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Journal of the American Society of... Aug 2022Sodium glucose cotransporter 2 (SGLT2) inhibitors and mineralocorticoid receptor antagonists (MRAs) reduce the urinary albumin-to-creatinine ratio (UACR) and confer... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Sodium glucose cotransporter 2 (SGLT2) inhibitors and mineralocorticoid receptor antagonists (MRAs) reduce the urinary albumin-to-creatinine ratio (UACR) and confer kidney and cardiovascular protection in patients with CKD. We assessed efficacy and safety of the SGLT2 inhibitor dapagliflozin and MRA eplerenone alone and in combination in patients with CKD.
METHODS
We conducted a randomized open-label crossover trial in patients with urinary albumin excretion ≥100 mg/24 hr, eGFR 30-90 ml/min per 1.73 m, who had been receiving maximum tolerated stable doses of an ACE inhibitor (ACEi) or angiotensin receptor blocker (ARB). Patients were assigned to 4-week treatment periods with dapagliflozin 10 mg/day, eplerenone 50 mg/day, or their combination in random order, separated by 4-week washout periods. Primary outcome was the correlation in UACR changes between treatments. Secondary outcome was the percent change in 24-hour UACR from baseline.
RESULTS
Of 57 patients screened, 46 were randomly assigned (mean eGFR, 58.1 ml/min per 1.73 m; median UACR, 401 mg/g) to the three groups. Mean percentage change from baseline in UACR after 4 weeks of treatment with dapagliflozin, eplerenone, and dapagliflozin-eplerenone was -19.6% (95% confidence interval [CI], -34.3 to -1.5), -33.7% (95% CI, -46.1 to -18.5), and -53% (95% CI, -61.7 to -42.4; <0.001 versus dapagliflozin; =0.01 versus eplerenone). UACR change during dapagliflozin or eplerenone treatment did not correlate with UACR change during dapagliflozin-eplerenone (=-0.13; =0.47; =-0.08; =0.66, respectively). Hyperkalemia was more frequently reported with eplerenone (=8; 17.4%) compared with dapagliflozin (=0; 0%) or dapagliflozin-eplerenone (=2; 4.3%; =0.003).
CONCLUSIONS
Albuminuria changes in response to dapagliflozin and eplerenone did not correlate, supporting systematic rotation of these therapies to optimize treatment. Combining dapagliflozin with eplerenone resulted in a robust additive UACR-lowering effect. A larger trial in this population is required to confirm long-term efficacy and safety of combined SGLT2 inhibitor and MRA treatment.
CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER
European Union Clinical Trials Register, EU 2017-004641-25.
Topics: Albuminuria; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Benzhydryl Compounds; Cross-Over Studies; Eplerenone; Glomerular Filtration Rate; Glucosides; Humans; Renal Insufficiency, Chronic; Sodium-Glucose Transporter 2 Inhibitors
PubMed: 35440501
DOI: 10.1681/ASN.2022020207 -
Stroke and Vascular Neurology Jun 2018Resistant hypertension (failure to achieve target blood pressures with three or more antihypertensive drugs including a diuretic) is an important and preventable cause... (Review)
Review
Resistant hypertension (failure to achieve target blood pressures with three or more antihypertensive drugs including a diuretic) is an important and preventable cause of stroke. Hypertension is highly prevalent in China (>60% of persons above age 65), and only ~6% of hypertensives in China are controlled to target levels. Most strokes occur among persons with resistant hypertension; approximately half of strokes could be prevented by blood pressure control. Reasons for uncontrolled hypertension include (1) non-compliance; (2) consumption of substances that aggravated hypertension, such as excess salt, alcohol, licorice, decongestants and oral contraceptives; (3) therapeutic inertia (failure to intensify therapy when target blood pressures are not achieved); and (4) diagnostic inertia (failure to investigate the cause of resistant hypertension). In China, an additional factor is lack of availability of appropriate antihypertensive therapy in many healthcare settings. Sodium restriction in combination with a diet similar to the Cretan Mediterranean or the DASH (Dietary Approaches to Stop Hypertension) diet can lower blood pressure in proportion to the severity of hypertension. Physiologically individualised therapy for hypertension based on phenotyping by plasma renin activity and aldosterone can markedly improve blood pressure control. Renal hypertension (high renin/high aldosterone) is best treated with angiotensin receptor antagonists; primary aldosteronism (low renin/high aldosterone) is best treated with aldosterone antagonists (spironolactone or eplerenone); and hypertension due to overactivity of the renal epithelial sodium channel (low renin/low aldosterone; Liddle phenotype) is best treated with amiloride. The latter is far more common than most physicians suppose.
Topics: Aged; Antihypertensive Agents; Blood Pressure; China; Diet, Healthy; Diet, Mediterranean; Dietary Approaches To Stop Hypertension; Drug Resistance; Drug Therapy, Combination; Humans; Hypertension; Male; Medication Adherence; Middle Aged; Risk Assessment; Risk Factors; Risk Reduction Behavior; Stroke; Treatment Outcome
PubMed: 30022799
DOI: 10.1136/svn-2017-000138 -
The New England Journal of Medicine Jan 2011Mineralocorticoid antagonists improve survival among patients with chronic, severe systolic heart failure and heart failure after myocardial infarction. We evaluated the... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Mineralocorticoid antagonists improve survival among patients with chronic, severe systolic heart failure and heart failure after myocardial infarction. We evaluated the effects of eplerenone in patients with chronic systolic heart failure and mild symptoms.
METHODS
In this randomized, double-blind trial, we randomly assigned 2737 patients with New York Heart Association class II heart failure and an ejection fraction of no more than 35% to receive eplerenone (up to 50 mg daily) or placebo, in addition to recommended therapy. The primary outcome was a composite of death from cardiovascular causes or hospitalization for heart failure.
RESULTS
The trial was stopped prematurely, according to prespecified rules, after a median follow-up period of 21 months. The primary outcome occurred in 18.3% of patients in the eplerenone group as compared with 25.9% in the placebo group (hazard ratio, 0.63; 95% confidence interval [CI], 0.54 to 0.74; P<0.001). A total of 12.5% of patients receiving eplerenone and 15.5% of those receiving placebo died (hazard ratio, 0.76; 95% CI, 0.62 to 0.93; P=0.008); 10.8% and 13.5%, respectively, died of cardiovascular causes (hazard ratio, 0.76; 95% CI, 0.61 to 0.94; P=0.01). Hospitalizations for heart failure and for any cause were also reduced with eplerenone. A serum potassium level exceeding 5.5 mmol per liter occurred in 11.8% of patients in the eplerenone group and 7.2% of those in the placebo group (P<0.001).
CONCLUSIONS
Eplerenone, as compared with placebo, reduced both the risk of death and the risk of hospitalization among patients with systolic heart failure and mild symptoms. (Funded by Pfizer; ClinicalTrials.gov number, NCT00232180.).
Topics: Aged; Cardiovascular Agents; Cardiovascular Diseases; Combined Modality Therapy; Defibrillators, Implantable; Double-Blind Method; Eplerenone; Female; Follow-Up Studies; Heart Failure; Hospitalization; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Proportional Hazards Models; Spironolactone
PubMed: 21073363
DOI: 10.1056/NEJMoa1009492 -
Clinical Cardiology Apr 2008Improved understanding of the adverse pharmacological properties of aldosterone has prompted investigation of the clinical benefits of blocking aldosterone at the... (Comparative Study)
Comparative Study Review
Improved understanding of the adverse pharmacological properties of aldosterone has prompted investigation of the clinical benefits of blocking aldosterone at the receptor level. This article reviews the pharmacology, clinical efficacy, and tolerability of the two available blocking agents, spironolactone and eplerenone. A Medline search identified clinical studies assessing spironolactone and eplerenone. Priority was given to large, well-controlled, clinical trials and comparative studies. Pharmacological differences between spironolactone and eplerenone include lower affinity of eplerenone for progesterone, androgen, and glucocorticoid receptors; more consistently demonstrated nongenomic properties for eplerenone; and the presence of long-acting metabolites for spironolactone. Both agents effectively treat hypertension and heart failure but comparisons are complicated by the deficiency of head-to-head trials and differences between patient populations. There are differences in the tolerability profiles; spironolactone is associated with dose-dependent sexual side effects. Both agents produce dose-dependent increases in potassium concentrations, although the effect with spironolactone appears to be greater when both agents are administered at recommended doses. Choice of a specific agent should be based on individual patient issues, such as the nature of heart failure and patient concerns about adverse events.
Topics: Eplerenone; Heart Failure; Humans; Hypertension; Mineralocorticoid Receptor Antagonists; Spironolactone
PubMed: 18404673
DOI: 10.1002/clc.20324 -
Reviews in Endocrine & Metabolic... Feb 2023Primary aldosteronism (PA) is the most common form of secondary hypertension. Although hypertensive disorders seem to affect around 5-10% of pregnancies worldwide,... (Review)
Review
Primary aldosteronism (PA) is the most common form of secondary hypertension. Although hypertensive disorders seem to affect around 5-10% of pregnancies worldwide, literature counts less than 80 cases of PA diagnosed during the peri-partum period. In this review we discuss about current knowledge on pathophysiology, natural history, diagnosis and treatment of PA in pregnancy. Because of the physiologic changes in the renin-angiotensin-aldosterone system (RAAS) and the contraindication to both confirmatory test and subtype differentiation, diagnosis of PA during pregnancy is challenging and relies mostly on detection of low/suppressed renin and high aldosterone levels. The course of pregnancy in patients with PA is highly variable, ranging from progesterone-induced amelioration of blood pressure (BP) control to severe and resistant hypertension with potential maternal and fetal complications. Mineralcorticoid receptor antagonists (MRA) are the recommended and most effective drugs for treatment of PA. As the anti-androgenic effect of spironolactone can potentially interfere with sexual development, their prescription is not recommended during pregnancy. On the other side, eplerenone, has proven to be safe and effective in 6 pregnant women and may be added to conventional first line drug regimen in presence of resistant hypertension or persistent hypokalemia. Ideally, patients with unilateral forms of PA should undergo adrenalectomy prior to conception, however, when PA is diagnosed during pregnancy and medical therapy fails to adequately control hypertension or its complications, adrenalectomy can be considered during the second trimester in case of unilateral adrenal mass at MRI-scan.
Topics: Humans; Female; Pregnancy; Hyperaldosteronism; Mineralocorticoid Receptor Antagonists; Spironolactone; Hypertension; Eplerenone
PubMed: 35536535
DOI: 10.1007/s11154-022-09729-6 -
European Heart Journal Jul 2016To evaluate oral doses of the non-steroidal mineralocorticoid receptor antagonist finerenone given for 90 days in patients with worsening heart failure and reduced... (Randomized Controlled Trial)
Randomized Controlled Trial
AIMS
To evaluate oral doses of the non-steroidal mineralocorticoid receptor antagonist finerenone given for 90 days in patients with worsening heart failure and reduced ejection fraction and chronic kidney disease and/or diabetes mellitus.
METHODS AND RESULTS
Miner Alocorticoid Receptor antagonist Tolerability Study-Heart Failure (ARTS-HF) was a randomized, double-blind, phase 2b multicentre study (ClinicalTrials.gov: NCT01807221). Of 1286 screened patients, 1066 were randomized. Patients received oral, once-daily finerenone (2.5, 5, 7.5, 10, or 15 mg, uptitrated to 5, 10, 15, 20, or 20 mg, respectively, on Day 30) or eplerenone (25 mg every other day, increased to 25 mg once daily on Day 30, and to 50 mg once daily on Day 60) for 90 days. The primary endpoint was the percentage of individuals with a decrease of >30% in plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) from baseline to Day 90. A key exploratory endpoint was a composite clinical endpoint of death from any cause, cardiovascular hospitalizations, or emergency presentation for worsening HF until Day 90. Mean age ranged from 69.2 to 72.5 years in different treatment groups (standard deviation 9.7-10.6 years). Decreases in NT-proBNP of >30% from baseline occurred in 37.2% of patients in the eplerenone group and 30.9, 32.5, 37.3, 38.8, and 34.2% in the 2.5→5, 5→10, 7.5→15, 10→20, and 15→20 mg finerenone groups, respectively (P = 0.42-0.88). Except for the 2.5→5 mg finerenone group, the composite clinical endpoint occurred numerically less frequently in finerenone-treated patients compared with eplerenone; this difference reached nominal statistical significance in the 10→20 mg group (hazard ratio 0.56, 95% confidence interval, CI, 0.35; 0.90; nominal P = 0.02), despite the fact that this phase 2 study was not designed to detect statistical significant differences. A potassium level increase to ≥5.6 mmol/L at any time point occurred in 4.3% of patients, with a balanced distribution among all treatment groups.
CONCLUSION
Finerenone was well tolerated and induced a 30% or greater decrease in NT-proBNP levels in a similar proportion of patients to eplerenone. The finding of reduced clinical events in the finerenone 10→20 mg group should be further explored in a large outcomes trial.
Topics: Aged; Chronic Disease; Diabetes Mellitus; Double-Blind Method; Eplerenone; Heart Failure; Humans; Mineralocorticoid Receptor Antagonists; Natriuretic Peptide, Brain; Peptide Fragments; Renal Insufficiency, Chronic; Spironolactone
PubMed: 27130705
DOI: 10.1093/eurheartj/ehw132 -
The New England Journal of Medicine Apr 2003Aldosterone blockade reduces mortality and morbidity among patients with severe heart failure. We conducted a double-blind, placebo-controlled study evaluating the... (Clinical Trial)
Clinical Trial Comparative Study Randomized Controlled Trial
BACKGROUND
Aldosterone blockade reduces mortality and morbidity among patients with severe heart failure. We conducted a double-blind, placebo-controlled study evaluating the effect of eplerenone, a selective aldosterone blocker, on morbidity and mortality among patients with acute myocardial infarction complicated by left ventricular dysfunction and heart failure.
METHODS
Patients were randomly assigned to eplerenone (25 mg per day initially, titrated to a maximum of 50 mg per day; 3319 patients) or placebo (3313 patients) [correction] in addition to optimal medical therapy. The study continued until 1012 deaths occurred. The primary end points were death from any cause and death from cardiovascular causes or hospitalization for heart failure, acute myocardial infarction, stroke, or ventricular arrhythmia.
RESULTS
During a mean follow-up of 16 months, there were 478 deaths in the eplerenone group and 554 deaths in the placebo group (relative risk, 0.85; 95 percent confidence interval, 0.75 to 0.96; P=0.008). Of these deaths, 407 in the eplerenone group and 483 in the placebo group were attributed to cardiovascular causes (relative risk, 0.83; 95 percent confidence interval, 0.72 to 0.94; P=0.005). The rate of the other primary end point, death from cardiovascular causes or hospitalization for cardiovascular events, was reduced by eplerenone (relative risk, 0.87; 95 percent confidence interval, 0.79 to 0.95; P=0.002), as was the secondary end point of death from any cause or any hospitalization (relative risk, 0.92; 95 percent confidence interval, 0.86 to 0.98; P=0.02). There was also a reduction in the rate of sudden death from cardiac causes (relative risk, 0.79; 95 percent confidence interval, 0.64 to 0.97; P=0.03). The rate of serious hyperkalemia was 5.5 percent in the eplerenone group and 3.9 percent in the placebo group (P=0.002), whereas the rate of hypokalemia was 8.4 percent in the eplerenone group and 13.1 percent in the placebo group (P<0.001).
CONCLUSIONS
The addition of eplerenone to optimal medical therapy reduces morbidity and mortality among patients with acute myocardial infarction complicated by left ventricular dysfunction and heart failure.
Topics: Aged; Blood Pressure; Death, Sudden, Cardiac; Double-Blind Method; Eplerenone; Female; Heart Failure; Hospitalization; Humans; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Potassium; Spironolactone; Survival Analysis; Ventricular Dysfunction, Left
PubMed: 12668699
DOI: 10.1056/NEJMoa030207 -
Hypertension (Dallas, Tex. : 1979) Jan 2020Mineralocorticoid receptors (MRs) are implicated in the pathology of hypertension. MR blockers are recommended for the treatment of salt-sensitive or resistant... (Comparative Study)
Comparative Study Randomized Controlled Trial
Mineralocorticoid receptors (MRs) are implicated in the pathology of hypertension. MR blockers are recommended for the treatment of salt-sensitive or resistant hypertension. However, use of currently available MR blockers is limited by adverse events. This phase 3 multicenter, randomized, double-blind study compared the efficacy and safety of esaxerenone, a new selective nonsteroidal MR blocker, at 2.5 and 5 mg/day and eplerenone 50 mg/day in Japanese patients with essential hypertension. After a 4-week washout period, 1001 eligible adults with hypertension were randomized evenly to esaxerenone 2.5 or 5 mg/day or eplerenone 50 mg/day treatments, taken orally once daily for 12 weeks. Primary end points were changes in sitting systolic or diastolic blood pressure (BP) from baseline at the end of treatment. Esaxerenone 2.5 mg/day was noninferior to eplerenone for reductions in sitting and 24-hour BP. Reductions in BP with esaxerenone 5 mg/day were significantly greater than those with esaxerenone 2.5 mg/day. Changes in diurnal BP showed persistent 24-hour antihypertensive effects in all treatment groups. The proportions of patients achieving target sitting BP (<140/90 mm Hg) were 31.5%, 41.2%, and 27.5% with esaxerenone 2.5 and 5 mg/day and eplerenone 50 mg/day, respectively. Incidences of adverse events (all mild or moderate) were similar across treatment groups. These results indicate that esaxerenone is an effective and well-tolerated MR blocker in Japanese patients with essential hypertension, with BP-lowering activity at least equivalent to eplerenone. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT02890173.
Topics: Aged; Antihypertensive Agents; Blood Pressure; Double-Blind Method; Eplerenone; Essential Hypertension; Female; Humans; Male; Middle Aged; Pyrroles; Sulfones; Treatment Outcome
PubMed: 31786983
DOI: 10.1161/HYPERTENSIONAHA.119.13569