Comparative Effects of Emerging Lp(a)-Lowering Agents and PCSK9-Directed Therapies on Lipoprotein(a): A Network Meta-Analysis of Randomised Clinical Trials
Abstract
Aims: Elevated lipoprotein(a) [Lp(a)] is a genetic ASCVD risk factor that often persists despite intensive LDL-C lowering. We compared the efficacy and safety of emerging Lp(a)-targeted therapies (siRNAs, antisense oligonucleotides and an oral assembly inhibitor) with PCSK9-directed therapies.
Materials and methods: We searched PubMed, Embase, Web of Science and Cochrane CENTRAL through December 6, 2025, for randomised trials in adults (≥ 18 years) with ≥ 8-week follow-up reporting Lp(a). The primary outcome was placebo-adjusted mean difference (MD) in percent change from baseline in Lp(a) (percentage points, pp). Secondary outcomes included LDL-C, other lipid parameters and safety outcomes (injection-site reactions, serious adverse events (SAEs), discontinuations). We performed a frequentist random-effects network meta-analysis in R (netmeta) and ranked interventions using P-scores.
Results: Fifty-one trials (17 810 participants) formed a 16-node network. Olpasiran 225 mg Q12W was associated with the greatest Lp(a) reduction versus placebo (MD -98.94 pp, 95% CI -114.36 to -83.52); pelacarsen, muvalaplin, zerlasiran and lepodisiran were also associated with large reductions. PCSK9-directed therapies were associated with more modest Lp(a) reductions (evolocumab 140 mg Q2W: MD -31.58 pp), but greater LDL-C lowering. The primary Lp(a) network showed high heterogeneity (I 2 = 90.9%) and funnel plot asymmetry, although treatment rankings remained directionally consistent across…
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Evidence Hub reads this as a meta-analysis, done in people. Its evidence level is 1 of 5 (Highest · pooled evidence). Pooled evidence from several studies sits at the top of the evidence pyramid. Reported size: 17 participants or records.
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