Corrective Re-analysis of the Alirocumab ODYSSEY Outcomes Trial Suggests the Clinical Importance of Lipoprotein(a) Remain Substantially Underestimated

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. 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.