Background: Uncontrolled hypertension (UH), a severe form of hypertension, persists despite the use of three or more antihypertensive medications. Its growing prevalence, particularly in patients with comorbidities, necessitates novel therapeutic options. Lorundrostat, a selective aldosterone synthase inhibitor, presents a promising mechanism of action by directly reducing aldosterone synthesis while sparing cortisol production, potentially offering an effective and safer alternative to mineralocorticoid receptor antagonists.
Objectives: Three randomized controlled trials (RCTs) comprising 1568 participants were included to evaluate the efficacy and safety of lorundrostat in adults with UH as a primary objective, with a decrease in diastolic blood pressure and the incidence of hyperkalemia, hypotension, and serious adverse events, including life-threatening conditions, hospitalization, significant disability, and events resulting in death, as secondary outcomes of the study.
Methods: A systematic search of PubMed, Embase, ScienceDirect, Cochrane, and ClinicalTrials.gov up to July 2025 was conducted per PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Included RCTs compared lorundrostat to placebo in adult patients with resistant/UH. Outcomes were pooled using a random-effects model. Meta-regression explored moderators, including age, BMI, and comorbidities.
Results: Three RCTs (n = 1568) met inclusion criteria. Lorundrostat significantly reduced systolic blood pressure [mean difference (MD) = -8.40 mmHg, 95% confidence interval (CI) (-9.81, -6.99), P < 0.00001, I 2 = 0%] and diastolic blood pressure [MD = -3.84 mmHg, 95% CI (-5.06, -2.63), P < 0.00001, I 2 = 0%]. Adverse events were more frequent in the lorundrostat group [risk ratio (RR) = 1.41], with notable risks of hypotension (RR = 3.10) and hyperkalemia (RR = 7.31), though serious adverse events were not significantly increased (RR = 1.28).
Conclusion: Lorundrostat demonstrates significant antihypertensive efficacy and a manageable safety profile in UH patients. Larger, long-term trials are warranted to further validate its safety across broader populations and complete its efficacy profile, emphasizing the unknown long-term cardiovascular outcomes of the intervention
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