Abstract 4348302: Olpasiran Outperforms Other Subcutaneous Lipoprotein(a)-Lowering Agents in Efficacy and Safety: A Network Meta-Analysis of Randomized Controlled Trials

Introduction: Elevated lipoprotein(a) [Lp(a)] is an independent and causal risk factor for cardiovascular disease (CVD). Research Question: Several investigational agents have shown promise in reducing Lp(a), but comparative efficacy and safety remain unclear. Methods: We conducted a systematic review and network meta-analysis (NMA) of randomized controlled trials (RCTs) evaluating small interfering RNA-based and antisense oligonucleotide therapies targeting Lp(a). We searched CENTRAL, PubMed, Scopus, and Web of Science through April 10, 2025. All doses of each drug were pooled into a single treatment node. The primary outcome was percent change in Lp(a) from baseline. Secondary outcomes included changes in LDL-C and ApoB, all-cause mortality (ACM), adverse events (AEs), serious AEs (SAEs), and AEs leading to discontinuation (AELD). Frequentist random-effects NMAs were used, and p-scores were used to rank drug effects per outcome. Subgroup analyses were performed for primary vs. secondary CVD prevention populations. Results: Six RCTs including 1,185 patients met inclusion criteria. Compared to placebo, olpasiran showed the largest reduction in Lp(a) (MD: –87.72%; 95% CI: –113.78 to –61.66), followed by zerlasiran (–66.68%), lepodisiran (–54.61%), and pelacarsen (–54.15%). Subgroup analyses showed consistent benefit across both primary and secondary CVD prevention populations, with olpasiran and zerlasiran yielding >80% reductions in secondary prevention. Olpasiran (p-score: 0.96) and zerlasiran (p-score: 0.67) ranked highest in decreased Lp(a) in comparison to other drugs. LDL-C (MD: -25.15%; 95% CI: -36.49 to -13.82) and ApoB (MD: -24.39%; 95 CI: -31.78 to -17.0) were favorably reduced by olpasiran and pelacarsen, respectively. Olpasiran (p-score: 0.90) and pelacarsen (p-score: 0.96) ranked highest in decreasing LDL-C and ApoB, respectively, in comparison to other drugs. While olpasiran non-significantly reduced the risk of SAEs (-52%) and ACM (-92%) vs. placebo, no significant differences were found in SAEs, ACM, or AELD among other agents. Olpasiran ranked highest in decreasing ACM (p-score: 0.90) and SAEs (p-score: 0.96), while lepodisiran ranked highest in decreasing AEs (p-score: 1.00) and AELD (p-score: 0.89). Conclusions: Among Lp(a)-targeted therapies, olpasiran showed the largest Lp(a), LDL-C, ApoB, and ACM lowering effects, ranking better than other drugs. Olpasiran and lepodisiran ranked better for reducing safety outcomes than other drugs.