Showing papers on "Spironolactone published in 2023"

Spironolactone as a Potential New Treatment to Prevent Arrhythmias in Arrhythmogenic Cardiomyopathy Cell Model

Abstract: Arrhythmogenic cardiomyopathy (ACM) is a rare genetic disease associated with ventricular arrhythmias in patients. The occurrence of these arrhythmias is due to direct electrophysiological remodeling of the cardiomyocytes, namely a reduction in the action potential duration (APD) and a disturbance of Ca2+ homeostasis. Interestingly, spironolactone (SP), a mineralocorticoid receptor antagonist, is known to block K+ channels and may reduce arrhythmias. Here, we assess the direct effect of SP and its metabolite canrenoic acid (CA) in cardiomyocytes derived from human-induced pluripotent stem cells (hiPSC-CMs) of a patient bearing a missense mutation (c.394C>T) in the DSC2 gene coding for desmocollin 2 and for the amino acid replacement of arginine by cysteine at position 132 (R132C). SP and CA corrected the APD in the muted cells (vs. the control) in linking to a normalization of the hERG and KCNQ1 K+ channel currents. In addition, SP and CA had a direct cellular effect on Ca2+ homeostasis. They reduced the amplitude and aberrant Ca2+ events. In conclusion, we show the direct beneficial effects of SP on the AP and Ca2+ homeostasis of DSC2-specific hiPSC-CMs. These results provide a rationale for a new therapeutical approach to tackle mechanical and electrical burdens in patients suffering from ACM.

Advances in Heart Failure with Preserved Ejection Fraction Management - The role of Sacubitril-Valsartan, Pirfenidone, Spironolactone and Empagliflozin: Is Success a Series of Small Victories?

Abstract: BACKGROUND Heart failure with preserved ejection fraction (HFpEF) is a syndrome characterized by marked heterogeneity in comorbidities and etiopathology substrates, leading to a diverse range of clinical manifestations and courses. Treatment options have been extremely limited and up to this day, there are virtually no pharmaceutical agents proven to reduce mortality in these patients. OBJECTIVE The primary objective of this narrative review is to critically summarize existing evidence regarding the use of Angiotensin Receptor-Neprilysin Inhibitor (ARNI), spironolactone, pirfenidone and empagliflozin in HFpEF. METHODS Medline (via PubMed) and Scopus were searched - from inception up to May 2022- using adequately selected keywords. Additional hand-search was also performed using the references of the articles identified as relevant (snowball strategy). RESULTS Angiotensin Receptor-Neprilysin Inhibitor (ARNI) and spironolactone, despite being very successful in HFrEF, did not do well in clinical trials of HFpEF, although there appear to be certain subsets of patients who may derive benefit. Data regarding pirfenidone are limited and come from small trials; as a result, it would be premature to draw firm conclusions, although it seems improbable that this agent will ever become a mainstay in the general population of HPpEF patients, while there may be a niche for the drug in individuals with comorbidities associated with an intense fibrotic activity. Finally, empagliflozin, largely welcomed as the first agent to have a "positive" randomized clinical trial in HFpEF, does not seem to evade the general pattern of reduced hospitalizations for HF with no substantial effect on mortality, seen in ARNI and spironolactone HFpEF trials. CONCLUSION Recent research in drug treatment for HFpEF has resulted in an overall mixed picture, with trials showing potential benefits from certain classes of drugs, such as sodium-glucose co-transporter 2 inhibitors, and no benefit from other drugs, which have shown to be effective in patient with reduced ejection fraction. However, small steps may be the way to go in HFpEF, and success is sometimes just a series of small victories.

An IL-6/STAT3/MR/FGF21 axis mediates heart-liver cross-talk after myocardial infarction

Abstract: The liver plays a protective role in myocardial infarction (MI). However, very little is known about the mechanisms. Here, we identify mineralocorticoid receptor (MR) as a pivotal nexus that conveys communications between the liver and the heart during MI. Hepatocyte MR deficiency and MR antagonist spironolactone both improve cardiac repair after MI through regulation on hepatic fibroblast growth factor 21 (FGF21), illustrating an MR/FGF21 axis that underlies the liver-to-heart protection against MI. In addition, an upstreaming acute interleukin-6 (IL-6)/signal transducer and activator of transcription 3 (STAT3) pathway transmits the heart-to-liver signal to suppress MR expression after MI. Hepatocyte Il6 receptor deficiency and Stat3 deficiency both aggravate cardiac injury through their regulation on the MR/FGF21 axis. Therefore, we have unveiled an IL-6/STAT3/MR/FGF21 signaling axis that mediates heart-liver cross-talk during MI. Targeting the signaling axis and the cross-talk could provide new strategies to treat MI and heart failure.

Finerenone: Efficacy of a New Nonsteroidal Mineralocorticoid Receptor Antagonist in Treatment of Patients With Chronic Kidney Disease and Type 2 Diabetes

Abstract: Mineralocorticoid receptor stimulation by aldosterone can cause various cardiovascular and renal disease complications. Finerenone is a new oral nonsteroidal mineralocorticoid receptor antagonist that has been approved for clinical use by the Federal Drug Aministration, and has been shown in clinical trials to reduce the risk of sustained estimated glomerular filtration rate decline, end-stage renal disease, nonfatal myocardial infarction, hospitalization for heart failure and cardiovascular death in adult patients with chronic kidney disease associated with type 2 diabetes. The drug has also been shown to have fewer side effects than the steroidal mineralocorticoid receptor antagonists like spironolactone and eplerenone. In this review article, the authors will discuss the clinical pharmacology of finerenone, its clinical application and the additional studies that are now underway to further assess the efficacy of the drug in diabetic patients having cardiac and renal disease.

Influence of SGLT2i and RAASi and Their Combination on Risk of Hyperkalemia in DKD: A Network Meta-Analysis

Abstract: This network meta-analysis investigated the effect of various combined regimens of sodium-glucose cotransporter-2 inhibitors (SGLT2is) and renin-angiotensin-aldosterone system inhibitors (RAASis) on the occurrence of hyperkalemia in diabetic kidney disease.The risk of hyperkalemia was compared using the random-effects model of network meta-analysis, with results expressed as odds ratios (ORs) with 95% confidence intervals (CIs). The comparative effects of all medications and their combinations with placebo were ranked using the surface under the cumulative ranking probabilities.In total, 27 eligible studies involving 43,589 participants with diabetic kidney disease were included. Major findings showed that the use of mineralocorticoid receptor antagonists (MRAs) on top of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) prominently increased hyperkalemia incidence when compared with placebo (OR, 6.08; 95% CI, 2.30 to 16.08), ACEI (OR, 3.07; 95% CI, 1.14 to 8.31), ARB (OR, 2.57; 95% CI, 1.10 to 6.02), SGLT2i (OR, 9.22; 95% CI, 2.99 to 28.46), renin inhibitors+ACEI/ARB (OR, 2.23; 95% CI, 1.14 to 4.36), or SGLT2i+ACEI/ARB (OR, 4.10; 95% CI, 2.32 to 7.26). Subgroup analysis among different generations of MRA found that spironolactone had the strongest effect in combination with ACEI/ARB, even higher than the combined use of ACEI and ARB (OR, 2.89; 95% CI, 1.26 to 6.63). In addition, SGLT2i had a significantly lower incidence of hyperkalemia compared with ACEI (OR, 0.33; 95% CI, 0.12 to 0.91), ARB (OR, 0.28; 95% CI, 0.13 to 0.61), dual RAASi (ACEI combined with ARB; OR, 0.17; 95% CI, 0.06 to 0.47), or MRA or renin inhibitors combined with ACEI/ARB (OR, 0.11; 95% CI, 0.04 to 0.33; OR, 0.24; 95% CI, 0.08 to 0.76, respectively.). Moreover, adding SGLT2i to the combination of MRA and ACEI/ARB, as well as the combinations of different RAASis, markedly reduced the occurrence of hyperkalemia.Among the therapeutic drugs with the potential risk of increasing serum potassium in patients with diabetic kidney disease, MRA added an extra risk of hyperkalemia while SGLT2i had the opposite effect and could even reverse the elevation of serum potassium caused by the combined regimen, including MRAs.

Spironolactone use for acne is not associated with an increased risk of venous thromboembolism: A matched, retrospective cohort study.

Abstract: To the Editor: Combined oral contraceptives (COCs) are associated with an increased risk of venous thromboembolism (VTE), and there have been concerns about whether the risk is even greater with drospirenone containing combined oral contraceptives. 1 Jick S.S. Hernandez R.K. Risk of non-fatal venous thromboembolism in women using oral contraceptives containing drospirenone compared with women using oral contraceptives containing levonorgestrel: case-control study using United States claims data. BMJ. 2011; 342: d2151 Crossref PubMed Scopus (211) Google Scholar Drospirenone has antimineralocorticoid properties that may modify hemostasis leading to decreased coagulability. This provides a potential mechanism by which drospirenone containing COCs could result in an increased risk of thrombosis compared to other COCs. Since drospirenone is molecularly related to spironolactone, it is possible that spironolactone might also be associated with an increased risk for VTE. The purpose of this study was to evaluate whether patients with acne treated with spironolactone are at increased risk for VTE.

Effectiveness of spironolactone for women with acne vulgaris (SAFA) in England and Wales: pragmatic, multicentre, phase 3, double blind, randomised controlled trial

Abstract: Abstract Objective To assess the effectiveness of oral spironolactone for acne vulgaris in adult women. Design Pragmatic, multicentre, phase 3, double blind, randomised controlled trial. Setting Primary and secondary healthcare, and advertising in the community and on social media in England and Wales. Participants Women (≥18 years) with facial acne for at least six months, judged to warrant oral antibiotics. Interventions Participants were randomly assigned (1:1) to either 50 mg/day spironolactone or matched placebo until week six, increasing to 100 mg/day spironolactone or placebo until week 24. Participants could continue using topical treatment. Main outcome measures Primary outcome was Acne-Specific Quality of Life (Acne-QoL) symptom subscale score at week 12 (range 0-30, where higher scores reflect improved QoL). Secondary outcomes were Acne-QoL at week 24, participant self-assessed improvement; investigator’s global assessment (IGA) for treatment success; and adverse reactions. Results From 5 June 2019 to 31 August 2021, 1267 women were assessed for eligibility, 410 were randomly assigned to the intervention (n=201) or control group (n=209) and 342 were included in the primary analysis (n=176 in the intervention group and n=166 in the control group). Baseline mean age was 29.2 years (standard deviation 7.2), 28 (7%) of 389 were from ethnicities other than white, with 46% mild, 40% moderate, and 13% severe acne. Mean Acne-QoL symptom scores at baseline were 13.2 (standard deviation 4.9) and at week 12 were 19.2 (6.1) for spironolactone and 12.9 (4.5) and 17.8 (5.6) for placebo (difference favouring spironolactone 1.27 (95% confidence interval 0.07 to 2.46), adjusted for baseline variables). Scores at week 24 were 21.2 (5.9) for spironolactone and 17.4 (5.8) for placebo (difference 3.45 (95% confidence interval 2.16 to 4.75), adjusted). More participants in the spironolactone group reported acne improvement than in the placebo group: no significant difference was reported at week 12 (72% v 68%, odds ratio 1.16 (95% confidence interval 0.70 to 1.91)) but significant difference was noted at week 24 (82% v 63%, 2.72 (1.50 to 4.93)). Treatment success (IGA classified) at week 12 was 31 (19%) of 168 given spironolactone and nine (6%) of 160 given placebo (5.18 (2.18 to 12.28)). Adverse reactions were slightly more common in the spironolactone group with more headaches reported (20% v 12%; p=0.02). No serious adverse reactions were reported. Conclusions Spironolactone improved outcomes compared with placebo, with greater differences at week 24 than week 12. Spironolactone is a useful alternative to oral antibiotics for women with acne. Trial registration ISRCTN12892056

Serum potassium level and mineralocorticoid receptor antagonist dose in a large cohort of chronic heart failure patients

Abstract: Hyperkalaemia is observed frequently in heart failure (HF) patients and is associated with an impaired prognosis and underuse of mineralocorticoid receptor antagonists (MRAs). However, the effects of serum potassium on prescription of the full guideline recommended daily dose of 50 mg in real‐world daily practice are unknown. Therefore, we investigated serum potassium and its association with the prescribed MRA dose in a large cohort of chronic HF patients.

Management of hypertension in obstructive sleep apnea

Abstract: Obstructive sleep apnea (OSA) plays an important role in the development of hypertension. Thus, this review summarizes pharmacological and non-pharmacological approaches to blood pressure (BP) control in patients with OSA. Current treatments for OSA, such as continuous positive airway pressure, are effective at lowering BP. However, they only provide a modest BP reduction, and pharmacological treatment remains important for achieving optimal BP control. Furthermore, current guidelines for the treatment of hypertension do not make specific recommendations on pharmacological treatment protocols for controlling BP in patients with OSA. Moreover, the BP-lowering effects of various classes of antihypertensives may be different in hypertensive patients with OSA than in those without OSA due to the underlying mechanisms that promote hypertension in OSA. The acute and chronic increase in sympathetic nerve activity in patients with OSA explain the effectiveness of beta blockers in controlling BP in these patients. As activation of the renin-angiotensin-aldosterone system may also promote hypertension in OSA, angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers have generally been found effective for lowering BP in hypertensive patients with OSA. The aldosterone antagonist spironolactone also produces a good antihypertensive response in patients with OSA and resistant hypertension. However, there are limited data available that compare the effects of various classes of antihypertensive medication on BP control in those with OSA, and most data have been obtained from small-scale studies. This demonstrates the need for large-scale randomized controlled trials to evaluate a range of BP-lowering regimens in patients with OSA and hypertension.

A machine learning derived echocardiographic algorithm identifies people at risk of heart failure with distinct cardiac structure, function, and response to spironolactone: findings from the HOMAGE trial.

Abstract: BACKGROUND An echocardiographic algorithm derived by machine learning (e'VM) characterizes preclinical individuals with different cardiac structure and function, biomarkers, and long-term risk of heart failure (HF). Our aim was the external validation of the e'VM algorithm and to explore whether it may identify subgroups who benefit from spironolactone. METHODS The HOMAGE (Heart OMics in Aging) trial enrolled participants at high risk of developing HF randomly assigned to spironolactone or placebo over 9 months. The e'VM algorithm was applied to 416 participants (mean age 74±7years, 25% women) with available echocardiographic variables (i.e., e' mean, left ventricular [LV] end-diastolic volume and mass indexed by body surface area [LVMi]). The effects of spironolactone on changes in echocardiographic and biomarker variables were assessed across e'VM phenotypes. RESULTS A majority (>80%) had either "diastolic changes (D)", or "diastolic changes with structural remodeling (D/S)" phenotype. D/S phenotype had the highest LVMi, left atrial volume, E/e', natriuretic peptide and troponin levels (all p<0.05). Spironolactone significantly reduced E/e' and b-type natriuretic peptide (BNP) levels in D/S phenotype (p<0.01), but not in other phenotypes (p>0.10; Pinteraction <0.05 for both). These interactions were not observed when considering guideline-recommended echocardiographic structural and functional abnormalities. The magnitude of effects of spironolactone on LVMi, left atrial volume and a type I collagen marker was numerically higher in D/S phenotype than D phenotype but the interaction test did not reach significance. CONCLUSIONS In the HOMAGE trial, the e'VM algorithm identified echocardiographic phenotypes with distinct responses to spironolactone as assessed by changes in E/e' and BNP. This article is protected by copyright. All rights reserved.

Amiodarone vs. metoprolol succinate in HFrEF complicated with persistent atrial fibrillation with rapid ventricular response: A prospective observational study

Abstract: Background β-blockers have been recommended for patients with heart failure (HF) and atrial fibrillation (AF), but studies have shown that β-blockers do not reduce all-cause mortality or cardiovascular mortality in patients with HF and AF. Objective To investigate the difference in efficacy between oral amiodarone and metoprolol succinate for patients with HF with reduced ejection fraction (HFrEF) and persistent atrial fibrillation (pAF) with rapid ventricular response (RVR). Methods Patients with HFrEF complicated with pAF with RVR treated in the People's Hospital of Chongqing Hechuan between March 2018 and March 2019 were enrolled in this prospective observational study. The primary outcomes were cardiovascular mortality and the first hospitalization for HF rate. The secondary outcomes were type B pro-brain natriuretic peptide (NT-proBNP) before/after treatment, left ventricular ejection fraction (LVEF) before/after treatment, average heart rate (AhR), and the rate of sinus rhythm after 1 year of follow-up. Results A total of 242 patients with HFrEF complicated with pAF with RVR were enrolled and divided into amiodarone + perindopril + spironolactone+ routine drug (amiodarone group, n = 121) and metoprolol succinate + perindopril + spironolactone +routine drug (metoprolol succinate group, n = 121) according to their treatment strategy. Cardiovascular mortality (4.9 vs. 12.4%, HR: 2.500, 95%CI: 1.002–6.237, P = 0.040) and first hospitalization for HF (52.9 vs. 67.8%, HR: 1.281, 95%CI: 1.033–1.589, P = 0.024) were significantly lower in the amiodarone group than in the metoprolol group. The mean ventricular rate in the amiodarone group was significantly lower than in the metoprolol group (64.5 ± 3.2 vs. 72.4 ± 4.2, P < 0.001). After 1 year of follow-up, the sinus rhythm rate was significantly higher in the amiodarone group than in the metoprolol group (38.8 vs. 7.4%, HR: 0.191, 95%CI: 0.098–0.374, P < 0.001). The difference in proBNP (3,914.88 vs. 2,558.07, P < 0.001) and LVEF (−6.89 vs. −0.98, P < 0.001) before and after treatment was significantly higher in the amiodarone group than in the metoprolol group. Conclusion In conclusion, in this prospective observational study, the amiodarone group had lower risk of cardiovascular death and the first hospitalization for HF than metoprolol in HFrEF and persistent atrial fibrillation (pAF) with RVR. The mechanism may be related to improved cardiac function, rhythm control and ventricular rate control. Registration number ChiCTR2200057816; Registered 7 March 2022–Retrospectively registered: http://www.medresman.org.cn/pub/cn/proj/projectshshow.aspx?proj=4222.

Combination of spironolactone and sitagliptin improves clinical outcomes of outpatients with COVID-19: a prospective cohort study.

Abstract: BACKGROUND There are evidences showing that sitagliptin and spironolactone can potentially improve the clinical outcomes of COVID-19 cases. In this observational study on acutely symptomatic outpatient COVID-19 cases, we investigated the effects of spironolactone and sitagliptin on the outcomes of the disease. METHODS This is a prospective, naturally randomized cohort study. We followed mild to moderate symptomatic COVID-19 patients, who were treated with either combination (spironolactone 100 mg daily and sitagliptin 100 mg daily) or standard (steroid, antiviral and/or supportive care) therapy up to 30 days. The primary outcome was hospitalization rate. The secondary outcomes included ER visit, duration of disease, and complications, such as hypoglycemia, low blood pressure or altered mental status. RESULTS Of the 206 patients referred to clinics randomly, 103 received standard therapy and 103 treated with combination therapy. There were no significant differences in baseline characteristics, except for slightly higher clinical score in control group (6.92 ± 4.01 control, 4.87 ± 2.92 combination; P < 0.0001). Treatment with combination therapy was associated with lower admission rate (5.8% combination, 22.3% control; P = 0.0011), ER visits (7.8% combination, 23.3% control; P = 0.0021) and average duration of symptoms (6.67 ± 2.30 days combination, 18.71 ± 6.49 days control; P ≤ 0.0001). CONCLUSIONS The combination of sitagliptin and spironolactone reduced duration of COVID infection and hospital visits better than standard therapeutic approaches in outpatients with COVID-19. The effects of combination of sitagliptin and spironolactone in COVID-19 patients should be further verified in a double-blind, randomized, placebo-controlled trial.

Js-ng-8: case report: possible new channelopathy associated with elevated aldosterone levels

Abstract: Background: Potassium channelopathies are associated with prolonged QT cardiac syndrome. New potassium channelopathies in somatic cells, including KCNJ5 mutations, also underlie some forms of primary hyperaldosteronism. We present a first-in-human report of an association between a KCNQ1 loss of function mutation manifesting with life threatening-ventricular tachycardia (VT), severe hypokalemia and presumed hyperaldosteronism. Case Presentation: The patient is a 51-year-old Asian woman known for obesity, Wolff-Parkinson-White post ablation, and recurrent syncopal episodes with polymorphic VT due to prolonged QTc, requiring an implantable cardioverter defibrillator. On initial presentation for syncope, spontaneous hypokalemia was discovered at 3.1 mmol/L. She had multiple hospitalizations for torsade storms and persistent hypokalemia resistant to aggressive potassium supplementation until addition of spironolactone. Investigations revealed a suppressed plasma renin activity < 0.05 ng/L/s, serum aldosterone concentration at 302 pmol/L, and an aldosterone to renin ratio (ARR) > 6040. Repeated ARR was > 10980. Confirmatory saline suppression testing or adrenal vein sampling were not performed due to risk of recurrent VT associated with spironolactone cessation. A comprehensive evaluation for the etiology of this patient's clinical presentation revealed a mutation in the KCNQ1 gene type 1. Literature review: The voltage-dependent K(+) channel responsible for activating delayed K(+) current is composed of pore-forming KCNQ1 and regulatory KCNE1/3 subunits which loss of function predispose to sustained torsade de pointes. Animal models demonstrate that KCNQ1 and KCNE1 mRNAs are expressed in the zona glomerulosa of adrenal glands where potassium channels directly participate in the control of aldosterone production. Although KCNE3 is not expressed in mouse adrenals, its deletion is thought to cause activation of lymphocytes targeting adrenal glands, leading to hyperaldosteronism. Furthermore, administration of spironolactone to KCNE3 knockout mice ameliorates their QT prolongation and predisposition to VT. There have been no case reports of an association between KCNQ1/E1/E3 loss of function and hyperaldosteronism in humans. Conclusion: This raises the question if this mechanism can also be a component of human KCNQ1 and KCNE1/3-linked arrhythmogenesis and hyperaldosteronism. Alternatively, we can further speculate that patients with hyperaldosteronism who develop malignant arrhythmias during hypokalemia are subjects with impaired repolarization reserve as a consequence of variants in genes known to cause long QT syndrome. The variants, leading to subclinical ion channel dysfunction, are typically silent until unmasked by electrolytes abnormalities such as hypokalemia. To our knowledge, this case is a first report of a potentially novel channelopathy associated with hyperaldosteronism in humans. These findings are hypothesis generating and require further investigations.

Data from A Preclinical Study to Repurpose Spironolactone for Enhancing Chemotherapy Response in Bladder Cancer

Abstract: <div>Abstract<p>Neoadjuvant chemotherapy (NAC) followed by radical cystectomy is the standard-of-care for patients with muscle-invasive bladder cancer (MIBC). Defects in nucleotide excision repair (NER) are associated with improved responses to NAC. Excision Repair Cross-Complementation group 3 (ERCC3) is a key component of NER process. No NER inhibitors are available for treating patients with bladder cancer. We have developed an <i>ex vivo</i> cell-based assay of 6–4 pyrimidine–pyrimidinone (6–4PP) removal as a surrogate measure of NER capacity in human bladder cancer cell lines. The protein expression of ERCC3 was examined in human MIBC specimens and cell lines. Small molecule inhibitors were screened for NER inhibition in bladder cancer cell lines. Spironolactone was identified as a potent NER inhibitor. Combined effects of spironolactone with chemo-drugs were evaluated <i>in vitro</i> and <i>in vivo</i>. The efficacy between platinum and spironolactone on cytotoxicity was determined by combination index. A correlation between NER capacity and cisplatin sensitivity was demonstrated in a series of bladder cancer cell lines. Further, siRNA-mediated knockdown of ERCC3 abrogated NER capacity and enhanced cisplatin cytotoxicity. Spironolactone inhibited ERCC3 protein expression, abrogated NER capacity, and increased platinum-induced cytotoxicity in bladder cancer cells <i>in vivo</i> and in patient-derived organoids. Moreover, spironolactone exhibited the potential synergism effects with other clinical chemotherapy regimens in bladder cancer cell lines. Our data support the notion of repurposing spironolactone for improving the chemotherapy response of NAC in patients with MIBC. Further clinical trials are warranted to determine the safety and efficacy of spironolactone in combination with chemotherapy.</p></div>

#3068 potassium levels and egfr do not predict severe hyperkalemia following spironolactone introduction in patients with ckd at high risk of hyperkalemia

Abstract: Mineralocorticoid receptor antagonists (MRA) reduce blood pressure, albuminuria and the rate of disease progression in patients with chronic kidney disease (CKD) and albuminuria. Despite these apparent benefits, only a very small fraction of patients with CKD are treated with an MRA. This may in part be due to the fear of hyperkalemia (HK), which in the most severe cases can cause life-threatening arrythmias. Indeed, international guidelines and previous studies have excluded patients believed to be at high risk of severe HK from treatment with MRA including patients with pre-existing high serum potassium. To examine if the risk of HK can in fact be predicted by baseline potassium levels or eGFR, we performed a clinical study testing the effect of introducing spironolactone on plasma potassium (P-K) levels in closely monitored, high-risk patients excluded from other studies. Secondly, we analyzed the effect of spironolactone on eGFR and albuminuria. We included patients with eGFR 25-60 ml/min/1.73 m2 on maximal tolerated RAAS-blockade (ACEi or ARB) and a history of at least two HK-episodes (P-K > 4.5mmol/l) within 24 months prior to inclusion. Following dietary counselling on avoidance of potassium-rich foods, spironolactone was initiated at 25 mg daily. If tolerated as defined by a decline in eGFR < 30%, a P-K ≤ 5.5mmol/l and the absence of severe hypotension, the dose was increased to 50 mg after two weeks. Total follow-up was four weeks measuring P-K, eGFR, blood pressure and spot urine albumin creatinine ratio. Results from maximal tolerated dose were compared to baseline using paired t-test. In a post-hoc analysis, patients were grouped based on the occurrence of severe HK (P-K > 5.5mmol/l) or not, and baseline characteristics and the change from baseline to maximal dose were compared using unpaired t-test. Linear regression model was used to test the association between baseline P-K vs. P-K at maximal dose of spironolactone and the change in P-K from baseline to maximal dose of spironolactone vs. baseline eGFR. Fifty-eight patients were included with a mean age of 65 years. Forty-seven were males and 23 had diabetes. Forty-eight patients reached a spironolactone dose of 50 mg. Following spironolactone introduction, mean eGFR declined from 39 at baseline to 34ml/min/1.73 m2 (p<0.001) and albuminuria was reduced from a median of 1276mg/g to 654 mg/g (49%; 95%CI: 44 – 54%) with no significant change in blood pressure. Mean P-K increased 0.5mmol/l (95% CI 0.3 - 0.7mmol/l) from 4.7mmol/l to 5.2mmol/l. Seventeen patients developed severe HK with a P-K > 5.5mmol/l and four were briefly admitted with a P-K > 6.2mmol/l. Importantly, there was no difference in baseline P-K nor eGFR in patients that developed severe HK when compared with those that did not (4.70 vs 4.67 mmol/L, p = 0.83 and 36.2 vs. 40.1 ml/min/1.73 m2, p = 0,13). Furthermore, baseline P-K did not correlate with P-K at maximum spironolactone dose (Figure 1) and the change in P-K did not significantly correlate with baseline eGFR (Figure 2). Short-term treatment with spironolactone in patients with CKD at high risk of HK leads to similar reductions in albuminuria and eGFR when compared with low-risk cohorts. With dietary counseling, 30% of patients will develop severe HK within 4 weeks. Importantly and contrary to common belief, neither baseline P-K levels nor baseline eGFR were associated with the development of severe HK. Thus, excluding patients from MRA treatment based solely on eGFR and P-K levels is not appropriate. Instead, we believe an empirical approach based on dietary counseling and close monitoring of P-K should be used.

Primary Aldosteronism in a Patient Treated With Spironolactone

Abstract: Mineralocorticoid receptor antagonists (MRAs) (e.g., spironolactone and eplerenone) prevent aldosterone from activating the receptor, resulting, sequentially, in sodium loss, a decrease in plasma volume, and an elevation in renin. If plasma renin activity (PRA) or plasma renin concentration (PRC) is not suppressed in a patient treated with a MRA, then no further primary aldosteronism (PA)-related testing can be performed and the MRA should be discontinued for 6 weeks before retesting. However, if the patient is hypokalemic despite treatment with a MRA, then the mineralocorticoid receptors are not fully blocked, and PRA or PRC should be suppressed in such a patient with PA. In addition, most patients with PA are treated with suboptimal dosages of MRAs, and the mineralocorticoid receptors are not fully blocked. Thus for case detection testing, blood pressure medications, including MRAs, should not be discontinued. In the setting of suppressed PRA or PRC, clinicians can proceed with case detection testing in all patients treated with MRAs, and the MRA does not need to be discontinued for confirmatory or subtype testing with adrenal venous sampling (AVS).

Association between spironolactone use and COVID-19 outcomes in population-scale claims data: a retrospective cohort study

Abstract: Background: Spironolactone has been proposed as a potential modulator of SARS-CoV-2 cellular entry. We aimed to measure the effect of spironolactone use on the risk of adverse outcomes following COVID-19 hospitalization. Methods: We performed a retrospective cohort study of COVID-19 outcomes for patients with or without exposure to spironolactone, using population-scale claims data from the Komodo Healthcare Map. We identified all patients with a hospital admission for COVID-19 in the study window, defining treatment status based on spironolactone prescription orders. The primary outcomes were progression to respiratory ventilation or mortality during the hospitalization. Odds ratios (OR) were estimated following either 1:1 propensity score matching (PSM) or multivariable regression. Subgroup analysis was performed based on age, gender, body mass index (BMI), and dominant SARS-CoV-2 variant. Findings: Among 898,303 eligible patients with a COVID-19-related hospitalization, 16,324 patients (1.8%) had a spironolactone prescription prior to hospitalization. 59,937 patients (6.7%) met the ventilation endpoint, and 26,515 patients (3.0%) met the mortality endpoint. Spironolactone use was associated with a significant reduction in odds of both ventilation (OR 0.82; 95% CI: 0.75-0.88; p < 0.001) and mortality (OR 0.88; 95% CI: 0.78-0.99; p = 0.033) in the PSM analysis, supported by the regression analysis. Spironolactone use was associated with significantly reduced odds of ventilation for all age groups, men, women, and non-obese patients, with the greatest protective effects in younger patients, men, and non-obese patients. Interpretation: Spironolactone use was associated with a protective effect against ventilation and mortality following COVID-19 infection, amounting to up to 64% of the protective effect of vaccination against ventilation and consistent with an androgen-dependent mechanism. The findings warrant initiation of large-scale randomized controlled trials to establish a potential therapeutic role for spironolactone in COVID-19 patients.

Combination therapy in female pattern hair loss.

Abstract: Patterned hair loss is a common type of non-scarring alopecia, characterized by miniaturization of hair follicles. The etiology of female pattern hair loss (FPHL) is not clearly linked to androgens or other hormones thereby making it a challenging condition to treat. Various treatment modalities, like minoxidil (topical or oral), spironolactone, finasteride, have been tried alone or in combination with variable results. Combination therapy is superior to the monotherapy, since these multiple treatment modalities act by targeting different pathogenetic pathways, making the treatment aggressive and more effective.

Integrative analysis of functional genomic screening and clinical data identifies a protective role for spironolactone in severe COVID-19

Abstract: We demonstrate that integrative analysis of CRISPR screening datasets enables network-based prioritization of prescription drugs modulating viral entry in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by developing a network-based approach called Rapid proXimity Guidance for Repurposing Investigational Drugs (RxGRID). We use our results to guide a propensity-score-matched, retrospective cohort study of 64,349 COVID-19 patients, showing that a top candidate drug, spironolactone, is associated with improved clinical prognosis, measured by intensive care unit (ICU) admission and mechanical ventilation rates. Finally, we show that spironolactone exerts a dose-dependent inhibitory effect on viral entry in human lung epithelial cells. Our RxGRID method presents a computational framework, implemented as an open-source software package, enabling genomics researchers to identify drugs likely to modulate a molecular phenotype of interest based on high-throughput screening data. Our results, derived from this method and supported by experimental and clinical analysis, add additional supporting evidence for a potential protective role of the potassium-sparing diuretic spironolactone in severe COVID-19.

Association between dosing of spironolactone and outcomes in heart failure with preserved ejection fraction patients combined with chronic kidney disease------Balance of efficacy and risk

Abstract: Aims: Few studies have compared the association between dosing of spironolactone and outcomes in patients with heart failure with preserved ejection fraction (HFpEF), and whether spironolactone dose could significantly affect the prognosis of HFpEF patients combined with chronic kidney disease (CKD) remains unclear. Our aim was to directly compare ‘high vs. low’ doses of spironolactone in an attempt to find a benefit-risk-balanced point, and infer an adequate dose for HFpEF with CKD patients. Methods: Overall, 4,321 symptomatic heart failure inpatients were initially screened from January 2013 to December 2019, and all enrolled patients were followed-up for 36 months; After including patients who meet the diagnostic criteria of HFpEF and CKD with ejection fraction > 45% and estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73 m2, a total of 387 patients was selected. Primary outcome was a composite of all-cause death, heart failure (HF) hospitalization and non-fatal stroke. The key safety outcome was hyperkalemia rates during the follow-up period. Results: The primary outcome event rates in patients with or without spironolactone were 12.74 and 21.45 per 100 person-years, respectively. Compared with patients not taking spironolactone, the adjusted hazard ratio (HR) [95% confidence interval (CI)] was 0.55 (0.38–0.79) with spironolactone group for primary outcomes. After grouped by the daily dose of spironolactone, low-dose group (≤ 40 mg) was associated with lower relative risk for the primary efficacy outcome [adjusted HR (95% CI) was 0.43 (0.23–0.81), 0.50 (0.33–0.76) and 0.74 (0.36–2.79) with < 40 mg, 40 mg and >40 mg, respectively]. During 3-year follow-up, the risk for hyperkalemia was amplified in the higher dose group (>40 mg) while showed no significant difference compared with low dose group (p = 0.425). Conclusion: HFpEF with CKD patients using spironolactone had lower risk of adverse cardiovascular outcomes. And the use of low-dose spironolactone (≤ 40 mg) showed the best efficacy and safety, therefore we may recommend ≤ 40 mg as the optimal initial dose for these patients. However, this was a relatively small sample size, retrospective study, and further adequately powered randomized trials are needed to verify these results.

Neutral Effect of Skeletal Muscle Mineralocorticoid Receptor on Glucose Metabolism in Mice

Abstract: The mineralocorticoid receptor (MR) is able to regulate the transcription of a number of genes in the myotube, although its roles in skeletal muscle (SM) metabolism still await demonstration. SM represents a major site for glucose uptake, and its metabolic derangements play a pivotal role in the development of insulin resistance (IR). The aim of this study was to investigate the contribution of SM MR in mediating derangements of glucose metabolism in a mouse model of diet-induced obesity. We observed that mice fed a high-fat diet (HFD mice) showed impaired glucose tolerance compared to mice fed a normal diet (ND mice). Mice fed a 60% HFD treated with the MR antagonist Spironolactone (HFD + Spiro) for 12 weeks revealed an improvement in glucose tolerance, as measured with an intraperitoneal glucose tolerance test, compared with HFD mice. To investigate if blockade of SM MR could contribute to the favorable metabolic effects observed with pharmacological MR antagonism, we analyzed MR expression in the gastrocnemius, showing that SM MR protein abundance is downregulated by HFD compared to ND mice and that pharmacological treatment with Spiro was able to partially revert this effect in HFD + Spiro mice. Differently from what we have observed in adipose tissue, where HDF increased adipocyte MR expression, SM MR protein was down-regulated in our experimental model, suggesting a completely different role of SM MR in the regulation of glucose metabolism. To confirm this hypothesis, we investigated the effects of MR blockade on insulin signaling in a cellular model of IRin C2C12 myocytes, which were treated with or without Spiro. We confirmed MR protein downregulation in insulin-resistant myotubes. We also analyzed Akt phosphorylation upon insulin stimulation, and we did not observe any difference between palmitate- and palmitate + Spiro-treated cells. These results were confirmed by in vitro glucose uptake analysis. Taken together, our data indicate that reduced activity of SM MR does not improve insulin signaling in mouse skeletal myocytes and does not contribute to the favorable metabolic effects on glucose tolerance and IR induced by systemic pharmacological MR blockade.