Efficacy and safety of lipoprotein(a)-targeted therapeutics: a systematic review and network meta-analysis

Background Lipoprotein(a)–targeted therapies are emerging approaches for lowering lipoprotein(a) [lp(a)]. Objective We conducted a systematic review and network meta-analysis to evaluate the efficacy and safety of lipoprotein(a)–targeted therapies in patients. Methods We searched PubMed, Embase, Web of Science, and the Cochrane Central Register of Controlled Trials (CENTRAL) up to May 6, 2025, for randomized controlled trials (RCTs) with intervention duration of at least 12 weeks. The primary outcomes were percentage and absolute changes in Lp(a). Secondary outcomes included changes in low-density lipoprotein cholesterol (LDL-C) and apolipoprotein B (apoB), and safety outcomes including adverse events (AEs), serious adverse events (SAEs), and injection-site reactions. A frequentist framework network meta- analysis was performed. Results Nine studies involving 1,432 participants were included. All six Lp(a)-targeted therapies significantly reduced Lp(a) levels. Compared with placebo, Olpasiran was the most effective therapy for both percentage [mean difference: −92.06, 95% (−109.80; −74.32), P -score: 0.94] and absolute reductions [−250.70 (−262.04; −239.36), P -score: 0.99], followed by Zerlasiran [−78.33 (−92.18; −64.48), P -score: 0.70], [−205.63 (−217.24; −194.03), P -score: 0.76]. In between-drug comparisons, Olpasiran was superior to Pelacarsen. Both Olpasiran and Zerlasiran were associated with improved LDL-C and apoB concentrations. Zerlasiran, Lepodisiran, and Pelacarsen were found to increase the risk of injection-site reactions. Conclusions Lp(a)-targeted therapies achieved substantial reductions in Lp(a). Olpasiran was the most effective agent in lowering Lp(a) levels. These therapies also improved LDL-C and apoB. The majority of Lp(a)-targeted therapies demonstrate generally favorable safety profiles; However, injection-site reactions, particularly with Zerlasiran, warrant careful consideration. Systematic Review Registration https://www.crd.york.ac.uk/PROSPERO/view/CRD420251069288 , PROSPERO CRD420251069288.