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N Engl J Med. 2016 Nov 10;375(19):1834-1844. Epub 2016 Sep 15.

Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes.

Collaborators (1271)

Fitchett D, Bebchuk JD, Boon N, Gardner T, Inzucchi S, Chaitman BR, Bach R, Gosselin G, Laddu AA, Albert SG, Gyawali CP, Mullady DK, Block G, Bushinsky D, Martin K, Alsheklhee A, Cruz-Flores S, Feen ES, Jacoby MA, Picus J, Schroeder MA, Akduman L, Dudney BW, Aberkane K, Bachaoui M, Benali LN, Berra A, Bouacha Y, Bouziani N, Charef TE, Dahliz S, Far M, Griene S, Guessas M, Guettaf NEH, Hachelaf FZ, Hannane SI, Lakabi Z, Salah Mansour A, Merabet H, Moussaoui A, Nechadi A, Ouardane S, Rahou A, Bianchi G, Caeiro G, Calveyra M, Cestari H, Cluigt N, Diaz E, Ferrari D, Finkelstein H, Frechtel G, Galeano G, Garate L, Geronazzo V, Gili G, Heredia C, Hermida S, Issa C, Lapolla S, Lovecchio S, Lozano M, Marianacci A, Martinez P, Moukarzel J, Muller C, Olivera C, Oviedo A, Parysow E, Ponce F, Pozzi J, Ridner E, Sanabria H, Sernia V, Solis S, Sposetti G, Varela P, Visco V, Waitman J, Yohena S, Bennett J, Davis T, Ding SA, Fulcher G, Gilfillan C, Ho J, Hocking S, Lau SL, Lee M, Lin J, Lynch K, MacIsaac R, Makepeace A, McLean M, Naderpoor N, Nathow T, Radhakutty A, Rank E, Reddy K, Roberts A, Sachithanandan N, Simpson R, Stranks S, Teng J, Ward G, Zhang J, Akerman G, Alves E, Alves B, Alves J, Berlinger P, de Bem A, Bona R, Carolina A, Castro D, Cercato C, Costa M, Felício J, Franco D, Genestreti P, Gonçalves R, Grossman M, Gross J, Guimarães C, Jonasson T, Justus F, Ladeira S, Melo F, Miléo K, Miyahara M, Perlamagna L, Rea R, Regina C, Rodovalho S, Santomauro A, Saraiva J, Sartori C, Silvia F, Siqueira K, Turatti L, Uehara M, Valenti A, Visconti G, Zanatta L, Zanella MT, Asyova Z, Boyadzhieva M, Daskalova I, Ganeva-Todorova S, Hristozov K, Kibarova G, Kokareshkov V, Kolcheva G, Lefterov I, Popova N, Todorova K, Toneva A, Totomirova T, Trifonova B, Veleva N, Advani A, Burs S, Chouinard S, Chu M, Conway J, Dube F, El Boreky F, Fikry S, Garceau C, Gervais B, Ghosh M, Girard JM, Hanna A, Hruczkowski T, Hurd C, Josse R, Joy T, Jutras M, Khosla M, Kirouac I, Labonte I, Li S, Liutkus J, Hramiak IM, McDonald C, Nanji A, Padwal R, Patasi B, Paul T, Pedersen S, Raby K, Rosenbloom A, Scharf L, Senior P, Shaikholeslami R, Sivakumar C, Tapardel A, Theriault G, Tsoukas G, Tsoukas M, Tarnow L, Gregersen S, Grethe A, Hermansen K, Larsen M, Knop FK, Olesen T, Madsbad S, Dahl D, Deuse U, Esser M, Gaede K, Hagenow A, Kilimnik A, Lammers D, Laubner K, Lüdemann HP, Lüdemann J, Mittag D, Pohlmeier H, Rose L, Schaum T, Thaler J, Wendisch U, Abo-Salook M, Azzam I, Bar-Dayan Y, Bar-or I, Bashkin A, Benbassat C, Cahn A, Chananashvili L, Eizenberg Y, Feldman D, Gershkov S, Gorshtein A, Halabe A, Hirsch D, Hochman I, Ilany J, Inbal U, Izkhakov E, Karasik A, Kuyantseva E, Leibovitch I, Lieberman GS, Masri-Iraqi H, Michael L, Mosenzon O, Nodelman M, Percik R, Potekhin M, Raz I, Robenshtok E, Serebro M, Shaklai S, Shimon I, Shpitz D, Singer J, Slutzky I, Stern N, Tilis Y, Tirosh A, Tsvetov G, Vollach I, Wainstein J, Yaron M, Zvulunov E, Baldassarre MPA, Belligoli A, Bettini V, Di Biagio R, Bianchini S, Carta I, Ceccarelli E, Conci S, Corona G, Dodesini AR, Dotta F, Fabris R, Febo F, Di Fulvio P, Isoni S, Nigi L, Di Pizio L, Prà CD, Scaranna C, Serra R, Sforza A, Tinari C, Tonolo G, Torricelli V, Trevisan R, Vettor R, Vujosevic S, Zabeo E, Zanato V, Ahmad WAW, Amin NH, Cham YL, Chua S, Erng T, Fong AYY, Ghapar AKA, Khiew NZ, Kuan YC, Laubner BK, Lee G, Lim KC, Mahendran KA, Malek AMA, Ong TK, Rozario F, Said A, Sari NA, Sothiratnam R, Sridhar G, Tan F, Tan SK, Tay LK, Tey J, Vijayasingham S, Voon CY, Chan KLY, Baez-Campos A, Martinez-Nolasco B, González-Valencia C, Villasana-Galeana C, Olvera C, Castillo Reveles D, Larios-Mora D, Montaño-Gonzalez E, Pacheco Aranda E, Hernandez Lopez E, Chavez Manzanera E, Luna-Martínez F, Lopez-Hernandez F, Medina Alemán F, Rodriguez Briones I, Peralta-Cantu I, Olvera-Alvarez I, Haro Ortiz JA, Marin-Lopez JJ, Garcia Garcia J, Chávez Torres J, Sauque-Reyna L, Aguilar-Parra L, Virgen-Carrillo L, Amaya Morante LA, Carmona Furusho L, Reynaga L, Montaño-Gonzalez M, del Carmen Juarez Cervantes M, Martinez-Trejo N, Gomez P, Diaz De Leon-Reyes PP, Frenk PB, Sanchez Vargas P, Violante Ortiz RM, Estrada Garcia R, Rodriguez Briones R, Gonzalez-Perez R, Lopez Covarrubias R, Guerrero-Reyes R, Chong-Garcia Torres S, Jimenez-Ramos S, Cichocka E, Czernecka E, Dabrowska M, Gladysz I, Gumprecht J, Jusiak K, Knychas D, Laszewska G, Mazerska M, Nabrdalik K, Poplawska E, Poplawski A, Puch U, Romanczuk P, Szydlowski W, Szyprowska E, Walczak A, Wolnik B, Arushanova Matveeva Y, Astamirova K, Bukhalova E, Dubova V, Dvoryashina I, Edemskaya E, Gaysina L, Gromova S, Iskhakova Tyutyunnikova I, Kalashnikova M, Kargapoltseva O, Kargina L, Kholmatova K, Kiseleva T, Komissarova E, Kovaleva S, Kovalevskaia E, Krivosheeva I, Kufelkina T, Kunitsyna M, Kurbanova V, Likhodey N, Lomova A, Lvova L, Lysenko T, Malceva A, Martinovich A, Ogorodnikova E, Osipova O, Ostrovskaya I, Postoeva A, Prigoda N, Reshedko D, Reshedko L, Reshedko G, Rodionova T, Ruyatkin D, Ruyatkina L, Samylina I, Sardinov R, Sergeeva-Kondrachenko M, Shabanova E, Shatkovskaya N, Shilina Kutuzova N, Shimokhina O, Shuvaeva A, Sorkina E, Sorokin M, Suvorova L, Sych Y, Talalaeva N, Valeeva A, Valeeva F, Vinokurova V, Yanovskaya E, Yanovskaya M, Zakharova T, Zhukova E, Zimina I, Zinenko A, Znamenshchikova G, Arr Arroyo BP, Beltrán M, García Bidón H, Cepero D, Sedeño Díaz JM, Elvira J, Rivas Fernández M, Obiols Fornells MA, García Ordóñez MÁ, Bascuñana Quirell A, Mezquita Raya P, Reyes R, Ruiz Serra A, Serrarols Soldevila M, López Suarez A, Terns M, Chen JY, Chou CW, He CT, Hsieh CH, Hsu BR, Hua SC, Huang CH, Huang YY, Hung YJ, Lee C, Lin CW, Lin CH, Liou MJ, Lu WT, Lu CH, Sun JH, Tai TS, Tien KJ, Wang CC, Wu LY, Yang CY, Yen FC, Yu HI, Boonyasirinant T, Boonyavarakul A, Deerochanawong C, Katekao W, Maneesai A, Naeowong W, Pumprueg S, Srichomkwun P, Sriratanasathavorn C, Sritara P, Sunthornyothin S, Tejavanija S, Thirawuth V, Wangpatharawanit P, Wattanachanya L, Wongpraparut N, Ahbab S, Akin F, Akinci B, Akyay O, Altunbas H, Apaydin M, Asik M, Ataoglu E, Atasoy A, Bahadir MA, Beysel S, Cakal E, Calan M, Caliskan M, Cavdar U, Comlekci A, Delibasi T, Demir T, Demirci T, Dogan B, Dönmez H, Ergen A, Eroglu M, Erturk M, Guler S, Gumus T, Gur S, Imga N, Kan S, Karakilic E, Karakose M, Kizilgul M, Mesci BA, Oguz A, Orbay E, Ozcelik O, Ozcelik S, Ozisik S, Saglam F, Sagun H, Samanci N, Sari R, Selek A, Semerci A, Tahmaz M, Tarkun I, Topaloglu O, Topsakal S, Turker F, Tutal E, Ucan B, Ukinc K, Yaylali G, Yener S, Yenigun M, Yerlikaya E, Abraham P, Aftab S, Bellary S, Cadzow A, Chhokar B, Deshpande M, Devany L, Dokhe P, Elshashai A, Febbraro S, Inkster J, Jayia P, Kurup U, Lascar N, MacKay J, Rajeev S, Seetho I, Shiels H, Shukla U, Smith J, Stanciu D, Subramanian G, Taylor J, Weeraratne D, Wilding J, Abreu M, Agaiby J, Agaiby E, Aguillon A, Ahmed S, Alaoui R, Alarcon S, Alexander L, Ali A, Allen K, Al-Maliky T, Alvi M, Andersen J, Anthony V, Arcon-Rios S, Arkin D, Arodak B, Arroyo S, Asmar I, Attel S, Azar M, Aziz A, Azizad M, Bachand T, Baier M, Bajaj C, Baker C, Baker C, Baker C, Balentine T, Ballard T, Banarer S, Banks J, Barchini G, Barra J, Barrett J, Bartilucci D, Bauer N, Baum H, Baumann M, Bax J, Bays H, Becerra K, Bedel G, Behl N, Bell A, Benavidez B, Bender W, Bergamo K, Bernstein R, Berry M, Bestermann W, Beyea M, Bhambri R, Bice CR, Bilas A, Bishop K, Bixler L, Blair C, Boncu O, Bonner J, Borromeo A, Botros E, Boyd G, Bragg C, Brassfield A, Breen J, Brennan M, Brewington S, Bricker C, Brickner C, Brown M, Brown A, Bryant D, Buck G, Buckley B, Budzinski S, Bukowski J, Bunyard H, Burdette T, Burgess-Blalock C, Burton A, Busch R, Buse J, Bushong D, Butler N, Byars W, Bybee K, Bye R, Byers J, Caldwell R, Calvin K, Camacho A, Cameron J, Cannon M, Cannon D, Cannon K, Capuchino J, Cardella S, Carmolli-Cornette L, Carpio G, Casagni K, Cassell B, Castay C, Catenacci V, Cerullo J, Chaidarun S, Chambers J, Chaykin L, Cherry A, Cheyne T, Chochinov R, Choe J, Chow C, Christina M, Christopher S, Chu J, Chuang E, Church L, Ciampa A, Cohen E, Cohen N, Collins B, Combs J, Comi R, Conn B, Cook D, Correll C, Cortes G, Cortez A, Covington D, Critchson S, Culmer D, Cunningham L, Curll J, Daboul N, Dagogo-Jack S, Daly-Barnes K, Dang A, Daniels D, Darlington H, Davis M, Daynes R, Dayton T, Dean J, DeAtkine D, Delgado E, DeMicco M, DeSalle D, Desouza C, Devlin D, Dezube M, DiCerbo N, DiDonato M, Diesburg-Stanwood A, Dilembo J, Diller P, Diner J, Dluge-Aungst D, Dodis R, Donoho A, Dor I, Doremus N, Doriguzzi D, Dostou J, Douglass S, Dowell M, Draper B, Drincic A, Du H, Duckor S, Duclos M, Duffy-Hidalgo B, Duma C, Duncan S, Durant R, Durham N, Dusek J, Eagerton D, Ebeling K, Ebenibo S, Edeoga C, Edgett R, Edwards G, Edwin J, Egelhof R, Ekwensi J, Elliott TO, Elmore M, Elson D, Emmert L, Entriken L, Van Epps H, Erie M, Everhart B, Farmer M, Farnesi D, Fernandes L, Ferrington B, Fink V, Fishman N, Florida C, Forker A, Forward J, Freudemann K, Fuller G, Fuller G, Fusco F, Gagianas P, Galagan R, Galloway A, Gansner E, Gaona R, Garcia I, Garcia G, Garvin M, Gaudiani L, Gault J, Gavazov M, Gawad M, Gedbaw C, Gerace C, Gilbert M, Godwin S, Goebel T, Goley A, Golici L, Gonzalez MA, Goodhart C, Gosmanov A, Goswami K, Gray S, Greco S, Green C, Greenberg C, Griffen J, Gruenther P, Guadron-Hernandez L, Guasp L, Guice M, Gunther D, Gustin H, Gutierrez H, Haggag A, Haggar M, Hammond J, Hanyok A, Hardy C, Harper W, Harrell W, Harris E, Harrison L, Hartsell R, Haseeb M, Hastings A, Hayes D, Hedrick C, Helman L, Helman M, Helton A, Hendrick M, Hendrickson C, Hennekes G, Herbst A, Hernandez G, Herring C, Hess E, Hilliard B, Hoagland E, Hoberman E, Hoffman L, Hoffmann A, Hogan E, Hook K, Van Hoornbeek D, Hope M, Hopson B, Horner J, Horobetz C, Houser P, Htun W, Hudson T, Huerta B, Huizar S, Hullett M, Hummer K, Hwang SY, Ingram W, Ingram M, Ismail-Beigi F, Iverson L, Jackson T, Jackson T, Jackson R, Jacqmein J, Jantzi C, Joffrion I, St John J, Johnson M, Jones S, Juarez M, Juergens T, Jutras S, Kain A, Kapogiannis C, Kassem L, Kaster S, Katalenich B, Kawa A, Keiran S, Ketchum M, Keuchel J, Khadka P, Khamousia N, Khan K, Khan A, Khan J, Kiester J, Kim G, Kimmel M, King K, Kirkman MS, Kniffen W, Koehler T, Konigsberg S, Koren M, Korngut I, Krishnasamy S, Kuettel K, Kulow T, Kumar M, Kumar S, Kunst E, Kwan R, Kwon E, LaBryer L, Laliberte A, Lane T, Lane J, Lang J, Largay J, Larrabee P, Larsen D, Latif K, Lattinville B, Lawrence J, Leonard M, Leonard K, Lewis C, Lewis M, Licklider D, Lim J, Lipps J, Lisovskiy S, Liu MH, Livingston Y, Lloyd S, Loeck A, Loesch R, Lopez L, Loreto M, Lovre D, Lu P, Lucas K, Luevano G, Luna B, Lung J, De La Luz M, Lynch M, Lyons T, Mack D, Madder R, Magee J, Mahakala A, Maheshwari H, Mallitz M, Maluchnik B, Malyszko S, Manessis A, Mann K, Marney A, Marshall L, Martin M, Maw K, May M, Mayfield R, Mazhar G, Mbogua C, McCartney M, McDuffie R, McKendall-Lewis C, McKenzie L, McKibben K, McNair R, Mehta P, Meisner C, Melchor N, Mello C, Meredith M, Michael D, Micklewright G, Midyett C, Miller J, Miller A, Miller T, Miller N, Miller K, Minyon-Sarver D, Mittadodla S, Moeller J, Mohammadbhoy A, Mokshagundam S, Moloughney M, Monaco S, Montgomery C, Moody K, Mooney J, Moore M, Morawski E, Moreau C, Morekas D, Morin D, Mueller T, Muir D, Mullen J, Murak D, Naderi B, Naidu J, Ndukwu I, Nelson L, Nelson L, Nelson C, Neuberger C, Neumeister A, Nichols M, Nickerson N, Nockerts N, O'Brien H, Oden W, O'Donnell P, Odugbesan A, Oiknine R, Olio T, Oliver M, Olmeda C, Olsen S, O'Neil C, Ortega T, Ostrowski P, Otah K, Otero H, Packard K, Painter K, Pangtay D, Pangtay S, Papacostea O, Papierniak N, Parker A, Pascal A, Pascal-Doriguzzi A, Patel A, Patel C, Patel M, Patel B, Patterson M, Paulus C, Peek M, Pegg A, Phelps S, Phillips B, Piccola J, Pickett A, Pinero G, Pitts A, Platt J, Poduri M, Poehls J, Ponte G, Pop L, Power E, Price E, Priest D, Quadrel M, Quinney R, Quyyumi S, Rabalais M, Rabideau D, Rahman J, Raidl C, Ramirez K, Ramsey S, Rangaraj U, Rao V, Rasmussen B, Rasouli N, Rauch R, Ray S, Recker B, Redding J, Redrick S, Reheis J, Reiling J, Reiling S, Rems L, Rettig K, Reusch J, Reynolds M, Ricci C, Rice L, Rickard H, Rios-Santiago J, Ritchey B, Rivera S, Rizos D, Rizvi SF, Robbins R, Robison D, Rocco S, Roche C, Rodes A, Perdomo Rodriguez JP, Rodriguez M, Rojas M, Rokoff N, Roney C, Rooker-Morris L, Root C, Roozen C, Ross I, Roth M, Roth E, Rothman J, Roura M, Russell K, Russell E, Rutherford C, Salazar J, Salazar J, Sanagorski R, Sandy A, Santiago J, Saunders J, Schmidt H, Schneider C, Schramm E, Schramm R, Schultzaberger R, Schweppe L, Scott R, Scribner A, Seddon T, Seekford J, Segel S, Severance R, Severson M, Shah K, Shaw J, Shay M, Sheets M, Shelton C, Shelton L, Shelton S, Shikany J, Shippey J, Shivaswamy V, Shlesinger Y, Shlotzhauser T, Shook M, Shore D, Shvarts M, Siddiqui M, Silver R, Simon H, Singh M, Sites MJ, Sitton D, Sivalingam K, Smith D, Smith K, Smith N, Smith T, Smith J, Snyder J, Snyder B, Sood A, Soon J, Sorrentino L, Sortor J, Sosnowchik J, Soufer J, Spears J, Spector L, Speicher R, Stacey A, Stafford M, Stanford J, Stayer M, Stell C, Stenger E, Stockhammer S, Stoneman J, Straatmann D, Sugimoto D, Sugimoto M, Sultan F, Suryadevara S, Sutton D, Swan D, Sy C, Talley S, Talsania M, Tan A, Taylor P, Thethi T, Thomas S, Thompson C, Thottan A, Tiktin M, Tillson R, Timpe R, Tinney I, Tirado-Bernardini R, Tobias C, Tobin T, Toe F, Torello C, Tousson A, Tousson J, Toven J, Tran C, Trantow C, Travaglini S, Traylor H, Tripp D, Tumyan A, Turner J, Twine M, Tyson T, Underkofler C, Uzoaga E, Valdivia V, Valencia P, Valitutto M, Vanderheiden A, Varavenkataraman R, Vickery D, Vincent S, Wadud K, Wahl T, Walker F, Walsh K, Wang A, Wardell K, Weindorff K, Weir M, Weisbrot A, Weiss S, Weiter K, Wenker M, Wenocur H, West M, White E, White J, Whitehead R, Whittle J, Wigley C, Wilkins F, Williams H, Williams M, Williamson C, Wilson LE, Windsor S, Wingo L, Winkle P, Wishard L, Wisneski S, Witte M, Wolfman L, Wollet J, Wood R, Wyatt H, Yassini P, Yeoman G, York D, Young L, Young T, Zaretzky J, Ziboh M, Zimmer E.

Abstract

BACKGROUND:

Regulatory guidance specifies the need to establish cardiovascular safety of new diabetes therapies in patients with type 2 diabetes in order to rule out excess cardiovascular risk. The cardiovascular effects of semaglutide, a glucagon-like peptide 1 analogue with an extended half-life of approximately 1 week, in type 2 diabetes are unknown.

METHODS:

We randomly assigned 3297 patients with type 2 diabetes who were on a standard-care regimen to receive once-weekly semaglutide (0.5 mg or 1.0 mg) or placebo for 104 weeks. The primary composite outcome was the first occurrence of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. We hypothesized that semaglutide would be noninferior to placebo for the primary outcome. The noninferiority margin was 1.8 for the upper boundary of the 95% confidence interval of the hazard ratio.

RESULTS:

At baseline, 2735 of the patients (83.0%) had established cardiovascular disease, chronic kidney disease, or both. The primary outcome occurred in 108 of 1648 patients (6.6%) in the semaglutide group and in 146 of 1649 patients (8.9%) in the placebo group (hazard ratio, 0.74; 95% confidence interval [CI], 0.58 to 0.95; P<0.001 for noninferiority). Nonfatal myocardial infarction occurred in 2.9% of the patients receiving semaglutide and in 3.9% of those receiving placebo (hazard ratio, 0.74; 95% CI, 0.51 to 1.08; P=0.12); nonfatal stroke occurred in 1.6% and 2.7%, respectively (hazard ratio, 0.61; 95% CI, 0.38 to 0.99; P=0.04). Rates of death from cardiovascular causes were similar in the two groups. Rates of new or worsening nephropathy were lower in the semaglutide group, but rates of retinopathy complications (vitreous hemorrhage, blindness, or conditions requiring treatment with an intravitreal agent or photocoagulation) were significantly higher (hazard ratio, 1.76; 95% CI, 1.11 to 2.78; P=0.02). Fewer serious adverse events occurred in the semaglutide group, although more patients discontinued treatment because of adverse events, mainly gastrointestinal.

CONCLUSIONS:

In patients with type 2 diabetes who were at high cardiovascular risk, the rate of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke was significantly lower among patients receiving semaglutide than among those receiving placebo, an outcome that confirmed the noninferiority of semaglutide. (Funded by Novo Nordisk; SUSTAIN-6 ClinicalTrials.gov number, NCT01720446 .).

PMID:
27633186
DOI:
10.1056/NEJMoa1607141
[Indexed for MEDLINE]

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