Effects Of Mineralocorticoid Receptor Antagonists Research Articles

Comparison of eplerenone and spironolactone treatment in patients with ischemic heart disease hospitalized due to ventricular tachycardia

Abstract Background The beneficial effects of mineralocorticoid receptor antagonists (MRAs) regarding sudden cardiac death (SCD) risk and cardiac remodeling are well known, moreover, they also reduce episodes of ventricular tachycardia (VT). However, superiority in effectiveness between receptor selective eplerenone and conventional spironolactone is unknown. Purpose Our aim was to assess the effect of eplerenone and spironolactone on ventricular tachycardia (VT) recurrence in patients with ischemic heart disease (IHD). Methods We collected data of 563 patients with IHD following hospitalization due to a sustained VT episode in a structured registry. Propensity score matching was performed based on age, hypertension, diabetes, history of acute myocardial infarction, left ventricular ejection fraction (LVEF) and presentation with incessant VT. The matched population consisted of 188 patients and was further analyzed. Predictors were assessed using univariate and multivariate Cox regression models. Kaplan-Meier curves were used for time-to-event analyses. Results The median age was 70 years with 81% being male. One third of the patients had an ICD implanted, while 43 (23%) had CRT. The median LVEF was 30%. Twenty-five (13%) patients presented with an electrical storm and 19 (10%) had incessant VT. In 86 cases (46%), the VT caused hemodynamic instability. Ablation was performed in 66 patients (35%), while 4 required mechanical circulatory support. During the median follow-up of 856 [399-1624] days, 69 patients had VT recurrence and 118 patients died. Eplerenone use significantly reduced the risk of VT recurrence compared to spironolactone (HR: 0.48 [0.29-0.78], log-rank p=0.003). This effect was consistent in the multivariate model as well (p=0.006). Conclusions Eplerenone use may be more beneficial in terms of VT recurrence in patients with IHD who present with a sustained VT. Further analysis is required to confirm these findings.

Prediction of endogenous mineralocorticoid receptor activity by depressor effects of mineralocorticoid receptor antagonists in patients with primary aldosteronism

Prediction of endogenous mineralocorticoid receptor activity by depressor effects of mineralocorticoid receptor antagonists in patients with primary aldosteronism

Prediction of endogenous mineralocorticoid receptor activity by depressor effects of mineralocorticoid receptor antagonists in patients with primary aldosteronism.

Patients with primary aldosteronism have an increased risk of developing cardiovascular disease. The response to mineralocorticoid receptor antagonists varies among individuals, indicating diverse mineralocorticoid receptor activities in these patients. This study explored the factors linked to the efficacy of blood pressure reduction through mineralocorticoid receptor antagonists in patients with primary aldosteronism. We examined the relationship between the reduction in blood pressure and patient characteristics in a group of 41 patients with primary aldosteronism (24 males, mean age 55 ± 13 years, including 34 patients diagnosed with bilateral primary aldosteronism) before and after undergoing treatment with mineralocorticoid receptor antagonists. Significant reductions in office blood pressure were observed 3 and 6 months after treatment initiation. Single correlation analyses showed that the urinary chloride-to-potassium ratio displayed the strongest positive association with blood pressure reduction, surpassing plasma aldosterone concentration, plasma renin activity, and urinary sodium-to-potassium ratio, at 3 and 6 months. Multiple correlation analyses revealed a consistent and independent positive correlation between the urinary chloride-to-potassium ratio and blood pressure reduction at 3 and 6 months. The optimal threshold for the urinary chloride-to-potassium ratio with respect to its ability to lower blood pressure, was determined as 3.18. These results imply that the urinary chloride-to-potassium ratio may be independently associated with the effectiveness of blood pressure reduction facilitated by mineralocorticoid receptor antagonists. Moreover, it could potentially serve as a valuable predictor of the effectiveness of these agents and function as an indicator of endogenous mineralocorticoid receptor activity in patients with primary aldosteronism.

Comprehensive characterization of the effect of mineralocorticoid receptor antagonism with spironolactone on the renin-angiotensin-aldosterone system in healthy dogs.

To characterize the dose-exposure-response effect of spironolactone on biomarkers of the classical and alternative arms of the renin-angiotensin-aldosterone system (RAAS) in healthy dogs. Ten healthy purpose-bred Beagle dogs. Study dogs were randomly allocated to 2 spironolactone dosing groups (2 mg/kg PO q24hr, 4 mg/kg PO q24hr). The dogs received 7-day courses of spironolactone followed by a 14-day washout period in a crossover (AB/BA) design. Angiotensin peptides and aldosterone were measured in serum using equilibrium analysis, and plasma canrenone and 7-α-thiomethyl spironolactone (TMS) were quantified via liquid chromatography-mass spectrometry/mass spectroscopy (LC-MS/MS). Study results were compared before and after dosing and between groups. Following spironolactone treatment, dogs had a significant increase in serum aldosterone concentration (P = 0.07), with no statistical differences between dosing groups. Significant increases in angiotensin II (P = 0.09), angiotensin I (P = 0.08), angiotensin 1-5 (P = 0.08), and a surrogate marker for plasma renin activity (P = 0.06) were detected compared to baseline following spironolactone treatment during the second treatment period only. Overall, changes from baseline did not significantly differ between spironolactone dosages. RAAS analytes were weakly correlated (R < 0.4) with spironolactone dosage and plasma canrenone or plasma TMS. There were no adverse clinical or biochemical effects seen at any spironolactone dosage during treatment. Treatment with spironolactone increased serum aldosterone concentration in healthy dogs and impacted other biomarkers of the classical and alternative arms of the RAAS. There was no difference in effect on the RAAS between 2 and 4 mg/kg/day dosing. Dosage of 4 mg/kg/day was safe and well-tolerated in healthy dogs.

Spironolactone improves left atrial function and atrioventricular coupling in patients with resistant hypertension.

To determine the blood pressure independent effects of spironolactone on left atrial (LA) size and function in patients with resistant hypertension (RHTN). Patients with RHTN (n = 36, mean age 55 ± 7) were prospectively recruited. Spironolactone was initiated at 25mg/day and increased to 50mg/day after 4 weeks. Other antihypertensives were withdrawn to maintain constant blood pressure. Cardiac magnetic resonance imaging was performed at baseline and after 6 months of spironolactone treatment and changes in LA functional metrics were assessed. LA size and function parameters were improved (p < 0.05) from baseline to month-6: LA volumes indexed to body surface area (LAVI) were reduced (LAVImaximum 41.4±12 vs. 33.2±9.7 mL/m2; LAVIpre-A 32.6±9.8 vs. 25.6±8.1 mL/m2; median LAVIminimum 18.5 [13.9-24.8] vs. 14.1 [10.9-19.2] mL/m2); left atrioventricular coupling index was reduced (28.2±11.5 vs. 22.7±9.2%); LA emptying fractions (LAEF) were increased (median total LAEF 52.4 [48.7-60.3] vs. 55.9 [50.3-61.1] %; active LAEF 40.2±8.6 vs. 43.1±7.8%). LA global longitudinal strain in the active phase was increased (16.3±4.1 vs. 17.8±4.2%). The effect of spironolactone was similar in patients with high (N = 18) and normal (N = 18) aldosterone status (defined by plasma renin activity and 24-h urine aldosterone). Treatment of RHTN with spironolactone is associated with improvements in LA size and function, and atrioventricular coupling, regardless of whether aldosterone levels were normal or high at baseline. This study suggests the need for larger prospective studies examining effects of mineralocorticoid receptor antagonists on atrial function and atrioventricular coupling.

Renoprotective Effects of Mineralocorticoid Receptor Antagonists Against Diabetic Kidney Disease.

Diabetic kidney disease (DKD) is a growing epidemic worldwide and a leading cause of end-stage kidney disease. Mineralocorticoid receptor (MR) blockade using Finerenone is a recently approved therapeutic approach to slow down the progression of DKD in patients with type 2 diabetes in addition to other therapies such as angiotensin-II converting enzyme inhibitors (ACEIs), angiotensin II receptor blockers (ARBs), sodium-glucose co-transporter 2 (SGLT2) inhibitors, and glucagon-like peptide 1 (GLP-1) analogs. This review elaborates on the pathophysiologic pathways activated by aldosterone (the human mineralocorticoid) in DKD, the pharmacology of three different generations of mineralocorticoid receptor antagonists (MRAs), specifically, spironolactone, eplerenone, and finerenone, and the mechanisms by which these MRAs elicit their protective effects on the kidney under diabetic settings.

Reversal of arterial stiffness in medically and surgically treated unilateral primary aldosteronism.

Hyperaldosteronism has adverse effects on cardiovascular structure and function. Laparoscopic adrenalectomy is the gold standard for patients with unilateral primary aldosteronism. For unilateral primary aldosteronism patients unable or unwilling to undergo surgery, the effects of mineralocorticoid receptor antagonists (MRAs) on the reversibility of arterial stiffness and other clinical data remain unclear. We aimed to compare the reversibility of arterial stiffness using pulse wave velocity (PWV) and other clinical parameters between surgically and medically treated unilateral primary aldosteronism patients. We prospectively enrolled 306 unilateral primary aldosteronism patients, of whom 247 received adrenalectomy and 59 received medical treatment with MRAs. Detailed medical history, basic biochemistry and PWV data were collected in both groups before treatment and 1 year after treatment. After propensity score matching (PSM) for age, sex, SBP and DBPs, 149 patients receiving adrenalectomy and 54 patients receiving MRAs were included for further analysis. After PSM, the patients receiving adrenalectomy had a greater reduction in blood pressure, increase in serum potassium, and change in PWV (ΔPWV, -53 ± 113 vs. -10 ± 140 cm/s, P = 0.028) than those receiving MRAs 1 year after treatment. Multivariable regression analysis further identified that surgery (compared with MRA treatment), baseline PWV, baseline DBP, the change in DBP and the use of diuretics were independently correlated with ΔPWV. Adrenalectomy is superior to MRA treatment with regards to vascular remodeling when treating unilateral primary aldosteronism patients.

Abstract 17781: Spironolactone Improves Left Atrial Function and Atrioventricular Coupling in Resistant Hypertension

Purpose: To determine the blood pressure independent effects of spironolactone on left atrial (LA) size and function in patients with resistant hypertension (RHTN). Methods: Patients with RHTN (N=36, 55±7 years) were prospectively recruited. Spironolactone was initiated at 25 mg/day and increased to 50 mg/day after four weeks. Other antihypertensives were withdrawn to maintain constant blood pressure. Cardiac magnetic resonance imaging was performed at baseline and after six months of spironolactone treatment and changes in LA functional metrics were assessed (Figure 1). The statistical analysis was conducted using two-sided tests of significance. Results: LA size and function parameters improved from baseline to month-six: LA volumes indexed to body surface area (LAVI) were reduced (LAVI max 41.4±12 vs 33.2±9.7 ml/m 2 ; LAVI pre-A 32.6±9.8 vs 25.6±8.1 ml/m 2 ; LAVI min 18.5 [13.9 - 24.8] vs 14.1 [10.9 - 19.2] ml/m 2 ; all p &lt; 0.05); left atrioventricular coupling index was reduced (28.2±11.5 vs 22.7±9.2 %, p &lt; 0.05); LA emptying fractions (LAEF) were increased (total LAEF 52.4 [48.7 - 60.3] vs 55.9 [50.3 - 61.1] %; active LAEF 40.2±8.6 vs 43.1±7.8 %, both p &lt; 0.05). There was a substantial increase in reservoir strain (29.1 ± 8.5 % vs 30.9 ± 5.5 %, p = 0.068) whereas active strain was significantly increased from baseline (16.3 ± 4.1 % vs 17.8 ± 4.2 %, p &lt; 0.05). Changes in passive strain and strain rates were not statistically significant (p &gt; 0.1). The effect of spironolactone was similar in patients with high (N = 18) and normal (N = 18) aldosterone status (defined by plasma renin activity and 24-hour urine aldosterone). Conclusion: Treatment of RHTN with spironolactone is associated with improvements in LA size and function regardless of whether aldosterone levels were normal or high. This study suggests the need for larger prospective studies examining effects of mineralocorticoid receptor antagonists on atrial function and atrioventricular coupling.

The problem of timely diagnosis of primary hyperaldosteronism. Clinical case

A clinical case is presented of delayed diagnosis of primary hyperaldosteronism (PHA) due to aldosterone-producing adenoma. Suspicion of PHA arises in case of persistent combination of hypertension with hypokalemia of various severity, a specific neuromuscular syndrome, as well as a high risk of cardiomyopathy, heart failure, and deterioration of kidney function, which are not typical for banal hypertension. Unsatisfactory blood pressure control with a standard combination of pharmacotherapy, an unexpected positive effect of mineralocorticoid receptor antagonists, high blood pressure in young people, as well as a family history of early high blood pressure or stroke at a young age, paroxysmal course of hypertension itself increases the risk of PHA. For a long time, a disease in our patient was considered a banal hypertension, although the diagnostic hypothesis of PHA should appear immediately after severe neuromuscular syndrome, rapid progression of cardiomyopathy and clinically significant heart failure began to dominate in the clinical picture. A 44-year-old female patient came to the attention of rheumatologists with suspicion of inflammatory myopathy due to frequent episodes of muscle weakness whose origin remained unclear. Key complaints of pronounced paroxysmal generalized muscle weakness, especially in the limbs, numbness and paresthesias in the extremities, calf muscle cramps against the background of hypertension were regarded as a neuromuscular syndrome specific to PHA. The PHA hypothesis was supported by the presence of cardiomyopathy, heart failure, clinically significant hypokalemia, and elevated aldosterone level. Computed tomography of the retroperitoneal space confirmed the presence of adrenal adenoma. Unfortunately, with a delay, after 13 years of hypertension, the diagnosis of PHA against the background of aldosterone-producing adenoma was confirmed. Consultation with a surgeon endocrinologist was suggested, as well as administration of eplerenone 50 mg daily in combination with lercanidipine 20 mg daily. Already after 6 weeks of pharmacotherapy, a positive therapeutic effect was obtained regarding the control of hypertension, heart failure, and the severity of neuromuscular syndrome. The differential diagnosis of secondary endocrine hypertension can be successful only with the possession of skills for early clinical detection of endocrine pathology, even in subclinical disease presentation. The diagnosis of PHA makes it possible to offer a patient radical surgical treatment, as well as to choose optimal approaches to pharmacotherapy.

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.

The impact of heart failure therapy in patients with mildly reduced ejection fraction: a network meta-analysis.

Recent heart failure (HF) guidelines have re-classified HF patients with left ventricular ejection fraction (LVEF) between 41% and 49% as HF with mildly reduced ejection fraction (HFmrEF). HFmrEF treatment is often considered a grey zone as no randomized controlled trials (RCTs) were conducted exclusively on these patients. A network meta-analysis (NMA) was performed to compare treatment effect of mineralocorticoid receptor antagonists (MRA), angiotensin receptor neprilysin inhibitor (ARNi), angiotensin receptor blockers (ARB), angiotensin-converting-enzyme inhibitors (ACEi), sodium-glucose cotransporter-2 inhibitors (SGLT2i), and beta-blockers (BB) in HFmrEF cardiovascular (CV) outcomes. RCTs sub-analyses evaluating the efficacy of pharmacological treatment in HFmrEF patients were searched. Hazard ratios (HRs) and their variance were extracted from each RCT for (i) composite of CV death or HF hospitalizations, (ii) CV death, and (iii) HF hospitalizations. A random-effects NMA was performed to compare and assess the treatment efficiency. Six RCTs with subgroup analysis according to participants' ejection fraction, a patient-level pooled meta-analysis of two RCTs, and an individual patient-level analysis of eleven BB RCTs were included, totalling 7966 patients. To our primary endpoint, SGLT2i vs. placebo was the only comparison with significant results, with a 19% risk reduction in the composite of CV death or HF hospitalizations [HR 0.81, 95% confidence interval (CI) 0.67-0.98]. In HF hospitalizations, the impact of the pharmacological therapies was more notorious, and ARNi reduced in 40% the risk of HF hospitalizations (HR 0.60, 95% CI 0.39-0.92), SGLT2i in 26% (HR 0.74, 95% CI 0.59-0.93) and renin-angiotensin system inhibition (RASi) with ARB and ACEi in 28% (HR 0.72, 95% CI 0.53-0.98). Although BBs were globally less beneficial, they were the only class that supported a reduced risk of CV death (HR vs. placebo: 0.48, 95% CI 0.24-0.95). We did not observe a statistically significant difference in any comparison between active treatments. There was a sound reduction with ARNi on the primary endpoint (HR vs. BB: 0.81, 95% CI 0.47-1.41; HR vs. MRA 0.94, 95% CI 0.53-1.66) and on HF hospitalizations (HR vs. RASi 0.83, 95% CI 0.62-1.11; HR vs. SGLT2i 0.80, 95% CI 0.50-1.30). In addition to SGLT2i, pharmacological treatment recommended for HF with reduced LVEF, namely, ARNi, MRA, and BB, can also be effective in HFmrEF. This NMA did not show significant superiority over any pharmacological class.

Effects of Mineralocorticoid Receptor Antagonists in Early-Stage Heart Failure With Preserved Ejection Fraction

BackgroundHospitalization with a first episode of heart failure (HF) is a serious event associated with poor clinical outcomes in HF with preserved ejection fraction (HFpEF). Identification of HFpEF via detection of elevated left ventricular filling pressure at rest or during exercise may allow early intervention. Benefits of treatment with mineralocorticoid receptor antagonists (MRAs) in established HFpEF have been reported, but use of MRAs is not well studied in early HFpEF without prior HF hospitalization. MethodsWe retrospectively studied 197 patients with HFpEF who did not have prior hospitalization but had been diagnosed by exercise stress echocardiography or catheterization. We examined changes in natriuretic peptide levels and echocardiographic parameters reflecting diastolic function following MRA initiation. ResultsOf the 197 patients with HFpEF, MRA treatment was initiated for 47 patients. After a median 3-month follow-up, reduction in N-terminal pro-B-type natriuretic peptide levels from baseline to follow-up was greater in patients treated with MRA than in those who were not (median, -200 pg/mL [interquartile range, -544 to -31] vs 67 pg/mL [interquartile range, -95 to 456], P < 0.0001 in 50 patients with paired data). Similar results were observed for the changes in B-type natriuretic peptide levels. Reduction in the left atrial volume index was also greater in the MRA-treated group than in the non-MRA-treated group after a median 7-month follow-up (77 patients with paired echocardiographic data). Patients with lower left ventricular global longitudinal strain experienced a greater reduction in N-terminal pro-B-type natriuretic peptide levels following MRA treatment. In the safety assessment, MRA modestly decreased renal function but did not change potassium levels. ConclusionsOur results suggest that MRA treatment has potential benefits for early-stage HFpEF.

Effects of sodium-glucose cotransporter 2 inhibitors, mineralocorticoid receptor antagonists, and their combination on albuminuria in diabetic patients.

Diabetes mellitus (DM) is the leading cause of chronic kidney disease. Albuminuria is associated with an increased risk of cardiovascular mortality. Sodium-glucose cotransporter 2 inhibitors (SGLT2-Is) and mineralocorticoid receptor antagonists (MRAs) protect against albuminuria; however, their combined effects on albuminuria are unclear. We performed a network meta-analysis to investigate the effects of SGLT2-Is, MRAs and their combination on albuminuria in type 2 DM. We systematically searched PubMed, Medline, EMBASE and the Cochrane Library from inception up to 20 November 2022. We selected randomized control and crossover trials that compared MRAs, SGLT2-Is, MRAs + SGLT2-Is, or a placebo in patients with type 2 DM with a urinary albumin-creatinine ratio (UACR) ≥30 mg/g creatinine. The primary outcome was the change in the UACR. This meta-analysis analysed 17 studies with 34 412 patients. The use of combination treatment with SGLT2-Is and MRAs was associated with lower albuminuria compared with the use of SGLT2-Is, MRAs, or the placebo alone [mean difference (95% CI): -34.19 (-27.30; -41.08), -32.25 (-24.53; -39.97) and -65.22 (-57.97; -72.47), respectively]. Treatment with SGLT2-Is or MRAs alone caused a significant reduction in UACR compared with the placebo [mean difference (95% CI): -31.03 (-28.35; -33.72) and -32.97 (-29.68; -36.27), respectively]. The effects of MRAs on the UACR are comparable with those of SGLT2-Is. Sensitivity analyses showed similar results. Combination therapy with SGLT2-Is and MRAs was associated with lower albuminuria in patients with type 2 DM compared with monotherapy with SGLT2-Is or MRAs alone.

The effects of mineralocorticoid receptor antagonists on cardiovascular outcomes in patients with end-stage renal disease and heart failure.

Mineralocorticoid receptor antagonists (MRAs) have been shown to provide survival benefits in patients with heart failure; however, MRA use in patients with chronic kidney disease has been limited by safety concerns. The effects of MRAs on outcomes in patients with end-stage renal disease (ESRD) and heart failure remain unknown. The aim of this study was to evaluate the effects of MRAs on cardiovascular outcomes in patients with heart failure under maintenance dialysis in a real-world setting. A retrospective cohort study was conducted by collecting data from the Taiwan National Health Insurance Research Database (NHIRD). Patients diagnosed with heart failure and ESRD and who started maintenance dialysis between 1 January 2001 and 31 December 2013 were identified. Patients were grouped according to MRA prescription. The outcomes of interest included cardiovascular (CV) death, hospitalization for heart failure (HHF), all-cause mortality, acute myocardial infarction (AMI), ischaemic stroke, any coronary revascularization procedures, and new-onset hyperkalaemia. Propensity score matching was performed at a 1:3 ratio between MRA users and non-users to minimize selection bias. A total of 50 872 patients who satisfied our inclusion and exclusion criteria were identified. After 1:3 matching, 2176 patients were included in the MRA group, and 6528 patients were included in the non-MRA group. The risk of CV death was significantly lower among patients who received MRAs than those who did not (hazard ratio [HR] 0.88, 95% confidence interval [CI] 0.80-0.95), as was the risk of all-cause mortality (HR 0.88, 95% CI 0.83-0.94). Reductions in the risks of CV death and all-cause mortality were more prominent among patients undergoing haemodialysis and those with coronary artery disease. In patients undergoing regular dialysis who are diagnosed with heart failure, the use of MRAs is associated with lower risks of all-cause mortality and CV death. The benefits of MRA treatment in heart failure may persist in patients with ESRD. Further investigations through randomized controlled trials are needed to assess the efficacy and safety of MRAs in this high-risk population.

Association of Finerenone Use With Reduction in Treatment-Emergent Pneumonia and COVID-19 Adverse Events Among Patients With Type 2 Diabetes and Chronic Kidney Disease

Patients with chronic kidney disease and type 2 diabetes have a higher risk of developing pneumonia as well as an increased risk of severe COVID-19-associated adverse events and mortality. Therefore, the anti-inflammatory effects of mineralocorticoid receptor antagonists via blockade of the mineralocorticoid receptor may alter the risk of pneumonia and COVID-19-associated adverse events in patients with chronic kidney disease and type 2 diabetes. To evaluate whether the selective, nonsteroidal mineralocorticoid receptor antagonist finerenone is associated with protection against pneumonia and COVID-19 adverse events in patients with type 2 diabetes and chronic kidney disease. This secondary analysis used patient-level data from FIDELITY, a prespecified pooled analysis of 2 multicenter, double-blind, placebo-controlled, event-driven, phase 3 randomized clinical trials: FIDELIO-DKD and FIGARO-DKD, conducted between September 2015 and February 2021. Patients in FIDELIO-DKD or FIGARO-DKD with type 2 diabetes and chronic kidney disease (urine albumin to creatine ratio, 30-5000 mg/g, estimated glomerular filtration rate ≥25 mL/min/1.73 m2) were assessed. Data were analyzed from May 15, 2021, to July 28, 2022. Patients were randomized to finerenone (10 or 20 mg once daily) or matching placebo. The main outcomes were investigator-reported incidences of treatment-emergent infective pneumonia adverse events and serious adverse events (during and up to 3 days after treatment) and any COVID-19 adverse events. Of 13 026 randomized patients (mean [SD] age, 64.8 [9.5] years; 9088 [69.8%] men), 12 999 were included in the FIDELITY safety population (6510 patients receiving finerenone; 6489 patients receiving placebo). Over a median (range) treatment duration of 2.6 (0-5.1) years, finerenone was consistently associated with reduced risk of pneumonia and serious pneumonia vs placebo. Overall, 307 patients (4.7%) treated with finerenone and 434 patients (6.7%) treated with placebo experienced pneumonia (hazard ratio [HR], 0.71; 95% CI, 0.64-0.79; P < .001). Serious pneumonia occurred in 171 patients (2.6%) treated with finerenone and 250 patients (3.9%) treated with placebo (HR, 0.69; 95% CI, 0.60-0.79; P < .001). Incidence proportions of COVID-19 adverse events were 86 patients (1.3%) in the finerenone group and 118 patients (1.8%) in the placebo group (HR, 0.73; 95% CI, 0.60-0.89; P = .002). These findings suggest that mineralocorticoid receptor blockade with finerenone was associated with protection against pneumonia and COVID-19 adverse events in patients with type 2 diabetes and chronic kidney disease. Further clinical studies may be warranted. ClinicalTrials.gov identifiers: FIDELIO-DKD: NCT02540993; FIGARO-DKD: NCT02545049.

Aldosterone as a Mediator of Cardiovascular Damage.

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.

Effect of mineralocorticoid receptor antagonist at baseline on the efficacy of sodium-glucose cotransporter-2 inhibitors in patients with heart failure: a meta-analysis of randomized controlled trials.

Effect of mineralocorticoid receptor antagonist at baseline on the efficacy of sodium-glucose cotransporter-2 inhibitors in patients with heart failure: a meta-analysis of randomized controlled trials.

The Mineralocorticoid Receptor: An Emerging Pharmacotherapeutic Target for Alcohol Use Disorder?

Despite the high prevalence and negative consequences associated with alcohol use disorder (AUD), currently available pharmacotherapies are limited in number and efficacy. Several neuroendocrine pathways have been identified and are under investigation as potential pharmacotherapeutic targets for AUD. Here, we present the promise of the mineralocorticoid receptor (MR) as a novel target and discuss associations between the aldosterone/MR system and AUD, the effects of MR antagonism on alcohol consumption, and the underlying neurobiology of these effects.

Association between Mineralocorticoid Receptor Antagonist and Mortality in SARS-CoV-2 Patients: A Systematic Review and Meta-Analysis.

Since the onset of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, various potential targeted therapies for SARS-CoV-2 infection have been proposed. The protective effects of mineralocorticoid receptor antagonists (MRA) against tissue fibrosis, pulmonary and systemic vasoconstriction, and inflammation have been implicated in potentially attenuating the severity of SARS-CoV-2 infection by inhibiting the deleterious effects of aldosterone. Furthermore, spironolactone, a type of MRA, has been suggested to have a beneficial effect on SARS-CoV-2 outcomes through its dual action as an MRA and antiandrogen, resulting in reduced transmembrane protease receptor serine type 2 (TMPRSS2)-related viral entry to host cells. In this study, we sought to investigate the association between MRA antagonist therapy and mortality in SARS-CoV-2 patients via systematic review and meta-analysis. The systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. MEDLINE and EMBASE databases were searched for studies that reported the incidence of mortality in patients on MRA with SARS-CoV-2 infection. Pooled odds ratio (OR) and 95% confidence interval (CI) of the outcome were obtained using the random-effects model. Five studies with a total of 1,388,178 subjects (80,903 subjects receiving MRA therapy) met the inclusion criteria. We included studies with all types of MRA therapy including spironolactone and canrenone and found no association between MRA therapy and mortality in SARS-CoV-2 infection (OR = 0.387, 95% CI: 0.134–1.117, p = 0.079).

Spironolactone and eplerenone are cardioprotective during early phase of ischemia in rats submitted to acute coronary occlusion

Introduction: Mineralocorticoid receptor antagonists (MRAs) are effective in reducing left ventricle remodeling and sudden death after acute myocardial infarction (AMI). Objectives: MRAs in vitro display cardioprotective effects, independent of MR; however, it is unknown whether the rapid effects of MRAs are cardioprotective in vivo. This study evaluated the acute effects of spironolactone and eplerenone in the first minutes of AMI. Methods: Wistar Rats, submitted or not to bilateral adrenalectomy, were treated orally with spironolactone (20 mg/kg) or eplerenone (10 mg/kg), and submitted to the left coronary ligation, under anesthesia. Electrocardiogram (ECG) recordings were obtained to evaluate ST-T segment, QT, and QTc intervals. Arterial pressure was also measured before (baseline) and after coronary ligation. Results: Spironolactone or eplerenone given, one hour before coronary ligation, prevented ST-T segment elevation in adrenalectomized and non-adrenalectomized. QT interval analysis showed that MRAs prevented its prolongation after coronary ligation. QT and QTc intervals remained similar to baseline and were smaller than the values displayed by the non-treated group. Animals treated with spironolactone, regardless of adrenalectomy, showed a 3-fold reduced mortality rates compared to the control group. Conclusion: MRAs display acute cardioprotective effects in early phase of AMI, which are independent of aldosterone.