Remnant cholesterol - The transition from biomarker to risk factor

Remnant cholesterol (RC), the cholesterol transported in triglyceride-rich lipoprotein (TRL) remnants, has emerged as a major contributor to residual atherosclerotic cardiovascular disease (ASCVD) risk. We review epidemiologic, genetic, and interventional data supporting TRL-remnant cholesterol (TRL-RC) as a causal risk factor and outline concrete implications for cardiovascular outcomes trial design.

We summarize classical and genetic epidemiology, mechanistic studies, and clinical trials of established and emerging TRL-lowering therapies, focusing on RC measurement, atherogenic mechanisms, and absolute risk reduction modelling.

Prospective cohorts and Mendelian randomization studies consistently associate elevated RC (typically >39 mg/dL [1.0 mmol/L]) with higher risk of myocardial infarction, stroke, peripheral artery disease, cardiovascular mortality, and all-cause mortality, independent of low-density lipoprotein cholesterol and high-density lipoprotein cholesterol. Genetic instruments for lifelong RC elevation confer larger effect sizes than corresponding observational estimates, supporting causality. TRL remnants penetrate the arterial wall, are avidly retained and taken up by macrophages, and promote endothelial dysfunction and inflammation, particularly when enriched in apolipoprotein C-III. Novel therapies targeting apolipoprotein C-III and angiopoietin-like protein 3 (ANGPTL3 and/or ANGPTL3/8) achieve large RC reductions and are now poised for outcomes testing.

Convergent epidemiologic, genetic, and mechanistic evidence supports TRL-RC as a causal, modifiable driver of ASCVD risk. Definitive cardiovascular outcomes trials should prioritize agents that lower both RC and apolipoprotein B, enrich patients with markedly elevated TRL-RC and incorporate contemporary therapies and competing metabolic endpoints.