Albuminuria-Lowering Effect of Dapagliflozin, Eplerenone, and their Combination in Patients with Chronic Kidney Disease: A Randomized Cross-Over Clinical Trial

Background SGLT2 inhibitors and MRAs reduce the urinary albumin-to-creatinine ratio (UACR) and confer kidney and cardiovascular protection in patients with chronic kidney disease (CKD). We assessed efficacy and safety of the SGLT2 inhibitor dapagliflozin and mineralocorticoid receptor antagonists (MRA) eplere-none alone and in combination in patients with CKD. Methods We conducted a randomized open-label crossover trial in patients with urinary albumin excretion >= 100 mg/24 hours, eGFR 30-90 ml/min per 1.73 m(2), who had been receiving maximum tolerated stable doses of an ACE inhibitor (ACEi) or angiotensin receptor blocker (ARB). Patients were assigned to 4-weektreatment periods with dapagliflozin 10 mg/day, eplerenone 50 mg/day, or their combination in randomorder, separated by 4-week washout periods. Primary outcome was the correlation in UACR changes between treatments. Secondary outcome was the percent change in 24-hour UACR from baseline. Results Of 57 patients screened, 46 were randomly assigned (mean eGFR 58.1 ml/min per 1.73 m(2),median UACR 401 mg/g) to the three groups. Mean percentage change from baseline in UACR after 4weeks of treatment with dapagliflozin, eplerenone, and dapagliflozin-eplerenone was-19.6% (95% CI,-34.3 to-1.5),-33.7% (95% CI,-46.1 to-18.5), and-53% (95% CI,-61.7 to-42.4;P < 0.001 versus dapagli-flozin; P > 0.01 versus eplerenone). UACR change during dapagliflozin or eplerenone treatment did notcorrelate with UACR change during dapagliflozin-eplerenone (r5-0.13;P50.47;r5-0.08;P50.66, respectively). Hyperkalemia was more frequently reported with eplerenone (n58; 17.4%) compared with dapagliflozin (n50; 0%) or dapagliflozin-eplerenone (n52; 4.3%;P(between-groups)50.003). Conclusions Albuminuria changes in response to dapagliflozin and eplerenone did not correlate, supporting systematic rotation of these therapies to optimize treatment. Combining dapagliflozin with eplerenoneresulted in a robust additive UACR-lowering effect. A larger trial in this population is required to confirmlong-term efficacy and safety of combined SGLT2 inhibitor and MRA treatment. Clinical Trial registry name and registration number: European Union Clinical Trials Register, EU 2017-004641-25.

Automated summary

This study assessed the efficacy and safety of SGLT2 inhibitors and mineralocorticoid receptor antagonists in patients with CKD. The results showed that changes in urinary albumin did not correlate between dapagliflozin and eplerenone, but the combination of these drugs resulted in a strong additive effect in lowering UACR.