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European Journal of Heart Failure Oct 2023
Topics: Humans; Aldosterone; Heart Failure; Myocardium; Mineralocorticoid Receptor Antagonists
PubMed: 37661940
DOI: 10.1002/ejhf.3026 -
The Canadian Journal of Cardiology Dec 2023Aldosterone was initially identified as a hormone primarily related to regulation of fluid and electrolyte homeostasis. However, over the past 20 years there has been an... (Review)
Review
Aldosterone was initially identified as a hormone primarily related to regulation of fluid and electrolyte homeostasis. However, over the past 20 years there has been an increasing appreciation of its role in regulation of vascular function and pathophysiology in the setting of hypertension, atherosclerosis, and heart failure. This review highlights recent advances in our understanding the biology of aldosterone as it relates to the pathophysiology and the management of vascular disease-especially related to hypertension. The review focuses on 3 key areas: 1) advances in our understanding of the cellular mechanisms by which aldosterone mediates its cellular effects, 2) identification of the hidden epidemic of aldosteronism as a mediator of hypertension, and 3) appreciating new therapeutic advances in the clinical pharmacology of aldosterone inhibition in cardiovascular and renal disease.
Topics: Humans; Aldosterone; Hypertension; Hyperaldosteronism; Cardiovascular System; Heart Failure; Mineralocorticoid Receptor Antagonists
PubMed: 37734710
DOI: 10.1016/j.cjca.2023.08.035 -
Scientific Reports Sep 2023The purpose of this study was to identify the effect of antihypertensive medication on risks of open-angle glaucoma (OAG) among patients diagnosed with hypertension...
The purpose of this study was to identify the effect of antihypertensive medication on risks of open-angle glaucoma (OAG) among patients diagnosed with hypertension (HTN). A total of 5,195 patients, who were diagnosed with HTN between January 1, 2006 and December 31, 2015, and subsequently diagnosed with OAG, were selected for analysis. For each OAG patient, 5 non-glaucomatous, hypertensive controls were matched (n = 25,975) in hypertension diagnosis date, residential area, insurance type and economic status. Antihypertensive medications were stratified into 5 types: angiotensin converting enzyme inhibitor (ACEi), angiotensin receptor blockers (ARB), calcium channel blockers (CCB), β-blockers and diuretics. Relative risks were calculated. After adjusting for age, sex, body mass index, lifestyle, comorbidities, blood pressure (BP), follow-up duration, and use of other types of antihypertensive drugs, ARB and CCB were found to slightly increase OAG risks (RR 1.1087 (95% CI 1.0293-1.1942); 1.0694 (1.0077-1.1349), respectively). Combinations of ARB with diuretics (1.0893 (1.0349-1.1466)) and CCB (1.0548 (1.0122-1.0991)) also increased OAG risks. The risks for OAG were found to increase by antihypertensive medication use, but the effects appeared to be small. Further studies are necessary to identify the associations of increased BP, medication and therapeutic effect with OAG.
Topics: Humans; Antihypertensive Agents; Angiotensin-Converting Enzyme Inhibitors; Angiotensin Receptor Antagonists; Glaucoma, Open-Angle; Calcium Channel Blockers; Hypertension; Diuretics
PubMed: 37758842
DOI: 10.1038/s41598-023-43420-3 -
JACC. Heart Failure Jan 2024The EMPEROR-Reduced (EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Reduced Ejection Fraction) trial established the efficacy of empagliflozin... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
The EMPEROR-Reduced (EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Reduced Ejection Fraction) trial established the efficacy of empagliflozin in reducing heart failure (HF) outcomes among patients with heart failure with reduced ejection fraction (HFrEF).
OBJECTIVES
The authors examined the outcomes of EMPEROR-Reduced as a function of background diuretic therapy.
METHODS
The EMPEROR-Reduced trial was a double-blind, randomized controlled trial of placebo vs empagliflozin 10 mg among 3,730 HFrEF patients. Herein, the population was stratified into 4 groups: no diuretic and diuretic dose equivalent to furosemide <40, 40, and >40 mg daily at baseline.
RESULTS
A total of 3,656 patients from the EMPEROR-Reduced trial were available for analysis. Of those patients, 482 (13.2%) were receiving no diuretic therapy, and 731 (20.0%), 1,411 (38.6%), and 1,032 (28.2%) were receiving <40 mg, 40 mg, and >40 mg, respectively. The efficacy of empagliflozin on the primary outcome (time to first event of hospitalization for HF or cardiovascular [CV] death) was consistent regardless of background diuretic therapy (>40 mg: HR: 0.88 [95% CI: 0.71-1.10]; 40 mg: HR: 0.65 [95% CI: 0.51-0.82]; <40 mg: HR: 0.65 [95% CI: 0.46-0.92]); no diuretic agents: HR: 0.78 [95% CI: 0.47-1.29]; P = 0.192). Baseline diuretic doses did not influence the effect of empagliflozin on body weight, systolic blood pressure, NT-proBNP, or hematocrit at 52 weeks. The safety profile of empagliflozin vs placebo was unaffected by baseline diuretic dose; however, independently of treatment allocation, total rates of adverse events were higher among patients with higher baseline doses of diuretic agents.
CONCLUSIONS
Empagliflozin exhibits a consistent effect on time to CV death or HF hospitalization and an unaltered safety profile regardless of baseline diuretic therapy. (EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Reduced Ejection Fraction [EMPEROR-Reduced]; NCT03057977).
Topics: Humans; Benzhydryl Compounds; Chronic Disease; Diuretics; Heart Failure; Stroke Volume; Ventricular Dysfunction, Left
PubMed: 37715769
DOI: 10.1016/j.jchf.2023.06.036 -
Arthritis & Rheumatology (Hoboken, N.J.) Apr 2024Using trial data comparing treat-to-target allopurinol and febuxostat in gout, we examined participant characteristics associated with serum urate (SU) goal achievement. (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
Using trial data comparing treat-to-target allopurinol and febuxostat in gout, we examined participant characteristics associated with serum urate (SU) goal achievement.
METHODS
Participants with gout and SU ≥6.8 mg/dL were randomized to allopurinol or febuxostat, titrated during weeks 0 to 24, and maintained weeks 25 to 48. Participants were considered to achieve SU goal if the mean SU from weeks 36, 42, and 48 was <6.0 mg/dL or <5 mg/dL if tophi were present. Possible determinants of treatment response were preselected and included sociodemographics, comorbidities, diuretic use, health-related quality of life (HRQoL), body mass index, and gout measures. Determinants of SU response were assessed using multivariable logistic regression with additional analyses to account for treatment adherence.
RESULTS
Of 764 study participants completing week 48, 618 (81%) achieved SU goal. After multivariable adjustment, factors associated with a greater likelihood of SU goal achievement included older age (adjusted odds ratio [aOR] 1.40 per 10 years), higher education (aOR 2.02), and better HRQoL (aOR 1.17 per 0.1 unit). Factors associated with a lower odds of SU goal achievement included non-White race (aORs 0.32-0.47), higher baseline SU (aOR 0.83 per 1 mg/dL), presence of tophi (aOR 0.29), and the use of diuretics (aOR 0.52). Comorbidities including chronic kidney disease, hypertension, diabetes, and cardiovascular disease were not associated with SU goal achievement. Results were not meaningfully changed in analyses accounting for adherence.
CONCLUSIONS
Several patient-level factors were predictive of SU goal achievement among patients with gout who received treat-to-target urate-lowering therapy (ULT). Approaches that accurately predict individual responses to treat-to-target ULT hold promise in facilitating personalized management and improving outcomes in patients with gout.
Topics: Humans; Allopurinol; Uric Acid; Febuxostat; Gout Suppressants; Goals; Quality of Life; Treatment Outcome; Gout; Diuretics
PubMed: 37842953
DOI: 10.1002/art.42731 -
European Journal of Heart Failure Oct 2023In patients hospitalized for acute heart failure (AHF) empagliflozin produced greater clinical benefit than placebo. Many patients with AHF are treated with... (Randomized Controlled Trial)
Randomized Controlled Trial
AIMS
In patients hospitalized for acute heart failure (AHF) empagliflozin produced greater clinical benefit than placebo. Many patients with AHF are treated with mineralocorticoid receptor antagonists (MRAs). The interplay between empagliflozin and MRAs in AHF is yet to be explored. This study aimed to evaluate the efficacy and safety of empagliflozin versus placebo according to MRA use at baseline in the EMPULSE trial (NCT04157751).
METHODS AND RESULTS
In this analysis all comparisons were performed between empagliflozin and placebo, stratified by baseline MRA use. The primary outcome included all-cause death, heart failure events, and a ≥5 point difference in Kansas City Cardiomyopathy Questionnaire (KCCQ) total symptom score at 90 days, assessed using the win ratio (WR). First heart failure hospitalization or cardiovascular death was a secondary outcome. From the 530 patients randomized, 276 (52%) were receiving MRAs at baseline. MRA users were younger, had lower ejection fraction, better renal function, and higher KCCQ scores. The primary outcome showed benefit of empagliflozin irrespective of baseline MRA use (WR 1.46, 95% confidence interval [CI] 1.08-1.97 and WR 1.27, 95% CI 0.93-1.73 in MRA users and non-users, respectively; interaction p = 0.52). The effect of empagliflozin on first heart failure hospitalization or cardiovascular death was not modified by MRA use (hazard ratio [HR] 0.58, 95% CI 0.30-1.11 and HR 0.85, 95% CI 0.47-1.52 in MRA users and non-users, respectively; interaction p = 0.39). Investigator-reported and severe hyperkalaemia events were infrequent (<6%) irrespective of MRA use.
CONCLUSIONS
In patients admitted for AHF, initiation of empagliflozin produced clinical benefit and was well tolerated irrespective of background MRA use. These findings support the early use of empagliflozin on top of MRA therapy in patients admitted for AHF.
Topics: Humans; Mineralocorticoid Receptor Antagonists; Heart Failure; Stroke Volume; Treatment Outcome; Hospitalization
PubMed: 37540060
DOI: 10.1002/ejhf.2982 -
Current Opinion in Nephrology and... Jan 2024The purpose of this review is to summarize the latest evidence on the prevention and progression of diabetic kidney disease (DKD), as well as novel pharmacological... (Review)
Review
PURPOSE OF REVIEW
The purpose of this review is to summarize the latest evidence on the prevention and progression of diabetic kidney disease (DKD), as well as novel pharmacological interventions from preclinical and early clinical studies with promising findings in the reduction of this condition's burden.
RECENT FINDINGS
We will cover the latest evidence on the reduction of proteinuria and kidney function decline in DKD achieved through established renin-angiotensin-aldosterone system (RAAS) system blockade and the more recent addition of SGLT2i, nonsteroidal mineralocorticoid receptor antagonists (MRAs) and GLP1-RA, that combined will most likely integrate the mainstay for current DKD treatment. We also highlight evidence from new mechanisms of action in DKD, including other haemodynamic anti-inflammatory and antifibrotic interventions, oxidative stress modulators and cell identity and epigenetic targets.
SUMMARY
Renal specific outcome trials have become more popular and are increasing the available armamentarium to diminish the progression of renal decline in patients at greater risk of end-stage kidney disease (ESKD) such as diabetic individuals. A combined pharmaceutical approach based on available rigorous studies should include RAAS blockade, SGLT2 inhibitors, nonsteroidal MRA and expectedly GLP1-RA on a personalized based-intervention. New specific trials designed to address renal outcomes will be needed for innovative therapies to conclude on their potential benefits in DKD.
Topics: Humans; Diabetic Nephropathies; Angiotensin-Converting Enzyme Inhibitors; Renin-Angiotensin System; Kidney; Kidney Failure, Chronic; Mineralocorticoid Receptor Antagonists; Diabetes Mellitus
PubMed: 37889557
DOI: 10.1097/MNH.0000000000000935 -
Journal of Clinical Hypertension... Dec 2023The current screening and diagnostic recommendations for detecting Primary Hyperaldosteronism (PHA) focus on diagnosing the more severe and overt instances of... (Review)
Review
The current screening and diagnostic recommendations for detecting Primary Hyperaldosteronism (PHA) focus on diagnosing the more severe and overt instances of renin-independent aldosterone production. However, milder forms of autonomous aldosterone secretion have been demonstrated to exist below the diagnostic thresholds of current PHA guidelines, and associate with clinically relevant cardiovascular risk. PHAencompasses a spectrum of renin independent aldosterone production, progressing from a subclinical state in normotensives to a full-blown clinical syndrome representing the resistant hypertension population. The authors propose the Syndrome of Inappropriately Elevated Aldosterone Secretion (SIALDS) concept as a potential new paradigm for understanding and diagnosing PHA and expanded diagnostic approach to improve early detection even in well-controlled hypertension. The authors also delve into the impact of treatments, including mineralocorticoid receptor antagonists and emerging aldosterone synthase inhibitors. Furthermore, The authors outline future research directions, proposing clinical trials to investigate the long-term identification and treatment outcomes of SIALDS.
Topics: Humans; Hypertension; Aldosterone; Hyperaldosteronism; Renin; Blood Pressure; Mineralocorticoid Receptor Antagonists; Syndrome
PubMed: 37877173
DOI: 10.1111/jch.14740 -
Clinical Pharmacokinetics Dec 2023Finerenone, a selective and nonsteroidal antagonist of the mineralocorticoid receptor, has received regulatory approval with the indication of cardiorenal protection in... (Review)
Review
Finerenone, a selective and nonsteroidal antagonist of the mineralocorticoid receptor, has received regulatory approval with the indication of cardiorenal protection in patients with chronic kidney disease associated with type 2 diabetes. It is rapidly and completely absorbed and undergoes first-pass metabolism in the gut wall and liver resulting in a bioavailability of 43.5%. Finerenone can be taken with or without food. The pharmacokinetics of finerenone are linear and its half-life is 2 to 3 h in the dose range of up to 20 mg. Cytochrome P450 (CYP) 3A4 (90%) and CYP2C8 (10%) are involved in the extensive biotransformation of finerenone to pharmacologically inactive metabolites, which are excreted via both renal (80%) and biliary (20%) routes. Moderate or severe renal impairment, or moderate hepatic impairment result in area-under-the-curve increases of finerenone (< 40%), which do not require a dose adjustment per se, as the starting dose is based on estimated glomerular filtration rate (eGFR) and titrated according to serum potassium levels and eGFR decline. No relevant effects of age, sex, body size or ethnicity on systemic finerenone exposure were identified. Modulators of CYP3A4 activity were found to affect finerenone exposure, consistent with its classification as a sensitive CYP3A4 substrate. Serum potassium should be monitored during drug initiation or dosage adjustment of either a moderate or weak CYP3A4 inhibitor or finerenone, and the dose of finerenone should be adjusted as appropriate. Its use with strong inhibitors is contraindicated and strong or moderate inducers of CYP3A4 should be avoided. Finerenone has no potential to affect relevant CYP enzymes and drug transporters.
Topics: Humans; Cytochrome P-450 CYP3A; Mineralocorticoid Receptor Antagonists; Diabetes Mellitus, Type 2; Potassium; Renal Insufficiency, Chronic
PubMed: 37875671
DOI: 10.1007/s40262-023-01312-9 -
European Journal of Heart Failure Mar 2024In VICTORIA, vericiguat compared with placebo reduced the risk of cardiovascular death (CVD) and heart failure hospitalization (HFH) in patients enrolled after a... (Randomized Controlled Trial)
Randomized Controlled Trial
AIMS
In VICTORIA, vericiguat compared with placebo reduced the risk of cardiovascular death (CVD) and heart failure hospitalization (HFH) in patients enrolled after a worsening heart failure (WHF) event. We examined clinical outcomes and efficacy of vericiguat as it relates to background use of loop diuretics in patients with WHF.
METHODS AND RESULTS
We calculated the total daily loop diuretic dose equivalent to furosemide dosing at randomization and categorized these as: no loop diuretic, 1-39, 41-80, 40, and >80 mg total daily dose (TDD). The primary composite outcome of CVD/HFH and its components were evaluated based on TDD loop diuretic and expressed as adjusted hazard ratios with 95% confidence intervals. Post-randomization rates of change in TDD were also examined. Of 4974 patients (98% of the trial) with diuretic dose information available at randomization, 540 (10.8%) were on no loop diuretic, 647 (13.0%) were on 1-39, 1633 (32.8%) were on 40, 1185 (23.8%) were on 41-80, and 969 (19.4%) were on >80 mg TDD. Patients with higher TDD had a higher rate of primary and secondary clinical outcomes. There were no significant interactions with TDD at randomization and efficacy of vericiguat versus placebo for any outcome (all p > 0.5). Post-randomization diuretic dose changes for vericiguat and placebo showed similar rates of up-titration (19.6 and 20.2/100 person-years), down-titration (16.8 and 18.1/100 person-years), and stopping diuretics (22.9 and 24.2/100 person-years).
CONCLUSIONS
Loop diuretic TDD at randomization was independently associated with worse outcomes in this high-risk population. The efficacy of vericiguat was consistent across the range of diuretic doses.
Topics: Humans; Heart Failure; Male; Female; Stroke Volume; Aged; Sodium Potassium Chloride Symporter Inhibitors; Middle Aged; Treatment Outcome; Furosemide; Dose-Response Relationship, Drug; Hospitalization; Pyrimidines; Double-Blind Method
PubMed: 38450878
DOI: 10.1002/ejhf.3179