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This study aimed to identify the residual risk of ASCVD associated with remnant cholesterol in a primary prevention setting. The key finding was that elevated levels of remnant cholesterol were associated with risk of incident ASCVD independent of traditional cardiovascular risk factors, including LDL-C and apoB. Excess risk due to elevated remnant cholesterol was apparent even at low LDL-C levels. These findings therefore provide a rationale for identifying remnant cholesterol-related residual risk in a primary prevention setting, especially timely with ongoing clinical development of novel therapies targeting triglyceride (TG)-rich lipoproteins which contain remnant cholesterol (1).

There has been consistent assertion that total apoB particle concentration reflects the atherogenic risk attributed to remnant, LDL, and lipoprotein(a) particles. In support, Mendelian randomization studies of genetic variants associated with LDL- or TG-lowering showed that the clinical benefit of lowering either was proportional to the absolute change in apoB (2). In the current study, however, remnant cholesterol-related residual risk persisted even after adjustment for apoB. Similar conclusions were made in another study, in which on-treatment and changes in remnant cholesterol levels were linked to coronary atheroma progression after adjustment for apoB (3). Together, these findings suggest that the cholesterol content of remnants or other harmful effects of these particles may modify ASCVD risk information beyond the total atherogenic particle burden, meriting further study to understand the underlying mechanisms.

The authors acknowledge several strengths and limitations of their study. The study used a large, pooled data cohort implying wider generalisability. In each of the studies in this pooled cohort, incident ASCVD events were adjudicated independently. The authors also calculated LDL-C using the Martin/Hopkins equation, which provides a more accurate estimation of remnant cholesterol than with the Friedewald equation. The authors do, however, acknowledge the possibility of residual confounding which is a limitation of all observational studies. Moreover, because of the extended follow-up (18 years), individuals recruited early may have been less likely to be on lipid-lowering therapy than those enrolled later.

Despite these limitations, the findings provide a basis for considering assessment of remnant cholesterol to provide important information regarding residual risk beyond LDL-C, non-HDL-C and apoB, especially among individuals with mild to moderate hypertriglyceridemia.