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2 November 2021
New study makes the case for identifying remnant cholesterol-related residual risk in primary prevention
Analysis of pooled data from individuals free of atherosclerotic cardiovascular disease (ASCVD) showed that levels of remnant cholesterol were associated with ASCVD independent of traditional cardiovascular risk factors, including low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (HDL-C) or apolipoprotein B levels
Quispe R, Martin S, Michos ED et al. Remnant cholesterol predicts cardiovascular disease beyond LDL and ApoB: a primary prevention study. Eur Heart J 2021 doi: 10.1093/eurheartj/ehab432. Online ahead of print.
Objective: To estimate remnant cholesterol-related risk beyond LDL-C and apolipoprotein B (apoB) in patients without known ASCVD.
Study design: Pooled primary prevention cohort with long-term follow-up.
Study population: 17,532 ASCVD-free individuals (mean age 52.3 years, 56.7% women, 34% black) derived from the Atherosclerosis Risk in Communities [ARIC] study (n = 9748); the Multi-Ethnic Study of Atherosclerosis (n = 3049); and the Coronary Artery Risk Development in Young Adults (n = 4735).
Mains study variables: • Remnant cholesterol, calculated as total cholesterol minus HDL-C minus calculated LDL-C.
• Incident ASCVD, defined as definite or probable myocardial infarction, definite coronary death, and definite or probable stroke (all three cohorts); ARIC investigators also conducted continuous surveillance for all cardiovascular disease-related hospitalizations and deaths; these were adjudicated by the ARIC study investigators.

Nested Cox proportional hazard models were used to assess the independent association between continuous log-transformed remnant cholesterol levels and incident ASCVD.

Discordance was defined using >10 difference in percentile units (remnant cholesterol percentile minus LDL-C percentile). The population was divided into:
• Discordantly low remnant cholesterol: <LDL-C percentile by >10 percentile units
• Concordant: Remnant cholesterol and LDL-C within ±10 percentile units; and
• Discordantly high remnant cholesterol: > LDL-C percentile by >10 percentile units.
Associations between remnant cholesterol and LDL-C concordant/discordant groups and incident ASCVD were assessed using the difference in percentile units, LDL-C clinical cut points, and medians.


Over a median follow-up of 18.7 years there were 2,143 ASCVD events. Using multivariable adjustment including LDL-C and apo B, log remnant cholesterol was associated with 65% higher ASCVD risk (hazard ratio 1.65, 95% confidence interval 1.45-1.89). Approximately one third of individuals (34.2%) were in the high remnant cholesterol/low LDL-C discordance group. In this group, there was a 21% increase in incident ASCVD even with low LDL-C (HR 1.21, 95% confidence interval 1.08-1.35). By comparison, individuals in the low remnant cholesterol/high LDL-C discordant group had similar ASCVD risk compared to the concordant group (Table). The proportion of patients in the high remnant cholesterol/low LDL-C discordance group increased at lower LDL-C levels, to 81% of those with LDL-C< 70mg/dl (<1.8 mmol/L).


Table. Incident ASCVD by discordant groups; Hazard ratio (95% confidence interval)



Discordant low remnant cholesterol/high LDL-C

0.93 (0.83–1.04)



Discordant high remnant cholesterol/low LDL-C

1.21 (1.08–1.34)

Authors’ conclusion: In ASCVD-free individuals, elevated remnant cholesterol levels were associated with ASCVD independent of traditional risk factors, LDL-C, and apoB levels. The mechanisms of remnant cholesterol association with ASCVD, surprisingly beyond apoB, and the potential value of targeted remnant cholesterol lowering in primary prevention need to be further investigated.


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.

References 1. Nordestgaard BG. Triglyceride-rich lipoproteins and atherosclerotic cardiovascular disease: new insights from epidemiology, genetics, and biology. Circ Res 2016;118:547–63.
2. Ference BA, Kastelein JJP, Ray KK, et al. Association of triglyceride lowering LPL variants and LDL-C-lowering LDLR variants with risk of coronary heart disease. JAMA 2019;321:364–373.
3. Elshazly MB, Mani P, Nissen S, et al. Remnant cholesterol, coronary atheroma progression and clinical events in statin-treated patients with coronary artery disease. Eur J Prev Cardiol 2020;27:1091–1100
Key words remnant cholesterol; cardiovascular risk; apoB; discordance