Effects of Dapagliflozin in Patients With Kidney Disease, With and Without Heart Failure

Abstract

Objectives: The purpose of this paper was to investigate the effects of dapagliflozin in chronic kidney disease (CKD) patients, with and without heart failure (HF).

Background: Patients with CKD, with and without type 2 diabetes, were enrolled in the DAPA-CKD (Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease) trial. Some patients had HF at baseline.

Methods: A total of 4,304 participants were randomized to dapagliflozin 10 mg daily or placebo. The primary composite endpoint was ≥50% decline in estimated glomerular filtration rate, end-stage kidney disease, or kidney/cardiovascular death. Secondary endpoints were a kidney composite (primary endpoint minus cardiovascular death), the composite of cardiovascular death/HF hospitalization, and all-cause death. Analysis of outcomes according to HF history was prespecified.

Results: HF patients (n = 468; 11%) were older and had more coronary disease, atrial fibrillation, and type 2 diabetes. Mean estimated glomerular filtration rate was similar in patients with and without HF. Rates of HF hospitalization/cardiovascular death and death from any cause were higher in HF patients, but the secondary kidney failure outcome occurred at the same rate in people with and without HF. Dapagliflozin reduced the risk of the primary outcome equally in patients with HF (HR: 0.58 [95% CI: 0.37-0.91]) and without HF (HR: 0.62 [95% CI: 0.51-0.75]) (P interaction = 0.59). The proportional risk-reductions were similar in patients with and without HF for the cardiovascular death/HF hospitalization composite (HR: 0.68 [95% CI: 0.44-1.05] vs HR: 0.70 [95% CI: 0.51-0.97], respectively; P interaction = 0.90), and all-cause death (HR: 0.56 [95% CI: 0.34-0.93] vs HR: 0.73 [95% CI: 0.54-0.97], respectively; P interaction = 0.39), although absolute risk reductions were larger in HF patients. Adverse event rates were low and did not differ among patients with or without HF.

Conclusions: Dapagliflozin reduced the risk of kidney failure and cardiovascular death/HF hospitalization and prolonged survival in CKD patients with or without type 2 diabetes, independently of history of HF. (A Study to Evaluate the Effect of Dapagliflozin on Renal Outcomes and Cardiovascular Mortality in Patients With Chronic Kidney Disease [DAPA-CKD]; NCT03036150).

Keywords: SGLT2 inhibitor; cardiovascular disease; chronic kidney disease; dapagliflozin; heart failure.

Conflict of interest statement

Funding Support and Author Disclosures The DAPA-CKD trial was funded by AstraZeneca. Prof McMurray is supported by a British Heart Foundation Centre of Research Excellence Grant RE/18/6/34217; his employer, Glasgow University, has received payment for his work on clinical trials, consulting, and other activities from Alnylam, Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Cardurion, Cytokinetics, GlaxoSmithKline, Novartis, Pfizer, Theracos; and he has received personal lecture fees from the Corpus, Abbott, Hickma, Sun Pharmaceuticals, and Medsca. Dr Wheeler has received honoraria and/or consultancy fees from Amgen, AstraZeneca, Boehringer Ingelheim, Bayer, GlaxoSmithKline, Janssen, Napp, Mundipharma, Medscape, Merck Sharp and Dohme, Pharmacosmos, Reata, Takeda, and Vifor Fresenius. Drs Stefánsson, Sjöström, and Langkilde are employees and stockholders of AstraZeneca. Dr Correa-Rotter has received honoraria from AbbVie, AstraZeneca, GlaxoSmithKline, Medtronic, and Boehringer Ingelheim; has lectured for Amgen, Janssen, Takeda, AstraZeneca, and Boehringer Ingelheim; and has received research support from GlaxoSmithKline, Novo Nordisk, and AstraZeneca. Dr Chertow has received fees from AstraZeneca for the DAPA-CKD trial steering committee; has received research grants from NIDDK and Amgen; is on the board of directors for Satellite Healthcare; has received fees for advisory boards for Baxter, Cricket, DiaMedica, and Reata; holds stock options for Ardelyx, CloudCath, Durect, DxNow, and Outset; has received fees from Akebia, Sanifit, and Vertex for trial steering committees; and has received fees for DSMB service from Angion, Bayer, and ReCor. Dr Hou has received honoraria from AbbVie and AstraZeneca. Dr Rossing has received honoraria to Steno Diabetes Center Copenhagen for consultancy from AstraZeneca, Astellas, Bayer, Boehringer Ingelheim, Gilead, Novo Nordisk, Merck, Mundipharma, Sanofi, and Vifor; and has received research support from AstraZeneca, and Novo Nordisk. Dr Solomon has received research grants from Actelion, Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, Bristol Myers Squibb, Celladon, Cytokinetics, Eidos, Gilead, GlaxoSmithKline, Ionis, Lilly, Lone Star Heart, Mesoblast, MyoKardia, National Institutes of Health/National Heart, Lung, and Blood Institute, Neurotronik, Novartis, NovoNordisk, Respicardia, Sanofi Pasteur, and Theracos, and has consulted for Abbott, Action Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi-Sankyo, Gilead, GlaxoSmithKline, Ironwood, Lilly, Merck, MyoKardia, Novartis, Roche, Takeda, Theracos, Quantum Genetics, Cardurion, AoBiome, Janssen, Cardiac Dimensions, Tenaya, Sanofi-Pasteur, Dinaqor, Tremeau, CellProThera, Moderna, and American Regent. Dr Toto has served as a consultant for AstraZeneca, Amgen, Bayer, Boehringer Ingelheim, Medscape, Otsuka, Reata, and Relypsa. Dr Heerspink has served as a consultant for AbbVie, AstraZeneca, Bayer, Boehringer Ingelheim, Chinook, CSL Pharma, Gilead, Janssen, Merck, Mundi Pharma, Mitsubishi Tanabe, Novo Nordisk, and Retrophin; and has received research support from Abbvie, AstraZeneca, Boehringer Ingelheim, and Janssen. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

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