Efficacy and safety of zilebesiran in adults with hypertension: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Hypertension is a major modifiable risk factor for cardiovascular disease, yet global control rates remain low. Zilebesiran, an investigational RNA interference therapy, targets angiotensinogen to modulate the renin-angiotensin-aldosterone system. While previous reviews exist, updated evidence is needed to better characterize its efficacy and safety. METHODS: A systematic search of PubMed, Cochrane Library, Google Scholar, Embase, and ClinicalTrials.gov was conducted using MeSH and free-text terms. Two reviewers independently extracted data and assessed risk of bias using RoB 2.0. A random-effects model was applied in RevMan 5.4, with heterogeneity evaluated using I² statistics. RESULTS: Four studies involving 1,412 adults with mild to moderate hypertension were included. The primary outcome, placebo-adjusted change in office systolic blood pressure (SBP), showed a pooled mean difference (MD) of -7.16 mmHg (95% CI: -13.63 to -0.70). Secondary outcomes demonstrated significant reductions in 24-hour ambulatory SBP (MD: -9.92 mmHg; 95% CI: -18.74 to -1.10), daytime SBP (MD: -9.76 mmHg; 95% CI: -19.46 to -0.06), nighttime SBP (MD: -9.95 mmHg; 95% CI: -16.71 to -3.19), and 24-hour ambulatory diastolic blood pressure (DBP) (MD: -7.27 mmHg; 95% CI: -11.13 to -3.41). In subgroup analysis by follow-up duration, the reduction in daytime SBP was significantly greater at 3 months than at 6 months (P = 0.02), suggesting a potential attenuation of the antihypertensive effect over time. Zilebesiran markedly reduced angiotensinogen levels (MD: -1.00; 95% CI: -1.15 to -0.85). Overall adverse events were significantly more frequent with Zilebesiran compared with placebo (OR: 1.46), including increased risks of hyperkalemia and injection-site reactions, while serious adverse events did not differ significantly between groups. CONCLUSION: Overall, zilebesiran produced significant and consistent BP reductions, especially in ambulatory measures, with a favorable safety profile. However, evidence remains limited by small sample sizes and reliance on placebo comparators, and larger trials with active antihypertensive controls are needed to validate long-term efficacy and safety.