Nonsteroidal Mineralocorticoid Receptor Antagonists: Exploring Role in Cardiovascular Disease

Abstract

:Aldosterone, a mineralocorticoid hormone, plays a role in the pathophysiology of many cardiovascular disease states. Mineralocorticoid receptor antagonists (MRAs) have been shown to improve clinical outcomes in select patient populations. However, use of available steroidal receptor antagonists, eplerenone and spironolactone, is often limited by the risk or development of hyperkalemia. Nonsteroidal MRAs have been designed to overcome this limitation. The nonsteroidal MRAs have been studied in patients with heart failure with reduced ejection fraction, hypertension, and to lower the risk of cardiac and renal outcomes in those with type 2 diabetes and renal disease. In this review, the pharmacology of the MRAs is compared, the data evaluating the use of nonsteroidal MRAs are examined, and the place of this new generation of therapy is discussed. At this time, it seems that there could be a future role for nonsteroidal MRAs to reduce the risk of renal outcomes in high-risk individuals.

The Cardiac Mineralocorticoid Receptor (MR): A Therapeutic Target Against Ventricular Arrhythmias

“…Nevertheless, the marked beneficial action of MR antagonism demonstrated in the treatment of cardiac failure, often in the absence of elevated aldosterone or sodium retention, strongly suggests that a similar therapeutic approach would be worth of investigation in the context of different pathophysiological situations, including cardiomyopathies associated with diabetes mellitus, Cushing syndrome, or reperfusion after ischemia. This assumption is somehow supported by the recent use of novel, selective nonsteroidal MR antagonists, like finerenone (49,50), in the management of diabetic nephropathy and associated cardiovascular risk.…”

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“…[ 208 , 227 , 228 ] Steroidal mineralocorticoid receptor antagonists (MRA) such as spironolactone are often characterized as potassium sparing; however, especially in the presence of renal disease, spironolactone may cause hyperkalemia. Nonsteroidal MRA are in development for treatment of hypertension, heart failure, and to reduce the progression of renal disease (i.e., diabetes nephropathy) [229] . Finerenone is a nonsteroidal mineralocorticoid receptor antagonist (MRA) approved to reduce risk of estimated glomerular filter decline, end stage kidney disease, CVD death, non-fatal myocardial infarction, and hospitalization for heart failure in adult patients with chronic kidney disease associated with T2DM.…”

“…[414] Future study results will better determine if nonsteroidal mineralocorticoid receptor antagonists (e.g., esaxerenone, apararenone, and KBP-5074) will improve renal outcomes in high-risk individuals. [ 229 , 415 ] Existing data suggests that finerenone may delay the progression of diabetes nephropathy and reduce cardiovascular morbidity in patients with diabetes nephropathy. [ 416 , 417 ] Meta-analyses support statin therapy as reducing CVD events in primary prevention among patients with mild to moderate renal insufficiency (not on dialysis); [418] however, the relative risk reduction in major vascular event risk diminishes as eGFR declines.…”

“…[414] Future study results will better determine if nonsteroidal mineralocorticoid receptor antagonists (e.g., esaxerenone, apararenone, and KBP-5074) will improve renal outcomes in high-risk individuals. [ 229 , 415 ] Existing data suggests that finerenone may delay the progression of diabetes nephropathy and reduce cardiovascular morbidity in patients with diabetes nephropathy. [ 416 , 417 ]…”