Abstract: PO0642
Combined Efficacy of the Novel Nonsteroidal and Selective Mineralocorticoid Receptor Antagonist Finerenone and the SGLT2 Inhibitor Empagliflozin in a Non-Diabetic Cardiorenal Rat Model
Session Information
- CKD Mechanisms - 2
October 22, 2020 | Location: On-Demand
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 2103 CKD (Non-Dialysis): Mechanisms
Authors
- Kolkhof, Peter, BAYER AG, Pharmaceuticals, Research & Development, Cardiovascular Research, Wuppertal, Germany
- Pavkovic, Mira, BAYER AG, Pharmaceuticals, Research & Development, Biomarker Research, Wuppertal, Germany
- Hartmann, Elke, BAYER AG, Pharmaceuticals, Research & Developent, Research Pathology, Wuppertal, Germany
- Sandner, Peter, BAYER AG, Pharmaceuticals, Research & Development, Cardiovascular Research, Wuppertal, Germany
- Mathar, Ilka, BAYER AG, Pharmaceuticals, Research & Development, Cardiovascular Research, Wuppertal, Germany
- Hüser, Jörg, BAYER AG, Pharmaceuticals, Research & Development, Cardiovascular Research, Wuppertal, Germany
- Eitner, Frank, BAYER AG, Pharmaceuticals, Research & Development, Cardiovascular Research, Wuppertal, Germany
Background
Finerenone and SGLT2 inhibitors have demonstrated clinical benefits in CKD patients with T2D. Efficacy of finerenone and SGLT2i, especially in combination, is unknown in non-diabetic kidney disease.
Methods
Cardiorenal morbidity and mortality was studied in hypertensive and proteinuric L-NAME (20 mg/L) treated renin-transgenic (mRen2)27 rats. Rats (10-11 weeks old female, n=13-17/group) were treated once daily orally for up to 7 weeks with placebo, finerenone (1 and 3 mg/kg), empagliflozin (3 and 10 mg/kg), or a combination of the respective low doses. Key outcome parameters included mortality, blood pressure, proteinuria, kidney histology and gene expression.
Results
Placebo-treated rats demonstrated a 50% mortality rate over the course of 7 weeks (figure). Drug treatment resulted in variable degrees of survival benefit, most prominent and statistically significant in the low dose combination group (figure). Low dose combination revealed an early, sustained and efficacious proteinuria reduction (-86%, p<0.05) and was highly efficient on renal histology parameters. Monotherapies of finerenone (-27% @ 1 mg/kg, p = n.s.; -87% @ 3 mg/kg, p<0.05) and empagliflozin (-38% @ 3 mg/kg, p = n.s.; -64% @ 10 mg/kg, p = n.s.) dose-dependently reduced proteinuria with a comparable protection from renal lesions at higher dosages. Treatment with finerenone and the combination significantly decreased systolic blood pressure while empagliflozin alone and in combination acted strongly glucosoric.
Conclusion
Both, MRA by finerenone and SGLT2i by empagliflozin confer renal protection in preclinical non-diabetic, hypertensive kidney disease. Combination of these two modes of action at low dosages revealed efficacious reduction in proteinuria and mortality indicating a strong potential for combined clinical use in respective cardiorenal patient populations.
Funding
- Commercial Support –