Abstract Body (Do not enter title and authors here): 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.