Lipoprotein(a) Inhibition: Current Evidence, Therapeutic Landscape, and Future Directions

Lipoprotein(a) [Lp(a)] is a genetically determined, apolipoprotein B-containing lipoprotein that contributes to cardiovascular risk through atherogenic, proinflammatory, and potentially antifibrinolytic mechanisms. Genetic, epidemiological, and mechanistic evidence supports a causal role for elevated Lp(a) in atherosclerotic cardiovascular disease and calcific aortic valve disease. In contrast, associations with other cardiovascular phenotypes are less consistent. Since circulating concentrations are largely inherited and only modestly affected by lifestyle measures and conventional lipid-lowering therapies, Lp(a) represents an important component of residual cardiovascular risk. This review summarizes the structural, genetic, and pathogenic characteristics of Lp(a), examines the strength of evidence across coronary artery disease, ischemic stroke, peripheral artery disease, abdominal aortic aneurysm, calcific aortic valve disease, and heart failure, and discusses measurement, clinical interpretation, and potential biomarkers. The therapeutic landscape has expanded rapidly. Antisense oligonucleotides and small interfering RNA agents substantially suppress hepatic apolipoprotein(a) synthesis, oral small-molecule inhibitors prevent Lp(a) particle assembly, and in vivo gene-editing strategies aim to provide highly durable reductions. Early-phase trials have demonstrated marked lowering of circulating Lp(a); however, most were not designed to assess cardiovascular outcomes, so direct comparisons among agents are limited by differences in study populations, assays, dosing schedules, and follow-up. Ongoing cardiovascular outcome trials will determine whether selective Lp(a) lowering reduces clinical events and which patients are most likely to benefit. Until these results are available, Lp(a) measurement can refine risk stratification and support intensive management of modifiable risk factors, whereas biomarker reduction alone should not be equated with proven clinical benefit.