Angiotensinogen RNA Interference with Zilebesiran for Blood Pressure Lowering in Hypertension

Background: Poor blood pressure control remains a major contributor to cardiovascular morbidity and mortality. Zilebesiran, a hepatocyte-targeted small interfering RNA that suppresses angiotensinogen synthesis, offers prolonged blood pressure lowering with infrequent dosing and may address adherence-related limitations of conventional therapy. Methods: We conducted a systematic review and meta-analysis of randomized trials evaluating zilebesiran in adults with hypertension. Databases and trial registries were searched from inception through April 2026. The primary endpoint was change from baseline in 24-hour ambulatory systolic blood pressure at approximately 3 months. A random-effects generic inverse-variance model was used to pool least-squares mean differences. Prespecified subgroup analyses examined background antihypertensive therapy and degree of heterogeneity among study results were assessed using I-square statistic. Results: Six randomized comparisons from phase 2 studies were included. Zilebesiran significantly reduced 24-hour ambulatory systolic blood pressure versus placebo or standard therapy, with a pooled mean difference of -11.92 mm Hg (95% CI -15.68 to -8.17; p < 0.001). Heterogeneity was substantial (I 2 = 78.9%), largely driven by background therapy. The effect was greatest in monotherapy cohorts, where the pooled reduction was -15.61 mm Hg (95% CI -18.41 to -12.81; I 2 = 0%). Add-on therapy also demonstrated benefit, though attenuated, with reductions of -12.10 mm Hg with indapamide, -9.70 mm Hg with amlodipine, and -4.50 mm Hg with olmesartan. All comparisons favored zilebesiran. Short-term safety was acceptable, with no consistent signal for serious renal events, hyperkalemia, or severe hypotension. Further, the subgroup differences are highly significant (χ 2 = 23.12, df = 3, p < 0.0001), indicating that treatment effects differ meaningfully across subgroups (monotherapy, indapamide, amlodipine, olmesartan). This supports the conclusion that concomitant antihypertensive therapy modifies the efficacy of zilebesiran. Conclusions: In randomized phase 2 trials, zilebesiran produced clinically meaningful and sustained reductions in ambulatory blood pressure, particularly as monotherapy, with a favorable short-term safety profile. These findings support AGT-targeting RNA interference as a promising long-acting strategy for hypertension and justify ongoing phase 3 outcome evaluation.