Abstract / Summary
Lipoprotein(a) [Lp(a)] is a low-density lipoprotein-like particle covalently linked to apolipoprotein(a) [apo(a)] and is increasingly recognized as a genetically determined, independent, and potentially causal risk factor for atherosclerotic cardiovascular disease (ASCVD).Although low-density lipoprotein cholesterol (LDL-C) lowering remains central to cardiovascular prevention, a substantial proportion of high-risk patients continue to experience recurrent events despite optimized LDL-C management.Elevated Lp(a) may contribute to this residual cardiovascular risk through proatherogenic, proinflammatory, and prothrombotic mechanisms, including the carriage of oxidized phospholipids.Conventional lipid-lowering therapies have limited effects on Lp(a), creating a need for therapies that selectively and profoundly suppress Lp(a) production.Olpasiran is an N-acetylgalactosamine-conjugated small interfering RNA designed to target hepatic messenger RNA encoding apo(a), thereby reducing apo(a) synthesis and circulating Lp(a) levels.Preclinical and phase 1 studies demonstrated potent and sustained Lp(a) lowering.In the phase 2 OCEAN(a)-DOSE trial, olpasiran produced dose-dependent Lp(a) reductions exceeding 95% at higher doses in patients with established ASCVD and elevated Lp(a).Subsequent extension data showed prolonged off-treatment Lp(a) suppression, whereas biomarker analyses demonstrated marked reductions in oxidized phospholipids on apolipoprotein B without significant changes in systemic inflammatory biomarkers such as high-sensitivity C-reactive protein or interleukin-6.The ongoing OCEAN(a)-Outcomes trial will determine whether profound Lp(a) lowering with olpasiran translates into reductions in major cardiovascular events.This review summarizes the biological rationale, molecular mechanism, preclinical and clinical evidence, comparative landscape, limitations, and future directions of olpasiran as a therapeutic strategy for Lp(a)mediated residual cardiovascular risk.