Old and New Lines of Therapy Targeting Lipoprotein(a)

Elevated lipoprotein(a) (Lp[a]) is a prevalent, lifelong, and genetically determined causal cardiovascular risk factor, associated with a wide spectrum of cardiovascular disease, including atherosclerotic coronary artery disease, aortic stenosis, ischemic stroke, and peripheral vascular disease. This review aims to: examine the evolving therapeutic landscape for Lp(a), concisely summarize results from preclinical work and ongoing clinical trials of novel pharmacologic and gene-based therapies, and contextualize their potential role in cardiovascular disease prevention.

Randomized clinical trials are now underway for several promising therapeutics targeting LPA gene translation, including antisense oligonucleotides (pelacarsen) and small interfering RNAs (olpasiran, lepodisiran, zerlasiran), with the earliest of these expected to read out in 2026. An oral small-molecule inhibitor (muvalaplin) has also demonstrated substantial Lp(a) lowering by disrupting apo(a)-apoB assembly. In parallel, gene-editing approaches using CRISPR/Cas9 have shown durable suppression of LPA expression in preclinical models, although these therapies remain at an early, proof-of-concept stage. Large, randomized phase 3 clinical trials are ongoing to determine whether significant reductions in Lp(a) will result in a meaningful reduction in downstream clinical events. Lp(a) is an important cardiovascular risk factor for which no approved targeted therapies currently exist. Universal one-time Lp(a) screening is increasingly recommended, underscoring a growing gap between risk identification and mitigation. A robust pipeline of Lp(a)-lowering therapies - spanning injectable gene-silencing therapeutics, oral small molecules, and next-generation gene-editing technologies - has the potential to fundamentally alter our current risk prevention paradigm. The results of these ongoing clinical trials will be crucial in determining whether targeted Lp(a) reduction can meaningfully reduce residual cardiovascular risk and establish Lp(a) as a modifiable risk factor in both primary and secondary prevention.