Effects of dapagliflozin on mortality in patients with chronic kidney disease: a pre-specified analysis from the DAPA-CKD randomized controlled trial
Authors: Heerspink Hiddo J L , Sjöström C David , Jongs Niels , Chertow Glenn M , Kosiborod Mikhail , Hou Fan Fan , McMurray John J V , Rossing Peter , Correa-Rotter Ricardo , Kurlyandskaya Raisa , Stefansson Bergur V , Toto Robert D , Langkilde Anna Maria , Wheeler David C ,   for the DAPA-CKD Trial Committees and Investigators, 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 
Published: February 2021

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.