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Nonsteroidal and Steroidal Mineralocorticoid Antagonists: Rationale, Evidence, and Unanswered Questions
Josephine L Harrington1, Mario E Canonico1, Abdelghani El Rafei1
1Colorado Prevention Center, Aurora, Colorado, USA; Division of Cardiology, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado, USA.
JACC. Heart Failure
|August 31, 2025
Summary
New nonsteroidal mineralocorticoid receptor antagonists (MRAs) show promise for heart failure, diabetes, and kidney disease. Further research is needed to compare these emerging therapies with existing steroidal MRAs.
Area of Science:
- Cardiology
- Nephrology
- Endocrinology
Background:
- Steroidal mineralocorticoid receptor antagonists (MRAs) like spironolactone are beneficial for heart failure with reduced ejection fraction but have uncertain efficacy and tolerability in other heart failure types.
- Emerging therapies targeting the mineralocorticoid receptor or aldosterone production offer alternative strategies.
- Finerenone, a nonsteroidal MRA, has demonstrated efficacy in patients with type 2 diabetes mellitus and chronic kidney disease, and in certain heart failure populations.
Purpose of the Study:
- To critically assess the distinctions between steroidal and nonsteroidal MRAs and other emerging therapies.
- To summarize current evidence for these agents across heart failure, diabetes, and chronic kidney disease.
- To highlight research addressing unanswered questions in this evolving field.
Main Methods:
- Review of structural and mechanistic differences between steroidal and nonsteroidal MRAs.
- Synthesis of existing clinical trial data for MRAs and related therapies.
- Identification of ongoing and future research directions.
Main Results:
- Nonsteroidal MRAs and other emerging therapies present distinct mechanisms and potential advantages.
- Evidence suggests efficacy in specific patient groups, including those with type 2 diabetes mellitus, chronic kidney disease, and certain heart failure classifications.
- A significant gap exists in direct comparative outcome studies between steroidal and emerging MRAs.
Conclusions:
- Emerging therapies targeting the aldosterone-mineralocorticoid receptor axis offer promising alternatives, particularly nonsteroidal MRAs like finerenone.
- Further large-scale, direct comparative studies are crucial to establish the optimal use of these agents across cardiovascular, renal, and metabolic diseases.
- Continued research is essential to address remaining uncertainties and optimize treatment strategies.
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