The Kidney Protective Effects of the Sodium-Glucose Cotransporter-2 Inhibitor, Dapagliflozin, Are Present in Patients With CKD Treated With Mineralocorticoid Receptor Antagonists

Abstract

Introduction: Mineralocorticoid receptor antagonists (MRAs) and sodium-glucose cotransporter-2 (SGLT2) inhibitors reduce the risk of kidney failure in chronic kidney disease (CKD). We performed an analysis of the Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease (DAPA-CKD) trial by baseline conventional MRA (spironolactone and eplerenone) prescription.

Methods: Participants with CKD (estimated glomerular filtration rate [eGFR] 25-75 ml/min per 1.73 m²; urinary albumin-to-creatinine ratio 200-500 mg/g), with or without type 2 diabetes, were randomized 1:1 to dapagliflozin 10 mg or placebo, once daily. The primary outcome was a composite of sustained ≥50% eGFR decline, end-stage kidney disease, or kidney or cardiovascular (CV) death. A prespecified kidney-specific secondary outcome was as the primary outcome but without CV death. Hyperkalemia (serum potassium ≥6.0 mmol/l) was an exploratory end point. Time-to-event analyses (proportional hazards [Cox] regression) assessed dapagliflozin versus placebo in patient subgroups defined by baseline conventional MRA use.

Results: A total of 229 of 4304 DAPA-CKD participants (5.3%) were receiving conventional MRAs at baseline (dapagliflozin n = 109, placebo n = 120). The effect of dapagliflozin on the primary outcome was consistent in participants prescribed (hazard ratio [HR] 0.76, 95% CI 0.40-1.47) and not prescribed (HR 0.60, 95% CI 0.50-0.72, P-interaction = 0.59) MRAs. This consistency was maintained for the kidney-specific outcome. The effect of dapagliflozin on hyperkalemia (HR 0.87, 95% CI 0.70-1.09) was consistent among those prescribed (HR 0.94, 95% CI 0.41-2.20) and not prescribed (HR 0.87, 95% CI 0.69-1.10, P-interaction = 0.96) MRAs. Adverse events (AEs) leading to discontinuation and serious AEs were similar between treatment groups, regardless of baseline MRA prescription.

Conclusion: Dapagliflozin was similarly safe and efficacious in reducing major adverse kidney outcomes in participants with CKD who were or were not prescribed MRAs at baseline.

Keywords: DAPA-CKD; chronic kidney disease; dapagliflozin; hyperkalemia; mineralocorticoid receptor antagonists; sodium–glucose cotransporter-2 inhibitor.

Figure 1

Outcomes for participants with and without MRA use at baseline. (a) Outcomes for the primary composite, the secondary kidney-specific composite outcome, eGFR decline ≥50%, ESKD, hospitalization for heart failure or CV death, and all-cause death. (b) Cumulative incidence of the secondary kidney-specific outcome. CV, cardiovascular; eGFR, estimated glomerular filtration rate; ESKD, end-stage kidney disease; MRA, mineralocorticoid receptor antagonist.

Figure 2

eGFR over time in participants with and without MRA use at baseline. (a) With MRA use at baseline. (b) Without MRA use at baseline. eGFR, estimated glomerular filtration rate; LS, least-squared; MRA, mineralocorticoid receptor antagonist.

Figure 3

UACR over time in participants with and without MRA use at baseline. (a) With MRA use at baseline. (b) Without MRA use at baseline. MRA, mineralocorticoid receptor antagonists; LS, least-squared; UACR, urine albumin-to creatinine ratio.