Abstract 4371716: Efficacy of Zilebesiran in Hypertension: A Meta-analysis with Dose-Response and Angiotensinogen Correlation from KARDIA Trials

Background: Zilebesiran, a novel small interfering RNA (siRNA) therapeutic targeting hepatic angiotensinogen (AGT), has demonstrated promising antihypertensive effects in recent phase 2 trials. This meta-analysis aimed to quantify the pooled reduction in systolic blood pressure (SBP) following zilebesiran treatment, assess dose-response effects, and explore the association between AGT suppression and SBP reduction. Methods: A random-effects meta-analysis was conducted using data from six treatment arms across the KARDIA-1 and KARDIA-2 trials, evaluating zilebesiran monotherapy and add-on therapy in adults with mild to moderate hypertension. Pooled mean SBP reduction and 95% confidence intervals (CIs) were estimated. Meta-regression was performed using dose (mg) as a continuous moderator. Additionally, a linear regression model was used to examine the relationship between percentage AGT suppression and SBP reduction. All analyses were performed in R (version 4.3.2) using the metafor package. Results: The pooled analysis demonstrated a significant SBP reduction of –11.80 mmHg (95% CI: –15.70 to –7.89; p < 0.0001), with high heterogeneity (I 2 = 81.6%). Meta-regression did not reveal a significant dose-dependent trend (β = 0.0127 mmHg per mg, p = 0.231; R 2 = 13.2%), indicating that SBP reductions were not linearly associated with zilebesiran dose across the 150–600 mg range. Furthermore, no significant correlation was found between AGT suppression and SBP change (β = –0.23, p = 0.491), despite a moderate R 2 of 0.51, limited by small sample size (n = 3). Conclusions: Zilebesiran significantly reduces 24-hour systolic blood pressure across dosing regimens. However, no clear dose-response relationship or direct link between AGT suppression and SBP reduction was observed. These findings highlight the need for further trials with harmonized dosing and biomarker reporting to clarify predictors of response.