Combining Dapagliflozin and Eplerenone Further Reduces Albuminuria in CKD

In a randomized trial, the combination of dapagliflozin and eplerenone produced a "robust and clinically meaningful reduction in albuminuria suggesting that the effects of both agents on albuminuria were independent and additive," according to investigators.

Combining a sodium-glucose cotransporter 2 inhibitor (SGLT2i) and a steroidal mineralocorticoid receptor antagonist (MRA) further decreases albuminuria compared with either therapy alone in patients with chronic kidney disease (CKD), investigators reported in the Journal of the American Society of Nephrology.

“The combination of dapagliflozin-eplerenone produces a robust and clinically meaningful reduction in albuminuria suggesting that the effects of both agents on albuminuria were independent and additive,” Hiddo J.L. Heerspink, PhD, PharmD, of University Medical Center Groningen in Groningen, The Netherlands, and colleagues concluded.

In the ROTATE-3 crossover trial, investigators randomly assigned 46 patients to 3 consecutive 4-week treatments of dapagliflozin 10 mg once daily, eplerenone 50 mg once daily, or a combination of these therapies, separated by washout periods. Per protocol, patients needed to have a baseline urinary albumin excretion rate of 100-3500 mg/24h and an estimated glomerular filtration rate (eGFR) of 31-89 mL/min/1.73 m², despite stable doses of angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARB). Baseline serum potassium needed to be 5.0 mmol/L or less.

After 4 weeks of treatment, the urinary albumin to creatinine ratio (UACR) significantly declined 19.6%, 33.7%, and 53.0% from baseline with dapagliflozin, eplerenone, and the combination, respectively, Dr Heerspink’s team reported..

UACR change during dapagliflozin or eplerenone monotherapy did not correlate with UACR change during combination therapy, “suggesting that patients who failed to respond to one of these treatments may benefit from the other,” according to the investigators.

Hyperkalemia occurred at significantly higher rates after use of eplerenone (17.4%) compared with dapagliflozin (0%) or the combination (4.3%).

“These data suggest that dapagliflozin in combination with eplerenone is an attractive option to slow the progression of kidney disease in patients with chronic kidney disease which requires confirmation in a large prospective clinical trial,” according to Dr Heerspink’s team.

Disclosure: Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.

Reference

Provenzano M, Puchades M, Garofalo C, et al. Albuminuria-lowering effect of dapagliflozin, eplerenone, and their combination in patients with chronic kidney disease: a randomized cross-over clinical trial. J Am Soc Nephrol. Published online April 19, 2022. doi:10.1681/ASN.2022020207