Safety and Efficacy of Novel Agents: Pelacarsen, Obicetrapib, and Beyond

Cardiovascular disease remains the leading global cause of mortality. Residual atherosclerotic risk persists despite intensive low-density lipoprotein cholesterol (LDL-C) lowering, in part due to genetically determined lipoprotein(a) [(Lp(a)}. Strong associations exist between increased atherogenic lipoproteins and cardiovascular risk. Although Lp(a) is an independent risk factor, most international guidelines have not yet endorsed therapeutic lowering of plasma Lp(a), while novel, non-statin agents now show promising reductions in Lp(a). Lifestyle and traditional therapies exert minimal effects on Lp(a); however, ribonucleic acid (RNA)-targeted agents and selective cholesteryl ester transfer protein (CETP) inhibition show substantial promise. Multiple RNA-based therapeutics are in development – most advanced is the antisense oligonucleotide pelacarsen (Phase 3, Lp(a)HORIZON). Obicetrapib, a highly selective CETP inhibitor, further lowers LDL-C and apoB when added to maximally tolerated therapy. This chapter reviews Lp(a) biology, epidemiology, clinical measurement, and the evidence base for emerging Lp(a)-lowering therapies (pelacarsen, olpasiran, lepodisiran, zerlasiran, and muvalaplin) as well as obicetrapib and advanced triglyceride-lowering agents. Practical pathways for screening and implementation in preventive cardiology are provided.