Efficacy and safety of zilebesiran for inadequately controlled hypertension: a systematic review and meta-analysis

Background Hypertension remains the leading modifiable risk factor for cardiovascular disease, yet control rates are suboptimal due to poor adherence and blood pressure (BP) variability with daily oral regimens. Zilebesiran is an investigational RNA interference therapeutic targeting hepatic angiotensinogen (AGT) synthesis. Previous data demonstrated that a single subcutaneous dose achieves dose-dependent, durable reductions in serum AGT and BP for up to 24 weeks. Purpose To evaluate the antihypertensive efficacy and safety of zilebesiran compared with placebo as an add-on therapy in patients with mild-to-moderate hypertension inadequately controlled by a stable dose of standard-of-care monotherapy. Methods This meta-analysis followed PRISMA guidelines. A systematic search (PubMed/Embase) identified randomised controlled trials (RCTs) comparing single-dose subcutaneous zilebesiran with placebo in adults with inadequately controlled hypertension (SBP 130–160 mmHg) despite stable monotherapy. The primary outcome was change in 24-h ambulatory SBP at Month 3. Safety endpoints included hyperkalaemia, hypotension, and eGFR decline ≥ 30%. Data were analysed using RStudio. Continuous efficacy data used Mean Differences (MD) via a Restricted Maximum Likelihood (REML) random-effects model; binary safety data used Risk Ratios (RR) via the Mantel-Haenszel method. Heterogeneity was assessed using I2. Results The search identified 64 records; after screening, 3 RCTs comprising 1,320 patients were included. Regarding efficacy, zilebesiran demonstrated significant reductions in 24-h ambulatory SBP at Month 3 compared with placebo across all background therapies. The placebo-adjusted least-squares mean difference in SBP reduction ranged from -4.0 mmHg (95% CI -7.6 to -0.3) in the olmesartan cohort to 12.1 mmHg (95% CI - 16.5 to -7.6) in the indapamide cohort. High statistical heterogeneity (I2 = 91.2%) reflected variability based on background therapy. Regarding safety, zilebesiran was associated with a significantly higher risk of hyperkalaemia (RR 3.24; 95% CI 1.40 to 7.49; p < 0.01) and renal function decline (eGFR decrease ≥ 30%) (RR 2.80; 95% CI 1.38 to 5.67; p < 0.01). Hypotension events were numerically more frequent in the intervention group but did not reach statistical significance (RR 1.73; 95% CI 0.86 to 3.46). Conclusion Single-dose subcutaneous zilebesiran as an add-on therapy provides significant antihypertensive efficacy in adults with uncontrolled hypertension. However, this benefit is accompanied by increased risks of hyperkalaemia and renal function decline. These findings highlight the potential of RNA interference therapeutics but underscore the need for careful monitoring of renal parameters. Further large-scale RCTs are warranted to fully characterise the long-term safety profile and confirm these results in broader populations.