Effectiveness and Safety of Target-Specific RNA-Based Lipid-Lowering Therapies: A Systematic Review and Meta-Analysis...

RNA-based therapies target distinct pathways involved in lipid metabolism and may therefore exhibit differential pharmacological effects according to their molecular targets. However, comparative evidence regarding the effectiveness and safety of these target-specific therapies remains limited. This study aimed to evaluate the effectiveness and safety of PCSK9-, APOC3-, and ANGPTL3-targeting RNA-based therapies in patients with hyperlipidemia or hypertriglyceridemia. We conducted a systematic review and meta-analysis of randomized controlled trials comparing inclisiran, olezarsen, plozasiran, or zodasiran with placebo. Treatment effects were expressed as mean differences (MDs) or risk ratios (RRs) with 95% confidence intervals (CIs), and pooled analyses were stratified according to molecular target. Sixteen randomized controlled trials involving 6,982 participants were included. PCSK9-targeting therapy produced the greatest reductions in LDL-C (MD -53.01 mg/dL, 95% CI -57.56 to -48.45), ApoB (MD -39.59 mg/dL, 95% CI -43.33 to -35.85), and non-HDL-C (MD -44.62 mg/dL, 95% CI -47.73 to -41.51), whereas APOC3-targeting therapies produced the greatest reduction in triglycerides (MD -52.26 mg/dL, 95% CI -56.50 to -48.02). Total adverse events, serious adverse events, and adverse events leading to treatment discontinuation were comparable between RNA-based therapies and placebo. Overall, these findings indicate that RNA-based lipid-lowering therapies exhibit target-specific pharmacological effects, with PCSK9 inhibition predominantly reducing atherogenic lipoproteins and APOC3 inhibition producing greater triglyceride lowering. Although the overall safety profile was comparable with placebo, differences in individual adverse outcomes and the limited availability of long-term clinical outcome data highlights the need for further investigation.