Second-Generation Aldosterone Synthase Inhibitors for Hypertension

BackgroundSecond-generation aldosterone-synthase inhibitors (ASIs) may offer a novel treatment for hypertension.ObjectivesThe objective of the study was to assess the efficacy and safety of ASIs in this clinical setting.MethodsWe searched major databases for randomized controlled trials (RCTs) assessing ASIs (baxdrostat, lorundrostat, and vicadrostat) in patients with hypertension. For efficacy outcomes, mean differences (MD) with 95% credible intervals (CrIs) were estimated using a Bayesian random-effects model. For adverse events, OR with 95% CrI were estimated using a Bayesian binomial-normal hierarchical model. The protocol was registered in Prospective Register of Systematic Reviews (CRD420251132306).ResultsEight RCTs were included (n = 3,369; 2,430 [72%] randomized to ASI). ASI reduced systolic blood pressure (SBP) (MD: -6.7 mm Hg; CrI: −8.78, −4.59; τ2 3.24), diastolic blood pressure (MD: -2.09 mm Hg; CrI: −3.68, −0.44; τ2 1.44), and hypertensive urgency (OR: 0.36; CrI: 0.13, 0.90; τ2 0.07) compared with placebo. There was no difference in all-cause mortality (OR: 0.45; CrI: 0.06, 3.20; τ2 0.10) or adrenal insufficiency (OR: 0.5; CrI: 0.1, 3.1; τ2 0.3) between groups. However, ASIs increased the odds of hyperkalemia (OR: 7.1; CrI: 3.56, 15.2; τ2 0.23), hyponatremia (OR: 2.6; CrI: 1.25, 5.98; τ2 0.1), and hypotension (OR: 3.28; CrI: 1.43, 8.16; τ2 0.1). In subgroup analysis, the probability of achieving a clinically meaningful reduction in SBP (MD < −5 mm Hg) was 87.5% with baxdrostat and 94.3% with lorundrostat.ConclusionsSecond-generation ASIs had a high likelihood of a clinically significant reduction in SBP compared with placebo. However, hyperkalemia, hyponatremia, and hypotension were more frequent with ASIs.