Steroidal and non-steroidal mineralocorticoid receptor antagonists in cardiorenal medicine

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.

Finerenone and Cardiovascular Outcomes in Patients With Chronic Kidney Disease and Type 2 Diabetes

“…13 , 28 – 30 In addition, the expression of MR in myeloid cells may play an important role for both inflammation and fibrosis in the kidney and the heart, and knockout of the myeloid MR has been shown to suppress macrophage activity and protect the kidney in animal models. 31 However, to counter these hypotheses, the effect on cardiovascular outcomes and UACR change was consistent in subgroups both with and without previous CVD, and moreover the treatment benefit with finerenone for both kidney and cardiovascular composite outcomes was consistent across different subgroups of baseline systolic blood pressure ( Figure III in the Data Supplement ). 20 The ongoing FIGARO-DKD study (NCT02540993), which is investigating the effect of finerenone on reducing cardiovascular mortality and morbidity in 7437 patients, a large proportion of whom have less advanced stages of CKD and T2D, will provide greater insights into the mechanisms of kidney and cardiovascular benefits observed with finerenone.…”

“…In FIDELIO-DKD, changes in blood pressure were modest and similar between groups, suggesting a largely nonhemodynamic mechanism of action of finerenone, possibly caused by an effect of finerenone improving myocardial, vascular, and kidney inflammation and fibrosis. 15 , 24 , 25 , 31 , 33 , 34 However, early separation of the Kaplan–Meier curves for the cardiovascular outcomes suggests that some of the benefits of finerenone may be mediated in part by a natriuretic mechanism counteracting sodium and subsequent volume retention, as well as improvement in endothelial dysfunction and, with more prolonged treatment, vascular stiffness. 25 , 28 , 35 – 37…”

Aldosterone and Mineralocorticoid Receptor Signaling as Determinants of Cardiovascular and Renal Injury: From Hans Selye to the Present

“…Subsequently, increasing evidence implicated pathophysiological overactivation of the MR as a determinant of progression of CKD and its associated morbidity via a mechanism to promote inflammation and fibrosis. This formulation provides a rationale for investigating blockade of the MR as a novel treatment approach to retard the progression of CKD [24, 25].…”

Angiotensin-(1-7)—A Potential Remedy for AKI: Insights Derived from the COVID-19 Pandemic

“…Indeed, the introduction of ACE inhibitors (ACEi), and later of AT1R blockers (ARBs), was found to attenuate the progression of cardiovascular morbidities [8][9][10][11] and of declining kidney function in patients with CKD [12][13][14][15], with an evident reduction in the development of cardiac and renal fibrosis [16][17][18]. Aldosterone, a second and terminal messenger of Ang II, was also found to independently hasten organ fibrosis, a process amended by aldosterone antagonists [19].…”