Effects of dapagliflozin on mortality in patients with chronic kidney disease: a pre-specified analysis from the DAPA-CKD randomized controlled trial

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.

Keywords: Chronic kidney disease; Dapagliflozin; SGLT2 inhibitor.

Dapagliflozin prolonged survival irrespective of baseline patient characteristics, largely driven by reductions in non-CV death.

Figure 1

Cause of death in (A) the overall population and (B) patients with or without Type 2 diabetes. CV, cardiovascular; HF, heart failure; MI, myocardial infarction.

Figure 2

Kaplan–Meier curve for all-cause mortality in participants (A) with Type 2 diabetes and (B) without Type 2 diabetes. CI, confidence interval.

Figure 3

All-cause mortality outcome by pre-specified subgroups at baseline. CI, confidence interval; eGFR, estimated glomerular filtration rate.

Figure 4

Effect of dapagliflozin on cardiovascular, non-cardiovascular and undetermined causes of deaths. Main causes of cardiovascular and non-cardiovascular death are shown. Event numbers for other causes of cardiovascular or non-cardiovascular deaths were below 5 and are not reported. CI, confidence interval; MI, myocardial infarction.

Figure 5

Effect of sodium-glucose co-transporter 2 inhibitors on mortality in three clinical trials in patients with chronic kidney disease. Cardiovascular death was a component of the primary outcome in all trials. Because of loss of funding in the SCORED trial (sotagliflozin) not all endpoints were adjudicated and only investigator-reported endpoints were published. Data extracted from the CREDENCE (canagliflozin) and SCORED publications.^,, Relative risk ratios are presented for SCORED since hazard ratios could not be extracted. *In all trials undetermined causes of death were assumed to be of cardiovascular cause and were combined with cardiovascular causes of death. Quantitative assessment of effect on all-cause mortality and each cause of death was made by random-effects meta-analysis and calculating P-value for heterogeneity of the individual trial results. Summary statistics across trials are not provided because of heterogeneity for all-cause mortality and non-cardiovascular death.