Abstract 13695: Finerenone Added to RAS/SGLT2 Blockade for Non-Diabetic Chronic Kidney Disease. Results of a Preclinical Double-Blinded Randomized Controlled Trial

Abstract

Introduction: Dual inhibition of the renin-angiotensin system (RAS) plus sodium-glucose transporter (SGLT)-2 or plus the mineralocorticoid receptor (MR) demonstrated additive renoprotective effects in large clinical trials. Hypothesis: We hypothesized that triple therapy with a combination of RAS/SGLT2/MR inhibitors would be superior to dual RAS/SGLT2 blockade in attenuating CKD progression Methods: We performed a preclinical randomized controlled trial (PCTE0000266) in Col4a3-deficient mice with established Alport nephropathy. Treatment was initiated late (6 weeks of age) in mice with elevated serum creatinine and albuminuria and in presence of glomerulosclerosis, interstitial fibrosis and tubular atrophy. We block-randomized 40 male and 40 female mice to either nil (vehicle) or late onset food admixes of ramipril monotherapy (10 mg/kg), ramipril plus empagliflozin (30 mg/kg), or ramipril plus empagliflozin plus finerenone (10 mg/kg). Primary endpoint was mean survival. Results: Mean survival was 63.7 ± 10.0 days (vehicle), 77.3 ± 5.3 days (ramipril), 80.3 ± 11.0 days (dual), and 103.1 ± 20.3 days (triple), respectively. Sex did not affect outcome. Histopathology, pathomics, and RNA sequencing revealed that finerenone mainly suppressed the residual interstitial inflammation and fibrosis despite dual RAS/SGLT2 inhibition. Conclusions: This preclinical randomized controlled trial suggests that triple RAS/SGLT2/MR blockade may substantially improve renal outcomes in Alport syndrome and possibly other progressive chronic kidney disorders for synergistic effects on the glomerular and tubulointerstitial compartment, respectively.