Abstract and Introduction
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.
This review aims to provide an overview of the role of the mineralocorticoid receptor (MR) in inflammation and fibrosis and to discuss the discovery of agents that target the MR. We first explore steroidal MR antagonists (MRAs), such as spironolactone and eplerenone, and then the nonsteroidal MRAs. We also endeavour to conceptualize the molecular mechanisms of MR antagonism and downstream cardiorenal protection to better distinguish how the mechanisms of action of nonsteroidal MRAs differ from those of steroidal MRAs. Preclinical studies are described to set the stage for presenting nonsteroidal MRAs as a new treatment option in patients with cardiorenal disease. Specifically, in patients with Type 2 diabetes (T2D) and cardiorenal disease, we discuss why inflammation and fibrosis mediated by MR overactivation could present a novel treatment target beyond traditional treatments focusing primarily on metabolic and haemodynamic targets. Finerenone and esaxerenone are two new nonsteroidal MRAs under clinical development to treat patients with chronic kidney disease (CKD) and T2D.[1–3]
Eur Heart J. 2021;42(2):152-161. © 2021 Oxford University Press
Copyright 2007 European Society of Cardiology. Published by Oxford University Press. All rights reserved.