# Efficacy and Safety of Zilebesiran for the Management of Hypertension: An Updated Systematic Review and Meta-Analysis of Randomised Controlled Trials

## TL;DR

Zilebesiran, a new RNAi therapy, significantly lowers blood pressure in hypertensive patients with an acceptable safety profile.

## Contribution

This study provides a comprehensive meta-analysis of Zilebesiran's efficacy and safety in managing hypertension.

## Key findings

- Zilebesiran significantly reduces 24-hour ambulatory systolic and diastolic blood pressure at 12 and 24 weeks.
- It also lowers mean office systolic blood pressure significantly over the same periods.
- Zilebesiran has an acceptable safety profile with no significant increase in severe adverse events.

## Abstract

Zilebesiran is a novel RNA interference (RNAi) therapeutic agent that reduces the production of hepatic angiotensinogen, showing promising results in the management of hypertension. However, a comprehensive assessment of its efficacy and safety is still required. This meta-analysis included four randomised controlled trials (RCTs) with 1,037 participants across the United States, Europe, and Asia, assessing single and repeat subcutaneous doses, mostly in patients on background antihypertensive therapy. The primary outcomes were change from baseline in 24-hour ambulatory and mean office blood pressure (BP) outcomes (results expressed in mmHg), adverse events, and markers of renal function. An extensive search was conducted across five electronic databases to identify RCTs assessing the clinical impact of Zilebesiran. Review Manager version 5.4 (RevMan 5.4; The Cochrane Collaboration, London, England, UK) was used to analyse data under a random-effects model, and results were reported using mean difference (MD), standardised mean difference (SMD), and odds ratio (OR) with 95% confidence intervals (CI). Zilebesiran resulted in a significant reduction of 24-hour ambulatory systolic blood pressure (SBP) at 12 weeks (MD -11.90; 95% CI: -13.42, -10.38; p-value <0.00001) and 24 weeks (MD -9.05; 95% CI: -10.37, -7.73; p-value <0.00001). Mean office SBP was also significantly lowered at 12 weeks (MD -10.68; 95% CI: -12.21, -9.14; p-value <0.00001) and 24 weeks (MD -8.49; 95% CI: -9.70, -7.28; p-value <0.00001). Meaningful reductions in 24-hour ambulatory diastolic blood pressure (DBP) were observed at 12 weeks (MD -8.67; 95% CI: -9.89, -7.47; p-value <0.00001) and 24 weeks (MD -7.90; 95% CI: -9.12, -6.68; p-value <0.00001). Zilebesiran was associated with a modest increase in total adverse events (OR 1.37; 95% CI: 1.06, 1.76; p-value =0.01), but showed no significant difference in severe adverse events compared to placebo (OR 0.75; 95% CI: 0.36, 1.57; p-value =0.45). Changes in serum creatinine (SMD -0.01; 95% CI: -0.16, 0.13; p-value =0.20) and eGFR (estimated glomerular filtration rate) levels (SMD -0.06; 95% CI: -0.21, 0.08; p-value =0.39) were also not statistically significant. This meta-analysis confirms that Zilebesiran is consistently associated with significant reductions in both ambulatory and office blood pressure over 12 to 24 weeks, with an acceptable safety profile. Further trials are needed to evaluate the efficacy, dosing, and safety outcomes of Zilebesiran across diverse hypertensive populations.