Pelacarsen phase 3 Lp(a)HORIZON trial shows no primary endpoint benefit despite 80-95% Lp(a) reduction in phase 2 (J Cardiovasc Pharmacol 2026)

Lipoprotein(a) [Lp(a)] is a genetically determined apolipoprotein B-containing lipoprotein independently associated with atherosclerotic cardiovascular disease (ASCVD) and calcific aortic valve stenosis (CAVS). Circulating Lp(a) concentrations are largely inherited, minimally responsive to lifestyle modification, and not adequately addressed by conventional lipid-lowering pharmacotherapy. Patients with established ASCVD continue to experience recurrent cardiovascular events despite intensive guideline-directed therapy, and this residual risk reflects mechanisms - including persistently elevated Lp(a) - that are not captured by standard low-density lipoprotein cholesterol (LDL-C) management. In this narrative review, current evidence on Lp(a) biology, genetics, and pathophysiology is integrated with a critical appraisal of contemporary management, the emerging Lp(a)-lowering pharmacological landscape, and unresolved clinical implementation challenges. Current management relies on once-in-adulthood Lp(a) measurement for cardiovascular risk stratification, aggressive optimization of modifiable risk factors, and, in highly selected patients, lipoprotein apheresis; no Lp(a)-specific pharmacotherapy is approved by any major regulatory agency. RNA-targeted therapies - antisense oligonucleotides and small interfering RNA agents - and an oral inhibitor of Lp(a) particle assembly have produced pharmacodynamic Lp(a) reductions of 80-95% or more in phase 2 randomized trials. However, topline results from the phase 3 Lp(a)HORIZON trial showed that pelacarsen, despite lowering Lp(a), did not reduce the primary composite cardiovascular endpoint. Full trial data are awaited, while four other phase 3 cardiovascular outcome trials - OCEAN(a)-Outcomes, ACCLAIM-Lp(a), MOVE-Lp(a), and OCEAN(a)-PreEvent - remain ongoing. Should positive outcome data emerge, clinical implementation will require regulatory approval, evidence-based patient selection, standardized treatment thresholds, and equitable access strategies across diverse populations.