Olpasiran ranks as the most effective Lp(a)-lowering therapy, network meta-analysis of 1,432 patients (Front Cardiovasc Med 2026)

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

Front Cardiovasc Med · 1 January 2026 · 8

Hu J, Wang J, Zhang H, Jiang Y, Deng L, Long E, Liu S

PROSPERO-registered (CRD420251069288) systematic review and network meta-analysis of nine randomised trials (1432 participants, at least 12 weeks' intervention) of six Lp(a)-targeted therapies against placebo. All six therapies significantly reduced Lp(a). Olpasiran was the most effective for both percentage reduction (mean difference -92.06, 95% CI -109.80 to -74.32, P-score 0.94) and absolute reduction (-250.70, 95% CI -262.04 to -239.36, P-score 0.99), followed by zerlasiran (percentage -78.33, 95% CI -92.18 to -64.48, P-score 0.70; absolute -205.63, 95% CI -217.24 to -194.03, P-score 0.76); olpasiran was superior to pelacarsen in direct comparison. Olpasiran and zerlasiran also improved LDL-C and apoB, while zerlasiran, lepodisiran and pelacarsen increased injection-site reaction risk. The authors conclude Lp(a)-targeted therapies achieve substantial Lp(a) reductions with generally favourable safety, olpasiran being the most effective agent, though injection-site reactions with zerlasiran warrant attention.

Original abstract

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.

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