Efficacy and safety of selective aldosterone synthase inhibitors in uncontrolled hypertension: a systematic review and meta-analysis of randomized controlled trials

Abstract

Earlier Aldosterone synthase inhibitors (ASIs) were non-selective, with a risk of cortisol insufficiency. A new generation of ASIs has emerged with improved selectivity and pharmacological properties, although their efficacy and safety remain debated. This meta-analysis evaluates the efficacy and safety of selective ASIs in adults with uncontrolled primary hypertension. We selected randomized controlled trials (RCTs) from 6 databases/registries, comparing selective ASIs with placebo in adults aged ≥ 18 years with primary uncontrolled hypertension. Quality was assessed using the risk of bias 2 tool. Random-effects models were used to pool mean differences for continuous variables and calculate odds ratios (ORs) for binary outcomes. Certainty of evidence was rated using the Grading of Recommendations Assessment, Development, and Evaluation approach. Five RCTs, involving 2,456 patients, were included. Least-squares mean (LSM) systolic blood pressure (SBP) was significantly lower with ASIs than placebo in both standard-dose (difference in LSM [LSMD], −9.05 mmHg; 95% confidence interval [CI], −10.98 to −7.12; P < 0.001) and high-dose regimens (LSMD, −9.04 mmHg; 95% CI, −10.99 to −7.08; P < 0.001). LSM diastolic blood pressure was also significantly lower with ASIs using standard dose (LSMD, −3.54 mmHg; 95% CI, −4.99 to −2.09; P < 0.001) and high dose (LSMD, −4.17 mmHg; 95% CI, −5.72 to −2.62; P < 0.001) compared with placebo. For safety endpoints, mild hyperkalemia (5.5–6 mmol/L) was more frequent with ASIs at both standard dose (OR, 7.50; 95% CI, 2.46 to 22.85; P < 0.001) and high dose (OR, 11.63; 95% CI, 3.82 to 35.39; P < 0.001). The rate of moderate-to-severe hyperkalemia (greater than 6 mmol/L) was comparable between the ASI and placebo groups for standard doses. In contrast, high doses were associated with an increased rate in the ASI group (OR, 4.43; 95% CI, 1.10 to 17.82; P = 0.036). The certainty of evidence was high for both SBP and mild hyperkalemia, and moderate for moderate to severe hyperkalemia. Selective ASIs appear to be a promising treatment in terms of efficacy and safety for uncontrolled hypertensive patients. Larger RCTs with extended follow-up periods are warranted to establish long-term evidence. Trial Registration: PROSPERO Identifier: CRD420251108664.