Steroidal and Novel Non-steroidal Mineralocorticoid Receptor Antagonists in Heart Failure and Cardiorenal Diseases: Comparison at Bench and Bedside.
Characterization of mice with cell-specific deletion or overexpression of the mineralocorticoid receptor (MR) shed a new light on its role in health and disease. Pathophysiological MR activation contributes to a plethora of deleterious molecular mechanisms in the development of cardiorenal diseases like chronic kidney disease (CKD) and heart failure (HF). Accordingly, the available steroidal MR antagonists (MRAs) spironolactone (first generation MRA) and eplerenone (second generation MRA) have been shown to be effective in reducing cardiovascular (CV) mortality and morbidity in patients with chronic HF and a reduced left ventricular ejection fraction (HFrEF). However, they remain underutilized, in large part owing to the risk inducing severe adverse events including hyperkalemia and worsening of kidney function, particularly when given on top of inhibitors of the renin angiotensin system (RAS) to patients with concomitant kidney dysfunction. Novel, potent, and selective non-steroidal MRAs (third generation) were identified in drug discovery campaigns and a few entered clinical development recently. One of these is finerenone with different physicochemical, pharmacokinetics, and pharmacological properties in comparison with the steroidal MRAs. Available data from five clinical phase II trials with finerenone in more than 2,000 patients with HF and additional CKD and/or diabetes as well as in patients with diabetic kidney disease demonstrated that neither hyperkalemia nor reductions in kidney function were limiting factors to its use. Moreover, finerenone demonstrated a nominally improved outcome compared to eplerenone in a phase IIb trial with 1,066 patients with HFrEF and concomitant type 2 diabetes mellitus (T2DM) and/or CKD.
Drug Discovery, Cardiology Research, Bayer Pharma AG, Building 500, Aprather Weg 18a, 42096, Wuppertal, Germany. peter.kolkhof@bayer.com.
Peter
P
Kolkhof
INSERM, UMRS 1138, Team 1, Centre de Recherche des Cordeliers, Pierre et Marie Curie University, Paris Descartes University, Paris, France.
Frederic
F
Jaisser
Clinical Development, Bayer Pharma AG, 42096, Wuppertal, Germany.
So-Young
SY
Kim
Department of Cardiology, National and Kapodistrian University of Athens, School of Medicine, Attikon University Hospital, Rimini 1, Haidari, Athens, 12462, Greece.
Gerasimos
G
Filippatos
Clinical Development, Bayer Pharma AG, 42096, Wuppertal, Germany.
Christina
C
Nowack
University of Michigan Medical School, Ann Arbor, MI, USA.
Bertram
B
Pitt
D000818:Animals; D059347:Cardio-Renal Syndrome / Q000188:drug therapy*; D003928:Diabetic Nephropathies / Q000150:complications / Q000188:drug therapy*; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D000077545:Eplerenone; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006333:Heart Failure / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D006801:Humans; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D009131:Muscle, Smooth, Vascular; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D009287:Naphthyridines / Q000494:pharmacology / Q000627:therapeutic use*; D018161:Receptors, Mineralocorticoid / Q000378:metabolism; D013148:Spironolactone / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use*; D013318:Stroke Volume
D000451:Mineralocorticoid Receptor Antagonists; D009287:Naphthyridines; D018161:Receptors, Mineralocorticoid; C576501:finerenone; D013148:Spironolactone; D000077545:Eplerenone
Chronic kidney disease; Eplerenone; Finerenone; Heart failure; Mineralocorticoid receptor antagonists; Spironolactone