Introduction: There is a substantial unmet medical need for new and efficacious treatment options for HFpEF. Combination of pharmacological approaches could address different pathophysiological key-pathways in HFpEF patients which are characterized by heterogeneous phenotypes and co-morbidities. The soluble guanylate cyclase (sGC) stimulator Vericiguat and the nonsteroidal mineralocorticoid receptor antagonist (MRA) Finerenone are addressing completely different signaling pathways, and have already shown efficacy in clinical Phase II trials in HFrEF patients.
Hypothesis: The sGC stimulator Vericiguat and the nonsteroidal MRA Finerenone act synergistically in a preclinical rat model of hypertension-induced end-organ damage with features of HFpEF.
Methods: L-NAME-treated, hypertensive renin transgenic (RenTG) rats were treated with either placebo, Vericiguat alone, Finerenone alone, or with the combination thereof. Read-out parameters were overall mortality, plasma BNP-levels, proteinuria, histopathology of hearts and kidneys and gene expression profiles of biomarkers for heart and kidney damage.
Results: Both, Vericiguat and Finerenone given as stand-alone treatments, dose-dependently reduced mortality when compared to placebo. Vericiguat (0.3 mg/kg QD) and Finerenone (10 mg/kg QD) reduced mortality by 20% and 30%, respectively, whereas mortality in the placebo group was 70% after ≥5 weeks. In addition, a significant reduction of BNP: Vericiguat -20%, Finerenone -30%, of uPCR: Vericiguat -40%, Finerenone -60%, and of mRNA expression of e.g. KIM-1 and Osteopontin were found after treatment with single components. When Vericiguat and Finerenone were combined, the effects i.e. on heart and kidney function were synergistic (BNP: -50%, p<0.05 & uPCR -75%, p<0.001). Most strikingly, no mortality was observed in the combination groups.
Conclusions: Treatment with a combination of Vericiguat and Finerenone completely prevents mortality with synergistic improvement of heart and kidney parameters in the L-NAME/RenTG rat model. Thus, combination treatment of sGC stimulators and MRAs could be effective in HFpEF with substantial up-side potential in cardiovascular and cardiorenal diseases.