Effects of Dapagliflozin in Stage 4 Chronic Kidney Disease

Abstract

Background: In the Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease (DAPA-CKD) randomized, placebo-controlled trial, the sodium-glucose cotransporter 2 inhibitor dapagliflozin significantly reduced risk of kidney failure and prolonged survival in patients with CKD with or without type 2 diabetes.

Methods: Adults with eGFR of 25-75 ml/min per 1.73 m2 and urinary albumin-to-creatinine ratio of 200-5000 mg/g had been randomized to receive dapagliflozin 10 mg/d or placebo. Here, we conducted a prespecified analysis of dapagliflozin's effects in patients with stage 4 CKD (eGFR,30 ml/min per 1.73 m2) at baseline. The primary end point was a composite of time to ≥50% sustained decline in eGFR, ESKD, or kidney or cardiovascular death. Secondary end points were a kidney composite (same as the primary end point but without cardiovascular death), a composite of cardiovascular death or heart failure hospitalization, and all-cause death.

Results: A total of 293 participants with stage 4 CKD received dapagliflozin and 331 received placebo. Patients with stage 4 CKD randomized to dapagliflozin experienced a 27% (95% confidence interval [95% CI]: -2 to 47%) reduction in the primary composite endpoint, and 29% (-2 to 51%), 17% (-53 to 55%), and 32% (-21 to 61%) reductions in the kidney, cardiovascular and mortality endpoints, respectively, relative to placebo. Interaction P-values were 0.22, 0.13, 0.63, and 0.95, respectively, comparing CKD stages 4 versus 2/3. The eGFR slope declined by 2.15 and 3.38 ml/min per 1.73 m2 per year in the dapagliflozin and placebo groups, respectively (P=0.005). Patients treated with dapagliflozin or placebo had similar rates of serious adverse events and adverse events of interest.

Conclusions: Among patients with stage 4 CKD and albuminuria, the effects of dapagliflozin were consistent with those observed in the DAPA-CKD trial overall, with no evidence of increased risks.

Keywords: SGLT2 inhibitor; chronic kidney disease; dapagliflozin; stage 4 CKD.

Copyright © 2021 by the American Society of Nephrology.

Figures

Figure 1.

Participant flow chart by CKD stage. Box indicates subgroups in the current prespecified analysis; stage 4 CKD, eGFR2; stage 2/3 CKD, eGFR≥30 ml/min per 1.73 m2.

Figure 2.

Kaplan–Meier curves for the cumulative incidence of (A) the primary composite end points, (B) the kidney composite end point, (C) hospitalization for heart failure or cardiovascular death, and (D) all-cause death in patients with stage 4 CKD at baseline. Primary composite end point, sustained eGFR decline ≥50%, ESKD, or kidney or cardiovascular death; secondary kidney composite end point, sustained eGFR decline ≥50%, ESKD, or kidney death.

Figure 3.

Forest plots for the primary and secondary end points by baseline CKD stage. Stage 4 CKD, eGFR2; stages 2/3 CKD, eGFR≥30 ml/min per 1.73 m2. CV, cardiovascular; n, number with events; N, total number.

Figure 4.

LS mean change in eGFR over the study in those with baseline stage 4 or stages 2/3 CKD. On the basis of the two-slope model. Total slopes (SEM): stage 4 CKD, dapagliflozin −2.15 (0.32), placebo −3.38 (0.31); stage 2/3 CKD, dapagliflozin −2.98 (0.12), placebo −3.87 (0.12) ml/min per 1.73 m2 per year. Chronic slope (SEM): stage 4 CKD, dapagliflozin −1.33 (0.32), placebo −3.68 (0.12); stage 2/3 CKD, dapagliflozin −1.73 (0.12), placebo −3.68 (0.12) ml/min per 1.73 m2 per year. Acute slope (SEM): stage 4 CKD, dapagliflozin −2.10 (0.37), placebo −0.68 (0.35); stage 2/3 CKD, dapagliflozin −3.19 (0.15), placebo −0.64 (0.15) ml/min per 1.73 m2 per two weeks. Stage 4 CKD, eGFR<30 ml/min per 1.73 m2; stages 2/3 CKD, eGFR 30 ml/min per 1.73 m2. Error bars indicate SEM. LS, least squares; SEM, standard error of the mean.