Olpasiran tops a network meta-analysis of 51 trials (17,810 patients) ranking Lp(a)-lowering therapies against PCSK9 inhibitors (Diabetes Obes Metab 2026)

Original title: Comparative Effects of Emerging Lp(a)-Lowering Agents and PCSK9-Directed Therapies on Lipoprotein(a): A Network Meta-Analysis of Randomised Clinical Trials

Diabetes Obes Metab · 4 June 2026 · 8

Zayed JA, Al-Awamleh NA, Hamad M, Hdaib MIM, Ayesh H

Frequentist network meta-analysis of 51 randomised trials (17,810 participants, 16 treatment nodes) comparing emerging Lp(a)-targeted therapies (siRNAs, antisense oligonucleotides, an oral assembly inhibitor) with PCSK9-directed therapies on placebo-adjusted percentage change in Lp(a). Olpasiran 225 mg every 12 weeks gave the largest reduction (mean difference -98.94 percentage points, 95% CI -114.36 to -83.52), with pelacarsen, muvalaplin, zerlasiran and lepodisiran also showing large reductions. PCSK9-directed therapies were more modest on Lp(a) (evolocumab 140 mg every 2 weeks: -31.58 percentage points) but lowered LDL-C more; alirocumab 150 mg carried more injection-site reactions. Heterogeneity was high (I2 90.9%) with funnel plot asymmetry, so rankings, while directionally consistent across sensitivity analyses, should be read cautiously pending cardiovascular outcome trials.

Original 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 sensitivity analyses. No therapy was associated with higher SAEs or discontinuations versus placebo; alirocumab 150 mg was associated with more injection-site reactions.

Conclusions: Lp(a)-targeted therapies were associated with larger Lp(a) reductions than PCSK9-directed therapies, while PCSK9-directed therapies had greater LDL-C lowering. Given high heterogeneity, funnel plot asymmetry and low certainty for several estimates, these findings should be interpreted cautiously pending cardiovascular outcome trials.

Summary written by lp-a.org from the published abstract; figures as published. Page updated 17 August 2026. Methods.