Lipoprotein(a) Debate: Are We Losing, or Are We Asking the Wrong Question?
Lipoprotein(a) [Lp(a)] is a genetically determined cardiovascular risk factor associated with atherosclerotic cardiovascular disease through proatherogenic, proinflammatory, and prothrombotic mechanisms. The neutral primary outcome of the Lp(a)HORIZON trial, despite pharmacologic Lp(a) lowering with pelacarsen, challenges assumptions about the clinical benefits of targeting Lp(a) in patients with established cardiovascular disease. However, these findings do not necessarily invalidate Lp(a) as a causal risk factor or the clinical value of measuring Lp(a). Lp(a)HORIZON primarily tested whether lowering Lp(a) after established disease reduces recurrent events, which is a different question from whether lifelong exposure to elevated Lp(a) contributes to disease development or whether earlier intervention can prevent first cardiovascular events. Ongoing primary- and mixed-prevention trials may help address this distinction. The Lp(a) experience highlights the importance of separating risk assessment from therapeutic efficacy and raises broader questions about the timing, magnitude, and duration of biomarker-targeted interventions. Adaptive guideline frameworks and AI-assisted evidence synthesis may help integrate emerging trial data more rapidly while preserving rigorous human clinical judgment.