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European Heart Journal Jan 2021This review covers the last 80 years of remarkable progress in the development of mineralocorticoid receptor (MR) antagonists (MRAs) from synthesis of the first... (Review)
Review
This review covers the last 80 years of remarkable progress in the development of mineralocorticoid receptor (MR) antagonists (MRAs) from synthesis of the first mineralocorticoid to trials of nonsteroidal MRAs. The MR is a nuclear receptor expressed in many tissues/cell types including the kidney, heart, immune cells, and fibroblasts. The MR directly affects target gene expression-primarily fluid, electrolyte and haemodynamic homeostasis, and also, but less appreciated, tissue remodelling. Pathophysiological overactivation of the MR leads to inflammation and fibrosis in cardiorenal disease. We discuss the mechanisms of action of nonsteroidal MRAs and how they differ from steroidal MRAs. Nonsteroidal MRAs have demonstrated important differences in their distribution, binding mode to the MR and subsequent gene expression. For example, the novel nonsteroidal MRA finerenone has a balanced distribution between the heart and kidney compared with spironolactone, which is preferentially concentrated in the kidneys. Compared with eplerenone, equinatriuretic doses of finerenone show more potent anti-inflammatory and anti-fibrotic effects on the kidney in rodent models. Overall, nonsteroidal MRAs appear to demonstrate a better benefit-risk ratio than steroidal MRAs, where risk is measured as the propensity for hyperkalaemia. Among patients with Type 2 diabetes, several Phase II studies of finerenone show promising results, supporting benefits on the heart and kidneys. Furthermore, finerenone significantly reduced the combined primary endpoint (chronic kidney disease progression, kidney failure, or kidney death) vs. placebo when added to the standard of care in a large Phase III trial.
Topics: Diabetes Mellitus, Type 2; Heart Failure; Humans; Mineralocorticoid Receptor Antagonists; Mineralocorticoids; Spironolactone
PubMed: 33099609
DOI: 10.1093/eurheartj/ehaa736 -
The New England Journal of Medicine Feb 2023
Topics: Humans; Aldosterone; Hyperaldosteronism; Hypertension; Mineralocorticoid Receptor Antagonists; Monitoring, Physiologic
PubMed: 36724334
DOI: 10.1056/NEJMe2213559 -
American Journal of Kidney Diseases :... Nov 2022Mineralocorticoid receptor (MR) activation is involved in propagating kidney injury, inflammation, and fibrosis and in the progression of chronic kidney disease (CKD).... (Review)
Review
Mineralocorticoid receptor (MR) activation is involved in propagating kidney injury, inflammation, and fibrosis and in the progression of chronic kidney disease (CKD). Multiple clinical studies have defined the efficacy of MR antagonism in attenuating progressive kidney disease, and the US Food and Drug Administration recently approved the nonsteroidal mineralocorticoid receptor antagonist (MRA) finerenone for this indication. In this review, we consider the basic science and clinical applicability of MR antagonism. Because hyperkalemia constitutes a constraint to implementing evidence-based MR blockade, we review MRA-associated hyperkalemia in the context of finerenone and discuss evolving mitigation strategies to enhance the safety and efficacy of this treatment. Although the FIDELIO-DKD and FIGARO-DKD clinical trials focused solely on patients with type 2 diabetes mellitus, we propose that MR activation and the resulting inflammation and fibrosis act as a substantive pathogenetic mediator not only in people with diabetic CKD but also in those with CKD without diabetes. We close by briefly discussing both recently initiated and future clinical trials that focus on extending the attributes of MR antagonism to a wider array of nondiabetic kidney disorders, such as patients with nonalbuminuric CKD.
Topics: Humans; Mineralocorticoid Receptor Antagonists; Receptors, Mineralocorticoid; Aldosterone; Diabetes Mellitus, Type 2; Hyperkalemia; Mineralocorticoids; Renal Insufficiency, Chronic; Fibrosis; Inflammation
PubMed: 36057467
DOI: 10.1053/j.ajkd.2022.04.016 -
British Journal of Pharmacology Jul 2022Mineralocorticoid receptor antagonists (MRAs) are key agents in guideline-oriented drug therapy for cardiovascular diseases such as chronic heart failure with reduced... (Review)
Review
Mineralocorticoid receptor antagonists (MRAs) are key agents in guideline-oriented drug therapy for cardiovascular diseases such as chronic heart failure with reduced ejection fraction and resistant hypertension. Currently available steroidal MRAs are efficacious in reducing morbidity and mortality; however, they can be associated with intolerable side effects including hyperkalaemia in everyday clinical practice. Recently, a new class of non-steroidal MRAs (including esaxerenone, AZD9977, apararenone, KBP-5074 and finerenone) have been developed with an improved benefit-risk profile and a novel indication for finerenone for diabetic kidney disease. To better understand the non-steroidal MRAs, this review provides information on the molecular pharmacology as well as relevant current preclinical and clinical data on cardiorenal outcomes. A comparative review of all compounds in the class is discussed with regard to clinical efficacy and safety as well as a perspective outlining their future use in clinical practice. LINKED ARTICLES: This article is part of a themed issue on Emerging Fields for Therapeutic Targeting of the Aldosterone-Mineralocorticoid Receptor Signaling Pathway. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.13/issuetoc.
Topics: Heart Failure; Humans; Hypertension, Renal; Mineralocorticoid Receptor Antagonists; Mineralocorticoids; Nephritis; Piperidines; Pyrazoles; Quinolines
PubMed: 34811750
DOI: 10.1111/bph.15747 -
Hypertension (Dallas, Tex. : 1979) Sep 2022Besides the physiological regulation of water, sodium, and potassium homeostasis, aldosterone modulates several physiological and pathological processes in the... (Review)
Review
Besides the physiological regulation of water, sodium, and potassium homeostasis, aldosterone modulates several physiological and pathological processes in the cardiovascular system. At the vascular level, aldosterone excess stimulates endothelial dysfunction and infiltration of inflammatory cells, enhances the development of the atherosclerotic plaque, and favors plaque instability, arterial stiffness, and calcification. At the cardiac level, aldosterone increases cardiac inflammation, fibrosis, and myocardial hypertrophy. As a clinical consequence, high aldosterone levels are associated with enhanced risk of cardiovascular events and mortality, especially when aldosterone secretion is inappropriate for renin levels and sodium intake, as in primary aldosteronism. Several clinical trials showed that mineralocorticoid receptor antagonists reduce cardiovascular mortality in patients with heart failure and reduced ejection fraction, but inconclusive results were reported for other cardiovascular conditions, such as heart failure with preserved ejection fraction, myocardial infarction, and atrial fibrillation. In patients with primary aldosteronism, adrenalectomy or treatment with mineralocorticoid receptor antagonists significantly mitigate adverse aldosterone effects, reducing the risk of cardiovascular events, mortality, and incident atrial fibrillation. In this review, we will summarize the major preclinical and clinical studies investigating the cardiovascular damage mediated by aldosterone and the protective effect of mineralocorticoid receptor antagonists for the reduction of cardiovascular risk in patients with cardiovascular diseases and primary aldosteronism.
Topics: Aldosterone; Atrial Fibrillation; Cardiovascular System; Heart Failure; Humans; Hyperaldosteronism; Mineralocorticoid Receptor Antagonists
PubMed: 35766038
DOI: 10.1161/HYPERTENSIONAHA.122.17964 -
European Heart Journal Aug 2022Despite existing treatments, patients with heart failure and chronic kidney disease (CKD) remain at high risk for adverse outcomes and progression to end-stage disease....
Despite existing treatments, patients with heart failure and chronic kidney disease (CKD) remain at high risk for adverse outcomes and progression to end-stage disease. Steroidal mineralocorticoid receptor antagonists (MRAs) such as spironolactone and eplerenone reduce mortality but remain under-prescribed due to the perceived risk of hyperkalaemia and hormonal side effects. The discovery of non-steroidal MRAs represents a major new dimension in cardiorenal disease therapy. Non-steroidal MRAs have high affinity and specificity for the mineralocorticoid receptor (MR) and differ from both steroidal agents and each other with respect to important physiochemical, pharmacodynamic, and pharmacokinetic parameters. Similar to their steroidal counterparts, they have beneficial anti-inflammatory, anti-remodelling, and anti-fibrotic properties in the kidneys, heart, and vasculature. There are several non-steroidal MRAs under development and clinical assessment; of these, only esaxerenone and finerenone are approved for treatment globally. In Japan, esaxerenone is approved for essential hypertension and has been studied in diabetic nephropathy. Compared with steroidal MRAs, finerenone more potently inhibits MR co-regulator recruitment and fibrosis and distributes more evenly between the heart and kidneys. The landmark Phase III trials FIGARO-DKD and FIDELIO-DKD demonstrated that finerenone-reduced major kidney and cardiovascular events on top of maximally tolerated renin-angiotensin-aldosterone system inhibition in patients with CKD associated with Type 2 diabetes. Non-steroidal MRAs are currently under evaluation in heart failure and for synergistic treatment with sodium-glucose contransporter 2 inhibitors. These ground-breaking agents could become an important therapy across the spectrum of cardiorenal disease.
Topics: Diabetes Mellitus, Type 2; Heart Failure; Humans; Hypertension, Renal; Mineralocorticoid Receptor Antagonists; Mineralocorticoids; Naphthyridines; Nephritis; Receptors, Mineralocorticoid; Renal Insufficiency, Chronic
PubMed: 35713973
DOI: 10.1093/eurheartj/ehac299 -
American Journal of Hypertension Feb 2023Steroidal mineralocorticoid-receptor-antagonists (MRAs), such as spironolactone and eplerenone, are guideline-directed therapies in patients with heart failure with... (Review)
Review
Steroidal mineralocorticoid-receptor-antagonists (MRAs), such as spironolactone and eplerenone, are guideline-directed therapies in patients with heart failure with reduced ejection fraction or resistant hypertension. However, the associated risk of hyperkalemia and hormonal side effects limit their broad use and downstream cardiorenal protection in high-risk patients with type 2 diabetes mellitus (T2DM) and moderate-to-advanced chronic kidney disease (CKD). The critical unmet need to improve long-term cardiorenal outcomes in such patients with CKD has sparked considerable efforts to the discovery and development of a new class of compounds. Finerenone is a novel, nonsteroidal MRA that has recently received regulatory approval with the indication of cardiorenal protection in patients with CKD associated with T2DM. Two landmark phase 3 clinical trials, FIDELIO-DKD and FIGARO-DKD, demonstrated that among patients with T2DM and a broad spectrum of CKD, finerenone reduced the risk of "hard" cardiovascular and kidney failure outcomes as compared with placebo, with a minimal risk of hyperkalemia. Subgroup analyses of these trials also provided preliminary evidence that the efficacy and safety profile of finerenone was similar and irrespective of background therapy with other guideline-directed therapies, such as sodium-glucose co-transporter type 2 (SGLT-2) inhibitors and glucagone-like peptide 1 receptor agonists. Whether the combination of finerenone with a SGLT-2 inhibitor is more beneficial in patients with T2DM and CKD as compared with either therapy alone is a crucial research question that is currently under investigation in an ongoing clinical trial.
Topics: Humans; Mineralocorticoid Receptor Antagonists; Diabetes Mellitus, Type 2; Mineralocorticoids; Hyperkalemia; Renal Insufficiency, Chronic
PubMed: 36331811
DOI: 10.1093/ajh/hpac124 -
Endocrinology Apr 2022
Topics: Aldosterone; Glucocorticoids; Mineralocorticoids; Receptors, Mineralocorticoid
PubMed: 35148380
DOI: 10.1210/endocr/bqac016 -
Polski Merkuriusz Lekarski : Organ... Jun 2022Monogenic hypertension (MH) is a rare form of arterial hypertension (AH) in which a single gene mutation is responsible for developing the disease. This article... (Review)
Review
Monogenic hypertension (MH) is a rare form of arterial hypertension (AH) in which a single gene mutation is responsible for developing the disease. This article discusses the pathogenesis, genetics, phenotype, and treatment of monogenic forms of AH. According to Guyton's hypothesis, mutations responsible for MH development most often lead to increased renal sodium reabsorption, in a mineralocorticoid-dependent or -independent mechanism, resulting in fluid retention and increased blood pressure. MH most often appears in childhood or adolescence and is characterized by moderate to severe blood pressure elevation and resistance to standard treatment. The coexistence of water-electrolyte abnormalities, most commonly hypokalemia and metabolic alkalosis, is characteristic but not always present. Monogenic AH should also be considered in patients with precocious or delayed puberty, growth deficiency, brachydactyly, and severe symptoms or hypertension mediated-organ damage. Identifying patients with monogenic hypertension is of utmost importance to implement appropriate treatment and reduce the risk of cardiovascular complications.
Topics: Humans; Hypertension; Hypokalemia; Mineralocorticoids; Mutation
PubMed: 35801605
DOI: No ID Found -
International Journal of Molecular... Apr 2023Regulation and action of the mineralocorticoid receptor (MR) have been the focus of intensive research over the past 80 years. Genetic and physiological/biochemical... (Review)
Review
Regulation and action of the mineralocorticoid receptor (MR) have been the focus of intensive research over the past 80 years. Genetic and physiological/biochemical analysis revealed how MR and the steroid hormone aldosterone integrate the responses of distinct tubular cells in the face of environmental perturbations and how their dysregulation compromises fluid homeostasis. In addition to these roles, the accumulation of data also provided unequivocal evidence that MR is involved in the pathophysiology of kidney diseases. Experimental studies delineated the diverse pathological consequences of MR overactivity and uncovered the multiple mechanisms that result in enhanced MR signaling. In parallel, clinical studies consistently demonstrated that MR blockade reduces albuminuria in patients with chronic kidney disease. Moreover, recent large-scale clinical studies using finerenone have provided evidence that the non-steroidal MR antagonist can retard the kidney disease progression in diabetic patients. In this article, we review experimental data demonstrating the critical importance of MR in mediating renal injury as well as clinical studies providing evidence on the renoprotective effects of MR blockade. We also discuss areas of future investigation, which include the benefit of non-steroidal MR antagonists in non-diabetic kidney disease patients, the identification of surrogate markers for MR signaling in the kidney, and the search for key downstream mediators whereby MR blockade confers renoprotection. Insights into these questions would help maximize the benefit of MR blockade in subjects with kidney diseases.
Topics: Humans; Albuminuria; Aldosterone; Kidney; Mineralocorticoid Receptor Antagonists; Receptors, Mineralocorticoid; Renal Insufficiency, Chronic
PubMed: 37175424
DOI: 10.3390/ijms24097719