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

John J.V. McMurray, MD; David C. Wheeler, MD; Bergur V. Stefánsson, MD; Niels Jongs, MSC; Douwe Postmus, PHD; Ricardo Correa-Rotter, MD; Glenn M. Chertow, MD; Fan Fan Hou, MD; Peter Rossing, MD; C. David Sjöström, MD; Scott D. Solomon, MD; Robert D. Toto, MD; Anna Maria Langkilde, MD; Hiddo J.L. Heerspink, PHD

Disclosures

JACC Heart Fail. 2021;9(11):807-820. 

In This Article

Abstract and Introduction

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)

Introduction

Heart failure (HF) is common in patients with chronic kidney disease (CKD), reflecting the high prevalence of hypertension and diabetes in these individuals. These, along with premature and extensive atherosclerotic disease, impaired sodium and water homeostasis, and anemia, cause or aggravate cardiac and vascular hypertrophy and fibrosis as well as myocardial ischemia, leading to left ventricular diastolic and systolic dysfunction. HF is an important cause of hospitalization and a powerful and independent predictor of death in this population.[1–7] In the ARIC (Atherosclerosis Risk In Communities) study, the adjusted incidence of HF was 3-fold higher in people with an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 compared with those with eGFR >90 mL/min/1.73 m2.[1,4] Additional epidemiological studies confirmed these findings, showing that the magnitude of risk of HF in people with CKD was as high as that for coronary disease and higher than that for stroke.[1–7] The incidence and prevalence of HF is higher in patients with more severe CKD; recent reports from the US Renal Data System suggest that up to 30% of patients with CKD have concomitant HF, a much higher prevalence than in the general population.[6,7] HF is associated with a particularly poor survival in patients with CKD. Consequently, both prevention and treatment of HF in patients with CKD is a priority.

A series of large randomized controlled trials have demonstrated that sodium glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of HF hospitalization in patients with type 2 diabetes mellitus, including those with CKD.[8–12] More recently, this benefit of SGLT2 inhibitors was expanded to patients with CKD without type 2 diabetes in the DAPA-CKD (Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease) trial.[13] Whereas the SGLT2 inhibitor trials in patients with type 2 diabetes largely described prevention of incident HF, the effect of SGLT2 inhibitors in patients with CKD, diabetes, and prevalent HF was reported in the CREDENCE (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation) trial.[12,14] Here we extend these findings to patients with CKD and HF, with and without type 2 diabetes, reporting the effects of dapagliflozin on HF hospitalization, kidney outcomes, and mortality in patients with HF at baseline in DAPA-CKD.[13,15] This analysis is clinically relevant, given the suggestion that development of HF may accelerate the rate of decline in glomerular filtration rate, leading to a vicious circle whereby one condition exacerbates the other.[1–7] In addition, the greater concomitant use of diuretic therapy in patients with HF is also relevant here, given that these drugs can also worsen kidney function and that their action might be augmented by the diuresis caused by SGLT2 inhibitors.

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