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N Engl J Med. 2019 Jan 24;380(4):347-357. doi: 10.1056/NEJMoa1812389. Epub 2018 Nov 10.

Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes.

Collaborators (982)

Bansilal S, Furtado R, Fish MP, Gabovitch D, Jevne A, Ahern S, Im K, Goodrich EL, Lowe C, Fisher N, Gannon J, Trindade S, Towarowski A, Fox Y, Johnsson E, Ranft S, Faber B, Wallander M, Weiss A, Buskila A, Abola MTB, Ardissino D, Averkov O, Aylward P, Bode C, Bonnici F, Bonora E, Budaj AJ, Cernea S, Chiang CE, Cooper M, Dalby A, Deerochanawong C, Dellborg M, Diaz R, Dimulescu D, Eliaschewitz FG, Goudev AR, Hadjadj S, Herrera M, Huo Y, Jermendy G, Ji L, Kadowaki T, Kiss R, Kooy A, Kumar KMP, Lewis B, Litwak L, Lopez-Sendon J, Ma R, Merlini PA, Nauck MA, Nguyen TK, Nicolau JC, Ostgren CJ, Ophuis TO, Padilla F, Pais P, Park KS, Parkhomenko A, Ray K, Rosenstock J, Ruda M, Satman I, Shestakova M, Smahelova A, Spinar J, Strojek K, Sy R, Tankova T, Theroux P, Tkáč I, Van Gaal L, Wainstein J, Harrington RA, Droller MJ, Lee KL, Nesto RW, Tuomilehto J, Hedlin H, Desai M, Sayfer I, Alexanian S, Awtry E, Bentley-Lewis R, Berger CJ, Croce K, Desai A, Garg RK, Gelfand E, Gignac G, Goessling W, Ho C, Hochberg E, Lane A, Larrey D, Leeman DE, Lewis J, Link MS, McDonnell ME, Norden AD, Pande A, Rosenberg C, Rost N, Ruberg F, Schiff E, Silverman S, Singhal A, Wagner A, Wolpin B, Aizenberg D, Fernández M, Sala J, Maffei L, Luquez C, Waitman J, Rista L, Nardone L, Sposetti G, Cantero M, Alvarisqueta A, Montaña O, Cuadrado J, Cartasegna L, Baccaro C, Chertkoff A, Sanabria H, Vainstein N, Amerena J, Arya K, d'Emden M, Proietto J, Moses R, Colquhoun D, Stranks S, Lehman R, Hamilton A, Whelan A, Simpson R, Purnell P, Abhayaratna W, Hammett C, McKeirnan M, Sullivan D, Bach L, Hughes K, Mathieu C, Vercammen C, Scheen A, Van Gaal L, Duyck F, Cools F, De Wolf L, Verhaegen A, Nobels F, Missault L, Crenier L, Thoeng J, Wollaert B, Vandenbroucke M, Eliaschewitz F, Borges JLC, Turatti L, Lima FG, dos Santos F, Kerr Saraiva J, Pereira M, Pereira A, Precoma DB, Filho G FV, Reis G, Maia LN, Bacheva T, Temelkova-Kurktschiev T, Maneva S, Stoyanovska B, Boshnyashka R, Tankova T, Stoykova Y, Georgiev D, Tagarev Z, Dimitrova E, Vitkina M, Yordanova L, Temelkova M, Vasileva S, Kuneva T, Zyumbyuleva M, Daskalova I, Genadieva V, Boyanov L, Farah G, Lazarova G, Georgieva M, Krasteva S, Slavcheva A, Yabroudi N, Veleva N, Zlateva A, Damyanova V, Elenkova A, Kotselova T, Genov K, Lyubenova L, Temelkova N, Harizanova B, Zaharieva S, Bajaj H, Goldenberg R, Aronson R, Twum-Barima D, Dumas R, Kouz S, Kaiser SM, Ajala B, Cha J, Teitelbaum I, Chouinard G, Woo V, Dan Dattani I, Mazza G, Gaudet D, Poirier P, Conway J, Dion D, McKeough M, Manyari D, Harris S, St-Pierre B, Yale JF, Landry D, Gupta M, Hramiak I, Lau D, DeGrace M, Gallo R, Montigny M, Dzongowski P, Liutkus J, Frechette A, Gosselin G, Sabbah E, Langlois MF, Rabasa-Lhoret R, Bedard J, Hart R, Dowell A, Pandey A, O'Keefe D, Hill L, Weisnagel SJ, Muirhead N, Zimmermann R, Galiwango P, Leiter LA, Tobe S, Priestman B, Zinman B, Ma J, Zhao X, Wang C, Zhang A, Dong Y, Dong X, Luo M, Guo J, Zheng Z, Li Y, Liang Y, Li Y, Ji L, Peng D, Špinar J, Maděřič D, Šmahelová A, Špinarová L, Raclavská L, Ludka O, Řiháček I, Karasová J, Pelikánová M, Vlasáková H, Urbancová K, Zamrazil V, Hradec J, Vlašicová H, Račická E, Okénka L, Náplava R, Skopeček J, Pálová S, Krystl T, Píštěk Z, Oznerová M, Andresová A, Šarbochová R, Táborská P, Petrová I, Staněk L, Reichert P, Lorenc Z, Szabó M, Petit C, Krempf M, Hadjadj S, Boye A, Dubois S, Clavel S, Gourdy P, Elbaz M, Jazayeri S, Gouet D, Verges B, Couffinhal T, Sendeski M, Klausmann G, Appel K, Pein M, Thieme R, Schumm-Draeger P, Jacob S, Toursarkissian N, Kleinecke-Pohl U, Tschöpe D, Ott P, Haak T, Nauck M, Derwahl K, Bugger H, Ma R, Hui G, Tsang C, Zilahi Z, Püski L, Vangel S, Fülöp T, Jermendy G, Páll K, Hidvégi T, Révész K, Korányi L, Kajetán M, Kerényi Z, Pénzes J, Herczeg B, Lászlóczky Á, Turi T, Rapi J, Péntek Z, Gaál Z, Winkler G, Percs E, Czigány A, Harcsa E, Gurzó M, Tassaly J, Horthy R, Petró G, Faragó K, Müller G, Varju I, Kirschner R, Kiss I, Bakai J, Kancz S, Marton Z, Kodur R, Yajnik C, Thomas N, Ayyar V, Iyengar P, Bashkin A, Daoud D, Lewis B, Itzhak B, Katz A, Wainstein J, Tsur A, Nikolsky E, Atar S, Grossman A, Klainman E, Mosenzon O, Tsalihin D, Shotan A, Turgeman Y, Ferrario M, Merlini P, Bonora E, Piatti P, Zenari L, Trevisan R, Bosco B, Di Lorenzo L, Mannucci E, Avogaro A, Reimers B, Trimarco B, Silvestri O, Salvioni A, Nakagawa H, Sueyoshi A, Fukuda K, Yasumoto H, Matsubayashi S, Kawajiri K, Togashi Y, Senokuchi T, Ohta Y, Yamauchi T, Node K, Alcocer Gamba M, Herrera Marmolejo M, De los Rios Ibarra M, González Gálvez G, García Cantú E, Leguízamo Dimas A, Luna Ceballos R, Medina Pech C, Stobschinski de Alba C, González González J, Padilla Padilla F, Fanghänel Salmón G, Robles Torres F, López Rosas E, Pelayo Orozco E, Banda Elizondo R, Escalona Caamaño A, Frenk Baron P, Aguilar Salinas C, Mustieles Rocha C, Vidrio Velázquez M, Rodríguez Briones I, Saldate Alonso M, Velasco Sánchez R, Kooy A, Groenemeijer B, Ronner E, Kuijper A, Strikwerda S, Van Kempen W, Gijsbers S, Oude Ophuis A, Swart H, Hoogenberg K, Hovens M, van Hessen M, Westerink J, Kragten J, Nierop P, Bax W, Hartong S, Nieuwdorp M, Gonkel F, Al Windy N, Troquay R, Schaafsma H, Lieverse A, Knufman N, Hovens M, Tirador L, Guenon M, Ferrolino A, Sy R, Atilano A, Aportadera M, Que M, Denopol M, Tolentino M, Jimeno C, Wee J, Mirasol R, Panelo A, Roxas D, Abola M, Palmes P, Silva A, Salvador D, Rosita R, Maravilla L, Rogelio G, Pacheco E, Tin Hay L, Prado J, Krzyżagórska E, Witek R, Mikłaszewicz B, Sudnik W, Pomiećko W, Bochenek A, Fares I, Wujkowski M, Korol M, Powierża S, Strojek K, Goch A, Miękus P, Siegel A, Skierkowska J, Romańczuk P, Cygler J, Łanda K, Szyprowska E, Stachlewski P, Czerski T, Pawłowicz L, Sowiński D, Romanowski L, Rudzki H, Skórski M, Jasiel-Wojculewicz H, Stasiewski A, Budaj A, Kania G, Mirek-Bryniarska E, Wojnowski Ł, Korzeniak R, Oh T, Park K, Lee M, Lee K, Jang H, Kim S, Ku B, Cha B, Son H, Lee I, Park J, Yu S, Park J, Shon H, Rhee E, Kim S, Cho J, Park T, Nam J, Pintilei E, Popescu A, Nafornita V, Gutu O, Dumitrescu A, Bala C, Caceaune E, Mindrescu N, Morosanu M, Bradescu O, Munteanu M, Voitec M, Vlaiculescu M, Hancu N, Diaconu Sotropa M, Lupu S, Cernea S, Mateescu A, Carlan L, Marton R, Lupusoru D, Mot A, Coman A, Zaharie D, Rebrov A, Shutemova E, Bolieva L, Khalimov Y, Statsenko M, Galyavich A, Koziolova N, Shapovalova Y, Pavlysh E, Strongin L, Vertkin A, Vishneva E, Pavlova M, Khasanov N, Antsiferov M, Gavrisheva I, Sokolova N, Vorobyev S, Morugova T, Sinitsina I, Ezhov A, Kobalava Z, Belenkiy D, Supryadkina T, Kazakov Y, Oschepkova E, Dreval A, Novikova T, Vishnevsky A, Chizhov D, Akatova E, Vorokhobina N, Ivanov I, Dudinskaya E, Konstantinov V, Kanderková D, Pavlík L, Rašlová K, Paulovič V, Babíková J, Belešová K, Merčiaková M, Truban J, Vargová A, Fábryová Ľ, Tkáč I, Slovenská M, Plášil R, Tomášová L, Kollárová D, Spodniaková D, Košíková M, Džuponová J, Kurčová I, Skripova D, Gabrišová A, Kalinová S, Ranjith N, Burgess L, Mitha I, Conradie M, Distiller L, Pillai P, Pillay S, Horak A, Nethononda R, van den Berg E, Nortje H, Bayat J, Corbett C, Abelson M, van Zyl L, Pillay T, Wing J, Dalby A, Kapp C, Hidalgo Urbano R, Gonzalez Juanatey J, Blanco Coronado J, Bruguera Cortada J, Ferreiro Gutierrez J, Quesada Simon M, Castro A, Delgado Álvarez E, Freixa R, Boada A, Larnefeldt H, Mooe T, Koskinen P, Lagerbäck P, Linderfalk C, Liu B, Berndtsson Blom K, Tengmark B, Lindholm C, Östgren C, Oweling M, Albertsson P, Alvarsson M, Fant S, Berglund O, Dellborg M, Hsia C, Chiang C, Fang C, Ueng K, Wang K, Lai W, Mamanasiri S, Deerochanawong C, Wongvipaporn C, Kuanprasert S, Thongsri T, Srimahachota S, Boonyavarakul A, Suwanwalaikorn S, Tantiwong P, Sritara P, Sriwijitkamol A, Sanguanwong S, Chotinaiwattarakul C, Piyayotai D, Balci M, Orbay E, Satman I, Saygili F, Oguz A, Altuntas Y, Comlekci A, Karpenko O, Tkach S, Vlasenko M, Fushtey I, Pertseva T, Reshotko D, Mostovoy Y, Vizir V, Kraiz I, Amosova K, Batushkin V, Tseluyko V, Koval O, Strang C, Bodalia B, Pieters R, Turner W, Asamoah-Owusu N, White C, Calvert J, McNally D, Jones N, McKaig G, Thompson J, Mohr S, Simpson H, Conn P, McCoye A, Rivero O, Yazdani S, Ince C, Zeitlin J, Wharton T, Platt G, Anderson RJ, Angueira-Serrano E, Lillestol M, Hanlon B, Soufer J, Garcia B, Iteld B, Venugopal C, Ahmed A, Duardo-Guerra Y, Jetty P, Miranda A, Wahlen J, Lederman S, Cohen K, Lake L, French WJ, Tahirkheli N, Baker S, Stoltz R, Wilson J, Nadar V, Brown J, Larrain G, Wiseman A, Ruoff G, Williams M, Tan A, Hartman I, Singh N, Graf R, Wakefield P, McNeill R, Byars W, Reyes Almodovar R, Jones S, Kantaros L, Hegedosh N, Graves M, Bernstein M, Falkowski S, Bialow M, Paraschos A, Dagher G, Arif A, Condit J, Chaykin L, Grunstra B, Earl J, Unks D, Srivastava S, Benson M, Huffman C, Miller G, Willis J, Bender K, Martin E, Blackmore R, Rohr K, Chilka S, Gadowski G, Fitz-Patrick D, Benjamin S, Morin D, Zias Dilena A, Acosta R, Claassen D, Miranda F, Raad G, Inzerello A, Porter J, Bhattacharya A, Gutmann J, Korpas D, Syed M, Zieve F, Raisinghani A, Alam S, Bartkowiak A, Boccalandro F, Talano J, Mercado A, Krichmar P, Oldfield C, Adams K, Gorman T, Lewis D, Shah R, Shockey G, Lefebvre G, Andrawis N, Tami L, Bittar N, Khan MS, Rink L, Hendrix E, Wood J, Robinson J, Pavon H, Irfan M, Gonzalez E, Singal R, Shore K, Saba F, Bianco J, Erickson B, Gorson D, Puri S, Arauz-Pacheco C, Forman S, Akyea-Djamson A, Lieber I, Barker B, Desai P, Sotolongo C, Steinhoff J, Hill R, Radin M, Patel R, Lieberman S, Wenocur H, Dagogo-Jack S, Lupovitch S, Ison R, Bacharach JM, Diogo J, Mazzella M, Greenwald J, Quadrel M, Mayer N, Datu J, McCartney M, Bruce T, Singal D, Turner J, Videau B, Fritz R, Fox D, Calatayud G, Sheldon W, Kereiakes D, Thomas J, Salacata A, McCullum K, Harris B, de Souza J, Rahman A, Blumenthal S, Narayan P, Bloch M, Augenbraun C, Bernstein R, Perlman R, Berman J, LaBryer L, Wynne A, Fish J, Zarich S, Shah R, Gabra N, Popeil L, Hermany P, Barreto A, Pomposini D, Gonzalez-Campoy JM, Langer M, Bayron C, Suneja R, Kamlet J, Fang C, Wheeler K, Hurley S, Sharma S, Wefald F, Hershon K, O'Connor T, Pueblitz G, Laguerre J, Amin M, Nadar V, Alfonso T, Jaffrani N, Isserman S, Portnay E, Vlastaris A, Dy J, Hagan M, Noveck H, Kraft P, Andersen J, Foley B, Carr K, Gelormini J, Williams T, Landau C, Richwine R, Thakkar M, Karim A, Madhun Z, Francyk D, Lamantia J, Baker B, Zhang W, Lev V, Hasan M, Captain A, Herzog W, Friedman K, Lawson W, Desai V, Ow C, Simons R, Mandviwala M, Le T, Hack T, Zebrack J, Henderson D, DeJulia J, Mehta R, Reza S, Poonawala R, Awad A, Velasquez M, Mohiuddin S, Salazar Sharma M, Myrick G, Gottlieb D, Ovalle F, Alfieri A, Ahmed S, Bohula E, Donahoe SM, Longshaw K, Eshaghian S, Lash J, Goldberg RK, Fox B, Mostel E, Dobies D, Ward H, Burbano J, Puleo P, Lenhard MJ, Korn D, Thadani U, Bradley A III, Kmetzo J, Heasley E, Raikhel M, Mahr N, Bittar G, Fuentes F, Raghu P, Diep TTB, Tran QK, Tran N, Nguyen D, Nguyễn V.

Abstract

BACKGROUND:

The cardiovascular safety profile of dapagliflozin, a selective inhibitor of sodium-glucose cotransporter 2 that promotes glucosuria in patients with type 2 diabetes, is undefined.

METHODS:

We randomly assigned patients with type 2 diabetes who had or were at risk for atherosclerotic cardiovascular disease to receive either dapagliflozin or placebo. The primary safety outcome was a composite of major adverse cardiovascular events (MACE), defined as cardiovascular death, myocardial infarction, or ischemic stroke. The primary efficacy outcomes were MACE and a composite of cardiovascular death or hospitalization for heart failure. Secondary efficacy outcomes were a renal composite (≥40% decrease in estimated glomerular filtration rate to <60 ml per minute per 1.73 m2 of body-surface area, new end-stage renal disease, or death from renal or cardiovascular causes) and death from any cause.

RESULTS:

We evaluated 17,160 patients, including 10,186 without atherosclerotic cardiovascular disease, who were followed for a median of 4.2 years. In the primary safety outcome analysis, dapagliflozin met the prespecified criterion for noninferiority to placebo with respect to MACE (upper boundary of the 95% confidence interval [CI], <1.3; P<0.001 for noninferiority). In the two primary efficacy analyses, dapagliflozin did not result in a lower rate of MACE (8.8% in the dapagliflozin group and 9.4% in the placebo group; hazard ratio, 0.93; 95% CI, 0.84 to 1.03; P=0.17) but did result in a lower rate of cardiovascular death or hospitalization for heart failure (4.9% vs. 5.8%; hazard ratio, 0.83; 95% CI, 0.73 to 0.95; P=0.005), which reflected a lower rate of hospitalization for heart failure (hazard ratio, 0.73; 95% CI, 0.61 to 0.88); there was no between-group difference in cardiovascular death (hazard ratio, 0.98; 95% CI, 0.82 to 1.17). A renal event occurred in 4.3% in the dapagliflozin group and in 5.6% in the placebo group (hazard ratio, 0.76; 95% CI, 0.67 to 0.87), and death from any cause occurred in 6.2% and 6.6%, respectively (hazard ratio, 0.93; 95% CI, 0.82 to 1.04). Diabetic ketoacidosis was more common with dapagliflozin than with placebo (0.3% vs. 0.1%, P=0.02), as was the rate of genital infections that led to discontinuation of the regimen or that were considered to be serious adverse events (0.9% vs. 0.1%, P<0.001).

CONCLUSIONS:

In patients with type 2 diabetes who had or were at risk for atherosclerotic cardiovascular disease, treatment with dapagliflozin did not result in a higher or lower rate of MACE than placebo but did result in a lower rate of cardiovascular death or hospitalization for heart failure, a finding that reflects a lower rate of hospitalization for heart failure. (Funded by AstraZeneca; DECLARE-TIMI 58 ClinicalTrials.gov number, NCT01730534 .).

PMID:
30415602
DOI:
10.1056/NEJMoa1812389
[Indexed for MEDLINE]

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