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Review
. 2021 Jan 7;42(2):152-161.
doi: 10.1093/eurheartj/ehaa736.

Steroidal and non-steroidal mineralocorticoid receptor antagonists in cardiorenal medicine

Rajiv Agarwal  1 , Peter Kolkhof  2 , George Bakris  3 , Johann Bauersachs  4 , Hermann Haller  5 , Takashi Wada  6 , Faiez Zannad  7
Affiliations
Review

Steroidal and non-steroidal mineralocorticoid receptor antagonists in cardiorenal medicine

Rajiv Agarwal et al. Eur Heart J. .

Abstract

This review covers the last 80 years of remarkable progress in the development of mineralocorticoid receptor (MR) antagonists (MRAs) from synthesis of the first mineralocorticoid to trials of nonsteroidal MRAs. The MR is a nuclear receptor expressed in many tissues/cell types including the kidney, heart, immune cells, and fibroblasts. The MR directly affects _target gene expression-primarily fluid, electrolyte and haemodynamic homeostasis, and also, but less appreciated, tissue remodelling. Pathophysiological overactivation of the MR leads to inflammation and fibrosis in cardiorenal disease. We discuss the mechanisms of action of nonsteroidal MRAs and how they differ from steroidal MRAs. Nonsteroidal MRAs have demonstrated important differences in their distribution, binding mode to the MR and subsequent gene expression. For example, the novel nonsteroidal MRA finerenone has a balanced distribution between the heart and kidney compared with spironolactone, which is preferentially concentrated in the kidneys. Compared with eplerenone, equinatriuretic doses of finerenone show more potent anti-inflammatory and anti-fibrotic effects on the kidney in rodent models. Overall, nonsteroidal MRAs appear to demonstrate a better benefit-risk ratio than steroidal MRAs, where risk is measured as the propensity for hyperkalaemia. Among patients with Type 2 diabetes, several Phase II studies of finerenone show promising results, supporting benefits on the heart and kidneys. Furthermore, finerenone significantly reduced the combined primary endpoint (chronic kidney disease progression, kidney failure, or kidney death) vs. placebo when added to the standard of care in a large Phase III trial.

Keywords: Cardiorenal; Chronic kidney disease; Finerenone; Mineralocorticoid receptor antagonists; Mineralocorticoids.

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Figures

Figure 1
Figure 1
Key studies in the history of mineralocorticoid receptor antagonists.
Figure 2
Figure 2
Finerenone reduces cofactor recruitment to the mineralocorticoid receptor, thereby reducing downstream expression of pro-inflammatory and pro-fibrotic factors following mineralocorticoid receptor overactivation. MR, mineralocorticoid receptor.
Figure 3
Figure 3
Mean relative exposure of spironolactone and spironolactone metabolites in healthy volunteers (n = 12). AUC, area under the concentration–time curve.
Figure 4
Figure 4
Key results of the ARTS, ARTS-HF, and ARTS-DN Phase II studies. *Significant (P ≤ 0.001); #Nominal statistical significance in the finerenone 10–20 mg group (hazard ratio = 0.56, 95% confidence interval 0.35; 0.90, P = 0.02). CV, cardiovascular; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; HFrEF, heart failure with reduced ejection fraction; NT-proBNP, N-terminal pro-B-type natriuretic peptide; T2D, Type 2 diabetes; UACR, urine albumin-to-creatinine ratio.
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