Cardiovascular-Kidney-Metabolic Effects: Steroidal and Nonsteroidal Mineralocorticoid Receptor Antagonists

Abstract

Cardiovascular (CV)-kidney-metabolic (CKM) syndrome is a complex disorder characterized by the co-occurrence of CV risk factors, including chronic kidney disease (CKD), hypertension, and metabolic dysfunction, which creates a vicious cycle where one factor negatively impacts the others, ultimately leading to poor overall CV and kidney outcomes. Overactivation of the mineralocorticoid receptor, through binding with aldosterone and ligand-independent mechanisms, is implicated in the pathogenesis of CKM; mineralocorticoid receptor antagonists (MRAs) can block this interaction. Steroidal MRAs are currently recommended for people with heart failure (HF) with reduced ejection fraction and hypertension; however, the role of nonsteroidal MRAs in CKM is evolving. Indeed, steroidal MRAs have demonstrated efficacy against composite CV-related mortality and hospitalization, elevated systolic blood pressure, and hospitalizations for worsening HF in clinical trials of individuals with HF, CKD, and treatment-resistant hypertension. Moreover, the nonsteroidal MRA finerenone has demonstrated risk reductions for composite CV-related outcomes and CKD progression in patients with HF with mildly reduced or preserved ejection fraction and people with CKD associated with type 2 diabetes. Ongoing phase 3 trials are evaluating the efficacy and safety of nonsteroidal MRAs in individuals with HF and reduced ejection fraction, as well as those with mildly reduced or preserved ejection fraction, potentially expanding their role in managing CKM conditions. This review examines current clinical evidence for the use of MRAs in people with CKM syndrome.

Keywords: cardio-kidney-metabolic syndrome; heart failure; mineralocorticoid receptor antagonists.

Fig. 1.

The structural similarities and differences between steroidal and nonsteroidal mineralocorticoid receptor antagonists. CNS, central nervous system; MR, mineralocorticoid receptor; MRA, mineralocorticoid receptor antagonist.