Nonsteroidal Mineralocorticoid Receptor Antagonism by Finerenone—Translational Aspects and Clinical Perspectives across Multiple Organ Systems

Abstract

Perception of the role of the aldosterone/mineralocorticoid receptor (MR) ensemble has been extended from a previously renal epithelial-centered focus on sodium and volume homeostasis to an understanding of their role as systemic modulators of reactive oxygen species, inflammation, and fibrosis. Steroidal MR antagonists (MRAs) are included in treatment paradigms for resistant hypertension and heart failure with reduced ejection fraction, while more recently, the nonsteroidal MRA finerenone was shown to reduce renal and cardiovascular outcomes in two large phase III trials (FIDELIO-DKD and FIGARO-DKD) in patients with chronic kidney disease and type 2 diabetes, respectively. Here, we provide an overview of the pathophysiologic role of MR overactivation and preclinical evidence with the nonsteroidal MRA finerenone in a range of different disease models with respect to major components of the aggregate mode of action, including interfering with reactive oxygen species generation, inflammation, fibrosis, and hypertrophy. We describe a time-dependent effect of these mechanistic components and the potential modification of major clinical parameters, as well as the impact on clinical renal and cardiovascular outcomes as observed in FIDELIO-DKD and FIGARO-DKD. Finally, we provide an outlook on potential future clinical indications and ongoing clinical studies with finerenone, including a combination study with a sodium–glucose cotransporter-2 inhibitor.

Efficacy of finerenone in patients with type 2 diabetes, chronic kidney disease and altered markers of liver steatosis and fibrosis: A FIDELITY subgroup analysis

“…(a) fast decongestion, which may cause an immediate reduction in HHF, and/or (b) a high FIB‐4 score associated with NAFLD may also be a reflection of systemic inflammation, fibrosis and associated CVDs 47 . Preclinical animal model data for finerenone showed anti‐inflammatory and antifibrotic effects, 48 and although the clinical translation may be complex, the systemic antifibrotic effects may be effective in the long‐term, particularly in patients with elevated fibrosis markers. Moreover, finerenone has fewer side effects compared with other MRA antagonists 49 …”

Finerenone: Questions and Answers—The Four Fundamental Arguments on the New-Born Promising Non-Steroidal Mineralocorticoid Receptor Antagonist

“…Mineral receptors (MR) are expressed by several cell types of both epithelial and non-epithelial origin [6,36,99]. MR antagonism on non-epithelial cells (including fibroblasts, vascular smooth muscle cells, podocytes, and inflammatory cells) explain the anti-inflammatory and anti-fibrotic activities of finerenone in the kidneys and across multiple organs level [100,101]. Some lines of evidence support the notion that combination therapy of SGLT2i and finerenone may have a synergic effect through common and distinct pathophysiological pathways and possibly will reduce the residual cardio-renal risk noted after the registration trials of main molecules (Figure 5) [102].…”

Innate Immunity System in Patients With Cardiovascular and Kidney Disease

“…Other drugs are still untested or tested in low-power phase-2 trials with inconclusive results, like a trial that tested the IL-α antagonist Xilonix. 116 Sodium-glucose cotransporter-2 inhibitors (reduction of IL-1β) release by macrophages in vitro, an NLRP3-inflammasome induced effect 117 ) and mineralocorticoid receptor antagonists (interference on NF-κB activation induced by mineralocorticoid receptors 118 ) have anti-inflammatory properties, but these properties are still poorly characterized in clinical studies.…”