Key result
Zilebesiran lowers office SBP by ~7 mmHg vs placebo in mild to moderate hypertension.
Why the study?
Updated evidence is needed to better characterize the efficacy and safety of zilebesiran, an investigational RNA interference therapy for hypertension.
Does zilebesiran reduce blood pressure in adults with mild to moderate hypertension?
Meta-Analysis (n=1,412)
Yes
Does zilebesiran reduce blood pressure in adults with mild to moderate hypertension?
Mean Difference: -7.16 (95% CI -13.63–-0.7)
p-value: p=0.03
Zilebesiran significantly reduces office and ambulatory blood pressure in adults with mild to moderate hypertension, though it is associated with increased risks of hyperkalemia and injection-site reactions.
Supports zilebesiran development for hypertension; extends four-RCT evidence of efficacy while flagging hyperkalemia and injection-site risks for further study.
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.
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Hussain et al. (2026) conducted a meta-analysis in Mild to moderate hypertension (n=1,412). Zilebesiran vs. Placebo was evaluated on Placebo-adjusted change in office systolic blood pressure (SBP) (MD -7.16, 95% CI -13.63 to -0.70, p=0.03). Zilebesiran significantly reduced office systolic blood pressure by a mean difference of 7.16 mmHg compared to placebo in adults with mild to moderate hypertension.
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