Effects of Finerenone Combined with Empagliflozin in a Model of Hypertension-Induced End-Organ Damage

Abstract

<b><i>Introduction:</i></b> The nonsteroidal mineralocorticoid receptor (MR) antagonist finerenone and sodium-glucose cotransporter-2 (SGLT2) inhibitors have demonstrated clinical benefits in CKD patients with type 2 diabetes. Clinical data analyzing the potential value of a combination therapy are currently limited. We therefore investigated cardiorenal protection of respective mono- and combination therapy in a preclinical model of hypertension-induced end-organ damage. <b><i>Methods:</i></b> Cardiovascular (CV) morbidity and mortality were studied in hypertensive, N(ω)-nitro-L-arginine methyl ester-treated, renin-transgenic (mRen2)27 rats. Rats (10- to 11-week-old females, <i>n</i> = 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, proteinuria, plasma creatinine and uric acid, blood pressure, and cardiac and renal histology. <b><i>Results:</i></b> Placebo-treated rats demonstrated a 50% survival rate over the course of 7 weeks. Drug treatment resulted in variable degrees of survival benefit, most prominently in the low-dose combination group with a survival benefit of 93%. Monotherapies of finerenone or empagliflozin dose-dependently reduced proteinuria, while low-dose combination revealed an early, sustained, and over-additive reduction in proteinuria. Empagliflozin induced a strong and dose-dependent increase in urinary glucose excretion which was not influenced by finerenone coadministration in the combination arm. Low-dose combination but not respective low-dose monotherapies significantly reduced plasma creatinine and plasma uric acid after 6 weeks. Treatment with finerenone and the low-dose combination significantly decreased systolic blood pressure after 5 weeks. There was a dose-dependent protection from cardiac and kidney fibrosis and vasculopathy with both agents, while low-dose combination therapy was more efficient than the respective monotherapy dosages on most cardiorenal histology parameters. <b><i>Discussion/Conclusions:</i></b> Nonsteroidal MR antagonism by finerenone and SGLT2 inhibition by empagliflozin confer CV protection in preclinical hypertension-induced cardiorenal disease. Combination of these 2 independent modes of action at low dosages revealed efficacious reduction in important functional parameters such as proteinuria and blood pressure, plasma markers including creatinine and uric acid, cardiac and renal lesions as determined by histopathology, and mortality indicating a strong potential for combined clinical use in cardiorenal patient populations.

Network Meta-Analysis on the Effects of SGLT2 Inhibitors Versus Finerenone on Cardiorenal Outcomes in Patients With Type 2 Diabetes and Chronic Kidney Disease

“…Finerenone is a nonsteroidal and selective mineralocorticoid receptor antagonist which belongs to RAAS inhibitors. Moreover, the combination therapy of empagliflozin and finerenone showed greater cardiovascular benefits than the empagliflozin or finerenone monotherapy in rats with preclinical hypertension-induced cardiorenal disease ( Kolkhof et al, 2021 ). Therefore, a gliflozin combined with finerenone is promising to yield greater cardiorenal benefits in patients with diabetic kidney disease.…”

The Kidney Protective Effects of the Sodium–Glucose Cotransporter-2 Inhibitor, Dapagliflozin, Are Present in Patients With CKD Treated With Mineralocorticoid Receptor Antagonists

“…13 A preclinical rat study of cardio-renal disease demonstrated that combination therapy with empagliflozin and finerenone resulted in a synergistic effect on albuminuria lowering and improved survival compared with either therapy alone. 14 …”

Mineralocorticoid Receptor Antagonists in Diabetic Kidney Disease

“…Importantly, they found that finerenone exerted cardiorenoprotective effects independent of its blood pressure reduction ( Kolkhof et al, 2014 ). Combination therapy of empagliflozin and finerenone has also been shown to prevent proteinuria as well as cardiac and kidney fibrosis in hypertensive rats ( Kolkhof et al, 2021 ).…”