Frontiers in Cardiovascular Medicine · Oct 30, 2026
Remnant Lipoproteins and Remnant Cholesterol in Residual Atherosclerotic Cardiovascular Risk
By Luyao Ling, Feng Liu, Xiaoping Wang
Despite intensive lowering of low-density lipoprotein cholesterol (LDL-C), many patients continue to experience atherosclerotic cardiovascular disease (ASCVD) events, and cholesterol-enriched remnant lipoproteins contribute to this residual risk. This review examines the evidence linking remnant lipoproteins to residual ASCVD risk and asks which treatment-induced changes in remnant exposure are likely to reduce it. Lipoprotein lipase (LPL), transported to the capillary lumen by GPIHBP1, converts triglyceride-rich lipoproteins (TRLs) into smaller remnants, whose concentration is then determined by further remodeling and hepatic uptake. Remnants retained in the arterial wall deliver cholesterol to macrophages and promote inflammation. In cohort studies, remnant cholesterol (RC) predicts cardiovascular events even in patients receiving lipid-lowering therapy, and Mendelian randomization and coding-variant studies implicate LPL and its regulators in coronary disease. Trials of triglyceride-lowering therapy, however, have produced inconsistent results. In PROMINENT, pemafibrate lowered RC but raised apolipoprotein B (apoB) and did not reduce events. Agents targeting apolipoprotein C-III (APOC3) or angiopoietin-like protein 3 (ANGPTL3) lower triglycerides substantially, but their effects on RC, LDL-C, and apoB differ by agent and population; in the ESSENCE imaging study, olezarsen reduced both RC and apoB without significantly changing noncalcified plaque volume at one year. Building on recent syntheses, we propose that these findings are best interpreted by separating four related dimensions of exposure: the cholesterol carried per remnant particle, the number of remnant particles, total apoB-containing particle exposure, and the rate of particle clearance. We use this remnant-cholesterol-load framework to classify trial responses and to identify the measurements that future outcome trials should include. The framework is interpretive, and its dimensions are mathematically and kinetically related rather than independent; it has not been tested prospectively. At present, RC is a useful complement to the assessment of residual dyslipidemia; whether lowering it reduces events will be established only by outcome trials with serial lipid and particle measurements.