Lipoprotein (a): A new target for pharmacological research and an option for treatment.

Lipoprotein(a) [Lp(a)] is increasingly recognised as a crucial and independent risk factor for atherosclerotic cardiovascular disease (ASCVD), calcific aortic valve stenosis (AVS), and possibly heart failure and peripheral artery disease. Lp(a) consists of an LDL-like particle covalently bound to apolipoprotein(a) [apo(a)], a highly polymorphic protein encoded by the LPA gene. The Lp(a) level in plasma is predominantly genetically determined and remains stable throughout life, relatively unaffected by lifestyle, comorbidities or standard lipid-lowering therapies. Elevated Lp(a) levels are associated with a higher risk of ASCVD, particularly in individuals with familial hypercholesterolaemia or smaller apo(a) isoforms. Despite its clinical relevance, Lp(a) is rarely measured in daily clinical practice, although most guidelines recommend at least one lifetime measurement. Novel RNA-based therapies, including antisense oligonucleotides (pelacarsen) and small interfering RNAs (olpasiran, lepodisiran, zerlasiran)-have shown the potential to reduce Lp(a) levels by >80 %. The small oral molecule muvalaplin also shows promise in inhibiting Lp(a) formation. Large-scale clinical trials are underway to assess the effects of Lp(a)-lowering therapies on cardiovascular outcomes. Measurement of Lp(a) and characterisation of the isoforms remain a challenge, and standardisation of assays is still a matter of debate. As new therapeutic options are developed that specifically target Lp(a), the inclusion of Lp(a) in cardiovascular risk assessment could improve stratification and lead to targeted interventions, particularly in high-risk populations. The growing body of genetic, epidemiological and clinical evidence makes Lp(a) a critical target in cardiovascular research and therapy.