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

Abstract

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. 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. 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. 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. Hypertension is a highly prevalent condition and a major modifiable risk factor for cardiovascular disease, stroke, and chronic kidney disease. Despite the availability of multiple antihypertensive drug classes, global control rates remain low, highlighting the need for novel therapeutic options. Zilebesiran, an investigational small interfering RNA (siRNA), targets hepatic angiotensinogen production to suppress the renin-angiotensin-aldosterone system (RAAS) and lower blood pressure. Previous meta-analyses on Zilebesiran included only two randomized controlled trials with relatively small sample sizes, limiting the generalizability of findings. Hypertension is a highly prevalent condition and a major modifiable risk factor for cardiovascular disease, stroke, and chronic kidney disease. Despite the availability of multiple antihypertensive drug classes, global control rates remain low, highlighting the need for novel therapeutic options. Zilebesiran, an investigational small interfering RNA (siRNA), targets hepatic angiotensinogen production to suppress the renin-angiotensin-aldosterone system (RAAS) and lower blood pressure. Previous meta-analyses on Zilebesiran included only two randomized controlled trials with relatively small sample sizes, limiting the generalizability of findings. Builds on previous meta-analyses that included only 2 RCTs; this updated analysis incorporates 4 RCTs (1,412 participants), including Kardia 3 and Desai 2025. Adds daytime and nighttime ambulatory BP measurements and diastolic BP analysis, not reported in previous meta-analyses. Applies more rigorous methodology, including GRADE assessment and risk-of-bias evaluation Confirms that Zilebesiran significantly reduces office and 24-hour ambulatory systolic and diastolic BP, with strongest effects in daytime and nighttime readings. Demonstrates plasma angiotensinogen reduction, supporting RAAS-suppressive mechanism. Expanded safety analysis: includes detailed assessment of adverse events (hyperkalemia, injection-site reactions) and serious events, which were not fully analyzed in previous meta-analyses, confirming overall tolerability. Exploratory subgroup analyses evaluated potential differences according to dose and treatment duration; however, these findings should be interpreted cautiously because of the limited number of contributing trials Supports Zilebesiran as a promising novel antihypertensive, highlighting need for larger, long-term trials with active comparators to assess durability, safety, and cardiovascular outcomes. Builds on previous meta-analyses that included only 2 RCTs; this updated analysis incorporates 4 RCTs (1,412 participants), including Kardia 3 and Desai 2025. Adds daytime and nighttime ambulatory BP measurements and diastolic BP analysis, not reported in previous meta-analyses. Applies more rigorous methodology, including GRADE assessment and risk-of-bias evaluation Confirms that Zilebesiran significantly reduces office and 24-hour ambulatory systolic and diastolic BP, with strongest effects in daytime and nighttime readings. Demonstrates plasma angiotensinogen reduction, supporting RAAS-suppressive mechanism. Expanded safety analysis: includes detailed assessment of adverse events (hyperkalemia, injection-site reactions) and serious events, which were not fully analyzed in previous meta-analyses, confirming overall tolerability. Exploratory subgroup analyses evaluated potential differences according to dose and treatment duration; however, these findings should be interpreted cautiously because of the limited number of contributing trials Supports Zilebesiran as a promising novel antihypertensive, highlighting need for larger, long-term trials with active comparators to assess durability, safety, and cardiovascular outcomes.