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N Engl J Med. 2017 Sep 28;377(13):1228-1239. doi: 10.1056/NEJMoa1612917. Epub 2017 Sep 14.

Effects of Once-Weekly Exenatide on Cardiovascular Outcomes in Type 2 Diabetes.

Collaborators (899)

Califf RM, Patel R, George J, Sourij H, Wong YW, Hannan K, Sellers MA, Gottlieb P, Lavender P, Leloudis D, Meadows Y, Larson D, Anderson H, Elkins M, Stone A, Tisch A, Perkins L, Sanders K, Campbell C, Kennedy I, Heal P, Masterson M, Darbyshire J, Mumtaz L, Athwal R, Ferch A, Batra P, Durborow L, Vincent J, Woodall A, Flanagan T, Katona B, Reicher B, Pozzi E, Oulhaj A, Coleman R, Rouleau JL, Pocock SJ, Gorelick F, McMurray J, Riddle M, Gagel R, Collier T, Markovic T, Kong APS, Hian SK, Scott R, Panelo A, Yoon KH, Sheu W, Sritara P, Linong J, Pan C, Yong H, Schernthaner G, Mathieu C, Tankova T, Widimsky P, Hanefeld M, Keltai M, Wainstein J, del Prato S, Pirags V, Jakuboniene N, Kooy A, Dziemidok P, Veresiu IA, Dreval AV, Murin J, Torello AL, Sattar N, Parkhomenko O, Omar M, Diaz R, Lopes R, Lanas F, Urina Triana M, Leiva-Pons JL, Aguliera D, Bergenstal R, Goodman S, Yale JF, Caterson I, Weng J, Hu D, Junbo G, Zannad F, Anoop M, Ambrish M, Gallegos JA, Green JB, Akerblom A, Alexander K, Al-Khatib S, Armaganijan L, Barros P, Batit M, Bernacki G, Bernandez S, Bloomfield G, Clausen E, De Souza Brito F, DeVore A, Dombrowski K, Eapen Z, Gellad Z, George D, Guimaraes P, Halim S, Harrison R, Hawes J, Hess C, Hyland K, Jackson L, Jones S, Jordan D, Katz M, Kong D, Koshizaka M, Lakey W, LeBlanc T, Leonardi S, Luo N, Mahaffey K, Mandawat A, Mehta R, Melloni C, Morse M, Pagidpati N, Patel C, Patel K, Pokorney S, Posvic T, Rao M, Roe M, Shah B, Tillmann H, Truffa A, Wong YW, Zazula A, Zeitler E, Sicer M, Ulla MR, Maffei L, Klyver MI, Calella P, Alvarisqueta A, De La Fuente RL, Aizenberg D, Roque F, Cruciani A, Frechtel G, Gelersztein E, Villarino A, Mallagray M, Nardone L, Zaidman C, Novaretto L, Bartolacci I, de Salvo M, Delcourt C, Crimmins D, Jackson R, O’Neal D, Colman P, Jeffries W, Mah PM, Wittert G, Proietto J, Amerena J, Marks S, Tan R, Colquhoun D, Pieber T, Drexel H, Prager R, Schnack C, Hoppichler F, Fasching P, Francesconi C, Luger A, Schoenherr HR, Ebenbichler C, Paulweber B, Shernthaner G, Verhaegen A, Vanuytsel J, Thissen JP, Barros e Silva P, Gonzaga C, Borges J, Hissa M, Rea R, Rossi P, Chacra A, Eliaschewitz F, Garbelini B, Felicio J, Rassi N, Rossi F, Nunes dos Santos M, Bandeira e Farias F, Lisboa H, Costa e Forti A, Saraiva JK, Kovacheva S, Levterov G, Sheinkova G, Ilieva E, Lyubenova L, Damyanova V, Gushterova V, Mincheva L, Illiev D, Ivanov V, Bobeva R, Nikitov Z, Shumkova R, Lefterov IN, Zaharieva S, Videva V, Yakov A, Cheung S, Elliott T, Mehta P, Ross S, Sigal R, Woo V, Jaffer S, Kuritsky R, Bell A, Dumas R, Gosselin G, Robitaille Y, Greenspoon A, Lochnan H, Tytus R, Yale JF, Leiter L, Pandey A, Punthakee Z, Dube F, Sigalas J, Pearce M, Woodford T, Paul P, Bourgeois R, Conway R, Mazza G, Hatheway R, Misterski J, Raffo C, Olivares C, Godoy J, Potthoff S, Santibañez C, Larenas Yanez GJ, Gu W, Shen F, Ma J, Guo X, Li Q, Du Y, Hu J, Ji L, Li Y, Deng H, Feng Y, Liu L, Mu Y, Ma C, Qu S, Wang J, Wang Y, Yuan Z, Zhang L, Zhou S, Yang T, Dong Y, Liu D, Coronel Arroyo J, Perez Amador G, Botero Lopes R, Jaramilo C, Orozco Linares A, Cure Cure CA, Hernandez Triana E, Molina de Salazar DI, Marin CR, Jaramilo Gomez CJ, Kellinerova I, Adamkova V, Krami P, Brychta T, Havelkova J, Pantikova K, Schoper F, Pohl W, Schumm-Draeger PM, Julius U, Tschöpe D, Hamann A, Seissler J, Schellong S, Rose L, Becker B, Linn T, Oerter EM, Strotmann HJ, Mölle A, Pfutzner A, Forst T, Schäufele T, Mugge A, Lehrke M, Meyer-Pannwitt U, Mehling H, Simon-Wagner I, Schenkenberger I, Busch K, Hermes S, Milek K, Landers B, Grueneberg M, Braun M, Nothroff J, Kamke W, Hergdt G, Duengen HD, Kleinertz K, Kuesters D, Boenninghoff AH, Appel KF, Schaefer A, Bieler T, Ozaki R, Luk AOY, Chu DW, Cheung-Wong MM, Siu DC, Yan BPY, Kung K, Wong SYS, Tsang CC, Yeung VT, Cheung BM, Tse HF, Hodi G, Nagy K, Lippai J, Takacs J, Fulop T, Gaal Z, Pauker Z, Foldesi I, Simon J, Oroszan T, Futo L, Bezzegh K, Nagy A, Vandorfi G, Kiss J, Kesmarki N, Kis E, Takacs J, Papp A, Kovacs A, Szakal I, Palinkas A, Czegany Z, Voros P, Reiber I, Kerenyi Z, Dezso E, Wittman I, Penzes J, Ples Z, Taller A, Farago K, Kis JT, Zilahi Z, Molnar M, Barkai L, Mileder M, Szentpeteri I, Peterfai E, Lovasz O, Mosenzon O, Minuchin O, Jaffe A, Vishlitsky V, Shimon I, Bashkin A, Stern N, Elias N, Bental T, Butnaru A, Lewis B, Adawi F, Nseir W, Klainman E, Herskovits T, Cignarelli M, Rotella CM, Ambrosio G, Pozzilli P, Genovese S, Cavarape A, Salvioni A, Sokolova J, Strautina I, Teterovska D, Stalte V, Pastare S, Leitane I, Lagzdina L, Andersone I, Eglite R, Stelmane I, Levinger A, Barsiene L, Sulskiene M, Varanauskiene E, Danyte E, Urbanaviciene E, Urbanavicius V, Zabuliene L, Juskiene R, Velaviciene A, Kakariekiene V, Augusteniene A, Velickiene D, Lasiene J, Dauksiene D, Caponis J, Tan AT, Ramanathan L, Hassan MRA, Tan F, Ong TK, Foo SH, Ghani RA, Cheah WK, Leiva-Pons JL, Sanchez Mijangos JH, Cabrera Jardines R, Barrientos Perez M, Sauque Reyna L, Alcocer Gamba MA, Villeda Espinosa E, Tamez Perez HE, De La Garza Hernandez NE, Lopes SM, Ramirez Diaz SP, Reyes Sanchez R, Márquez-Rodriguez E, Köse V, Voors-Pette C, Oldenburg-Ligtenberg PC, van Kempen WW, Cox K, Hoogendyk J, Swinkels-Diepenmaat L, Rojas-Lingan G, Kentgens S, Schipperen S, de Valk HW, Swart H, van Bemmel B, Hoogslag PAM, Diamant M, Serné EH, Hamer A, Wilson S, Fisher N, Dixon P, Chaudhri O, Crawford V, Quinn D, Nirmalaraj K, Dunn P, Gillies J, Cutfield R, Krebs J, Helm C, Kerr J, Pryke J, Ebo G, Denopol M, Ang E, Uy N, Jimeno C, Mirasoi R, Paz Pacheco E, Custodio M, Nicodemus N Jr, Catindig EA, Magno M, Tirador L, Cylkowska B, Stasinksa T, Silwinska T, Sroka M, Piepiorka M, Korzeniak R, Mirecka H, Zaluska R, Pupek-Musialik D, Homenda W, Grabowska A, Okopien B, Niegowska J, Pogorzelska H, Mikolajczyk-Swatko A, Sikorski M, Sowinski D, Tahk SJ, Kim YN, Nam CW, Rim SJ, Kim CJ, Choi KM, Lee IK, Kim IJ, Namgung J, Moon KW, Kim KS, Oh BH, Lee WY, Choi SH, Kim ES, Moon S, Mindrescu NM, Aron G, Graur M, Hancu N, Mlitaru C, Nafornita V, Szilagyi I, Popa AR, Angelescu LM, Negrisanu GD, Zaharie DG, Culman MI, Vacaru G, Munteanu M, Constantinescu S, Tivadar S, Dreval A, Barbarash O, Strongin L, Dogadin S, Suplotova L, Izmozherova N, Marasaev V, Khokhlov A, Repin A, Turova E, Bondar I, Samoylova Y, Sherenkov A, Smolenskaya O, Zrahevskiy K, Koshelskaya O, Obrezan A, Dzupina A, Stevlik J, Buganova I, Pella D, Vinanska D, Jascur J, Micko K, Sosovec D, Philippiova A, Olexa P, Fedacko J, Selecky J, Nicolau J, Mediavilla Garcia J, Botella Serrano M, Lecube A, Arguelles I, Sabán J, Gómez Cerezo F, Soto A, Bellido D, Sucunza Alfonso N, Vendrell Ortega J, Alvarez L, Garcia Puig J, Angustias Quesada M, Contreras Gilbert J, Almeida CA, Tinahones FJ, Garcia Ortiz L, Gómez Marcos MA, Aomar I, Fernández Balsells M, Distiller L, Padayachee T, Badat A, Ebrahim I, Naiker P, Ranjith N, Kelfkens Y, Makan H, Mogashoa S, Fulat M, Carim-Ganey N, Omar M, Coetzee K, Govender T, Nortje H, Wilhase A, Seedat S, Gani M, Ellis G, Rheeder P, Wing J, Blignaut S, Kaplan H, Lottering H, Pillai P, Louw C, Coetzer T, Sheu WHH, Chen JF, Yang CY, Tseng ST, Wang CY, Lai WT, Hung YJ, Hsieh IC, Su SL, Pei D, Benjasuratwong Y, Purewal T, Milward A, Dimitropoulos I, Kumar S, Barber T, Wiles P, Dang C, Adler A, Philip S, Bellary S, Price D, Oelbaum R, Heller S, Sathayapalan T, Clark J, Leese G, Simpson H, Kilvert A, Dawson A, Hall T, Takhar A, Bundy C, Harvey P, Maxwell S, Asamoah-Owusu NJ, McKnight J, Chatterjee S, Calvert J, Wright A, Macrury S, MacFarlane D, Johnson A, Litchfield J, Field B, Koval O, Larin O, Levchenko O, Martynyuk L, Maslyanko V, Rudyk I, Suprun Y, Tseluyko V, Botsyurko V, Vatutin M, Fushtey I, Grishyna O, Kuskalo P, Panina S, Pererva L, Prysupa L, Teliatnikova Z, Sokolova L, Vlasenko M, Berenfus V, Gyrina O, Kopytsya M, Vizir V, Vayda M, Shanik M, Headapohl D, Pahl J, Aronoff S, Bartkowiak A Jr, Chang A, Gaudiani L, Kayne D, Look M, Patel N, Moran J, Stout E, Tsao J, Struble R, Fishman N, Rodbard H, Lucas K, Dugano-Daphnis P, Merrick B, Nadar V, Severa L, Sorli C, Chang M, Reed J III, Grunberger G, Bain C, Bestermann W Jr, Morawski E, White J, Azizad M, Ukwade P, Anekwe A, Jimenez A, Weiss D, Green S, Overcash J, Eaton C, Roseman H, Soler N, Mikell F, Manos P, Levinson L, Claxton E Jr, Weiss R, Argoud G, Bickel L, Wilson J, Short B, Webster B, McNeill R, Schnall A, Force R, Phillips L, Bybee K, Forker A, Denham D, VonderHaar T, Pullman J, Kruger D, Whitehouse F, Wysham C, Baron M, Kravitz A, Dushkin H, Manning MB, Wine A, Jaffrani N, Chadha C, Sperl-Hillen J, Busch R, Estevez R, Robbins D, Rassouli N, Garvey T, Oparil S, Eckel R, McDermott M, Rasouli N, McGill J, Corder C, Klonoff D, Mills R, Earl J, Kessel J, Cuddihy R, Zimmerman R, Dayamani P, Chang A, Oral E, Zimering M, Marks J, Farnsworth K, Sugimoto D, Toth P, Bhargava A, McGuire D, Rohatgi A, Davies M, Peden E, Wyne K, Alfonso L, Seyoum B, Akpunonu B, Feinglos M, Reaven P, Soule J, Luttrell L, Schactman B, Canadas R, Boggs B, Abbott L, Herring C, Roberts L, Hage-Korban E, Schubart U, Taylon A, Tannenbaum A, Kingsley J, Lenhard J, Biscoveanu M, Cohen J, Donovan D, Laferrere B, Thompson N, Wade T, Detweiler R, Henson B, White A, Cavale A, Ravi C, Thomas A, Goodman H, Kalen V, Fox D, Dauber I, Rizvi S, Marcus A, Mulford M, Higgins A, Chane M, Bland V, Osunkoya A, Suresh D, Khan S, Anastasi L, Bajaj M, Eisen H, Mudaliar SR, Powell S, Carr K, Tripathy D, Azad N, Wakefield P, Acheatel R, Bressler P, Dean J, El Shahawy M, Gilbert J, Haque I, Humiston D, Ison R, Karounos D, Lillestol M, Ferrier N, Labroo A, Vo A, D’Agostino R, Dulin M, McWilliams A, Hargrove J, Blumberg E, Jackson B, Staniloae C, Salacata A, Hidalgo H Jr, Nicol P, DiGiovanna M, Soufer J, Mahabadi V, Akinboboye O, Arauz-Pacheco C, Neutel J, Dungan K, Benson M, Powell T, Gandy W, Rovner S, Berk M, Khan A, Ledesma G, Madu I, Erickson B, Radbill M, Graves M, Kaczmarek G, Giep S, Baldauf C, Golden G, Lesh K, Davis C, Godbole N, Kirby W, Razzaque N, Bhatt B, Wilson M.

Abstract

BACKGROUND:

The cardiovascular effects of adding once-weekly treatment with exenatide to usual care in patients with type 2 diabetes are unknown.

METHODS:

We randomly assigned patients with type 2 diabetes, with or without previous cardiovascular disease, to receive subcutaneous injections of extended-release exenatide at a dose of 2 mg or matching placebo once weekly. The primary composite outcome was the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. The coprimary hypotheses were that exenatide, administered once weekly, would be noninferior to placebo with respect to safety and superior to placebo with respect to efficacy.

RESULTS:

In all, 14,752 patients (of whom 10,782 [73.1%] had previous cardiovascular disease) were followed for a median of 3.2 years (interquartile range, 2.2 to 4.4). A primary composite outcome event occurred in 839 of 7356 patients (11.4%; 3.7 events per 100 person-years) in the exenatide group and in 905 of 7396 patients (12.2%; 4.0 events per 100 person-years) in the placebo group (hazard ratio, 0.91; 95% confidence interval [CI], 0.83 to 1.00), with the intention-to-treat analysis indicating that exenatide, administered once weekly, was noninferior to placebo with respect to safety (P<0.001 for noninferiority) but was not superior to placebo with respect to efficacy (P=0.06 for superiority). The rates of death from cardiovascular causes, fatal or nonfatal myocardial infarction, fatal or nonfatal stroke, hospitalization for heart failure, and hospitalization for acute coronary syndrome, and the incidence of acute pancreatitis, pancreatic cancer, medullary thyroid carcinoma, and serious adverse events did not differ significantly between the two groups.

CONCLUSIONS:

Among patients with type 2 diabetes with or without previous cardiovascular disease, the incidence of major adverse cardiovascular events did not differ significantly between patients who received exenatide and those who received placebo. (Funded by Amylin Pharmaceuticals; EXSCEL ClinicalTrials.gov number, NCT01144338 .).

PMID:
28910237
DOI:
10.1056/NEJMoa1612917
[Indexed for MEDLINE]
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