LDL-C vs Lp(a): What We Know, the "Zero-LDL" Hypothesis, and Where We Stand in the PCSK9 Era

Despite significant breakthroughs in preventative medicine, atherosclerotic cardiovascular disease (ASCVD) is still the primary cause of morbidity and death worldwide. In this context, 2 apoB-containing particles-LDL and lipoprotein(a) [Lp(a)] have emerged as important but mechanistically separate causes of atherothrombotic illness. This review synthesizes current knowledge in lipid biology, epidemiology, measurement, and therapeutics to address 3 key questions: (1) how LDL-C/apoB and Lp(a) differ in structure, pathophysiology, and clinical risk; (2) what the evidence shows about the safety and efficacy of driving LDL-C to very low or near-zero levels; and (3) where PCSK9-based therapies and soon, dedicated Lp(a) -lowering agents-fit into modern prevention strategies. Randomized trials, MR studies, and population-level cohort data all contribute to a clear and convincing picture: LDL-C/apoB and Lp(a) are separate causative drivers of cardiovascular risk, with Lp(a) introducing an orthogonal risk axis determined by genetics rather than lifestyle. By combining both viewpoints, we propose a feasible, dual-axis strategy to ASCVD prevention that addresses both cumulative apoB load and genetically driven Lp(a) risk.