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Steroidal and Novel Non-steroidal Mineralocorticoid Receptor Antagonists in Heart Failure and Cardiorenal Diseases: Comparison at Bench and Bedside

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Book cover Heart Failure

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 243))

Abstract

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.

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Abbreviations

11β-HSD2:

11β-Hydroxysteroid dehydrogenase type 2

ACEI(s):

Angiotensin converting enzyme inhibitor(s)

AGP:

Alpha-1 acid glycoprotein

AngII:

Angiotensin II

ARB:

Angiotensin receptor blocker

BID:

Bis in die (twice daily)

BNP:

B-type natriuretic peptide

CCB:

Calcium channel blocker

CHF:

Chronic heart failure

CI:

Confidence interval

CKD:

Chronic kidney disease

COX-2:

Cyclooxygenase-2

CTGF:

Connective tissue growth factor

CV:

Cardiovascular

DHP:

Dihydropyridine

DKD:

Diabetic kidney disease

DM:

Diabetes mellitus

DN:

Diabetic nephropathy

DOC:

Desoxy-corticosterone

DOCA:

Desoxy-corticosterone acetate

ECM:

Extracellular matrix

eGFR:

Estimated glomerular filtration rate

ENaC:

Epithelial sodium channel

ER:

Estrogen receptor

HF:

Heart failure

HFpEF:

Heart failure with preserved ejection fraction

HFrEF:

Heart failure with reduced ejection fraction

HHF:

Hospitalization for heart failure

HR:

Hazard ratio

ICAM1:

Intercellular cell adhesion molecule 1

Ito:

Potassium transient outward current

K+ :

Potassium

l-NAME:

NG-nitro-l-arginine methyl ester

LV:

Left ventricular

LVSD:

Left ventricular systolic dysfunction

MCP-1:

Macrophage chemoattractant protein-1

MR:

Mineralocorticoid receptor

MRA:

Mineralocorticoid receptor antagonist

Na+ :

Sodium

Nedd4-2:

Neural precursor cell expressed developmentally down-regulated protein 4-2

NT-proBNP:

N-terminal of prohormone of BNP

OD:

Once daily

PAI-1:

Protein plasminogen activator inhibitor-1

PICP:

Procollagen type I carboxy-terminal peptide

PIIINP:

Procollagen type III amino-terminal peptide

PINP:

Procollagen type I amino-terminal peptide

RAAS:

Renin angiotensin aldosterone system

RAR:

Retinoic acid receptor

RAS:

Renin angiotensin system

ROMK:

Renal outer medullary potassium channel

ROS:

Reactive oxygen species

RXR:

Retinoid X receptor

SERM:

Selective ER modulators

Sgk1:

Serum glucocorticoid kinase1

SoC:

Standard of care

SRC-1:

Steroid receptor co-activator-1

T2DM:

Type 2 diabetes mellitus

TGFβ:

Transforming growth factor beta

Tnnt2:

Troponin T type 2

UACR:

Urinary albumin to creatinine ratio

VCAM1:

Vascular cell adhesion molecule 1

VSMC:

Vascular smooth muscle cell

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Authors and Affiliations

  1. Drug Discovery, Cardiology Research, Bayer Pharma AG, Building 500, Aprather Weg 18a, 42096, Wuppertal, Germany

    Peter Kolkhof

  2. INSERM, UMRS 1138, Team 1, Centre de Recherche des Cordeliers, Pierre et Marie Curie University, Paris Descartes University, Paris, France

    Frederic Jaisser

  3. Clinical Development, Bayer Pharma AG, 42096, Wuppertal, Germany

    So-Young Kim & Christina Nowack

  4. Department of Cardiology, National and Kapodistrian University of Athens, School of Medicine, Attikon University Hospital, Rimini 1, Haidari, Athens, 12462, Greece

    Gerasimos Filippatos

  5. University of Michigan Medical School, Ann Arbor, MI, USA

    Bertram Pitt

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  1. Peter Kolkhof
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  2. Frederic Jaisser
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  3. So-Young Kim
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  4. Gerasimos Filippatos
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  5. Christina Nowack
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  6. Bertram Pitt
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Correspondence to Peter Kolkhof .

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  1. Klinik für Kardiologie und Angiologie, Medizinische Hochschule Hannover Klinik für Kardiologie und Angiologie, Hannover, Niedersachsen, Germany

    Johann Bauersachs

  2. Heart Institute, Stony Brook University , Stony Brook, New York, USA

    Javed Butler

  3. Heart and Lung Diseases, Bayer Pharma Aktiengesellschaft Heart and Lung Diseases, Wuppertal, Nordrhein-Westfalen, Germany

    Peter Sandner

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Kolkhof, P., Jaisser, F., Kim, SY., Filippatos, G., Nowack, C., Pitt, B. (2016). Steroidal and Novel Non-steroidal Mineralocorticoid Receptor Antagonists in Heart Failure and Cardiorenal Diseases: Comparison at Bench and Bedside. In: Bauersachs, J., Butler, J., Sandner, P. (eds) Heart Failure. Handbook of Experimental Pharmacology, vol 243. Springer, Cham. https://doi.org/10.1007/164_2016_76

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