Corrective re-analysis suggests Lp(a) reduction accounts for 57-70% of PCSK9 inhibitor benefit in ASCVD.

Although Lp(a) is an established risk factor for ASCVD, our analysis indicates its importance remains substantially underestimated. Reanalyzing cardiovascular outcomes trial (CVOT) data for the PCSK9 antibody alirocumab stratified by Lp(a) quartiles, we find that approximately 70% of the observed benefit is attributable to absolute reductions in Lp(a), rather than to lowering of LDL-C. This result aligns with a prior post hoc analysis of the PCSK9 antibody evolocumab, which attributed 57% of the benefit to Lp(a) reduction. These findings challenge the prevailing assumption that the benefits of PCSK9 therapy are mediated primarily through LDL-C lowering. The manuscript discusses the conditions under which this counterintuitive conclusion could hold. A detailed re-examination of prior lipid-lowering therapies across different mechanisms suggests that the widely accepted linear relationship between LDL-C reduction and clinical benefit is not well supported at levels below 80 mg/dL. Lp(a) likely exerts its effects predominantly in the later stages of atherosclerosis, particularly during plaque destabilization, rather than throughout the entire course of plaque development as LDL-C does; consequently, it may not exhibit the same cumulative effect as LDL-C and could therefore demonstrate clinical benefit within relatively short follow-up periods. In addition, collider bias in secondary prevention populations with ASCVD may lead to an underestimation of the risk attributable to Lp(a). Based on the observed relationship, we project that late-stage, Lp(a)-targeted therapies could reduce the risk of major adverse cardiovascular events (MACE) by roughly 50~60% in phase 3 trials, which would be unprecedented in prior CVOT trials. Our projection also suggests that setting a therapeutic goal of a 15~20% reduction in MACE would confer benefit to roughly 40% of secondary-prevention patients with elevated Lp(a), well beyond the current eligibility range (13~21%). Further health-economic modeling suggests these therapies would have would have favorable health-economic value, as numbers-needed-to-treat would substantially lower than PCSK9 agents.