Discordance between remnant cholesterol and small dense LDL cholesterol obscures interpretation of the results of the PROMINENT trial.

BACKGROUND: The neutral cardiovascular outcome of the PROMINENT trial, despite substantial triglyceride (TG) reduction with pemafibrate, highlights limitations in conventional lipid biomarker interpretation. TG reduction was not accompanied by decreased apolipoprotein B (apoB), suggesting persistence of circulating atherogenic particle burden. OBJECTIVE: To propose a kinetic framework distinguishing biomarkers of remnant lipoprotein persistence from those reflecting downstream lipoprotein remodeling and to reconsider the interpretation of lipid changes observed in PROMINENT. METHODS: The PROMINENT findings were interpreted in the context of triglyceride-rich lipoprotein metabolism, focusing on TG, apoB, remnant cholesterol (RC), directly measured remnant markers, and small dense low-density lipoprotein cholesterol (sdLDL-C). Biomarkers were classified according to whether they primarily reflect particle burden, remnant persistence, or downstream remodeling. RESULTS: In PROMINENT, pemafibrate substantially reduced TG and calculated RC without reducing apoB or cardiovascular events. RC was calculated rather than directly measured, and sdLDL-C was not assessed. Because lipid concentrations reflect the balance among production, intravascular remodeling, and clearance, reductions in TG and calculated RC do not necessarily indicate reduced remnant particle burden. Remnant-associated markers reflect cholesterol-rich particles persisting because of incomplete clearance, whereas sdLDL-C represents downstream products of lipolytic remodeling. Discordance between apoB and cholesterol-based measures, and between calculated RC and directly measured remnants, further illustrates these limitations. CONCLUSION: Conventional lipid biomarkers primarily describe static concentrations and may not adequately distinguish remnant persistence from downstream remodeling. A kinetic interpretation of triglyceride-rich lipoprotein metabolism may improve biomarker assessment and cardiovascular risk stratification.