Lipoprotein(a) metabolism and emerging therapeutic targets: current insights and future perspectives

Lipoprotein(a) (Lp(a)) represents a unique atherogenic lipoprotein that has emerged as an independent and causal risk factor for atherosclerotic cardiovascular disease. Unlike other lipoproteins, circulating Lp(a) concentrations are largely genetically determined and remain resistant to conventional lipid-lowering therapies. This review summarizes the current understanding of Lp(a) metabolism, its pathophysiological mechanisms, and emerging therapeutic approaches targeting this critical cardiovascular risk factor. Recent advances in Lp(a) research have clarified the complex interplay among genetic determinants, metabolic pathways, and downstream cardiovascular outcomes. Novel RNA-targeted therapies, including antisense oligonucleotides and small interfering RNAs, have demonstrated unprecedented reductions in Lp(a) levels of approximately 80% to 95% and are currently being evaluated in pivotal phase 3 cardiovascular outcome trials. The development of specific Lp(a)-lowering therapies represents a paradigm shift in cardiovascular prevention, offering renewed promise for the estimated 1.5 billion individuals worldwide with elevated Lp(a) levels. Ongoing outcome trials will ultimately determine whether targeted Lp(a) reduction translates into clinically meaningful cardiovascular benefit.