Lipoprotein(a) and Cardiovascular Disease: A Review of Current Evidence and Future Directions

Abstract

Lipoprotein(a), Lp(a), is a type of low-density lipoprotein (LDL) that is now widely understood to be an independent and direct risk factor for atherosclerotic cardiovascular disease (ASCVD) and calcific aortic valve stenosis (CAVS). Plasma Lp(a) levels are predominantly (over 90%) genetically determined, making them relatively stable throughout life and unresponsive to lifestyle modifications or most currently available lipid-lowering therapies. The pathophysiology of Lp(a) is complex, involving pro-atherogenic, pro-inflammatory, and pro-thrombotic mechanisms, primarily driven by its unique protein component, apolipoprotein (a) (apo(a)), and its role as the primary carrier of oxidized phospholipids (OxPL). Despite challenges in measurement standardization, a global clinical consensus is emerging, recommending at least a one-time screening for Lp(a) in all adults. The field is on the cusp of a major therapeutic breakthrough with the development of specific Lp(a)-lowering RNA-based therapies, such as pelacarsen and olpasiran, as well as a novel oral agent, muvalaplin, which are in late-stage trials and promise to address this long-recognized risk factor for the first time.