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Background Lipoprotein(a) [Lp(a)] is a genetically determined cardiovascular risk factor with limited therapeutic options. Emerging small interfering RNA (siRNA) therapies offer targeted Lp(a) reduction, but their comparative efficacy and safety remain unclear. We conducted a network meta-analysis (NMA) of randomized controlled trials (RCTs) to provide a comprehensive assessment of these emerging treatments.Methods We performed a systematic review and frequentist NMA of RCTs evaluating siRNA therapies in adults (≥18 years) with dyslipidemia, with a minimum ≥12 weeks follow-up. Databases (MEDLINE, Embase, Cochrane CENTRAL, and ClinicalTrials.gov) were searched from inception to May 2020. Outcomes included changes in Lp(a). Safety outcomes comprised overall adverse events, serious adverse events, and injection-site reactions.Results We included 15 RCTs (n=5966) evaluating six siRNA agents. Olpasiran exhibited the greatest effect (MD: -92.24). Zerlasiran (MD: 84.60) and Lepodisiran (MD: -81.03) showed slightly lower efficacy. Among non-targeted agents, only Inclisiran produced a modest yet significant Lp(a) reduction (−22.05%) figure 1. Inclisiran was most effective for LDL-C (MD: −42.74%) and apoB reduction (MD: −31.39%), whereas Lp(a)-targeted siRNAs showed limited effects on these parameters. Safety profiles were generally favorable. However, injection-site reactions were markedly elevated with Zerlasiran (OR: 33.61) and Inclisiran (OR: 5.31) figure 1.Conclusion Targeted siRNA therapies produce substantial reductions in Lp(a) levels, with Olpasiran demonstrating the greatest efficacy. Overall, these agents exhibit favorable safety profiles, although injection-site reactions are more frequent with Zerlasiran and Inclisiran. These findings support siRNA-based interventions as an effective and generally well-tolerated strategy for managing elevated Lp(a) in patients with residual cardiovascular risk.Abstract 186 Figure 1