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N Engl J Med. 2011 Mar 3;364(9):818-28. doi: 10.1056/NEJMoa1006524.

Long-term effects of intensive glucose lowering on cardiovascular outcomes.

Collaborators (1240)

Gotto AM Jr, 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, Ismail-Beigi F, Gerstein HC, Ginsberg HN, Goff DC Jr, Grimm RH Jr, Probstfield JL, Simons-Morton DG, Gerstein HC, Yusuf S, Punthakee Z, Russo R, Anand S, Chrysler K, Cracknell B, Cukierman-Yaffe T, Gafni A, Guyatt G, Hall S, Kaszyca J, Lonn E, Mackie P, Reiding V, Shehadeh N, Tadeson B, Thompson K, Vallis M, Vasudeva V, Wilderman I, Wright D, Punthakee Z, Smith A, Stanton I, Capes S, Manjoo P, Valla T, Danby S, Harper W, Harvey P, Hunt D, Moroso A, Otto R, Prebtani A, 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, CoadyMcDonald 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, Hartmann D, Jeffrys A, Kumar U, MacDonald C, Makhani N, Mawani S, Morales F, Paty B, Pick M, Schwanke B, Stark A, Tennant M, Varma S, Weiss-Aburto D, WerbiskiWood 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, 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, Al Ansari G, Renouf N, Allaire N, Alawadhi MA, Belfer B, Blank DW, Bouchard F, BuoyPhang 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, Albiani D, Inducil M, Al Amoudi R, Broughton T, Hall L, Harrison B, Hirvi N, Lee R, Merkur A, 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, Clayton D, 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, Leader J, Ariani K, Karunaratne K, Azizad M, Chow C, Gutierrez H, Partamian J, Toven J, Toven J, Mular J, Sanders S, Haywood LJ, Kamdar V, DeQuattro DL, Wang L, Song Z, Becerra L, Cai AQ, Pruitt C, DeQuattro V, Failor R, Ellsworth A, Jackson N, Miller C, Britt D, Dobie S, Hirsch I, Khakpour D, Quaempts R, Stoffel W, Neighbor W, Cappocia K, Hawkins V, Tapp L, Force R, Macdonald M, Pettingill K, Liday C, Koester S, Pettinger T, Solbrig R, Waldron C, Woodhouse W, Hoover B, Lusk S, Wilcox T, Hachey D, Linz PE, Pepper PV, Kozlowski J, Chase C, Griffin C, Samuelson D, Gutierrez P, Gonzales C, Engle M, Coopersmith J, Griffin S, Lammers R, Leon J, Zirkle D, Hollingsworth S, 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, Gale D, Wysham C, Weeks D, Kuntsmann L, Maxwell L, Yedinak S, Pena H, Kistler J, White J, Dudl J, Lyons L, House B, Murray M, Stevenson R, Wu P, Palma A, Briere S, Wilson T, Becker D, Harden K, Hawley C, Dailey G, Baron M, Gianella A, Jacobson M, Farro E, Philis-Tsimikas A, Banares A, Bravo-Medina A, Horne J, Esquer E, Morrissey R, Grimm RH Jr, Kirpach BR, Bartkoske MM, Boyce CM, Druckman N, Gillett AM, Levin JA, Livingston GJ, Murray AM, Wood H, Margolis KL, Kempainen S, Madden M, Fareed MT, Hall K, Moor R, Wood K, Bergenstal R, Cuddihy R, Davick B, Hokanson J, Johnson M, Lausch M, List S, Monk A, Robinson R, Smith K, Whipple D, Damberg G, Hahn R, Koenig V, Magadan M, Sabin-Smith S, Stewart P, Strock E, Peremislov D, Gunyou K, Passi R, Ashanti C, Thomas L, Stoffels D, Seaquist ER, Mech MV, Benedict LE, Demmon DJ, Kendall D, Kumar AF, Martinson SM, Miller SA, Pease C, Rao JP, Redmon JB, Swanson JE, Wimmer JK, Okorocha Y, Stiles M, Kodl C, Chadha C, Peterson KA, Seaquist LA, Boese C, Cruciani M, Dodds E, Ek FP, Feldman JL, Fontaine P, Lange CJ, Mendenhall TJ, Peterson AM, Rudelt A, Schrock TM, Spielman DP, Velasco S, Weinhand JC, 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, Quinlan M, Fox CR, Bate BM, Cao QT, Ohnstad MM, Meyers PJ, 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, Smith K, Wells D, Genuth S, Ismail-Beigi F, Thibonnier M, Vargo L, Kelly C, Bongorno T, Dolish A, Pavlik L, Tiktin M, Isteitieh S, Bartlett A, Kulow T, Ismail-Beigi F, Krikorian A, Moore L, Richardson L, Coles-Herman E, Yee K, Frankino J, Jing M, Sood A, Hustak L, Julius M, Pavlik L, Ross T, Long L, Schwing W, Tiktin M, Sullivan MK, Strauss L, Behm K, Eskandari F, Hall C, Hayes D, Horowitz K, Isteitieh S, Madhun Z, Seeholzer E, Shina J, Taylor H, Schnall A, Huang S, Heeg M, Tang J, Belkin J, Lee MS, Joly T, Sadler LS, Griffith M, Hornsby A, Klyn K, Ospelt E, Long L, DeSmit M, McCann P, Schmidt NP, Gottfried C, Kulow T, Zaletal J, Kapadia MS, Smith L, Schnall AM, Dragmen L, Ellert R, Smith J, Leksan J, Sussman T, Huang S, Heeg M, Tang J, Belkin J, Lee MS, Joly T, Ismail-Beigi F, Hustak L, Julius M, Schwing W, Tiktin M, Anselmo J, Eskandari F, Daymeyer S, Hall C, Hayes D, Horowitz K, Isteitieh S, Johnson C, Kern E, Richmond MA, Richardson L, Roberts K, Shina J, Sood A, Suhan P, Taylor H, Watts S, Martin J, Moor L, Burtch B, Ober S, Strauss GJ, Leone A, Belkin J, Huang S, Frank K, Stephens D, Lee MS, Joly T, Hoogwerf BJ, Brakeman J, Matzinger M, Newsome J, Becker J, Bizjack S, Clingman B, Curtas-Thomas S, Depietro G, Ellert R, Horner C, Bunae G, Hamrahian A, Hawkins A, Head T, Iannica S, Jones L, Kaiser P, McCoy R, Mehta A, Olansky L, Orasko A, Reddy S, Ross D, Shockley L, Siraj E, Williams M, Zimmerman R, Hamaty M, Weiss D, Fagan KA, Hanslik TM, Farrell J, Brys P, Oligny M, Prokop K, Lenardic K, Karapanzcik T, Huang S, Heeg M, Tang J, Belkin J, Lee MS, Joly T, Akpunonu B, Franco-Saenz R, Gilmore J, Gilmore M, Godfrey L, Ross P, Bauer B, Chrisstie M, Lopez A, Mulrow P, Peters C, Pop-Busui R, Roman J, Smith C, Bick J, Blust Z, Nelsen PT, Marcus D, Osei K, Dziengelewski EA, Breedlove H, Boland D, Boyer CC, Cataland S, Kearns PA, Irwin JE, Schuster DP, Varga-Spangler JL, Bowles T, Weiland K, Arnold K, Evans T, Bouttamy J, Letson A, Craig E, Davidorf F, Cohen RM, Burton K, Craig J, Carter B, Harrer J, Hurd R, Lopez-Stickney D, Pritchard C, Pfefferman A, Ramlo-Halsted BA, McCormick C, Riley C, Strominger M, Knittel A, Groff G, Bailey C, Howald A, Anderson N, Bierschbach JL, Tyzinski M, Smith B, Krug S, Hershberger V, Hutchins RK, Raymond LA, Thomas A, Kahkonen DM, Cushman T, Roman M, Stys AM, White K, Austin M, Chatterton C, Francis JK, Jones C, Kruger D, McLellan A, Whitehouse F, Higgins E, Levy S, Schoenherr A, Edwards P, Grunberger G, Aman LC, Bandagi AH, Russell KM, Tucker C, Abidova Y, Amirikia A, Narduccio M, Billingsly B, Bigger JT, Lopez-Jimenez CR, Bornholdt R, Busaca L, Ginsberg HN, Gonzales P, Gosh D, Love P, Kosok A, Robinson E, Steinman R, Watson C, Reyes G, 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, Stewart AF, Brillon D, Cordero J, Richardson MA, Wei E, Ganz F, Meyer BR, Paley J, Anderson S, 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, Fischer R, 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, Getaneh A, Ramirez J, Vasquez EF, Kranwinkel G, Durant SA, Donovan DS, Febres G, Hernandez C, Jonaitis MA, Mesa L, Banerji MA, Norton M, Patel P, Daly V, Hirsch S, Jazmin C, Khillan R, Mendonca D, Relingado A, Sandoval E, Tiewala M, Banerji MA, Norton M, Patel P, Daly V, Hirsch S, Jazmin C, Khillan R, Mendonca D, Relingado A, Sandoval E, Tiewala M, Goff DC Jr, Summerson JH, Crago L, Blackwell CS, Bertoni A, Blaine RL, Kirk JK, Spach RL, Williamson J, Calles J, Katula J, Wishnietsky DB, Feinglos MN, Jones J, Mason MB, Furst MA, Bean WJ, Gedon-Lipscomb G, Green JB, Parham T, Satterwhite BM, Thacker CR, Padhiar D, Noel R, Padhiar N, West S, Braden J, Francis A, Atkinson HH, Dibari M, Allen J, Stanfield J, Delvalle-Fagan T, Gordineer LJ, Gordon L, Gordon M, Smith SL, Yates H, Pedley CF, Zurek G, Baird M, Dunn B, Kinder W, Mauney S, Buse JB, Duclos MD, Kirby RE, Largay JF, McDermott NM, Goley A, Braithwaite SS, Dostou JM, Fasy EA, Kelly DC, Metz CE, Jeffries J, Rubin D, Vukojicik K, Miller JL, Besterman W, Norton SM, Weatherly J, Bishop S, Cross B, Nuss K, Surgenor M, Alley D, Farmer A, Foard J, White J, Wood Y, Gross B, Dulin M, Konen J, Barringer T, Andrews K, Hoffman C, Morris C, Norton S, Tochiki P, Reinblatt G, Bruner P, Peace R, Stuart DO, Strickland J, Cummings L, Craig D, Stanfield J, Morgan J, Peace R, Stuart DO, Strickland J, Cummings L, Craig D, Stanfield J, Williams G, Crouse JR, Menon L, Marion S, Davis D, Cabrera B, Calles J, Chandler T, Ellis J, Kouba E, Riddle P, Myers E, Fonseca V, John-Kalarickal J, McDuffie RH, Asafu-Adjaye NO, Leger SM, Reilly P, 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, Johnson C, 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, Cushman WC, Geraci TS, Walsh SM, Coley LG, Elam MB, Pickering DI, Huff C, Elam MB, Thompson CW, Lichtermann L, Peeples S, Turner-Bates J, Heimberg M, Childress D, Turner J, Jasper J, Coley J, Hamilton BP, Hamilton J, Kuzbida G, Hatten W Jr, Lancaster A, Haywood J, Luck J, Bannerman-Wood D, Felicetta J, Bourne-Collo M, Svoboda ME, Clothier D, Deitz M, Flaugher C, Hayward P, Scheibe T, Velarde S, Heritage S, Nelson JP, Heritage D, Martinez C, Sweeney ME, Harrelson D, McConnell S, Watson F, Johnson R, Whittington L, Nanes M, Salles M, Rice C, Cowden C, Basile J, Ham DB, North-Lee B, Baig HA, Rehman SU, Mixson J, Nelson D, Kirchner KA, Hinton LA, Mack L, Adair C, James B, Spencer A, Jones A, Katz L, Richardson EA, Goldberg AG, Nieves A, Russo JE, Adams J, Sochalski SA, Coles M, Anderson S, Williams M, Hoffman D, Papademetriou V, Gregory B, Alignay R, Nylen E, Rajendran B, Hodges R, Amodeo S, Ross A, Notargiacomo A, Metcalfe M, Narayan P, Wojackovski D, Giddings S, Clark E, Pittler A, Davis R, Harris P, Waidmann K, Conwill L, Felton S, Chen A, Simmons DL, Cooper JJ, Dishongh K, Bates R, Bhaghayath K, Choksi P, Conley S, Elbein S, Faas F, Hamid Z, Johnson J, Johnson P, Mayo A, Moriarty MS, Nair G, Rani D, Rasouli N, Said S, Rassouli N, Rodriguez M, Thomas K, Watson K, Williams D, Makdissi A, Byington RP, Ambrosius WT, Anderson RT, Barnes J, Beal J, Bell C, Bonds DE, Burton S, Collins C, Cook D, Craven B, Craven T, Dunbar D, Evans GW, Feeney P, Furberg CD, Greven C, Griffin J, Harvin L, Hepler J, Howard L, Howard-Perdue LT, Hough M, Hwang W, Kimel A, Lefkowitz D, Lopina A, Lovato J, Lovato LC, Miller ME, Reboussin D, Rushing S, Sanders L, Sims L, Stowe C, Walkup M, Wilmoth S, Wilson K, Woolard N, Raisch D, Ringer R, Sather M, DelCurto B, Garnand D, Prineas R, Campbell C, Zhang Z, Kesler L, Hall S, Hensley S, Li Y, Soliman EZ, Milne D, Marcovina S, Chmielewski J, Gadbois K, Gaur V, Strylewicz G, Ramirez M, Waddell S, Mehan M, Bryan RN, Davatzkios C, Moonis G, Desiderio L, D'Arcy S, Davis M, Danis R, Gangaputra S, Hubbard L, Robinson N, Dingledine J, Thayer D, Wabers H, Neider M, Esser B, Harding T, Susman R, Hurtenbach C, Gama V, Schiffman M, Johnson S, Graham T, Simons-Morton DG, Cooper L, Domanski M, Nwachuku C, Rosenberg Y, Salive M, Savage P, Fleg JL, Cutler JA, Geller N, Follmann D, Proschan M, Jennings C, Schaeffer E, Mills P, Bittner J, Kirby R, Frommer P, Fine L, Chan J, Fradkin J, Malozowski S, Meyers C, Hostetter T, Launer L, Chew EY, Albright A, Narayan KM, Engelgau M, Zhang P.

Abstract

BACKGROUND:

Intensive glucose lowering has previously been shown to increase mortality among persons with advanced type 2 diabetes and a high risk of cardiovascular disease. This report describes the 5-year outcomes of a mean of 3.7 years of intensive glucose lowering on mortality and key cardiovascular events.

METHODS:

We randomly assigned participants with type 2 diabetes and cardiovascular disease or additional cardiovascular risk factors to receive intensive therapy (targeting a glycated hemoglobin level below 6.0%) or standard therapy (targeting a level of 7 to 7.9%). After termination of the intensive therapy, due to higher mortality in the intensive-therapy group, the target glycated hemoglobin level was 7 to 7.9% for all participants, who were followed until the planned end of the trial.

RESULTS:

Before the intensive therapy was terminated, the intensive-therapy group did not differ significantly from the standard-therapy group in the rate of the primary outcome (a composite of nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes) (P=0.13) but had more deaths from any cause (primarily cardiovascular) (hazard ratio, 1.21; 95% confidence interval [CI], 1.02 to 1.44) and fewer nonfatal myocardial infarctions (hazard ratio, 0.79; 95% CI, 0.66 to 0.95). These trends persisted during the entire follow-up period (hazard ratio for death, 1.19; 95% CI, 1.03 to 1.38; and hazard ratio for nonfatal myocardial infarction, 0.82; 95% CI, 0.70 to 0.96). After the intensive intervention was terminated, the median glycated hemoglobin level in the intensive-therapy group rose from 6.4% to 7.2%, and the use of glucose-lowering medications and rates of severe hypoglycemia and other adverse events were similar in the two groups.

CONCLUSIONS:

As compared with standard therapy, the use of intensive therapy for 3.7 years to target a glycated hemoglobin level below 6% reduced 5-year nonfatal myocardial infarctions but increased 5-year mortality. Such a strategy cannot be recommended for high-risk patients with advanced type 2 diabetes. (Funded by the National Heart, Lung and Blood Institute; ClinicalTrials.gov number, NCT00000620.).

Comment in

PMID:
21366473
[PubMed - indexed for MEDLINE]
PMCID:
PMC4083508
Free PMC Article

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