Sinay and Vladimir Soska and Steen Stender and Gyula Tam{\'a}s and Gianni Tognoni and Steen Stender",

note = "2010 Massachusetts Medical Society",

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doi = "10.1056/NEJMoa1001122",

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T1 - Effect of nateglinide on the incidence of diabetes and cardiovascular events

AU - Holman, Rury R

AU - Haffner, Steven M

AU - McMurray, John J

AU - Bethel, M Angelyn

AU - Holzhauer, Björn

AU - Hua, Tsushung A

AU - Belenkov, Yuri

AU - Boolell, Mitradev

AU - Buse, John B

AU - Buckley, Brendan M

AU - Chacra, Antonio R

AU - Chiang, Fu-Tien

AU - Charbonnel, Bernard

AU - Chow, Chun-Chung

AU - Davies, Melanie J

AU - Deedwania, Prakash

AU - Diem, Peter

AU - Einhorn, Daniel

AU - Fonseca, Vivian

AU - Fulcher, Gregory R

AU - Gaciong, Zbigniew

AU - Gaztambide, Sonia

AU - Giles, Thomas

AU - Horton, Edward

AU - Ilkova, Hasan

AU - Jenssen, Trond

AU - Kahn, Steven E

AU - Krum, Henry

AU - Laakso, Markku

AU - Leiter, Lawrence A

AU - Levitt, Naomi S

AU - Mareev, Viacheslav

AU - Martinez, Felipe

AU - Masson, Chantal

AU - Mazzone, Theodore

AU - Meaney, Eduardo

AU - Nesto, Richard

AU - Pan, Changyu

AU - Prager, Rudolf

AU - Raptis, Sotirios A

AU - Rutten, Guy E H M

AU - Sandstroem, Herbert

AU - Schaper, Frank

AU - Scheen, Andre

AU - Schmitz, Ole

AU - Sinay, Isaac

AU - Soska, Vladimir

AU - Stender, Steen

AU - Tamás, Gyula

AU - Tognoni, Gianni

AU - NAVIGATOR Study Group

N1 - 2010 Massachusetts Medical Society

PY - 2010/4/22

Y1 - 2010/4/22

N2 - 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.)

AB - 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.)

U2 - 10.1056/NEJMoa1001122

DO - 10.1056/NEJMoa1001122

M3 - Journal article

SN - 1531-7242

VL - 362

SP - 1463

EP - 1476

JO - Briefings from the New England Journal of Medicine

JF - Briefings from the New England Journal of Medicine

IS - 16

ER -

Effect of nateglinide on the incidence of diabetes and cardiovascular events

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