Efficacy and tolerability of targeted lipoprotein(a)-lowering therapies: A systematic review

Elevated plasma concentrations of lipoprotein(a) [Lp(a)] have been established as an independent risk factor for atherosclerotic cardiovascular disease, including coronary artery disease, myocardial infarction, and calcific aortic valve disease.

To systematically evaluate the efficacy and safety of emerging Lp(a)-lowering therapies.

A systematic search of PubMed, Embase, and ClinicalTrials.gov was conducted to identify clinical trials evaluating targeted Lp(a)-lowering agents. Studies reporting changes in circulating Lp(a) levels and safety outcomes were included. Therapies were categorized based on their mechanism of action, including antisense oligonucleotides, small interfering RNA (siRNA), and small-molecule inhibitors.

Targeted therapies demonstrated substantial reductions in circulating Lp(a) concentrations across early- and mid-phase clinical trials. Antisense oligonucleotide therapy with pelacarsen reduced Lp(a) levels by up to 80%, while siRNA-based therapies, including olpasiran, lepodisiran, and zerlasiran, achieved reductions of up to 80% to 95%. These agents generally demonstrated favorable safety and tolerability profiles, with most reported adverse events being mild and primarily related to injection-site reactions. In addition, muvalaplin, an oral small-molecule inhibitor targeting Lp(a) assembly, has shown promising reductions in Lp(a) levels in early-phase studies.

Emerging Lp(a)-targeted therapies achieve significant reductions in circulating Lp(a) concentrations and represent a promising strategy for addressing residual cardiovascular risk associated with elevated Lp(a). Ongoing large-scale cardiovascular outcome trials will determine whether pharmacologic lowering of Lp(a) translates into reductions in cardiovascular events.