Glomerular and Tubular Effects of Dapagliflozin, Eplerenone and their Combination in Patients with Chronic Kidney Disease: A Post-hoc Analysis of the ROTATE-3 Study

Diabetes Obes Metab. 2023; online ahead of print DOI: 10.1111/dom.15346

The ROTATE-3 cross-over trial in 46 adults with CKD and urinary albumin excretion ≥100 mg/24 h showed that dapagliflozin combined with eplerenone led to robust additive reductions in albuminuria compared with either agent alone. This post-hoc analysis aimed to characterise the effects of dapagliflozin, eplerenone and the combination on markers of glomerular and tubular function to better understand the mechanisms responsible for albuminuria lowering.

The mean percentage change from baseline in heparan sulphate, a marker of glomerular endothelial glycocalyx function, was significantly lower with dapagliflozin, but not eplerenone after 4 weeks. Eplerenone and the combination, but not dapagliflozin alone increased plasma aldosterone. Dapagliflozin decreased the rate of proximal absolute sodium reabsorption, while eplerenone decreased distal absolute sodium reabsorption. The combination of dapagliflozin plus eplerenone decreased proximal absolute sodium reabsorption but did not affect distal absolute sodium reabsorption.

These findings indicate that dapagliflozin and eplerenone exert different effects on markers of glomerular and tubular function, suggesting that different mechanistic pathways may account for their kidney protective effects.