Lipoprotein(a) in the statin era: from risk marker to therapeutic target

Lipoprotein(a) [Lp(a)] is a predominantly genetically determined lipoprotein whose concentration is generally stable over time, although clinically relevant within-person variation can occur. Elevated concentrations affect about one in five people. It has emerged as one of the most important causal contributors to the residual cardiovascular risk that persists despite effective LDL-cholesterol lowering in the statin era, and it is also causally implicated in calcific aortic valve stenosis. For decades Lp(a) was measurable yet effectively untreatable, because conventional lipid-lowering therapies do not reduce it to a clinically meaningful degree. Two practical obstacles further constrain its clinical use. Analytical standardization is incomplete: mass and molar units are not interchangeable, and some immunoassays are biased by apolipoprotein(a) isoform size. Real-world screening rates also remain very low, despite a guideline consensus on once-in-a-lifetime testing. This picture is now changing rapidly. RNA-targeted agents, comprising antisense oligonucleotides and small interfering RNAs, together with a first oral small-molecule inhibitor, lower Lp(a) by about 65% to more than 95%, differing in mechanism, route of administration, dosing interval and durability. Two questions remain open: how large an absolute reduction is needed for clinical benefit (the threshold hypothesis), and whether lowering Lp(a) reduces major adverse cardiovascular events at all. Several cardiovascular outcomes trials are now testing these questions directly. They include Lp(a)HORIZON, OCEAN(a)-Outcomes, and ACCLAIM-Lp(a), together with a dedicated aortic-valve trial, and the first readouts are anticipated. Framing Lp(a) as the residual cardiovascular risk target of the statin era, this review integrates measurement, screening, risk stratification, current management, and emerging targeted therapies into a single clinical and pharmacological roadmap for the outcomes-trial era.