Lipopotrein(a): from the complex metabolism to the optimal lowering drug

Lipoprotein(a) [Lp(a)] is a genetically determined lipoprotein particle associated with an increased risk of atherosclerotic cardiovascular disease (ASCVD), including coronary artery disease, ischemic stroke, peripheral artery disease, and calcific aortic valve stenosis. Structurally, Lp(a) consists of an LDL-like particle covalently bound to apolipoprotein(a), a plasminogen-like glycoprotein that confers distinct biological properties. In particular, Lp(a) is the main circulating carrier of oxidized phospholipids, which promote endothelial dysfunction and vascular inflammation. Lp(a) contributes to vascular injury through multiple mechanisms, including lipid retention within the arterial wall, inflammatory activation, impairment of fibrinolysis, and vascular calcification. These processes contribute to plaque development and progression. Circulating Lp(a) levels are largely determined by genetic variability within the LPA gene, particularly by kringle IV type 2 copy number variation, which influences apolipoprotein(a) isoform size and secretion. Despite its clinical relevance, therapeutic options specifically targeting Lp(a) remain limited. Lipoprotein apheresis is the main available strategy for a substantial reduction in selected high-risk patients, while conventional lipid-lowering therapies have minimal effects and PCSK9 inhibitors provide only partial reductions. However, several targeted therapies are currently under investigation. Antisense oligonucleotides and small interfering RNAs reduce hepatic LPA expression and achieve marked reductions in circulating Lp(a) levels, and novel small molecule agents interfere with Lp(a) particle formation. Gene-editing strategies are a potential future approach for long-term Lp(a) reduction. In conclusion, Lp(a) is a key determinant of residual cardiovascular risk. A better understanding of its pathophysiology and the development of targeted therapies may improve cardiovascular risk stratification and prevention strategies.