Targeting Aldosterone Biosynthesis in Uncontrolled and Resistant Hypertension: A Systematic Review and Meta-Analysis...

BackgroundAldosterone excess contributes to uncontrolled and resistant hypertension, making aldosterone synthase inhibition a promising therapeutic strategy. Recent randomized trials have evaluated the selective aldosterone synthase inhibitors Lorundrostat and Baxdrostat; however, their efficacy and safety have not been comprehensively synthesized.MethodsPubMed, Embase, and Cochrane CENTRAL were searched from inception through April 2026 for randomized controlled trials evaluating Lorundrostat or Baxdrostat in adults with uncontrolled or resistant hypertension. The primary efficacy outcome was placebo-adjusted change in systolic blood pressure (SBP). Safety outcomes included hyperkalemia, treatment-emergent adverse events (TEAEs), and serious adverse events (SAEs). Drug-specific pooled analyses were performed using random-effects models.ResultsThree randomized trials of Lorundrostat (n=1,568) demonstrated a significant reduction in SBP compared with placebo (mean difference [MD], -7.51 mmHg; 95% CI, -10.30 to -4.71; I² = 0%). Lorundrostat increased the risks of hyperkalemia (RR, 8.06; 95% CI, 2.92-22.27) and TEAEs (RR, 1.45; 95% CI, 1.27-1.66), without a significant increase in SAEs. Three placebo-controlled Baxdrostat trials (n = 1,483) also demonstrated significant reductions in office SBP (MD, -8.63 mmHg; 95% CI, -11.30 to -5.96; I² = 0%). Baxdrostat increased the risk of hyperkalemia (RR, 3.81; 95% CI, 1.82-7.97) but was not associated with significant increases in TEAEs or SAEs.ConclusionsSelective aldosterone synthase inhibition with Lorundrostat and Baxdrostat produced clinically meaningful reductions in SBP in patients with uncontrolled or resistant hypertension. Hyperkalemia emerged as the principal safety concern, whereas serious adverse events were not significantly increased. Larger and longer-term studies are needed to define long-term safety and cardiovascular outcomes.