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N Engl J Med. 2019 Jun 13;380(24):2295-2306. doi: 10.1056/NEJMoa1811744. Epub 2019 Apr 14.

Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy.

Collaborators (931)

Perkovic V, Mahaffey KW, Agarwal R, Bakris G, Brenner BM, Cannon CP, Charytan DM, de Zeeuw D, Greene T, Jardine MJ, Heerspink HJL, Levin A, Meininger G, Neal B, Pollock C, Wheeler DC, Zhang H, Zinman B, McGuire DK, Holman R, Home P, Scharfstein D, Parfrey P, Shahinfar S, August P, Chang T, Sinha AD, Januzzi J, Kolansky D, Amerena J, Hillis G, Gorelick P, Kissela B, Kasner S, Lindley R, Fulcher G, Ounadjela S, Hufert K, von Ingersleben G, Gaglia J, Harris R, Hudson M, Turchin A, Cheifetz A, Sheth S, Feuerstein J, Cohen S, Jardine M, Li N, Kolesnyk I, Aizenberg D, Pecoits-Filho R, Cherney D 3rd, Obrador G, Chertow G, Hawley C, Ji L, Wada T, Jha V, Lim SK, Lim-Abrahan MA, Santos F, Chae DW, Hwang SJ, Vazelov E, Rychlík I, Hadjadj S, Krane V, Rosivall L, De Nicola L, Dreval A, Nowicki M, Schiller A, Distiller L, Górriz JL, Kolesnyk M, Morren F, Goykhman S, David C, Yost L, Wang H, Hettiarachchi M, Thimmaiah R, Koppolu D, George S, Schmidt M, Ignjatovic J, Chapin L, Travis K, Destree M, Sood V, Coffee L, De Brouwer K, Zaviriukha V, Starzec A, Koizumi M, Lin G, Chen E, Lin P, Leia C, Mascaro D, Amigo A, Limos A, Abrahamsen I, Jaffer S, Ahuad Guerrero RA, Albisu JP, Alvarisqueta A, Bartolacci I, Berli MA, Bordonava A, Calella P, Cantero MC, Cartasegna LR, Cercos E, Coloma GC, Colombo H, Commendatore V, Cuadrado J, Cuneo CA, Cusumano AM, Douthat WG, Dran RD, Farias E, Fernandez MF, Finkelstein H, Fragale G, Fretes JO, Garcia NH, Gastaldi A, Gelersztein E, Glenny JA, Gonzalez JP, Gonzalez Colaso PDC, Goycoa C, Greloni GC, Guinsburg A, Hermida S, Juncos LI, Klyver MI, Kraft F, Krynski F, Lanchiotti PV, Leon de la Fuente RA, Marchetta N, Mele P, Nicolai S, Novoa PA, Orio SI, Otreras F, Oviedo A, Raffaele P, Resk JH, Rista L, Rodriguez Papini N, Sala J, Santos JC, Schiavi LB, Sessa H, Smith Casabella T, Ulla MR, Valdez M, Vallejos A, Villarino A, Visco VE, Wassermann A, Zaidman CJ, Cheung NW, Droste C, Fraser I, Johnson D, Mah PM, Nicholls K, Packham D, Proietto J, Roberts A, Roger S, Tsang V, Raduan RA, Alves da Costa FA, Amodeo C, Andreotti Turatti LA, Bregman R, Camelo Sanches FC, Canani LH, Chacra AR, Cunha Borges JL, Cunha Vêncio SA, da Silva Franco RJ, d'Avila D, de Souza Portes E, de Souza P, Deboni LM, Filho FF, Geloneze Neto B, Gomes M, Kohara SK, Keitel E, Kerr Saraiva JF, Kurtz Lisboa HR, de Carvalho Contieri FL, Milagres R, Montenegro Junior R, Moreira de Brito C, Nazzer Hissa M, Nazario Sabbag ÂR, Noronha I, Panarotto D, Pecoits Filho R, Pereira MA, Saporito W, Scotton AS, Schuch T, Simões de Almeida R, Slompo Ramos C, Soares Felício J, Thomé F, Tibes Hachmann JC, Yamada S, Yoiti Hayashida C, Zanata Petry TB, Zanella MT, Andreeva V, Angelova A, Dimitrov S, Genadieva V, Genova-Hristova G, Hristozov K, Kamenov Z, Koundurdjiev A, Lozanov L, Margaritov V, Nonchev B, Rangelov R, Shinkov A, Temelkova M, Velichkova E, Yakov A, Aggarwal N, Aronson R, Bajaj H, Chouinard G, Conway J, Cournoyer S, DaRoza G, De Serres S, Dubé F, Goldenberg R, Gupta A, Gupta M, Henein S, Khandwala H, Leiter L, Madore F, McMahon A, Muirhead N, Pichette V, Rabasa-Lhoret R, Steele A, Tangri N, Torshizi A, Woo V, Zalunardo N, Fernández Montenegro MA, Godoy Jorquera JG, Medina Fariña M, Saavedra Gajardo V, Vejar M, Chen N, Chen Q, Gan S, Kong Y, Li D, Li W, Li X, Lin H, Liu J, Lu W, Mao H, Ren Y, Song W, Sun J, Sun L, Tu P, Wang G, Yang J, Yin A, Yu X, Zhao M, Zheng H, Accini Mendoza JL, Arcos E, Avendano J, Diaz Ruiz JEA, Garcia Ortiz LH, Gonzalez A, Hernandez Triana E, Higuera JD, Malaver N, Molina de Salazar DI, Rosero R, Terront Lozano MA, Valderrama Cometa L, Valenzuela A, Vargas Alonso RD, Villegas I, Yupanqui H, Bartaskova D, Barton P, Belobradkova J, Dohnalova L, Drasnar T, Ferkl R, Halciakova K, Klokocnikova V, Kovar R, Lastuvka J, Lukac M, Pesickova S, Peterka K, Pumprla J, Rychlik I, Saudek F, Tesar V, Valis M, Weiner P, Zemek S, Alamartine E, Borot S, Cariou B, Dussol B, Fauvel JP, Gourdy P, Klein A, Le Meur Y, Penfornis A, Roussel R, Saulnier PJ, Thervet E, Zaoui P, Burst V, Faghih M, Faulmann G, Haller H, Jerwan-Keim R, Maxeiner S, Paschen B, Plassmann G, Rose L, Gonzalez Orellana RA, Haase FP, Moreira Diaz JP, Ramirez Roca LA, Sánchez Arenales JA, Sanchez Polo JV, Turcios Juarez E, Csecsei G, Csiky B, Danos P, Deak L, Dudas M, Harcsa E, Keltai K, Keresztesi S, Kiss K, Konyves L, Major L, Mileder M, Molnar M, Mucsi J, Oroszlan T, Ory I, Paragh G, Peterfai E, Petro G, Revesz K, Takacs R, Vangel S, Vasas S, Zsom M, Abraham O, Bhushan RS, Deepak D, Edwin FM, Gopalakrishnan N, Gracious N, Hansraj A, Jain D, Keshavamurthy CB, Khullar D, Manisha S, Peringat J, Prasad N, Satyanarayana RK, Sreedhar R, Sreelatha M, Sudhakar B, Vyasam RC, Bonadonna R, Castellino P, Ceriello A, Chiovato L, De Cosmo S, Derosa G, Di Carlo A, Di Cianni G, Frascà G, Fuiano G, Gambaro G, Garibotto G, Giorda C, Malberti F, Mandreoli M, Mannucci E, Orsi E, Piatti P, Santoro D, Sasso FC, Serviddio G, Stella A, Trevisan R, Veronelli AM, Zanoli L, Akiyama H, Aoki H, Asano A, Iitsuka T, Kajiyama S, Kashine S, Kawada T, Kodera T, Kono H, Koyama K, Kumeda Y, Miyauchi S, Mizuyama K, Niiya T, Oishi H, Ota S, Sakakibara T, Takai M, Tomonaga O, Tsujimoto M, Wakasugi M, Wakida Y, Watanabe T, Yamada M, Yanagida K, Yanase T, Yumita W, Gaupsiene E, Kozloviene D, Navickas A, Urbanaviciene E, Abdul Ghani R, Abdul Kadir K, Ali N, Che Yusof MD, Gan CL, Ismail M, Kong WY, Lam SW, Lee LY, Loh CL, Manocha AB, Ng KS, Nik Ahmad NNF, Ratnasingam V, Bin Shudim SS, Vengadasalam P, Abraira Munoz LD, Salazar MA, Cruz JB, Soto MB, Ramos JC, Wong AC, Correa Rotter JR, Diaz Escalante T, Enriquez Sosa FE, Flores Lozano F, Flota Cervera LF, Frenk Baron P, Garcia Ballesteros C, Gomez Rangel JD, Herrera Jimenez LE, Irizar Santana SS, Jimenez Florez F, Laviada Molina H, Luna Ceballos RI, Martin Del Camp Blanco B, Morales Franco G, Moreno Loza OT, Mustieles Rocha C, Obrador Vera G, Orozco Castellanos R, Peralta Calcaneo J, Reyes Rosano MA, Rodriguez Pattzi H, Rosas Guzman J, Rucker Joerg IE, Saaveddra Sanchez SB, Sanchez Mijangos JH, Serrano Sanson P, Tamayo Y Orozco JA, Tellez Chavez E, Valdes Depeda A, Venegas Carrillo L, Villagordoa Mesa J, Zamarripa Escobedo R, Baker J, Noonan P, Scott R, Walker R, Watson E, Williams M, Young S, Abejuela Z, Agra J, Aquitania G, Caringal C, Comia RS, Delos Santos L, Gomez O, Jimeno C, Tan G, Tolentino M, Yao C, Yap YE, Ygpuara MDL, Bijata-Bronisz R, Hotlos L, Januszewicz A, Kaczmarek B, Kaminska A, Lazuka L, Madej A, Mazur S, Mlodawska-Choluj D, Nowicki M, Orlowska-Kowalik G, Popenda G, Rewerska B, Sowinski D, Angelescu LM, Anghel V, Avram RI, Busegeanu MM, Cif A, Cosma D, Crisan C, Demian LD, Ferariu IE, Halmagyi I, Hancu N, Munteanu M, Negru D, Onaca AG, Petrica L, Popa AR, Ranetti AE, Serafinceanu C, Toarba C, Agafyina A, Barbarash O, Barysheva O, Chizhov D, Dobronravov V, Glinkina I, Grineva E, Khirmanov V, Kolmakova E, Koroleva T, Kvitkova L, Marasaev V, Mkrtumyan A, Morugova T, Nagibovich G, Nagibovich O, Nedogoda S, Osipova I, Raskina T, Samoylova Y, Sazonova O, Shamkhalova M, Shutemova E, Shwartz Y, Uriasyev O, Vorobyev S, Zateyshchikova A, Zateyshshikov D, Zykova T, Antic S, Djordjevic M, Kendereski A, Lalic K, Lalic N, Popovic-Radinovic V, Babikova J, Benusova O, Buganova I, Culak J, Dzupina A, Dzuponova J, Fulop P, Ilavska A, Martinka E, Ochodnicka Z, Pella D, Smatanova I, Ahmed F, Badat A, Breedt J, Distiller L, Govender V, Govender R, Joshi M, Jurgens J, Latiff G, Lombard L, Mookadam M, Ngcakani N, Nortje H, Oosthuizen H, Pillay-Ramaya L, Prozesky H, Reddy J, Rheeder P, Seeber M, Cho YM, Jeong IK, Kim SG, Kim YH, Kwon HS, Kwon MJ, Lee BW, Lee J, Lee MK, Nam MS, Oh KH, Park CY, Park SH, Yoon KH, Alvarez Garcia P, Asmarats Mercadal L, Barrios C, Cereto Castro F, Cigarran Guldris S, Dominquez Lopez M, Egido de Los Rios J, Fernandez Fresnedo G, Galan Serrano A, Garcia I, Gonzalez Martinez FJ, Jodar Gimeno JE, Muñoz Lopez Mendoza M, Malek Marin T, Morales Portillo C, Munar Vila MA, Muñoz Torres M, Nieto Iglesias J, Pantoja Perez J, Perez Vera M, Portoles Perez JM, Quesada Simón MA, Simo Canonge R, Soto Gonzalez A, Terns Riera M, Tinahones Madueno FJ, Plaza MV, Chang CT, Chuang LM, Hsia TL, Hsieh CH, Lin CC, Lu YC, Sheu WH, Barna O, Bilyk SD, Botsyurko V, Dudar I, Fushtey I, Godlevska O, Golovchenko O, Gyrina O, Kazmirchuk A, Komisarenko I, Korzh O, Kravchun N, Legun O, Mankovskyy B, Martynyuk L, Mostovoy Y, Pashkovska N, Pererva L, Pertseva T, Samoylov O, Smirnov I, Svyshchenko Y, Tomashkevych H, Topchii I, Tryshchuk N, Tseluyko V, Vizir V, Vlasenko M, Zlova T, Zub L, Abusnana S, Railey M, Abouglila K, Ainsworth P, Ali Z, Arutchelvam V, Barnard M, Bellary S, Davies E, Davies M, Davies S, Dawson A, El Kossi M, English P, Fraser D, Gnudi L, Gunstone A, Hall T, Hanif W, Jackson A, Johnson A, Joseph F, Krishnan S, Kumwenda M, MacDougall I, Nixon P, O'Hare J, Philip S, Ramtoola S, Saxena M, Sennik D, Simon G, Singh B, Stephens J, Strzelecka A, Symonds R, Turner W, Wahba M, Wakeling J, Wheeler D, Winocour P, Abdallah J, Abdullah R, Abramowitz M, Acosta I, Aiello J, Akright L, Akyea-Djamson A, Alappan R, Alicic R, Al-Karadsheh A, Allison DC, Arauz-Pacheco C, Arfeen S, Arif A, Arvind M, Atray N, Awad A, Barnhill P, Barranco E, Barrera C, Beacom M, Behara V, Belo D, Bentley-Lewis R, Berenguer R, Bermudez L, Bernardo M, Biscoveanu M, Bowman-Stroud C, Brandon D, Brusco O, Busch R, Canaan Y, Chilito A, Christensen T, Christiano C, Christofides E, Chuateco C, Cohen K, Cohen R, Cohen-Stein D, Cook C, Coyne D, Daboul N, Darwish R, Daswani A, Deck K, Desouza C, Dev D, Dhillon M, Dua S, Eder F, Elosegui AM, El-Shahawy M, Ervin J, Esquenazi A, Evans J, Fishbane S, Frias J, Galindo-Ramos E, Galphin C, Ghazi A, Gonzalez E, Gorson D, Gowda A, Greco B, Grubb S, Gulati R, Hammoud J, Handelsman S, Hartman I, Hershon K, Hiser D, Hon G, Jacob R, Jaime M, Jamal A, Kaupke C, Keightley G, Kern E, Khanna R, Khitan Z, Kim S, Kopyt N, Kovesdy C, Krishna G, Kropp J, Kumar A, Kumar J, Kumar N, Kusnir J, Lane W, Lawrence M, Lehrner L, Lentz J, Levinson D, Lewis D, Liss K, Maddux A, Maheshwari H, Mandayam S, Marar I, Mehta B, Middleton J, Mordujovich J, Moreda R, Moustafa M, Mujica Trenche S, Narayanan M, Narvarte J, Nassar T, Newman G, Nichol B, Nicol P, Nisnisan J, Nossuli AK, Obialo C, Olelewe S, Oliver M, O'Shaughnessy A, Padron J, Pankhaniya R, Parker R, Patel D, Patel G, Patel N, Pavon H, Perez A, Perez C, Perlman A, Pettis K, Pharr W, Phillips A, Purighalla R, Quesada-Suarez L, Ranjan R, Rastogi S, Reddy J, Rendell M, Rich L, Robinson M, Rodriguez H, Rosas S, Saba F, Sankaram R, Sarin R, Schreiman R, Scott D, Sekkarie M, Sensenbrenner J, Shakeel M, Shanik M, Shaw S, Smith S, Solomon R, Sprague A, Spry L, Suchinda P, Sultan S, Surampudi P, Sussman S, Tan A, Terrelonge A, Thompson M, Trespalacios F, Trippe B, Trueba P, Twahirwa M, Updegrove J, Van Buren P, Vannorsdall M, Varghese F, Velasquez-Mieyer P, Ventrapragada S, Vukotic G, Wadud K, Warren M, Watson H, Watts R, Weiner D, Welker J, Welsh J, Williams S, Zaniewski-Singh M.

Abstract

BACKGROUND:

Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium-glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes.

METHODS:

In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to <90 ml per minute per 1.73 m2 of body-surface area and albuminuria (ratio of albumin [mg] to creatinine [g], >300 to 5000) and were treated with renin-angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15 ml per minute per 1.73 m2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically.

RESULTS:

The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P = 0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P<0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P = 0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P = 0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001). There were no significant differences in rates of amputation or fracture.

CONCLUSIONS:

In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years. (Funded by Janssen Research and Development; CREDENCE ClinicalTrials.gov number, NCT02065791.).

PMID:
30990260
DOI:
10.1056/NEJMoa1811744
[Indexed for MEDLINE]

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