A Pairwise and Network Meta-Analysis Comparing the Efficacy and Safety of Ribonucleic Acid Interference Therapeutics in the Management of Hypertension

Background: Small interfering RNA (siRNA) and antisense agents targeting angiotensinogen are emerging antihypertensives. We synthesized their efficacy and safety. Methods: We searched PubMed, Web of Science, Scopus, and CENTRAL through 25 Nov 2024. Eligible studies were randomized controlled trials in adults with hypertension comparing RNA-interference therapeutics with placebo. Primary outcomes were the change in ambulatory and office systolic/diastolic blood pressure. We conducted random-effects pairwise meta-analyses and a network meta-analysis with SUCRA ranking, and appraised certainty with GRADE. Results: Four trials (n=486) met criteria. Versus placebo, RNA-interference therapy reduced ambulatory SBP (mean difference [MD] −15.46 mmHg; 95% CI −18.79 to −12.12) and DBP (MD −8.45 mmHg; −10.67 to −6.23), and lowered office SBP (MD −8.07 mmHg; −11.58 to −4.56) and DBP (MD −5.18 mmHg; −7.73 to −2.63). Injection-site reactions increased (risk ratio 5.26; 1.01–27.44); other adverse events, potassium, and eGFR were similar. In network analyses, zilebesiran 300 mg ranked highest for blood-pressure lowering; for AGT reduction, 800 mg ranked highest. GRADE certainty was high for blood-pressure outcomes and moderate for AGT, potassium, and eGFR. Few, short-term trials and sparse networks limit precision and generalizability; publication bias was not assessable. Conclusion: siRNAs effectively reduced BP in hypertensive adults with an acceptable safety profile. Despite the indistinguishable efficacy or safety between the doses or types of siRNAs, Zilebesiran 300 mg best reduced BP compared to placebo.