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Global Translational Medicine Mineralocorticoid receptor in CMD

MRAs can be categorized as steroidal and non-steroidal rapid increase in incidence of hyperkalemia following the
compounds based on their chemical class [133] . Steroidal online publication of the RALES trial. This is associated
MRAs include spironolactone and eplerenone, which have with an increase in spironolactone prescriptions for elderly
similar therapeutic effects but different pharmacological patients with HF [138] . Subsequent clinical studies have
characteristics . Finerenone is a third-generation, non- suggested that the judicious use of spironolactone and
[7]
steroidal MRA with less side effects compared with closer patient monitoring could reduce the incidence of
steroidal compounds [134] (Table 1). hyperkalemia [139,140] . Of note, it has been reported that 54%
Spironolactone is a first-generation MRA, which of hyperkalemia cases are associated with MRA treatments
[141]
has been used clinically for decades. It was originally in MI or HF patients .
approved as a diuretic for the treatment of edema, primary Eplerenone is a second-generation MRA with fewer
aldosteronism, and essential hypertension [135] . Subsequently, side effects than spironolactone and a greater selectivity
extensive studies have shown that spironolactone has for MR . However, it has lower affinity for MR than
[7]
significant benefits for severe HF, refractory hypertension, spironolactone, thus requiring a higher dose to achieve the
hypokalemia, and ascites secondary to cirrhosis [133] . same effect as the latter [135] . The results of Eplerenone Post-
The Randomized Aldactone Evaluation Study (RALES) Acute MI HF Efficacy and Survival Study (EPHESUS)
trial has proven that spironolactone improves mortality have revealed that eplerenone therapy reduces overall
and morbidity in patients with severe HF [136] . This morbidity and mortality among patients with acute MI
trial further supports the use of spironolactone in HF complicated by LV dysfunction and HF [142] . Similarly, the
patients. Spironolactone is a potent and competitive clinical benefits of eplerenone on mortality and morbidity
antagonist of MR. However, it also binds to androgen in patients with systolic HF and mild symptoms have
and progesterone receptors, causing endocrinal side also been demonstrated in other clinical studies [143] .
effects, such as gynecomastia, impotence, and menstrual A randomized clinical trial has found that early eplerenone
irregularities [136] . The major limitation of spironolactone in administration (within 3 – 7 days) post-acute MI improves
clinical application is the occurrence of hyperkalemia [137] . outcomes in patients with LV systolic dysfunction and
A pharmacoepidemiologic study has noted that there is a HF and this benefit is not evident when eplerenone is
administered at a later stage (≥7 days) [144] . Furthermore,
Table 1. Properties and applications of MR antagonists treatment with eplerenone during the acute phase of MI is
MRAs Spironolactone Eplerenone Finerenone safe and well-tolerated [145] .
Chemical Steroidal Steroidal Non-steroidal Finerenone is a novel, selective, nonsteroidal MRA,
composition compound compound compound with the higher selectivity for MR than spironolactone and
Affinity for High [149] Low [149] High [149] stronger MR-binding affinity compared to eplerenone [134] .
MR Finerenone effectively blocks inflammation, fibrosis,
Tissue Kidney>heart [137] Kidney>heart [137] Balanced in adverse cardiovascular, and renal events mediated by MR
distribution kidney and overactivation [146] . The phase III Finerenone in Reducing
heart [137] Kidney Failure and Disease Progression in Diabetic
Active 7α-TMS No active No active Kidney Disease (FIDELIO-DKD) and Finerenone in
metabolites Canrenone [150] metabolites [150] metabolites [150] Reducing Cardiovascular Mortality and Morbidity in
Half-life in 7α-TMS: 13.8 h 4–6 h [137] 2–3 h [150] Diabetic Kidney Disease (FIGARO-DKD) clinical trials
humans Canrenone: have shown that finerenone slows the progression of
16.5h [150]
Clinical Edema [135] Hypertension [142,143] DKD [147,148] kidney disease and reduces the risk of cardiovascular
. Finerenone
events and hospitalization for HF
[147,148]
applications Primary HF [142,143] HF with
aldosteronism [135] T2DM [146] confers beneficial effects on cardiovascular outcomes in
Hypertension [135] patients with chronic kidney disease and type 2 diabetes
HF [132,135] and is well-tolerated in these patients [147,148] . The MR
Side effects Gynecomastia [135] Hyperkalemia [137,150] Hyperkalemia Antagonist Tolerability Study- HF (ARTS-HF) study has
Impotence [135] (significantly shown that finerenone is well-tolerated and decreases the
Menstrual lower levels of N-terminal (NT)-pro hormone B-type natriuretic
irregularities [135] incidence) [137] peptide (NT-proBNP) to a similar extent compared with
Hyperkalemia [137]
MRAs: Mineralocorticoid receptor antagonists; 7α-TMS: eplerenone in patients with worsening HF with reduced
ejection fraction and chronic kidney disease and/or
7α-thiomethyl-spironolactone; HF: Heart failure;
DKD: Diabetic kidney disease; T2DM: Type 2 diabetes mellitus; diabetes mellitus, thus suggesting the beneficial effects
MR: Mineralocorticoid receptor of finerenone [146] . The effects of finerenone in other CMD

Volume 2 Issue 1 (2023) 10 https://doi.org/10.36922/gtm.v2i1.229