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.