Non-steroidal Mineralocorticoid Receptor Antagonists in Cardiorenal Disease

Arjun K. Pandey; Deepak L. Bhatt; Francesco Cosentino; Nikolaus Marx; Ori Rotstein; Bertram Pitt; Ambarish Pandey; Javed Butler; Subodh Verma

Disclosures

Eur Heart J. 2022;43(31):2931-2945. 

In This Article

Abstract and Introduction

Abstract

Graphical Abstract: Non-steroidal mineralocorticoid antagonists (MRAs) reduce adverse remodelling, inflammation, and fibrosis in the heart, kidneys, and vasculature. Finerenone has been shown to improve cardiovascular and kidney outcomes in patients with chronic kidney disease and Type 2 diabetes. Non-steroidal MRAs are currently being investigated in other settings such as heart failure.

Despite existing treatments, patients with heart failure and chronic kidney disease (CKD) remain at high risk for adverse outcomes and progression to end-stage disease. Steroidal mineralocorticoid receptor antagonists (MRAs) such as spironolactone and eplerenone reduce mortality but remain under-prescribed due to the perceived risk of hyperkalaemia and hormonal side effects. The discovery of non-steroidal MRAs represents a major new dimension in cardiorenal disease therapy. Non-steroidal MRAs have high affinity and specificity for the mineralocorticoid receptor (MR) and differ from both steroidal agents and each other with respect to important physiochemical, pharmacodynamic, and pharmacokinetic parameters. Similar to their steroidal counterparts, they have beneficial anti-inflammatory, anti-remodelling, and anti-fibrotic properties in the kidneys, heart, and vasculature. There are several non-steroidal MRAs under development and clinical assessment; of these, only esaxerenone and finerenone are approved for treatment globally. In Japan, esaxerenone is approved for essential hypertension and has been studied in diabetic nephropathy. Compared with steroidal MRAs, finerenone more potently inhibits MR co-regulator recruitment and fibrosis and distributes more evenly between the heart and kidneys. The landmark Phase III trials FIGARO-DKD and FIDELIO-DKD demonstrated that finerenone-reduced major kidney and cardiovascular events on top of maximally tolerated renin–angiotensin–aldosterone system inhibition in patients with CKD associated with Type 2 diabetes. Non-steroidal MRAs are currently under evaluation in heart failure and for synergistic treatment with sodium–glucose contransporter 2 inhibitors. These ground-breaking agents could become an important therapy across the spectrum of cardiorenal disease.

Introduction

Cardiorenal syndrome characterizes the complex interplay between diseases such as chronic kidney disease (CKD) and heart failure (HF) and affects millions of people worldwide.[1–3] Patients remain at persistently high risk for progression to end-stage disease even with existing treatments.[1–3]

Despite being launched over eight decades ago and demonstrating substantial mortality benefit in HF over two decades ago, clinical use of mineralocorticoid receptor antagonists (MRAs) has been limited by the perceived risk of hyperkalaemia and adverse hormonal side effects.[4–6] The discovery of non-steroidal MRAs represents an important new dimension in the treatment of cardiorenal disease.[4–6] Similar to their steroidal counterparts, these agents reduce fibrosis, inflammation, dysfunction, and adverse remodelling in the vasculature, kidney, and heart. This review will summarize the mechanisms and clinical evaluation of non-steroidal MRAs, as well as future perspectives on their role in the treatment of cardiorenal disease (Graphical Abstract).

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