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: Goff DC, Goff DC, Goff DC, Smith J, Fonseca V, Macdonald M, Evans GW, Brillon D, White J, Fleg JL, Choi H, Hall L, Reilly P, Ross P, Cook D, Guyatt G, Thomas A, Walker M, Li Y, Huang S, Huang S, Huang S, Huang S, Wang L, Bertoni A, Nelson JP, Brown A, Davis R, Anderson S, Murray M, Hall C, Hall C, Yusuf S, Miller JL, Smith C, Smith C, Furberg CD, Murphy B, Zhang Z, Gotto AM, Sood A, Sood A, Jang H, Hostetter T, Cutler JA, Cushman WC, Cushman WC, Cushman WC, Ambrosius WT, Fine L, Launer L, Clark E, Crago L, Reboussin D, Williamson J, Rushing S, Woolard N, Craven T, Griffin J, Collins C, Craven B, Ringer R, Sather M, Campbell C, Hensley S, Desiderio L, Smith A, Papademetriou V, Horner C, Ober S, Williams M, Long L, Long L, Schnall A, Banerji MA, Banerji MA, Gedon-Lipscomb G, Zurek G, Baird M, Gordon L, Jones C, Robinson E, Johnson C, Johnson C, Hall S, Hall S, Jones L, Getaneh A, Fischer R, Sweeney ME, Johnson R, McConnell S, Watson F, Whittington L, Basile J, Miller C, Miller C, Dishongh K, Johnson J, Johnson J, Katz L, Felicetta J, Weiss J, Giddings S, Gregory B, Ismail-Beigi F, Ismail-Beigi F, Ismail-Beigi F, Ismail-Beigi F, Ismail-Beigi F, Calles J, Calles J, Cohen RM, Cuddihy R, Genuth S, Genuth S, Grimm RH, Grimm RH, Grimm RH, Hamilton BP, Krikorian A, Pop-Busui R, Taylor H, Taylor H, Weiss D, Hramiak I, Friedewald WT, Friedewald WT, Friedewald WT, Buse JB, Buse JB, Buse JB, Bigger JT, Bigger JT, Bigger JT, Byington RP, Byington RP, Byington RP, Gerstein HC, Gerstein HC, Gerstein HC, Ginsberg HN, Ginsberg HN, Probstfield JL, Probstfield JL, Probstfield JL, Simons-Morton DG, Simons-Morton DG, Simons-Morton DG, Punthakee Z, Punthakee Z, Punthakee Z, Russo R, Anand S, Cracknell B, Cukierman-Yaffe T, Gafni A, Kaszyca J, Lonn E, Reiding V, Shehadeh N, Tadeson B, Thompson K, Vallis M, Vasudeva V, Wilderman I, Kirpach BR, Bartkoske MM, Boyce CM, Druckman N, Gillett AM, Levin JA, Livingston GJ, Murray AM, Wood H, Margolis KL, Lopez-Jimenez CR, Bornholdt R, Gonzales P, Gosh D, Love P, Kosok A, Steinman R, Watson C, Reyes G, Thibonnier M, Vargo L, Kelly C, Bongorno T, Dolish A, Pavlik L, Pavlik L, Tiktin M, Tiktin M, Tiktin M, Isteitieh S, Isteitieh S, Isteitieh S, Kulow T, Summerson JH, Blackwell CS, Blaine RL, Kirk JK, Spach RL, Katula J, Wishnietsky DB, Geraci TS, Walsh SM, Coley LG, Elam MB, Elam MB, Pickering DI, Kingry C, Line AS, Corson MA, Knopp R, Lipkin E, Sullivan MD, Griswold C, Liebert K, Juliano D, Kurashige EM, Moberg S, Stanton I, Capes S, Capes S, Manjoo P, Valla T, Danby S, Harper W, Harvey P, Hunt D, Moroso A, Otto R, Prebtani A, Davis A, 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, Sigal R, Williams G, Joyce C, Parsons M, Rowe B, Burton J, Chandurkar V, Coady-McDonald S, Gibbons D, Kovacs C, Smart R, Varghese S, Mereu L, Ryan E, Senior P, Kirkland P, Abe J, Dalton K, Gendall W, Germsheid J, Jeffrys A, MacDonald C, Makhani N, Mawani S, Mawani S, Morales F, Paty B, 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, 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, Bradley L, Buhrmann R, Cyr M, Gilchrist C, Hanlon B, Harley M, Jay K, Leech T, Malcolm J, McLean M, Parker E, Sullivan K, Yale JF, Segal SA, Renouf N, 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, Riopel C, Riopel S, Rivera JA, Rochon G, Roy M, Salera M, Sherman MH, Shingler M, Staples HE, 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Seaquist ER, Mech MV, Benedict LE, Demmon DJ, Kumar AF, Martinson SM, Miller SA, Pease C, Rao JP, Redmon JB, Swanson JE, Wimmer JK, Seaquist LA, Boese C, Cruciani M, Dodds E, Feldman JL, Fontaine P, Lange CJ, Mendenhall TJ, Peterson AM, Rudelt A, Schrock TM, Spielman DP, Velasco S, Sperl-Hillen JM, O'Connor PJ, Busch ME, Chung A, Klein BK, Krugen N, Bunkers-Lawson T, Ekstrom HL, Gunderson HS, Johnson BM, MacIndoe JH, Prewedo DJ, Rawl JL, Roethke CM, Sivitz WI, Wayson SM, Lower TA, Larson L, Ahrens LA, Bayless M, Beck SE, Chahal J, Chenard C, Doelle GC, Guzman VM, Kabadi UM, Ochs KA, Rahhal A, Spanheimer RG, Snetselaar L, Wells D, Schubart UK, Mendoza M, Goswami G, Laufer A, Russo J, Vincenty N, Alderman MH, Carroll L, Sanguily MJ, Gorkin JU, Mayer AC, Ramos L, Sessoms V, Cordero J, Richardson MA, Wei E, Ganz F, Meyer BR, Paley J, Charles C, Dwoskin A, Chiong R, Hyams K, Lorber DL, Arenstein T, Depree P, Elmorsy AA, Wendel JM, Zintl LL, August P, Beck M, Goldberg MD, Hofacker MJ, Marotta-Kollarus M, Ocampo EJ, Resta CA, Tibaldi JM, Bastien A, Grudzinski S, Niblack P, Abreu L, Brobyn T, Brown K, Casale M, Dougherty D, Haddad G, Heintz K, Kelly M, Linneman D, Olivia C, Salvador MA, Zee P, Hyman D, Brautigam DF, Chiarot JM, Scharf DM, Nunn B, Carlson J, Flanders C, Hagen MR, Newman S, Gordon TA, Goland R, Tuck CH, Kringas P, Hey-Hadavi J, Montes J, Vargas-Jerez J, Salas-Spiegel J, Ramirez J, Vasquez EF, Kranwinkel G, Donovan DS, Febres G, Hernandez C, Jonaitis MA, Mesa L, Norton M, Norton M, Patel P, Patel P, Daly V, Daly V, Hirsch S, Hirsch S, Jazmin C, Jazmin C, Khillan R, Khillan R, Mendonca D, Mendonca D, Relingado A, Relingado A, Sandoval E, Sandoval E, Tiewala M, Tiewala M, Moore L, Moore L, Richardson L, Richardson L, Coles-Herman E, Yee K, Frankino J, Jing M, Hustak L, Hustak L, Julius M, Julius M, Ross T, Schwing W, Schwing W, Sullivan MK, Strauss L, Behm K, Eskandari F, Eskandari F, Hayes D, Hayes D, Horowitz K, Horowitz K, Madhun Z, Seeholzer E, Shina J, Shina J, Heeg M, Heeg M, Heeg M, Tang J, Tang J, Tang J, Belkin J, Belkin J, Belkin J, Belkin J, Lee MS, Lee MS, Lee MS, Lee MS, Joly T, Joly T, Joly T, Joly T, Sadler LS, Griffith M, Hornsby A, Klyn K, Ospelt E, DeSmit M, McCann P, Schmidt NP, Gottfried C, Zaletal J, Kapadia MS, Schnall AM, Dragmen L, Ellert R, Ellert R, Leksan J, Sussman T, Anselmo J, Kern E, Richmond MA, Roberts K, Suhan P, Watts S, Martin J, Burtch B, Strauss GJ, Leone A, Frank K, Stephens D, Hoogwerf BJ, Brakeman J, Matzinger M, Newsome J, Becker J, Bizjack S, Clingman B, Depietro G, Bunae G, Hamrahian A, Hawkins A, Head T, Iannica S, Kaiser P, McCoy R, Mehta A, Olansky L, Orasko A, Reddy S, Ross D, Shockley L, Siraj E, Zimmerman R, Fagan KA, Hanslik TM, Farrell J, Brys P, Oligny M, Prokop K, Lenardic K, Karapanzcik T, Akpunonu B, Franco-Saenz R, Gilmore J, Gilmore M, Godfrey L, Bauer B, Chrisstie M, Lopez A, Mulrow P, Peters C, Roman J, Bick J, Blust Z, Nelsen PT, Marcus D, Osei K, Dziengelewski EA, Breedlove 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MD, Kirby RE, Largay JF, McDermott NM, Goley A, Braithwaite SS, Dostou JM, Fasy EA, Kelly DC, Metz CE, Jeffries J, Rubin D, Norton SM, Weatherly J, Bishop S, Cross B, Nuss K, Surgenor M, Wood Y, Konen J, Barringer T, Andrews K, Hoffman C, Morris C, Tochiki P, Reinblatt G, Bruner P, Peace R, Peace R, Stuart DO, Stuart DO, Strickland J, Strickland J, Cummings L, Cummings L, Craig D, Craig D, Crouse JR, Menon L, Marion S, Davis D, Cabrera B, Chandler T, Ellis J, Kouba E, Riddle P, Myers E, McDuffie RH, Asafu-Adjaye NO, Leger SM, Afner G, Arrey F, Asnani S, Borshard E, Boyd D, Cemo A, Chennur S, Dupart P, Garg R, Girindra GP, Gouda B, Itoua-N'Ganongo W, Innocent-Ituah I, Kuhadiya N, Kukreja M, Mangan-Mbondi I, Mason S, McLain C, Naylyanya J, Nazereth K, Nazereth S, Singh S, Thethi T, Varnado K, Williams R, Barzilay JI, Eley M, Bader K, Curry-Ball D, Goodman S, Stevens M, Thompson CW, Lichtermann L, Peeples S, Turner-Bates J, Heimberg M, Childress D, Turner J, Jasper J, Coley J, Hamilton J, 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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.)