Effects of intensive glucose lowering in type 2 diabetes.

Pubmed ID: 18539917

Pubmed Central ID: PMC4551392

Journal: The New England journal of medicine

Publication Date: June 12, 2008

MeSH Terms: Humans, Male, Adult, Female, Aged, Cardiovascular Diseases, Middle Aged, Hypertension, Proportional Hazards Models, Follow-Up Studies, Kaplan-Meier Estimate, Diabetes Mellitus, Type 2, Blood Glucose, Drug Therapy, Combination, Treatment Failure, Hypoglycemic Agents, Hypoglycemia, Glycated Hemoglobin

Grants: N01HC95184, Y01 HC001010, N01-HC-95180, Y01 HC009035, N01-HC-95184, IAA-Y1-HC-1010, N01HC95181, N01-HC-95182, N01HC95179, N01-HC-95183, N01-HC-95178, N01HC95182, N01HC95180, N01-HC-95179, N01-HC-95181, N01HC95178, IAA-Y1-HC-9035, N01HC95183, P30 NR005035

Authors: Gerstein HC, Miller ME, Byington RP, Goff DC, Bigger JT, Buse JB, Cushman WC, Genuth S, Ismail-Beigi F, Grimm RH, Probstfield JL, Simons-Morton DG, Friedewald WT, Gotto AM, Bailey K, Gohdes D, Haffner S, Hiss R, Jamerson K, Lee K, Nathan D, Sowers J, Walters L, Friedewald WT, Buse JB, Bigger JT, Byington RP, Cushman WC, Gerstein HC, Ginsberg HN, Goff DC, Grimm RH, Ismail-Beigi F, Probstfield JL, Simons-Morton DG, Gerstein HC, Yusuf S, Punthakee Z, Russo R, Anand S, Cracknell B, Cukierman-Yaffe T, Gafni A, Guyatt G, Hall S, Kaszyca J, Lonn E, McLeod D, Read K, Reiding V, Shehadeh N, Tadeson B, Thompson K, Vallis M, Vasudeva V, Wilderman I, Punthakee Z, Smith A, Stanton I, Capes S, Danby S, Harper W, Harvey P, Hunt D, Manjoo P, Moroso A, Otto R, Prebtani A, Valla T, Punthakee Z, Davis A, Capes S, Hill KL, McCarthy V, Edwards AL, Mitchell DJ, Clearwaters MA, Dielissen C, Gillam M, Hammond B, Jensen H, Kherani A, Lau D, Pringle V, Rabi D, Sigal R, Smith C, Walker M, Williams G, Joyce C, Parsons M, Rowe B, Burton J, Chandurkar V, Coady-McDonald S, Gibbons D, Kovacs C, Murphy B, Smart R, Varghese S, Mereu L, Ryan E, Senior P, Kirkland P, Abe J, Dalton K, Gendall W, Germsheid J, Hartman D, Jeffrys A, MacDonald C, Makhani N, Mawani S, Morales F, Paty B, Pick M, Schwanke B, Stark A, Tennant M, Varma S, Werbiski-Wood P, Woloschuk B, Zimmerman W, Bélanger A, Gauthier S, Bahsali G, Barbeau C, Caponi E, Duchesne R, Dumas R, Gauthier P, Girouard J, Kandalaft N, Labbé M, Palardy J, Pilon M, Raymond J, Schiffrin A, Hramiak I, Tereschyn S, Driscoll M, Gehring M, Gonder J, Lincoln C, McBeth W, McDonald C, McDonald T, Pauli P, Paul T, Powers S, Ronald N, Trinh V, Vancer L, Walsh G, Lochnan H, Ooi TC, Maranger J, Bate R, Bradley L, Buhrmann R, Cyr M, Gilchrist C, Hanlon B, Harley M, Jay K, Leech T, Malcolm J, McLean M, Parker E, Sigal R, Sullivan K, Yale JF, Segal SA, Renouf N, Allaire N, Alawadhi MA, Belfer B, Blank DW, Bouchard F, Buoy-Phang S, Carter J, Coppin L, Dalpe D, Delpech I, Doran PM, Emmian F, Fortin S, Garfield N, Gosselin M, Horan S, Kalergis M, Koutelias S, Légaré C, Lombardo A, Morais JA, Quigley M, Renouf N, Riopel C, Riopel S, Rivera JA, Rochon G, Roy M, Salera M, Sherman MH, Shingler M, Staples HE, Ulyatt L, Yared Z, Leiter LA, Booth G, Sparrow L, Choi H, Bedard DC, Berger A, Berndl LA, Cheng A, Evalmplev V, Goguen J, Hanna A, Josse RG, Kalas JA, Perry S, Pike M, Elliott T, Dawson K, Kong J, Inducil M, Al Amoudi R, Broughton T, Hall L, Harrison B, Hirvi N, Lee R, Norman E, Paty B, Potter M, Stevenson D, Vafadaran A, Woo V, Berard L, Anderlic T, Austman K, Bernard A, Catte D, Darvill P, Hak D, Hutchison K, Janzen L, Klopak T, Mandock C, Mathen M, Mawani S, Mawani A, Murphy L, Nyomba G, Penner B, Pockett S, Russell S, Stockl F, Studney J, Sukkau R, Abbott C, Ur E, Yuille M, Archibald M, Cruess A, Davis N, Fong H, Frizzell S, Hanway B, Hoskin-Mott A, Imran A, Ingraham C, McCarthy G, Murdock H, Palmer T, Patterson AM, Ransom T, Shu D, Tuttle J, Probstfield JL, Kingry C, Line AS, Corson MA, Knopp R, Lipkin E, Sullivan MD, Johnson J, Griswold C, Liebert K, Brown A, Juliano D, Kurashige EM, Moberg S, Ariani K, Karunaratne K, Azizad M, Chow C, Gutierrez H, Partamian J, Toven J, Mular J, Sanders S, Haywood LJ, Kamdar V, DeQuattro DL, Wang L, Song Z, Miller C, Becerra L, Qi Cai A, Pruitt C, DeQuattro V, Failor R, Ellsworth A, Jackson N, Miller C, Britt D, Dobie S, Hirsch I, Khakpour D, Quaempts R, Stoffel W, Wilcox T, Neighbor W, Cappocia K, Force R, Macdonald M, Lusk S, Liday C, Borzadek E, Koester S, Pettinger T, Solbrig R, Waldron C, Pettingill K, Woodhouse W, Hoover B, Linz PE, Pepper PV, Kozlowski J, Chase C, Samuelson D, Gutierrez P, Gonzales C, Engle M, Coopersmith J, Griffin S, Lammers R, Leon J, Riddle MC, Hanavan KA, McDaniel PA, Swift R, Ahmann AJ, Gammell-Matthews SC, Karl DM, Burden V, MacNeil B, MacMurray M, Weiss J, Carlson C, DesRochers SK, Negreanu D, Stephens EA, Wysham C, Weeks D, Kuntsmann L, Maxwell L, 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Cite As: Action to Control Cardiovascular Risk in Diabetes Study Group, Gerstein HC, Miller ME, Byington RP, Goff DC Jr, Bigger JT, Buse JB, Cushman WC, Genuth S, Ismail-Beigi F, Grimm RH Jr, Probstfield JL, Simons-Morton DG, Friedewald WT. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008 Jun 12;358(24):2545-59. Epub 2008 Jun 6.

Studies:

Abstract

BACKGROUND: Epidemiologic studies have shown a relationship between glycated hemoglobin levels and cardiovascular events in patients with type 2 diabetes. We investigated whether intensive therapy to target normal glycated hemoglobin levels would reduce cardiovascular events in patients with type 2 diabetes who had either established cardiovascular disease or additional cardiovascular risk factors. METHODS: In this randomized study, 10,251 patients (mean age, 62.2 years) with a median glycated hemoglobin level of 8.1% were assigned to receive intensive therapy (targeting a glycated hemoglobin level below 6.0%) or standard therapy (targeting a level from 7.0 to 7.9%). Of these patients, 38% were women, and 35% had had a previous cardiovascular event. The primary outcome was a composite of nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes. The finding of higher mortality in the intensive-therapy group led to a discontinuation of intensive therapy after a mean of 3.5 years of follow-up. RESULTS: At 1 year, stable median glycated hemoglobin levels of 6.4% and 7.5% were achieved in the intensive-therapy group and the standard-therapy group, respectively. During follow-up, the primary outcome occurred in 352 patients in the intensive-therapy group, as compared with 371 in the standard-therapy group (hazard ratio, 0.90; 95% confidence interval [CI], 0.78 to 1.04; P=0.16). At the same time, 257 patients in the intensive-therapy group died, as compared with 203 patients in the standard-therapy group (hazard ratio, 1.22; 95% CI, 1.01 to 1.46; P=0.04). Hypoglycemia requiring assistance and weight gain of more than 10 kg were more frequent in the intensive-therapy group (P<0.001). CONCLUSIONS: As compared with standard therapy, the use of intensive therapy to target normal glycated hemoglobin levels for 3.5 years increased mortality and did not significantly reduce major cardiovascular events. These findings identify a previously unrecognized harm of intensive glucose lowering in high-risk patients with type 2 diabetes. (ClinicalTrials.gov number, NCT00000620.)