Steroidal Mineralocorticoid Receptor Antagonists Research Articles

The changing landscape of mineralocorticoid receptor antagonists – finerenone in cardiovascular and renal health

Finerenone is a novel non-steroidal mineralocorticoid receptor antagonist (MRA) with high selectivity and affinity to mineralocorticoid receptor (MR). Steroidal MRAs, like spironolactone and eplerenone, have been in use for decades. They have an established position in the management of hypertension and heart failure with reduced ejection fraction (HFrEF). There are studies showing that MR antagonism has anti-inflammatory and anti-fibrotic effects resulting in cardiovascular and renal protection. However, broader use of steroidal MRAs is seriously limited by antiandrogenic side effects and the risk of hyperkalemia. The differences in structure as well as pharmacokinetic and pharmacodynamic properties between steroidal and non-steroidal MRAs result in reduced risk of side effects while offering the benefit of cardiorenal protection. Finerenone is currently the only non-steroidal MRA approved by European Medicines Agency (EMA). It is indicated for patients with chronic kidney disease (CKD) with albuminuria and type 2 diabetes mellitus (DM2). Several studies showed a reduction of the risk of cardiovascular and renal events in this group of patients compared to placebo. The risk of hyperkalemia was increased resulting in discontinuation of treatment in more patients than placebo, but the risk of serious adverse events did not differ significantly. The other indications for finerenone, including heart failure (HF) management, are currently being researched.

Abstract 12861: Steroidal Mineralocorticoid Receptor Antagonist Treatment Patterns and Predictors of Discontinuation

Introduction: Steroidal mineralocorticoid receptor antagonists (sMRA), spironolactone and eplerenone, are indicated for several cardiovascular (CV) conditions, including heart failure and hypertension. However, adverse drug reactions may lead to discontinuation. This study aimed to explore sMRA treatment patterns and predictors of discontinuation. Methods: This retrospective observational study used administrative claims from the Healthcare Integrated Research Database® to identify naïve adult users of sMRAs between 01 Jan 2016 and 31 May 2021 with at least 12 months of continuous health plan enrollment before initiation. Five subgroups were identified based on comorbidities before sMRA initiation - heart failure with preserved or reduced ejection fraction (HFpEF/HFrEF), undetermined heart failure (undHF), chronic kidney disease (CKD) and type 2 diabetes (T2D), and nondiabetic-CKD (ndCKD). sMRA treatment patterns and discontinuation (i.e., no refill within two prescription cycles) were described. Multivariate logistic regression modeling was used to explore predictors (i.e., demographics, comorbidity burden, specialist prescribing, CV disease, and medications) of discontinuation in all sMRA users and subgroups separately. Results: We identified 224,100 sMRAs users (99% spironolactone), including 8,553 HFpEF, 19,636 HFrEF, 20,336 undHF, 11,336 CKD and T2D, and 10,134 ndCKD, patients. Over a median of 655 days, a dose change was observed in 23% of patients. A dose increase was more common than a decrease (16% vs. 7%), a trend that was observed across all subgroups. Overall, 73% of sMRA users discontinued treatment after a median of 90 days. Discontinuation in subgroups was lower; 62% in HFpEF, 58% in HFrEF, 61% in undHF, and 66% in both CKD subgroups. No specific factors were consistently associated with increased odds of sMRA discontinuation. However, increased comorbidity burden, use of other CV medications, and cardiologist prescribers significantly decreased the odds of discontinuation across most subgroups. Conclusions: Most naïve sMRA users discontinue therapy within six months of initiation. No demographic or clinical factors were consistently associated with increased odds of sMRA discontinuation.

Effects of Mineralocorticoid Receptor Antagonists for Chronic Kidney Disease: A Systemic Review and Meta-Analysis

Background: Mineralocorticoid receptor blockade could be a potential approach for the inhibition of chronic kidney disease (CKD) progression. The benefits and harms of different mineralocorticoid receptor antagonists (MRAs) in CKD are inconsistent. Objectives: The aim of the study was to summarize the benefits and harms of MRAs for CKD patients. Methods: We searched MEDLINE, EMBASE, and the Cochrane databases for trials assessing the effects of MRAs on non-dialysis-dependent CKD populations. Treatment and adverse effects were summarized using meta-analysis. Results: Fifty-three trials with 6 different MRAs involving 22,792 participants were included. Compared with the control group, MRAs reduced urinary albumin-to-creatinine ratio (weighted mean difference [WMD], −90.90 mg/g, 95% CI, −140.17 to −41.64 mg/g), 24-h urinary protein excretion (WMD, −0.20 g, 95% CI, −0.28 to −0.12 g), estimated glomerular filtration rate (eGFR) (WMD, −1.99 mL/min/1.73 m², 95% CI, −3.28 to −0.70 mL/min/1.73 m²), chronic renal failure events (RR, 0.86, 95% CI, 0.79–0.93), and cardiovascular events (RR, 0.84, 95% CI, 0.77–0.92). MRAs increased the incidence of hyperkalemia (RR, 2.04, 95% CI, 1.73–2.40) and hypotension (RR, 1.80, 95% CI, 1.41–2.31). MRAs reduced the incidence of peripheral edema (RR, 0.65, 95% CI, 0.56–0.75) but not the risk of acute kidney injury (RR, 0.94, 95% CI, 0.79–1.13). Nonsteroidal MRAs (RR, 0.66, 95% CI, 0.57–0.75) but not steroidal MRAs (RR, 0.20, 95% CI, 0.02–1.68) significantly reduced the risk of peripheral edema. Steroidal MRAs (RR, 5.68, 95% CI, 1.26–25.67) but not nonsteroidal MRAs (RR, 0.52, 95% CI, 0.22–1.22) increased the risk of breast disorders. Conclusions: In the CKD patients, MRAs, particularly in combination with angiotensin-converting enzyme inhibitor/angiotensin receptor blocker, reduced albuminuria/proteinuria, eGFR, and the incidence of chronic renal failure, cardiovascular and peripheral edema events, whereas increasing the incidence of hyperkalemia and hypotension, without the augment of acute kidney injury events. Nonsteroidal MRAs were superior in the reduction of more albuminuria with fewer peripheral edema events and without the augment of breast disorder events.

Nonsteroidal Mineralocorticoid Receptor Antagonist (Finerenone) in Cardiorenal Disease.

Nonsteroidal mineralocorticoid receptor antagonists (MRAs) present a promising therapeutic option in cardiorenal diseases, mitigating the limitations of steroidal MRAs. Finerenone, a third-generation nonsteroidal MRA, has demonstrated beneficial effects in heart failure (HF) and chronic kidney disease (CKD). Clinical trials, including FIDELIO-DKD and FIGARO-DKD, revealed finerenone's efficacy in improving kidney and cardiovascular (CV) outcomes. Patients with CKD and type 2 diabetes (T2DM) on finerenone experienced reduced rates of cardiovascular events, including hospitalization for HF. However, these trials excluded symptomatic HF patients, focusing on asymptomatic or early-stage HF. The ongoing FINEARTS-HF trial evaluates finerenone in HF with preserved ejection fraction (HFpEF). Additionally, studies exploring finerenone and sodium-glucose cotransporter 2 (SGLT2) inhibitors' (Empagliflozin) combination effects in CKD and T2DM (CONFIDENCE) and the selective MR modulator AZD9977 with another SGLT2 inhibitor (dapagliflozin) in HF and CKD (MIRACLE) aim to expand treatment options. While SGLT-2 inhibitors were shown to reduce hyperkalemia risk in FIDELIO-DKD and potentially lower new-onset HF incidence in FIGARO-DKD, further research is essential. So far, the evidence for the beneficial effect of finerenone in the spectrum of cardiorenal diseases is based only on the results of studies conducted in patients with T2DM, and clinical trials of finerenone in patients with nondiabetic kidney disease are ongoing. Nonsteroidal MRAs hold significant potential as pivotal treatment targets across the cardiorenal disease spectrum. This review will focus on the effects of finerenone on cardiorenal disease.

Mineralocorticoid receptor antagonists in cardiovascular translational biology.

This review examines the role of mineralocorticoid receptor antagonists (MRAs) in cardiovascular biology and the molecular mechanisms involved in mineralocorticoid receptor antagonism. The data discussed suggest that MRAs can play an important role in decreasing the impact of inflammation and fibrosis on cardiorenal outcomes. Evidence derived from major randomized clinical trials demonstrates that steroidal MRAs reduce mortality in patients with heart failure and reduced ejection fraction. Initial positive findings observed in patients with chronic kidney disease and type 2 diabetes (T2D) indicate the possible mechanisms of action of nonsteroidal MRAs, and the clinical benefits for patients with cardiorenal disease and T2D. This article supports the application of basic science concepts to expand our understanding of the molecular mechanisms of action involved in pathophysiology. This approach encourages the development of treatment options before diseases clinically manifest. Video Abstract: http://links.lww.com/CAEN/A42.

Eplerenone improves hyperglycemia and sympathetic excitation in chronic renocardiac syndrome in rats.

We aimed to assess the efficacy of eplerenone, a steroidal mineralocorticoid receptor antagonist known to reduce blood pressure and mitigate cardiovascular disease (CVD) progression, in retarding the progression of chronic kidney disease (CKD) and CVD in a rat model of type 4 cardiorenal syndrome (CRS). We grouped rats into four experimental categories: sham surgery, sham treatment with eplerenone, nephrectomy without eplerenone (Nx), and nephrectomy with eplerenone (Nx + EP). For the Nx + EP group, rats received five-sixths nephrectomy, inducing CKD and CVD conditions such as renal hypertension and hyperglycemia, and were then treated with eplerenone (100mg/kg/day, orally) over 4weeks after an initial 4-week observation period. Heart rate, blood pressure, blood sugar levels, and sympathetic nerve excitation were monitored biweekly. In addition, assessments of renal and cardiac tissues, including evaluation of renal tubulointerstitial injury, glomerular injury, and cardiomyocyte hypertrophy, were conducted at week 8. Eplerenone administration mitigated CKD and CVD progression in the Nx + EP group, evident by improved blood pressure (217.3 ± 5.4 versus 175.3 ± 5.6), blood sugar (121.8 ± 1.3 versus 145.6 ± 6.0) level, reduced sympathetic nerve excitation, and cardiomyocyte hypertrophy compared to the Nx group. However, renal tubulointerstitial injury, glomerular injury, and cardiovascular dysfunction, which were increased in rats with type 4 CRS, did not show significant changes with eplerenone treatment. Our study demonstrated that eplerenone treatment did not exacerbate type 4 CRS but improved blood pressure, blood sugar levels, sympathetic nerve excitation, and cardiomyocyte hypertrophy in this model.

Molecular pharmacology of mineralocorticoid receptor antagonists: The role of co-regulators

Mineralocorticoid receptor (MR) antagonists have shown remarkable benefits in the treatment of cardiovascular disease. However, their underutilization in clinical practice may be attributed to concerns regarding the risk of hyperkalemia. An ideal selective MR modulator would inhibit the detrimental effects of MR in non-epithelial cells of the cardiovascular system while sparing its physiological function in kidney epithelial cells, thereby reducing the risk of adverse events. To address this issue, a new generation of non-steroidal MR antagonists, including esaxereneone, balcinrenone, ocedurenone, and finerenone, has been developed with distinct molecular structures and pharmacology. They share a mechanism of action that is different from the previously developed steroidal MR antagonists, leading to altered co-regulator interaction, potentially involving conformational changes of the receptor. Interfering with MR co-regulator interaction or the co-regulator itself may enable selective targeting of downstream signaling cascades and – in the long term – lead to more personalized medicine.In this review article, we summarize what is currently known about the mechanisms of action of the different MR antagonists with a focus on MR co-factor interaction and what may be inferred from this for future developments.

Cardiorenal interactions in heart failure - insights from recent therapeutic advances.

Heart failure is a syndrome that may develop when cardiovascular disease progresses or is insufficiently treated and associated with a poor quality of life, high mortality rates and increased health care expenditures. Prevention and treatment of heart failure is therefore of utmost importance. New therapies in patients with cardiovascular disease have recently been shown to be effective in the prevention and sometimes treatment of heart failure, and additional research is underway. Specifically, in high risk patients with either (a combination of) diabetes, chronic kidney disease and/or heart failure, three specific drug classes (sodium glucose cotransporter 2 inhibitors (SGLT2i), glucagon like peptide 1 receptor agonists (GLP-1-RA) and non steroidal mineralocorticoid receptor antagonists (MRA)) have taken center stage in therapeutic approach for these high cardiovascular risk patients. The commonality of these drugs is the finding that they improve cardiovascular and renal endpoints across the cardiorenal continuum, SGTL2i have already proven effective in all subtypes of heart failure, while we await data on non steroidal MRA therapy in heart failure. The story may be different for GLP-1-RA in patients with established heart failure, but these drugs are effective in reducing cardiovascular events in patients with diabetes. Taken together, these new therapies advance the treatment and improve the associated outcomes of patients with cardiorenal disease and diabetes, with similar characteristics and effectiveness in different conditions.

Mineralocorticoid receptor antagonist use in chronic kidney disease with type 2 diabetes: a clinical practice document by the European Renal Best Practice (ERBP) board of the European Renal Association (ERA).

Chronic kidney disease (CKD) in individuals with type 2 diabetes (T2D) represents a major public health issue; it develops in about 30%-40% of patients with diabetes mellitus and is the most common cause of CKD worldwide. Patients with CKD and T2D are at high risk of both developing kidney failure and of cardiovascular events. Renin-angiotensin system (RAS) blockers were considered the cornerstone of treatment of albuminuric CKD in T2D for more than 20 years. However, the residual risk of progression to more advanced CKD stages under RAS blockade remains high, while in major studies with these agents in patients with CKD and T2D no significant reductions in cardiovascular events and mortality were evident. Steroidal mineralocorticoid receptor antagonists (MRAs) are known to reduce albuminuria in individuals on RAS monotherapy, but their wide clinical use has been curtailed by the significant risk of hyperkalemia and absence of trials with hard renal outcomes. In recent years, non-steroidal MRAs have received increasing interest due to their better pharmacologic profile. Finerenone, the first compound of this class, was shown to effectively reduce the progression of kidney disease and of cardiovascular outcomes in participants with T2D in phase 3 trials. This clinical practice document prepared from a task force of the European Renal Best Practice board summarizes current knowledge on the role of MRAs in the treatment of CKD in T2D aiming to support clinicians in decision-making and everyday management of patients with this condition.

The association between dual RAAS inhibition and risk of acute kidney injury and hyperkalemia in patients with diabetic kidney disease: a systematic review and meta-analysis.

Dual renin-angiotensin-aldosterone system (RAAS) blockade involves dual therapy with a combination of angiotensin-converting enzyme inhibitors (ACEis), angiotensin receptor blockers (ARBs), direct renin inhibitors (DRIs) or mineralocorticoid receptor antagonists (MRAs). It is hypothesized that dual RAAS blockade would result in a more complete inhibition of the RAAS cascade. However, large clinical trials on dual RAAS inhibition have shown increased risk of acute kidney injury (AKI) and hyperkalemia without additional benefit on mortality, cardiovascular events, or CKD progression compared to RAAS inhibitor monotherapy in patients with diabetic kidney disease (DKD). The development of newer, more selective non-steroidal MRAs as cardiorenal protective therapies has created a new opportunity for dual RAAS inhibition. We conducted a systematic review and meta-analysis of the risks of AKI and hyperkalemia with dual RAAS blockade in patients with DKD. This is a systematic review and meta-analysis of the randomized controlled trials (RCT) published from 2006 to May 30, 2022. Study population included adult patients with DKD receiving dual RAAS blockade. A total of 31 RCTs and 33048 patients were included in the systematic review. Pooled risk ratios (RRs) and 95% confidence intervals (CIs) were calculated using random effects. There were 208 AKI events in 2690 patients on ACEi+ARB versus 170 in 4264 patients with ACEi or ARB monotherapy (pooled RR 1.48, 95% CI: 1.23-1.39). There were 304 hyperkalemia events in 2818 patients on ACEi+ARB versus 208 in 4396 patients with ACEi or ARB monotherapy (pooled RR 1.97, 95% CI: 1.32-2.94). A non-steroidal MRA+ACEi or ARB showed no increase in the risk of AKI (pooled RR 0.97, 95% CI: 0.81-1.16) compared to ACEi or ARB monotherapy but had a 2-fold higher risk of hyperkalemia with 953 events in 7837 patients in dual therapy versus 454 events in 6895 patients in monotherapy (pooled RR 2.05, 95% CI: 1.84-2.28). A steroidal MRA+ACEi or ARB had a 5-fold higher risk of hyperkalemia with 28 events in 245 at risk in dual therapy versus 5 events in 248 at risk in monotherapy (pooled RR 5.42 95% CI: 2.15-13.67). Dual therapy with RAASi is associated with an increased risk of AKI and hyperkalemia compared to RAASi monotherapy. Conversely, dual therapy with RAAS inhibitors and non-steroidal MRAs have no additional risk of AKI but a similar risk of hyperkalemia, which is lower than dual therapy with RAAS inhibitors and steroidal MRAs.

Characterising the burden of chronic kidney disease among people with type 2 diabetes in England: a cohort study using the Clinical Practice Research Datalink

ObjectivesTo describe prevalence of chronic kidney disease (CKD), demographic and clinical characteristics, treatment patterns and rates of cardiovascular and renal complications for patients with type 2 diabetes (T2D) treated in...

Benefits of the Non-Steroidal Mineralocorticoid Receptor Antagonist Finerenone in Metabolic Syndrome-Related Heart Failure with Preserved Ejection Fraction.

The mineralocorticoid receptor (MR) plays an important role in the development of chronic kidney disease (CKD) and associated cardiovascular complications. Antagonizing the overactivation of the MR with MR antagonists (MRA) is a therapeutic option, but their use in patients with CKD is limited due to the associated risk of hyperkalemia. Finerenone is a non-steroidal MRA associated with an improved benefit-risk profile in comparison to steroidal MRAs. In this study, we decided to test whether finerenone improves renal and cardiac function in male hypertensive and diabetic ZSF1 rats as an established preclinical HFpEF model. Finerenone was administered at 10 mg/kg/day for 12 weeks. Cardiac function/hemodynamics were assessed in vivo. ZSF1 rats showed classical signs of CKD with increased BUN, UACR, hypertrophy, and fibrosis of the kidney together with characteristic signs of HFpEF including cardiac fibrosis, diastolic dysfunction, and decreased cardiac perfusion. Finerenone treatment did not impact kidney function but reduced renal hypertrophy and cardiac fibrosis. Interestingly, finerenone ameliorated diastolic dysfunction and cardiac perfusion in ZSF1 rats. In summary, we show for the first time that non-steroidal MR antagonism by finerenone attenuates cardiac diastolic dysfunction and improves cardiac perfusion in a preclinical HFpEF model. These cardiac benefits were found to be largely independent of renal benefits.

Potential Impact of Non-Steroidal Mineralocorticoid Receptor Antagonists in Cardiovascular Disease.

Inappropriate mineralocorticoid receptor (MR) activation in different cardiovascular cell types has deleterious effects on cardiac remodeling and function. Therefore, MR inhibition is a crucial pharmacological strategy to overcome cardiovascular dysfunction. Despite efficient blockade of MR with steroidal MR antagonists (MRAs), their clinical application is unsatisfactory due to the adverse effects. Newer non-steroidal MRAs with greater potency could be suitable for clinical application, especially in patients with type 2 diabetes mellitus and chronic kidney disease. Although clinical evidence has shown the beneficial effects of non-steroidal MRAs on cardiovascular outcomes in patients with heart failure with reduced ejection fraction, clinical trials are ongoing to evaluate the efficacy of heart failure with preserved ejection fraction. Therefore, comparative pharmacological characterization of non-steroidal MRAs over classic steroidal MRAs is crucial. Here, we summarize the pre-clinical evidence of non-steroidal MRAs, which suggests an improvement in cardiac dysfunction, as well as the underlying molecular mechanisms in animal models mimicking different clinical conditions. In addition, we discuss up-to-date information from clinical trials regarding the beneficial effects of non-steroidal MRAs on meaningful cardiovascular outcomes. Both pre-clinical and clinical evidence support treatment with non-steroidal MRAs in patients with cardiovascular disease.

PS-BPC07-2: EFFECTS OF MINERALOCORTICOID RECEPTOR ANTAGONISTS ON SEX HORMONES AND BODY COMPOSITION IN PATIENTS WITH PRIMARY ALDOSTERONISM

Objective: Mineralocorticoid receptor antagonists are frequently used for the treatment of primary aldosteronism. Steroidal mineralocorticoid receptor antagonists may have antagonistic actions on androgen receptors, agonistic actions on progesterone receptors, and antagonistic actions on mineralocorticoid receptors. Because anti-androgen effects may cause body fat accumulation and skeletal muscle atrophy, there are concerns that this drug may have adverse effects on body composition. Design and method: Therefore, in this randomized prospective study, we compared the adverse effects of spironolactone, a steroidal mineralocorticoid receptor antagonist, and esaxerenone, a nonsteroidal mineralocorticoid receptor antagonist, on sex hormone levels and body composition in patients with primary aldosteronism without severe renal dysfunction. Results: The serum concentration of free testosterone was significantly higher in the spironolactone group than in the esaxerenone group in both males and females. However, the levels of estradiol, progesterone, luteinizing hormone, and follicle-stimulating hormone did not significantly increase. Changes in body fat percentage and muscle mass rate were not significantly different between the two groups. No patient showed a serum potassium level > 6.0 mEq/L; however, serum potassium levels were significantly higher in the spironolactone group than in the esaxerenone group. Conclusions: These data indicate that spironolactone may have antagonistic effects on androgen receptors. Esaxerenone did not show any apparent adverse effects, suggesting that it can be safely used in patients with primary aldosteronism.

ME-1: ROLE OF MINERALOCORTICOID RECEPTOR BLOCKERS IN RESISTANT AND REFRACTORY HYPERTENSION

Resistant hypertension is defined as blood pressure (BP) that remains above goal in spite of compliance with full doses of 3 or more antihypertensive medications of different classes. Ideally, a thiazide-like diuretic should be included in this 3 drug regimen. Classically, the recommendation has been to add a mineralocorticoid receptor antagonist such as spironolactone or eplerenone to the regimen of these resistant hypertensive patients to gain BP control. The study that deserves major credit for establishing this practice is the Prevention And Treatment of Hypertension With Algorithm based therapY (PATHWAY) study (Williams B, et al. Lancet. 386:2059–2068, 2015). PATHWAY compared the mineralocorticoid receptor antagonist spironolactone to doxazosin and bisoprolol in patients with resistant hypertension and demonstrated that spironolactone was overwhelmingly more successful in controlling the patient's BP and was also very well tolerated. The results of PATHWAY established aldosterone antagonists as the best add-on therapy for patients with resistant hypertension. However, spironolactone and other steroidal mineralocorticoid receptor antagonists such as eplerenone do have major adverse effects which can limit their use. These include sex hormone-related adverse effects such as gynecomastia and breast tenderness in women and erectile dysfunction and feminization in men. A solution to this problem, which is currently under active development, is use of non-steroidal mineralocorticoid receptor antagonists such as esaxerenone and finerenone (Figure 1). These non-steroidal mineralocorticoid receptor antagonists are bulky molecules which bind to the mineralocorticoid receptors and effectively prevent their activation. Specifically, esaxerenone has been shown to be as effective as eplerenone in lowering BP and to be well tolerated in Japanese patients with essential hypertension. Esaxerenone also has no sex hormone-dependent adverse effects. The question now is whether the non-steroidal mineralocorticoid receptor antagonists are to be the answer for resistant and refractory hypertension. Figure 1. Molecular Structures of Steroids and MR Blockers Adapted from: Tezuka Y, Ito S. The time to reconsider mineralocorticoid receptor blocking strategy: Arrival of nonsteroidal mineralocorticoid receptor blockers. Curr Hypertens Rep. 2022 Jul;24(7):215–224. doi: 10.1007/s11906-022-01177-6.

Primary Aldosteronism and the Role of Mineralocorticoid Receptor Antagonists for the Heart and Kidneys.

Primary aldosteronism (PA) is the most common cause of secondary hypertension but is frequently underrecognized and undertreated. Patients with PA are at a markedly increased risk for target organ damage to the heart and kidneys. While patients with unilateral PA can be treated surgically, many patients with PA are not eligible or willing to undergo surgery. Steroidal mineralocorticoid receptor antagonists (MRAs) are highly effective for treating PA and reducing the risk of target organ damage. However, steroidal MRAs are often underprescribed and can be poorly tolerated by some patients due to side effects. Nonsteroidal MRAs reduce adverse renal and cardiovascular outcomes among patients with diabetic kidney disease and are bettertolerated than steroidal MRAs. While their blood pressure-lowering effects remain unclear, these agents may have a potential role in reducing target organ damage in patients with PA.

A comparative post hoc analysis of finerenone and spironolactone in resistant hypertension in moderate-to-advanced chronic kidney disease.

Mineralocorticoid receptor antagonists (MRAs) reduce systolic blood pressure (SBP) and increase serum potassium concentration ([K+]). This indirect comparison investigated any differences in SBP-lowering and hyperkalemia risk between finerenone, a nonsteroidal MRA, and the steroidal MRA spironolactone±a potassium binder. In FIDELITY (a pooled analysis of FIDELIO-DKD and FIGARO-DKD), a subgroup of patients with treatment-resistant hypertension (TRH) and chronic kidney disease meeting eligibility criteria of the AMBER trial were identified (FIDELITY-TRH). The main outcomes were mean change in SBP, incidence of serum [K+] ≥5.5mmol/L and hyperkalemia-associated treatment discontinuation. Results at ∼17weeks were compared with 12weeks from AMBER. In 624 FIDELITY-TRH patients and 295 AMBER patients, the least squares mean change in SBP (mmHg) from baseline was -7.1 for finerenone and -1.3 for placebo {between-group difference -5.74 [95% confidence interval (CI) -7.99 to -3.49], P<.0001} versus -11.7 for spironolactone+patiromer and -10.8 for spironolactone+placebo [between-group difference -1.0 (95% CI -4.4-2.4), P=.58]. The incidence of serum [K+] ≥5.5mmol/L was 12% for finerenone and 3% for placebo versus 35% with spironolactone+patiromer and 64% with spironolactone+placebo. Treatment discontinuation due to hyperkalemia was 0.3% for finerenone and 0% for placebo versus 7% for spironolactone+patiromer and 23% for spironolactone+placebo. In patients with TRH and chronic kidney disease compared with spironolactone with or without patiromer, finerenone was associated with a lower SBP reduction and lower risk of hyperkalemia and treatment discontinuation.Trial Registration: AMBER (NCT03071263), FIDELIO-DKD (NCT02540993), FIGARO-DKD (NCT02545049).

Steroidal or non-steroidal MRAs: should we still enable RAASi use through K binders?

Renin-angiotensin-aldosterone system inhibitors (RAASi) and mineralocorticoid receptor antagonists (MRAs) are important interventions to improve outcomes in patients with chronic kidney disease and heart failure, but their use is limited in some patients by the development of hyperkalemia. The risk of hyperkalemia may differ between agents, with one trial showing lower risk of hyperkalemia with the novel non-steroidal MRA finerenone compared with steroidal MRA spironolactone. Novel potassium binders, including patiromer and sodium zirconium cyclosilicate, are available interventions to manage hyperkalemia and enable continuation of RAASi and MRAs in patients who could benefit from these treatments. These agents bind free potassium ions in the lumen of the gastrointestinal tract to prevent the absorption of dietary potassium and increase potassium secretion. Several studies showed that potassium binders are effective compared with placebo for preventing hyperkalemia or steroidal MRA discontinuation, but none has evaluated whether this strategy impacts clinically important endpoints such as cardiovascular events. Due to this and other limitations related to cost, clinical availability, pill burden and patient selection, alternative potential strategies to mitigate hyperkalemia may be more practical. Conservative strategies include increased monitoring and use of loop or thiazide diuretics to increase urinary potassium excretion. Non-steroidal MRAs may have a lower risk of hyperkalemia than steroidal MRAs and have stronger anti-inflammatory and anti-fibrotic effects with resultant reduced risk of kidney disease progression. Sodium-glucose cotransporter-2 inhibitors also decrease hyperkalemia risk in patients on MRAs and decrease cardiovascular events and kidney disease progression. These may be better first-line interventions to obviate the need for potassium binders and offer additional benefits.

Evolution of Mineralocorticoid Receptor Antagonists in the Treatment of Chronic Kidney Disease Associated with Type 2 Diabetes Mellitus.

Chronic kidney disease (CKD) is one of the most frequent complications associated with type 2 diabetes mellitus (T2DM) and is also an independent risk factor for cardiovascular disease. The mineralocorticoid receptor (MR) is a nuclear receptor expressed in many tissue types, including kidney and heart. Aberrant and long-term activation of MR by aldosterone in patients with T2DM triggers detrimental effects (eg, inflammation and fibrosis) in these tissues. The suppression of aldosterone at the early stage of T2DM has been a therapeutic strategy for patients with T2DM-associated CKD. Although patients have been treated with renin–angiotensin system (RAS) blockers for decades, RAS blockers alone are not sufficient to prevent CKD progression. Steroidal MR antagonists (MRAs) have been used in combination with RAS blockers; however, undesired adverse effects have restricted their usage, prompting the development of nonsteroidal MRAs with better target specificity and safety profiles. Recently conducted studies, Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease (FIDELIO-DKD) and Finerenone in Reducing Cardiovascular Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD), have reported that finerenone, a nonsteroidal MRA, improves both renal and cardiovascular outcomes compared with placebo. In this article, we review the history of MRA development and discuss the possibility of its combination with other treatment options, such as sodium-glucose cotransporter 2 inhibitors, glucagon-like peptide–1 receptor agonists, and potassium binders for patients with T2DM-associated CKD.

Efficacy and safety of finerenone for treatment of diabetic kidney disease: current knowledge and future perspective

ABSTRACT Introduction Diabetic kidney disease (DKD) represents a leading cause of morbidity and mortality in subjects with diabetes and develops in more than one third of diabetic patients. Steroidal mineralocorticoid receptor antagonists (MRAs – eplerenone and spironolactone) reduce mortality in patients with heart failure with reduced ejection fraction (HFrEF). However, in clinical practice the use of steroidal MRAs is limited by the significant risk of hyperkalemia, especially in patients with impaired renal function. Finerenone, a novel nonsteroidal MRA, shows a higher selectivity and binding affinity for mineralocorticoid receptor (MR) compared to steroidal MRAs and has been shown to reduce chronic kidney disease (CKD) progression and cardiovascular mortality in patients with CKD and T2DM. Areas covered This review summarizes the current evidence on efficacy and safety of finerenone in the treatment of patients with CKD and T2DM, and discusses its mechanisms of action investigated in preclinical studies. Expert opinion Pharmacological properties of finerenone and its unique tissue distribution are responsible for a lower risk of hyperkalemia. Therefore, finerenone represents a valuable therapeutic tool in patients with CKD/diabetic kidney disease (DKD). Recent studies have shown that finerenone delays the progression of CKD and reduce cardiovascular events in patients with DKD, highlighting its safety and efficacy in this high-risk population.