Targeting Lipoprotein(a): A New Era in Cardiovascular Disease Prevention

Lipoprotein(a), or Lp(a), is a genetically determined low-density lipoprotein-like particle that is elevated in approximately one in five individuals worldwide and represents an independent causal risk factor for atherosclerotic cardiovascular disease and calcific aortic stenosis. Elevated Lp(a) levels contribute significantly to residual cardiovascular risk despite optimal management of traditional risk factors. The pathogenicity of Lp(a) derives from its unique structure and enrichment with oxidized phospholipids, conferring proinflammatory, prothrombotic, and proatherogenic properties. Current guidelines recommend at least one-time universal screening, with elevated levels informing personalized decisions regarding lipid-lowering therapy intensification. Novel unapproved therapies, including an antisense oligonucleotide (pelacarsen), small interfering RNAs (olpasiran, lepodisiran), and an oral small molecule (muvalaplin), have demonstrated Lp(a) reductions of up to 99% and are being tested in ongoing phase 3 cardiovascular outcomes trials to determine whether pharmacologic Lp(a) lowering translates into reduced cardiovascular events. We discuss current knowledge on genetics, biology, epidemiology, and measurement of Lp(a), examine its causal association with cardiovascular disease, and discuss emerging therapeutic strategies that may usher in a new era of cardiovascular disease prevention.