Safety and Efficacy of Novel RNA Interference Therapeutic Agent Zilebesiran in People With Hypertension: A Systematic Review and Meta-Analysis

Abstract

Hypertension is a major risk factor for cardiovascular and renal diseases. Despite the availability of a wide variety of anti-hypertensive agents, a large number of patients on anti-hypertensive therapy have uncontrolled hypertension. Several factors, such as incorrect dosage and treatment non-adherence due to side effects, polypharmacy, and complex dosing regimens, can cause inadequate blood pressure regulation. Under phase 1 and 2 trials, Zilebesiran is a subcutaneously administered novel RNA interference therapeutic agent that reduces blood pressure by targeting angiotensinogen (AGT) synthesis. We conducted this systematic review and meta-analysis (SRMA) to evaluate the safety and efficacy of Zilebesiran in reducing blood pressure. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines, a literature search was carried out across Pubmed, Embase, and Cochrane Central databases. Our study included two randomized controlled trials (RCTs) involving adult participants receiving Zilebesiran or placebo. The primary outcomes assessed were changes in mean 24-hour ambulatory systolic and diastolic blood pressure and the incidence of adverse events at 12 weeks. Secondary outcomes included changes in serum creatinine and estimated glomerular filtration rate. Zilebesiran administration resulted in a significant reduction in 24-hour systolic blood pressure (-15.12 mmHg, 95% CI: -17.21 to -13.03) and diastolic blood pressure (-7.34 mmHg, 95% CI: -8.70 to -5.98) at 12 weeks compared to placebo with I² = 0%, indicating consistent results across trials. A statistically significant increase in total adverse events was noted (risk ratio: 1.15, 95% CI: 1.01 to 1.30), while serious adverse events did not differ significantly. The commonly encountered adverse effects included pain and erythema at the injection site and headache. Renal safety was supported by consistent serum creatinine and eGFR levels across the included studies. Zilebesiran demonstrates substantial efficacy in blood pressure reduction and exhibits a favorable safety profile, presenting a potential alternative for patients, particularly those struggling with adherence to daily oral medications. The inclusion of only two RCTS resulted in a small sample size, predominantly composed of white participants. This limits the generalizability of the results and highlights the need for further trials with a larger and more diverse study population. Further long-term investigations are also needed to establish the drug's impact on body weight, blood glucose levels, lipid profile, cardiovascular and hepatic health, and its efficacy when used alongside conventional antihypertensive medications.

Keywords: blood pressure; hypertension; raas; rna interference; systematic review and meta-analysis; zilebesiran.

Figure 1. PRISMA study flow diagram

Figure 2. Risk of bias traffic light plot

Figure 3. Risk of bias summary plot

Figure 4. Forest plot demonstrating the efficacy of Zilebesiran versus control showing changes in the mean 24-hour SBP at 12 weeks

References: [6,10]

Figure 5. Forest plot demonstrating the efficacy of Zilebesiran versus control showing changes in the mean 24-hour DBP at 12 weeks

References: [6,10]

Figure 6. Forest plot showing the safety of Zilebesiran versus placebo demonstrating change from baseline in mean serum creatinine levels at 12 weeks

References: [6,10]

Figure 7. Forest plot showing the safety of Zilebesiran versus placebo demonstrating change from baseline in mean eGFR at 12 weeks

References: [6,10]

Figure 8. Forest plot showing the safety of Zilebesiran versus placebo showing relative risks for total adverse events at 12 weeks

References: [6,10]

Figure 9. Forest plot showing the safety of Zilebesiran versus placebo showing relative risks for serious adverse events at 12 weeks

References: [6,10]