Eplerenone–A novel Mineralocorticoid receptor antagonist for the clinical application

Nan-Nan Wu; Yuan-Yuan Zhang; Dong Zhao

doi:10.4103/ed.ed_7_21

REVIEW ARTICLE

Year : 2022 | Volume : 7 | Issue : 1 | Page : 1-11

Eplerenone–A novel Mineralocorticoid receptor antagonist for the clinical application

Nan-Nan Wu, Yuan-Yuan Zhang, Dong Zhao
Beijing Key Laboratory of Diabetes Research and Care, Center for Endocrine Metabolism and Immune Diseases, Beijing Lu he Hospital, Capital Medical University, Beijing, China

Date of Submission	18-Apr-2021
Date of Decision	27-Nov-2021
Date of Acceptance	23-Dec-2021
Date of Web Publication	28-Mar-2022

Correspondence Address:
Dong Zhao
Beijing Key Laboratory of Diabetes Prevention and Research, Beijing Luhe Hospital, Capital Medical University, Beijing 101149
China

Source of Support: None, Conflict of Interest: None

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DOI: 10.4103/ed.ed_7_21

Abstract

Aldosterone is produced from the zona glomerulosa of the adrenal cortex in the adrenal gland, which is main mineralocorticoid hormone. Upon binding the mineralocorticoid receptor, it regulates sodium and potassium absorption, secretion, and retention, thereby maintaining stable blood pressure levels. However, abnormal aldosterone synthesis and metabolism could be pathogenic and contribute to multiple organ fibrosis and structural remodeling. For instance, hyperaldosteronemia is critically involved in the development of hypertension, heart failure (HF), and renal disease. Therefore, mineralocorticoid receptor antagonists (MRAs) that could fight against high concentrations of aldosterone play an important role in the treatment of diseases caused by hyperaldosteronism. Eplerenone, as a novel selective MRA, has better therapeutic efficiency and fewer side effects comparing to the classical drug spironolactone. In this review, first, we go through the biosynthesis and biologic properties of aldosterone and then introduce how hyperaldosteronemia facilitates certain diseases progression. Aldosterone is an important part of the renin-angiotensin-aldosterone system (RAAS), which plays a crucial role in essential hypertension, atrial tremor, and tissue fibrosis. Second, we summarize current evidence of clinical application of eplerenone in the control of primary aldosteronism, hypertension, HF, nephropathy, insulin resistance, and liver damage. It is exciting that many studies have shown that the use of eplerenone in these diseases yields good outcomes accompanied with fewer adverse effects such as hyperkalemia, metabolic acidosis, hypotension, and acute kidney failure, which indicates that eplerenone is a strong and safe MRA and inhibitor of RAAS system. This review focuses on therapeutic efficacy and disadvantages of eplerenone when treating a series of different diseases. Ultimately, we hope to shed light on future therapeutic strategies in diseases associated with hyperaldosteronemia.

Keywords: Aldosterone, eplerenone, mineralocorticoid receptor, renin–angiotensin–aldosterone system clinical application

How to cite this article:
Wu NN, Zhang YY, Zhao D. Eplerenone–A novel Mineralocorticoid receptor antagonist for the clinical application. Environ Dis 2022;7:1-11

How to cite this URL:
Wu NN, Zhang YY, Zhao D. Eplerenone–A novel Mineralocorticoid receptor antagonist for the clinical application. Environ Dis [serial online] 2022 [cited 2023 Mar 30];7:1-11. Available from: http://www.environmentmed.org/text.asp?2022/7/1/1/341193

Introduction

Aldosterone is a mineralocorticoid secreted by the adrenal cortex globular zone, mainly through reabsorbing water and sodium ions, excreting potassium ions, and regulating steady state in the body. In addition, abnormal aldosterone can induce pro-inflammatory activity, causing the progress of target organs such as fibrosis damage, remodeling of blood vessels, heart, and kidneys, then ultimately leading to target organ dysfunction and failure exhaust. It is closely related to the occurrence and progression of hypertension, congestive heart failure (CHF), and chronic kidney disease (CKD); Inhibiting the renin angiotensin aldosterone system (RAAS) can reduce aldosterone levels. Steroid mineralocorticoid receptor (MR) blockers currently in clinical use (mineralocorticoid receptor antagonists, [MRAs]) such as eplerenone have been shown to be effective in reducing the heart rate of CHF patients and vascular mortality. Eplerenone as a new type of oral nonsteroidal MRA can block MR caused by elevated aldosterone excessive activation, with high tolerance and selectivity. We summarize current evidence of clinical application of eplerenone in the control of primary aldosteronism (PA), hypertension, heart failure (HF), nephropathy, insulin resistance, and liver damage. It is exciting that many studies have shown that the use of eplerenone in these diseases yields good outcomes accompanied with fewer adverse effects such as hyperkalemia, metabolic acidosis, hypotension, and acute kidney failure, which indicates that eplerenone is a strong and safe MRA and inhibitor of RAAS system. This review focuses on therapeutic efficacy and disadvantages of eplerenone when treating a series of different diseases. Ultimately, we hope to shed light on future therapeutic strategies in diseases associated with hyperaldosteronemia.

Aldosterone

It plays a key role in regulating blood pressure (BP) RAAS. Renin is metabolized to produce angiotensin I, and further it converts into angiotensin II by angiotensin-converting enzyme (ACE). The binding of angiotensin II to angiotensin II type 1 receptor stimulates the contraction of vascular smooth muscle cells.^[1],[2],[3]

Aldosterone is a mineralocorticoid hormone within RAAS pathway. Aldosterone is synthesized in the glomerular zone of the adrenal cortex in two ways: one is classic RAAS pathway in which aldosterone is produced from the cortical bands of the adrenal gland;^[88] and the other is independent of RAAS in which aldosterone is found produced in heart, blood vessels, brain, and mesangial cells.^[108] The secretion of aldosterone is controlled by many factors, including adrenal cortex hormone, norepinephrine, potassium levels, and RAAS. Under normal circumstances, the renin–angiotensin mainly regulates the secretion of aldosterone and circulating aldosterone level is low. However, the juxtaglomerular cells secrete more renin in response to decreases in BP and renin activates angiotensinogen derived from liver into angiotensin I and then angiotensin II. Binding of angiotensin II to its cognate receptors stimulates arteriolar vasoconstriction, leading to the increase of total peripheral resistance and BP rapidly. At the same time, angiotensin II binds to its cognate receptors in the glomerulosa of the adrenal cortex to induce the synthesis and secretion of aldosterone, which enhances the reabsorption of water and sodium into renal tubules to reabsorb water, increases the extracellular fluid volume, and potentiates the elevation of BP [Figure 1].

Figure 1: Renin–angiotensin–aldosterone system in the control of blood pressure. when there is low sodium intake or decrease of blood volume and blood pressure, the renin is secreted by the juxtaglomerular apparatus in the renal cortex. Renin activates angiotensinogen derived from liver into angiotensin I and then angiotensin II. Binding of Angiotensin II to its cognate receptors stimulates arteriolar vasoconstriction, leading to the increase of total peripheral resistance and blood pressure rapidly. Meanwhile, angiotensin II binds to its cognate receptors in the glomerulosa of the adrenal cortex to induce the synthesis and secretion of aldosterone, which enhances the reabsorption of water and sodium into renal tubules to reabsorb water, elevating blood pressure

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MRs are ubiquitously expressed in many tissues and particularly in kidney. Upon aldosterone binding, MR is translocated from cell membrane to the nucleus where it transcriptionally activates a series of target genes to regulate electrolyte and fluid metabolism, which is called “genemic effect” of aldosterone.^[109] Therefore, RAAS system controls BP via smooth muscle cell constriction and fluid homeostasis.

Apart from genemic effect, aldosterone/MR signaling also mediates nongenemic effect. In disease such as PA, excessive aldosterone production induces abnormal activation of MR expressed in epithelial and nonepithelial tissues.^[4] Like downstream of aldosterone/MR signaling, MAPK pathways including ERK, JNK, and PI3K become activated. Phosphorylation of these kinases triggers the production of growth factors and inflammatory cytokines to enhance collagen deposition, fibrosis, and structural remodeling in heart, kidney, liver, and other organs.^[5],[6] This pathological effect is called “nongenemic effect” of aldosterone. Furthermore, redundant aldosterone enhances sodium reabsorption, thereby resisting the elevation of BP [Figure 2].

Figure 2: The genemic and nongenemic effects of aldosterone. Upon aldosterone binding to mineralocorticoid receptor on the membrane, mineralocorticoid receptor is translocated into the nucleus to initiate transcription of target genes, which is so called “genemic” effect of aldosterone. Apart from that, binding of aldosterone to mineralocorticoid receptor could elicit phosphorylation of PI3K, MAPK and JNK downstream of mineralocorticoid receptor, which is so called “nongenemic effect” of aldosterone

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Mineralocorticoid Receptor Antagonists

To counteract the “nongenemic effect,” MRAs have been developed and obtained beneficial effects for patients which suffered from high aldosterone concentration including PA, primary hypertension, and HF. MRAs are a group of medications that inhibit the effect of aldosterone on the MR.^[7] The main representatives of the MRs antagonists are steroidal-spironolactone, eplerenone, canrenone, and nonsteroidal-finerenone. These steroidal MRAs were first used as potassium-preserving diuretic in clinical practice. Later on, clinical results have found that MRAs could have a variety of roles on the cardiovascular disease, for example, alleviating myocardial fibrosis, correcting the phenomenon of “aldosterone escape,” lowering BP.^[8],[9] The nonsteroidal MRAs have demonstrated important differences in their distribution, binding mode to the MR, and subsequent gene expression.

Spironolactone and canrenone

Spironolactone is the earliest MRA in clinical application, its antagonism to aldosterone is comprehensive, not only can improve salt–water metabolism, but also counteract all bad effects of aldosterone on the cardiovascular disease.^[10] However, the disadvantage is that it is a nonselective MRA, which also acts on other hormone receptors; long-term application may produce some adverse reactions to sexual glands, including mammary gland hyperplasia, menstrual disorders in women.^[11] These adverse effects restrain its clinical use.

Canrenone is currently only used in Europe. It is a dethioacylated form of spironolactone and the main degradation product and main metabolite of spironolactone.^[12] It has a long half-life.

Finerenone

Finerenone is a novel potent selective non-steroidal MRA. Since finerenone's discovery, the drug has shown promising potential for the management of cardiorenal diseases, particularly in patients with HF and mild renal dysfunction.^[13] Finerenone seems to have lower rates of hyperkalemia than spironolactone but similar effects on NT-ProBNP and albuminuria.^{[14],[15],[16]} The biggest limitations to using finerenone are the lack of appropriately powered randomized clinical trial to support its use, the novelty of the medication, and the lack of the Food and Drug Administration approval given the ongoing phase 3 trials.

Eplerenone

Since about two decades ago, eplerenone has been developed and it has a similar or stronger antagonistic effect on aldosterone than spironolactone. It is a good substitute drug for spironolactone. The novel MRA eplerenone is derived from spironolactone. Epoxy bridge is introduced between the 9a and 11a of spironolactone to replace the 17a ketoacyl group with Carboxymethoxy group, endowing eplerenone high specificity for MR.^[110]

Compared with spironolactone and canrenone, eplerenone has better bioavailability but low affinity to the androgenic and progestational receptors,^[17] which could restrain the off-target effect of the drug. Moreover, eplerenone could result in sustained increases of aldosterone in plasma renin and serum. Based on these characteristics, eplerenone is a desirable antagonist of aldosterone for therapeutics. [Table 1] summarizes the differences between eplerenone and spironolactone. In the review below, we focus on the therapeutic aspects and problems of eplerenone in clinical treatment.

Table 1: Comparison between eplerenone and spironolactone

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Clinical Application of Eplerenone

Eplerenone in hypertension complications

Hypertension induces structural changes in cardiovascular disease, leading to atrial fibrillation, stroke, and HF.^[18],[19] It is reported that the hazard ratio of having the risk of cardiovascular disease-related mortality is doubled if systolic BP and diastolic BP increases 20 and 10 mmHg, respectively, in people aged 40–70 years.^[20]

In addition, increasing evidence has shown that MRAs play a vital role in the treatment of hypertension and even could overcome resistance. MRA therapy has been used for many years in the treatment of essential hypertension.^{[21],[22],[23]} A previous study showed that eplerenone is as good as other antihypertensive agents such as calcium channel blockers and spironolactone for decreasing BP.^{[6],[24],[25]} Another study showed that compared with the ACE inhibitor enalapril and the angiotensin receptor blocker losartan, eplerenone can significantly reduce SBP.^[26] Dose–response effect may occur when the dose exceeds 400 mg/day. A dose of 50–200 mg of eplerenone per day in people with primary hypertension could lower 9.21 mmHg systolic and 4.18 mmHg diastolic blood and doses of more than 50 mg/day do not produce further reduction.^[27]

Side effects during the treatment of hypertension are great concerns. The current study suggests that the adverse effects of eplerenone therapy are generally rare and mild when treating diseases including hyperkalemia, dizziness, and albuminuria. Compared with the placebo group, the eplerenone group had a higher incidence of adverse events, but there was no big difference in the incidence of serious adverse events or hyperkalemia between the two groups.^[6]

Eplerenone therapy has other benefits besides lowering BP. A study shows that eplerenone treatment is involved reducing stiffness, decreased collagen-elastin ratio, and reduced circulating inflammatory mediators comparing to atenolol,^[28] which suggests that eplerenone therapy may reduce left ventricular hypertrophy. CKD is the common complication of hypertension that usually impedes treatment process and efficiency. It sometimes is insufficient in lowering BP by applying first-line drugs such as angiotensin receptor blockers (ARBs) alone, that implies multidrug combination therapy is necessary to further improve the treatment efficiency.^[29],[30] In addition, a recent study showed that eplerenone might be useful therapy for atrial fibrosis in hypertension.^[31]

Eplerenone in heart failure

HF is a chronic, progressive condition in which the heart muscle cannot pump enough blood to meet needs of body. HF is usually associated with high mortality and morbidity.^[32],[33] The reduction ejection fraction for HF patients include ACEI, ARB, MRA, and beta-blockers.^[33],[34] However, recommended doses of guideline-directed medication of ACEI and ARB are not actually achieved.^[35] Previous drug interventions, such as ACEI,^[36] ARBs,^[37] and BBs,^[38] failed to significantly reduce the mortality rate caused by HF.

A series of clinical guidelines describe the role and status of MRAs in the treatment of HF. The classic steroidal MRAs (spironolactone and Eplerenone) have a Class 1A recommendation for CHF patients with reduced ejection fraction and left ventricular ejection fraction ≤35%, regardless of whether they have been implemented therapy with ACE inhibitors or beta-blockers.^[39],[40] Moreover, MRA-based treatment could reduce cardiovascular risk in CHF.

In the treatment of HF, eplerenone has similar efficacy compared with spironolactone. However, it had more favorable bad effect.^{[41],[42],[43]} Eplerenone could reduce both the risk of death and the risk of hospitalization comparing with placebo in HF patients.

Eplerenone in renal protection

Diabetic nephropathy (DN) is a well-known complication of diabetes, which ultimately progresses to end-stage diabetic kidney diseases.^[71] Accumulated studies have shown that patients with hypertension and nephropathy have “low renin hypertension^[44].” Although inhibiting RAAS has been the standard therapy to treat DN, it sometimes fails to block the progression of diabetic nephropathy to the end stage renal disease when accompanying with “aldosterone escape;”^[45],[48] but it can provide renal protection in DN patients independent of the extent of BP reduction.^[49] Addition of low-dose Eplerenone (50 mg/day) based on treatment renin-angiotensin system inhibitors might have reno-protective effects through reduction of albuminuria in hypertensive patients with non-diabetic chronic kidney disease.^[50] Adding eplerenone at 100 mg/kg BW/d along with enalapril in db/db mice reduced the expression markers of inflammation and oxidative stress.^[51] The study reported by Epstein group showed that coadministration of eplerenone 50 or 100 with an ACE inhibitor lasting 12 weeks significantly reduces by 41% and 48% of albuminuria relatively comparing to ACEI alone in patients with diabetes without producing significant increases in hyperkalemia.^[52]

An important pathological change of DN is glomerular sclerosis, accompanied by renal damage such as glomerular hypertrophy and deteriorating albuminuria. This phenomenon is related with the high expression of type I, type IV collagen, PAI1, transforming growth factor (TGF) beta, etc. A study from Guo showed that addition of eplerenone could revere the renal damage resulted from diabetes as well as increased renal cortical levels of MR protein, MR mRNA, TGF beta mRNA, and osteopontin mRNA.^[53] The study from Chen demonstrated that eplerenone could inhibit the development of renal fibrosis macrophage and monocyte infiltration and interstitial cell proliferation.^[54] There may be dose dependence when using eplerenone, rat model studies have shown the higher the dosage of Eplerenone , the better effect on the glomerulosclerosis, the lower expression of glomerular sclerosis related molecules.^[55]

Eplerenone not only plays a good effect on DN, but also could reduce structural and functional alterations induced by cyclosporine A (CsA), namely CsA nephrotoxicity. Adrenalectomized (ADX) rats were divided randomly into four groups and given sham-ADX, ADX, CsA, or eplerenone, respectively; the results show that the levels of TIF and COL-I, TGF-β1, and PAI-1 associated with renal alteration could be reduce by eplerenone.^[56]

Most of high-risk patients do not intend to make full use of eplerenone because of the adverse events. The kidney transplant recipients were given eplerenone 25 mg/d for 8 weeks, showing that no severe hyperkalemia occurred, and eplerenone could be safely given until glomerular filtration rate (GFR) falls to 30 ml/min/1.73 m². Yujiro Nakano et al. suggested that blockade of aldosterone action by eplerenone could partially reverse glomerular hyperfiltration in PA.^[57] There is no need to exclude eplerenone because of security concerns.

Eplerenone in glucose intolerance and insulin resistance

Many studies have shown that aldosterone is directly associated with insulin resistance and glucose level.^[58],[59] The predictor of the development of insulin resistance is plasma aldosterone level from a Japanese study over a 10-year observation period.^[60] Another study showed that plasma aldosterone levels are independently associated with metabolic syndrome and it rises as the risk factors for metabolic syndrome increase.^[61] Besides, Colussi G's research shows that plasma aldosterone levels and indexes such as plasma glucose levels, C-peptide, and the HOMA index (homeostasis model assessment-insulin resistance) have significant positive correlation; moreover, insulin sensitivity decreases as plasma aldosterone levels increase.^[62] Given these studies, aldosterone is one of the targets in the treatment of diabetes especially the well-known type 2 diabetes mellitus.

There is some evidence that could explain how aldosterone played an effect on the insulin sensitivity and glucose intolerance. On the one hand, aldosterone directly inhibited insulin-signaling pathway via reduction of the amounts of insulin receptor substrate (IRS) 1 and IRS 2 by glucocorticoid receptor-mediated production of reactive oxygen species.^[63] On the other hand, aldosterone could increase the gluconeogenesis by stimulating gene expression of enzymes associated with glucose production such as glucose-6-phosphatase and phosphoenolpyruvate carboxyl kinase in the human or mouse liver.^[64],[65]

Tsutomu Wada group suggests that Eplerenone could ameliorate glucose intolerance and insulin resistance in C57BL/6 mice due to high fat diet, further experimental data reveals Eplerenone could reduce the expression of inflammasome components, including Nlrp3 and Caspase1 in the eWAT and liver.^[66] Baudrand et al. reported that eplerenone treatment significantly decreased glycemia (P < 0.01) with no effect on insulin.^[67] In vivo, eplerenone improved insulin sensitivity through P38 MAPK pathway and increased adiponectin expression in the myocardia of high-fat diet rats.^[6] However, there were some negative results: Suman Srinivasa reported that HIV-patients were given 50 mg of eplerenone and placebo daily, the results show Eplerenone does not improve insulin sensitivity comparing with placebo;^[68] Low-dose Eplerenone treatment (50 mg daily) for 14 days did not affect basal or postprandial glucose and lipid levels in healthy adult males.^[69] The different results from these studies may be the doses and methods used of eplerenone.

Eplerenone in primary aldosteronism

PA refers to the excessive secretion of aldosterone by the adrenal cortex, resulting in sodium retention, potassium excretion, increasing in blood volume, and inhibition of renin angiotensin system activity. The main clinical manifestations are hypertension with hypokalemia. Excessive aldosterone is an important risk factor for cardiac hypertrophy, HF and impaired renal function. The target organs of hypertension, such as heart and kidney, are more seriously damaged in patients with PA. For example, patients with PA have a higher risk of cardiovascular complications, such as severe vascular disturbances, increased intima-media thickness, and arterial stiffness, further demonstrating the health hazards of excess aldosterone.^{[17],[70],[71],[72],[73],[74]} PA is the most common cause of secondary hypertension, accounting for 5%–10% of patients with hypertension.^{[75],[76],[77]} In addition, PA tends to result in glomerular hyperfiltration, which is a major pathogenic factor of renal damage.^{[78],[79],[80],[81]}

There are two therapeutic options for the treatment of PA: either unilateral laparoscopic adrenalectomy for patients with aldosterone-producing adenoma (APA) and unilateral adrenal hyperplasia, or treatment based on MRAs for patients with bilateral APA and idiopathic hyperaldosteronis.^[76] In addition, MRA treatment has been recommended for patients who unable or unwilling to undergo surgery.^[82] Patients should be treated with MRA to maintain potassium and renin levels before unilateral adrenalectomy, avoiding hyporeninemic hypoaldosteronism in the postoperative period.^[83] Researches show that an appropriate surgery or medical treatment including a MRA could significantly reduce cardiovascular events in patients with PA.^{[84],[85],[86]}

Eplerenone as a selective MRA could directly antagonize the MR and is an appealing alternative when dealing with PA. A prospective clinical study of Gaddam K demonstrates that eplerenone treatment for PA patients rapidly reverse left ventricular hypertrophy and intracardiac volume.^[87] In addition, many studies show that eplerenone treatment has great effects on increasing serum potassium level and improving vascular status in patients with PA. The effect of the eplerenone treatment on the GFR appeared to be modest when compared with adrenalectomy, which resulted in the complete resolution of hyperaldosteronism.^[57] Nevertheless, the blockade of aldosterone by eplerenone could reverse glomerular hyperfiltration surprisingly in PA.

It is encouraging that eplerenone will not bring about any endocrine side effects because of the low affinity for male hormones and progesterone.^{[22],[76],[89],[90],[91]} Similarly, eplerenone also is more capable to reduce the frequency of sex hormone-related adverse effects comparing with spironolactone.^[6] In addition, eplerenone has a great safety during pregnancy in PA, Gitelman syndrome, and diastolic HF.^{[92],[93],[94]}

However, double the dose is required actually to achieve an efficacy similar to that of spironolactone for lowering BP, and the ceiling effect appears to occur sooner.^[95] The approved dosage of eplerenone is limited to 100 mg/day in Japan, which is approximately equivalent to 50 mg spironolactone.^[96] Moreover, eplerenone must be administered twice daily to ensure activity throughout the day and is currently more expensive than spironolactone.^{[82],[95],[97]} Therefore, the choice of clinical treatment should base on the patient's specific conditions.

Eplerenone in nonalcoholic steatohepatitis

Schreier B et al. suggest that MR expression was reduced in hepatocytes located in rats' hypoxic areas of cirrhosis with ascites, and nuclear MR translocation from cytosolic to nuclei was hindered using eplerenone treatment.^[98] Another paper provides one explanation of this phenomenon that eplerenone could inhibit fibrosis-induced NOX4 protein expression.^[99]

The choice of treatment option of nonalcoholic steatohepatitis (NASH) is limited on account of that MR activation could influence hepatic fibro genesis; therefore, some studies indicate that MR is beneficial for NASH. Results from experimental NASH C57BL6 mice models suggest that eplerenone supplementation plays a role in hepatic antifibrotic effects and expression of MR correlates with inflammation and fibrosis development.^[100] Another research reveals that eplerenone could ameliorate histological abnormality such as hypertrophy and macrophage infiltration resulted from NASH in liver-specific SREBP-1c transgenic mice fed high-fat and high-fructose diet.^[101] However, there were some negative results. A study with the administration of eplerenone among human immunodeficiency virus patients for nonalcoholic fatty liver disease leads to an opinion eplerenone may not be an effective approach to treat hepatic steatosis in human immunodeficiency virus.^[102]

There are still exploratory studies reporting the potential hepatoprotective and anti-fibrotic effects of eplerenone. Taye's study shows that eplerenone exhibits hepatoprotective action via reducing oxidative stress and inflammatory due to CLL4-induced liver damage.^[103] In addition, eplerenone could also attenuate the development of bile duct ligation-induced hepatic fibrosis by reducing oxidative stress, suppressing activated hepatic stellate cells, and decreasing plasma ATII levels. The advantages and side effects of eplerenone are listed in [Table 2].

Table 2: The advantages and dis-advantages of eplerenone in different diseases

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Limitation and perspective

Although eplerenone has many favorable clinical manifestations, it still has limitations. Eplerenone shows a gender preference in acute decompensated HF; it is more beneficial for female patients than male patients in the aspects of side effects. Masayoshi Yamamoto's research shows that no better prognostic value of eplerenone was observed compared with spironolactone in male patients.^[10]

Eplerenone is metabolized by the ubiquitous Cytochrome (CYP) 3A4,^[104],[105] which is responsible for the metabolism of more than 50% of drugs used in clinical practice, and is highly polymorphic; This metabolism by CYP 3A4 increases the potential for clinically interactions of Eplerenone when administered with other drugs. These interactions may increase uncertain efficacy and possible mortality. Therefore, there is a need for more studies exploring impact of polymorphic CYP 3A4 on Eplerenone in different clinical settings.

In addition, although Eplerenone is more preferable due to fewer sex-related adverse effects than other MRAs, there is no much chooses among these agents in terms of hyperkalemia;^[105] Eplerenone shows limited effect on lowering BP in patients with PA. In fact, the decision to choose appropriate agent is based on many factors such as efficacy, safety, cost, and clinical experience.

Eplerenone may be less effective than other MRAs or placebo in treating other diseases. A double-masked randomized controlled trial concluded that eplerenone was safe but was not beneficial in patients with chronic central serous chorioretinopathy (CSCR) after short-term intervention.^[106] Willcox et al. tryed to fill a gap in the knowledge regarding the efficacy and safety of eplerenone for CSCR in long term.^[107] As patients with CSCR have limited therapeutic options, further evidence focusing on the action of eplerenone in CSCR would be helpful to inform future treatment decisions.

Summary

As a selective MRA and inhibitor of RAAS system, eplerenone is strong and safe in diseases related with excessive aldosterone such as PA, hypertension, HF, nephropathy, insulin resistance, and liver damage. Given the overall efficacy and safety, it is very promising and expecting to apply eplerenone widespread in the medicine field.

Acknowledgment

We would like to thank the author in the study. Nn W and Yy Z drafted the manuscript. D Z revised the article.

Financial support and sponsorship

This research was supported by the capital funds for healthy improvements and research (Grant #2020-4-7082).

Conflicts of interest

There are no conflicts of interest.

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