Nonsteroidal and Steroidal Mineralocorticoid Antagonists: Rationale, Evidence, and Unanswered Questions

Steroidal mineralocorticoid receptor antagonists (MRAs), such as spironolactone and eplerenone, have demonstrated substantial benefits in randomized controlled trials for patients with heart failure with reduced ejection fraction. However, their effectiveness in heart failure with mildly reduced ejection fraction and heart failure with preserved ejection fraction remains uncertain, and the implementation of this class has remained low, in part due to its side effects and tolerability profile. Emerging therapies that target the mineralocorticoid receptor and/or the production of aldosterone may offer alternative strategies to treat the aldosterone-mineralocorticoid receptor axis. For instance, the nonsteroidal MRA finerenone has shown efficacy in reducing cardiovascular and renal events in patients with type 2 diabetes mellitus and chronic kidney disease, as well as decreasing the combined endpoint of cardiovascular death and heart failure hospitalizations in heart failure with mildly reduced ejection fraction and heart failure with preserved ejection fraction populations. Large-scale, direct comparative outcome studies are currently lacking that compare steroidal MRAs vs emerging therapies. This review critically assesses the structural and mechanistic distinctions between nonsteroidal and nonsteroidal MRAs as well as mineralocorticoid receptor modulators and aldosterone synthase inhibitors; summarizes available evidence across heart failure, diabetes, and chronic kidney disease populations; and highlights ongoing and forthcoming research aimed at addressing key unanswered questions in this rapidly evolving therapeutic field.