Beyond LDL-C: Biomarker-Informed Risk Assessment and Management of Residual Cardiovascular Risk in the Era of Precision Prevention

Despite substantial reductions in atherosclerotic cardiovascular disease (ASCVD) events with intensive low-density lipoprotein cholesterol (LDL-C) lowering, considerable residual cardiovascular risk persists among individuals achieving guideline-recommended LDL-C targets. This residual risk reflects biological pathways not addressed by LDL-C lowering and remains a central challenge in preventive cardiology. This narrative review examines three overlapping domains: residual lipid risk related to triglyceride-rich lipoprotein remnants and excess apolipoprotein B-containing particles; genetically determined lipoprotein(a) [Lp(a)]-mediated risk; and residual inflammatory risk involving the NLRP3 inflammasome and downstream interleukin-1β and interleukin-6 signaling. Complementary biomarkers, including apolipoprotein B, non-HDL cholesterol, remnant cholesterol, Lp(a), and high-sensitivity C-reactive protein, may help characterize residual-risk phenotypes beyond LDL-C alone, although their incremental value and influence on management vary with the strength of prognostic and causal evidence and the availability of effective therapies. Icosapent ethyl and low-dose colchicine have demonstrated cardiovascular benefit in selected high-risk populations, whereas the cardiovascular benefits of therapies targeting apoC-III, ANGPTL3, and Lp(a) remain under evaluation. Recent phase 3 findings have further underscored uncertainty regarding the cardiovascular benefit of interleukin-6 inhibition. Integrating complementary biomarkers with therapies supported by randomized outcomes evidence may enable a more individualized approach to residual cardiovascular risk reduction.