Effects of dapagliflozin on mortality in patients with chronic kidney disease: a pre-specified analysis from the DAPA-CKD randomized controlled trial
Author:
Heerspink Hiddo J L12, Sjöström C David3, Jongs Niels1, Chertow Glenn M4, Kosiborod Mikhail256, Hou Fan Fan7, McMurray John J V8, Rossing Peter910ORCID, Correa-Rotter Ricardo11, Kurlyandskaya Raisa12ORCID, Stefansson Bergur V3ORCID, Toto Robert D13, Langkilde Anna Maria3, Wheeler David C142ORCID, Heerspink Hiddo J L, Wheeler David C, Chertow Glenn, Correa-Rotter Ricardo, Greene Tom, Fan Hou Fan, McMurray John, Rossing Peter, Toto Robert, Stefansson Bergur, Maria Langkilde. Anna, Maffei L E, Raffaele P, Solis S E, Arias C A, Aizenberg D, Luquez C, Zaidman C, Cluigt N, Mayer M, Alvarisqueta A, Wassermann A, Maldonado R, Bittar J, Maurich M, Gaite L E, Garcia N, Sivak L, Ramallo P O, Santos J C, Garcia Duran R, Oddino J A, Maranon A, Maia L N, D Avila D, Barros E J G, Vidotti M H, Panarotto D, Noronha I D L, Turatti L A A, Deboni L, Canziani M E, Riella M C, Bacci M R, Paschoalin R P, Franco R J, Goldani J C, St-Amour E, Steele A W, Goldenberg R, Pandeya S, Bajaj H, Cherney D, Kaiser S M, Conway J R, Chow S S, Bailey G, Lafrance J, Winterstein J, Cournoyer S, Gaudet D, Madore F, Houlden R L, Dowell A, Langlois M, Muirhead N, Khandwala H, Levin A, Hou F, Xue Y, Zuo L, Hao C, Ni Z, Xing C, Chen N, Dong Y, Zhou R, Xiao X, Zou Y, Wang C, Liu B, Chen Q, Lin M, Luo Q, Zhang D, Wang J, Chen M, Wang X, Zhong A, Dong J, Zhu C, Yan T, Luo P, Ren Y, Pai P, Li D, Zhang R, Zhang J, Xu M, Zhuang Y, Kong Y, Yao X, Peng X, Persson F I, Hansen T K, Borg R, Pedersen Bjergaard U, Hansen D, Hornum M, Haller H, Klausmann G, Tschope D, Kruger T, Gross P, Hugo C, Obermuller N, Rose L, Mertens P, Zeller-Stefan H, Fritsche A, Renders L, Muller J, Budde K, Schroppel B, Wittmann I, Voros P, Dudas M, Tabak G A, Kirschner R, Letoha A, Balku I, Hermanyi Z, Zakar G, Mezei I, Nagy G G, Lippai J, Nemeth A, Khullar D, Gowdaiah P K, Fernando Mervin E, Rao V A, Dewan D, Maddi V S K, Vyawahare M S, Pulichikkat R K, Sonkar S K, Gupta V K, Agarwal S, Asirvatham A J, Ignatius A, Chaubey S, Melemadathil S, Alva H, Kadam Y, Shimizu H, Sueyoshi A, Takeoka H, Abe Y, Imai T, Onishi Y, Fujita Y, Tokita Y, Makita Y, Idogaki A, Koyama R, Kikuchi H, Kashihara N, Hayashi T, Ando Y, Tanaka T, Shimizu M, Hidaka S, Gohda T, Tamura K, Abe M, Kamijo Y, Imasawa T, Takahashi Y, Nakayama M, Tomita M, Hirano F, Nakayama M, Fukushima Y, Kiyosue A, Kurioka S, Imai E, Kitagawa K, Waki M, Wada J, Uehara K, Iwatani H, Ota K, Shibazaki S, Tamura K, Katayama K, Narita I, Iinuma M, Matsueda S, Sasaki S, Yokochi A, Tsukamoto T, Yoshimura T, Kang S, Lee S, Lim C S, Chin H, Joo K W, Han S Y, Chang T I, Park S, Park H, Park C W, Han B G, Cha D R, Yoon S A, Kim W, Kim S W, Ryu D, Correa Rotter R, Irizar Santana S S, Hernandez Llamas G, Valdez Ortiz R, Secchi Nicolas N C, Gonzalez Galvez G, Lazcano Soto J R, Bochicchio Riccardelli T, Bayram Llamas E A, Ramos Ibarra D R, Melo M G S, Gonzalez Gonzalez J G, Sanchez Mijangos J H, Madero Robalo M, Garcia Castillo A, Manrique H A, Farfan J C, Vargas R, Valdivia A, Dextre A, Escudero E, Calderon Ticona J R, Gonzales L, Villena J, Leon L, Molina G, Saavedra A, Garrido E, Arbanil H, Vargas Marquez S, Rodriguez J, Isidto R, Villaflor A J, Gumba M A, Tirador L, Comia R S, Sy R A, Guanzon M L V V, Aquitania G, De Asis N C, Silva A A, Lim M E, Danguilan R A, Nowicki M, Rudzki H, Landa K, Kucharczyk-Bauman I, Gogola-Migdal B, Golski M, Olech-Cudzik A, Stompor T, Szczepanik T, Miklaszewicz B, Sciborski R, Kuzniewski M, Ciechanowski K, Wronska D, Klatko W, Mazur S, Popenda G, Myslicki M, Bolieva L Z, Berns S, Galyavich A, Abissova T, Karpova I, Platonov D, Koziolova N, Kvitkova L, Nilk R, Medina T, Rebrov A, Rossovskaya M, Sinitsina I, Vishneva E, Zagidullin N, Novikova T, Krasnopeeva N, Magnitskaya O, Antropenko N, Batiushin M, Escudero Quesada V, Barrios Barrea C, Espinel Garauz E, Cruzado Garrit J M, Morales Portillo C, Gorriz Teruel J L, Cigarran Guldris S, Praga Terente M, Robles Perez-Monteoliva N R, Infanta Cristina H, Tinahones Madueno F J, Soto Gonzalez A, Diaz Rodriguez C, Furuland H, Saeed A, Dreja K, Spaak J, Bruchfeld A, Kolesnyk M, Levchenko O, Pyvovarova N, Stus V, Doretskyy V, Korobova N, Horoshko O, Katerenchuk I, Mostovoy Y M, Orynchak M, Legun O, Dudar I, Bilchenko O, Andreychyn S, Levchenko A, Zub L, Tereshchenko N, Topchii I, Ostapenko T, Bezuglova S, Kopytsya M, Turenko O, Mark P, Barratt J, Bhandari S, Fraser D, Kalra P, Kon S P, Mccafferty K, Mikhail A, Kon S P, Alvarado O P, Anderson R, Andrawis N S, Arif A, Benjamin S A, Bueso G, Busch R S, Carr K W, Carr Kenneth W, Crawford P, Daboul N, De La Calle G M, Delgado B, Earl J, El-Shahawy M A, Graf R J, Greenwood G, Guevara A, Wendland E M, Mayfield R K, Montero M, Morin D J, Narayan P, Numrungroad V, Reddy A C, Reddy R, Samson M B, Trejo R, Butcher M B, Wise J K, Zemel L R, Raikhel M, Weinstein D, Hernandez P, Wynne A, Khan B V, Sterba G A, Jamal A, Ross D, Rovner S F, Tan A, Ovalle F, Patel R J, Talano J, Patel D R, Burgner A, Aslam N, Elliott M, Goral S, Jovanovich A, Umanath K, Waguespack D, Weiner D, Yu M, Schneider L, Le T, D T, Nguyen N, Nguyen H, Nguyen D, Nguyen V, Do T, Chu P, Ta D, Tran N, Nguyen D, Pfeffer Marc A, Pocock Stuart, Swedberg Karl, Rouleau Jean L, Chaturvedi Nishi, Ivanovich Peter, Levey Andrew S, Held Claes, Christersson Christina, Mann Johannes, Varenhorst Christoph,
Affiliation:
1. Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, PO Box 30 001, 9700 RB Groningen, Netherlands 2. The George Institute for Global Health, Level 5, 1 King Street, Newtown, Sydney, NSW 2042, Australia 3. Late-stage Development, Cardiovascular, Renal and Metabolism, Biopharmaceuticals R&D, AstraZeneca, Pepparedsleden 1, 431 50 Mölndal, Gothenburg, Sweden 4. Department of Medicine, 291 Campus Drive, Li Ka Shing Building, Stanford University School of Medicine, Stanford, CA 94305-5101 USA; Department of Epidemiology and Population Health, 150 Governor's LaneHRP Redwood Building Stanford University School of Medicine, Stanford, CA 94305-5405 USA 5. Saint Luke's Mid America Heart Institute, 4401 Wornall Rd. Kansas City, MO 64111, USA 6. University of Missouri-Kansas City, 5000 Holmes St, Kansas City, MO 64110, USA 7. Division of Nephrology, Nanfang Hospital, Southern Medical University, National Clinical Research Center for Kidney Disease, 1838 Guangzhou N Ave, Baiyun, Guangzhou, Guangdong Province, China 8. Institute of Cardiovascular and Medical Sciences, University of Glasgow, 126 University Pl, Glasgow, G12 8TA, UK 9. Steno Diabetes Center Copenhagen, Niels Steensens Vej 2, 2820 Gentofte, Denmark 10. Department of Clinical Medicine, University of Copenhagen, Blegdamsvej 3B, 33.5.18-21DK-2200 Copenhagen, Denmark 11. National Medical Science and Nutrition Institute Salvador Zubirán, Vasco de Quiroga 15, Belisario Dom쭧uez Secc 16, Tlalpan, 14080 Ciudad de México, CDMX, Mexico 12. Late-Stage Development, Cardiovascular, Renal and Metabolism, Biopharmaceuticals R&D, AstraZeneca, Postępu 14, 02-676 Warsaw, Poland 13. Department of Internal Medicine, UT Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390, USA 14. Department of Renal Medicine, UCL Medical School, University College London, Rowland Hill Street, London, NW3 2PF, UK
Abstract
Abstract
Aims
Mortality rates from chronic kidney disease (CKD) have increased in the last decade. In this pre-specified analysis of the DAPA-CKD trial, we determined the effects of dapagliflozin on cardiovascular and non-cardiovascular causes of death.
Methods and results
DAPA-CKD was an international, randomized, placebo-controlled trial with a median of 2.4 years of follow-up. Eligible participants were adult patients with CKD, defined as a urinary albumin-to-creatinine ratio (UACR) 200–5000 mg/g and an estimated glomerular filtration rate (eGFR) 25–75 mL/min/1.73 m2. All-cause mortality was a key secondary endpoint. Cardiovascular and non-cardiovascular death was adjudicated by an independent clinical events committee. The DAPA-CKD trial randomized participants to dapagliflozin 10 mg/day (n = 2152) or placebo (n = 2152). The mean age was 62 years, 33% were women, the mean eGFR was 43.1 mL/min/1.73 m2, and the median UACR was 949 mg/g. During follow-up, 247 (5.7%) patients died, of whom 91 (36.8%) died due to cardiovascular causes, 102 (41.3%) due to non-cardiovascular causes, and in 54 (21.9%) patients, the cause of death was undetermined. The relative risk reduction for all-cause mortality with dapagliflozin (31%, hazard ratio [HR] [95% confidence interval (CI)] 0.69 [0.53, 0.88]; P = 0.003) was consistent across pre-specified subgroups. The effect on all-cause mortality was driven largely by a 46% relative risk reduction of non-cardiovascular death (HR [95% CI] 0.54 [0.36, 0.82]). Deaths due to infections and malignancies were the most frequently occurring causes of non-cardiovascular deaths and were reduced with dapagliflozin vs. placebo.
Conclusion
In patients with CKD, dapagliflozin prolonged survival irrespective of baseline patient characteristics. The benefits were driven largely by reductions in non-cardiovascular death.
Publisher
Oxford University Press (OUP)
Subject
Cardiology and Cardiovascular Medicine
Cited by
91 articles.
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