Remnant Cholesterol and Cardiovascular Risk

Remnant cholesterol (RC) refers to the cholesterol carried in lipoprotein particles after the removal of triglycerides. This includes the cholesterol in hepatic-derived intermediate density lipoprotein (IDL) remnants and very low-density lipoprotein (VLDL) remnants (present in the fasting state), as well as the cholesterol in intestinal chylomicron remnants (present in the postprandial state).

RC can be calculated from a lipid profile, collected in the fasting or nonfasting state, using the following equation:

Remnant Cholesterol (RC) = Total Cholesterol – HDL – LDL

In situations where LDL cholesterol is calculated using the Friedewald equation, rather than measured directly, this equates to RC (in mmol/L) being equal to triglyceride concentration divided by 2.2 mmol/L (Doi et al., 2025). When LDL is calculated by the NIH method, RC estimations are comparable to those obtained with the Friedewald equation (Wadström et al., 2022). In practice, this means that RC levels derived from the Friedewald or NIH equations provide similar clinical information to the triglyceride concentration, and triglyceride levels have been used as a surrogate for RC in some studies. The European Atherosclerosis Society recommends direct measurement of LDL, which provides an RC estimate that is not entirely based on triglyceride levels (Nordestgaard et al., 2016), although most studies evaluating the association between RC and health outcomes have used calculated LDL to estimate RC.

RC is known to accumulate in the arterial intima, where it exerts pro-inflammatory effects and enhances atheroma progression, ultimately leading to the development of atherosclerotic cardiovascular disease in a manner similar to LDL cholesterol (Doi et al., 2025). RC is considered a significant risk factor for cardiovascular disease, potentially more predictive than conventional measures, such as LDL cholesterol, in certain contexts (Wadström, Pedersen, Wulff, & Nordestgaard, 2024; Bruemmer & Cho, 2021).

An expanding body of evidence has identified RC as a direct contributor to the development of atherosclerosis and a driver of cardiovascular risk. RC is predictive of the development of atherosclerotic cardiovascular disease, including peripheral artery disease and myocardial infarction, independent of traditional measures of vascular risk such as LDL (Raggi et al., 2024). Elevated RC is associated with an increased risk of cardiovascular disease, especially in individuals with combined hyperlipidemia, obesity, insulin resistance, and type 2 diabetes (Quispe et al., 2021). Furthermore, elevated nonfasting remnant cholesterol is equally associated with the risk of ischemic heart disease (IHD) and myocardial infarction (MI) as LDL cholesterol, and it is also linked to increased all-cause mortality (Varbo et al., 2014). In a large (>73,000 participants) Mendelian randomization study of people living in Copenhagen, every 1.0 mmol/L increase in RC was associated with an odds ratio of 2.8 for developing ischemic heart disease (Varbo et al., 2013). In a Danish health registry study, participants with a nonfasting calculated RC of ≥1.5 mmol/L had a 2.4x increased risk of coronary heart disease (Varbo et al., 2015) and 4.8x increased risk of peripheral arterial disease (Wadström et al., 2022), compared to those with RC <0.5 mmol/L. In east Asian populations, an increased risk of vascular events has been observed with RC above 0.7-0.8 mmol/L (Proctor et al., 2024).

As seen with triglycerides, conditions commonly associated with elevated RC are obesity, poorly controlled diabetes, and excessive alcohol intake. High estrogen levels, whether endogenous (i.e. in pregnancy) or from exogenous sources such as oral contraceptive pills or hormone replacement therapy, can result in high RC. Other contributors to increased RC include chronic kidney disease, glucocorticoid medications, and genetic variants (Raggi et al., 2024).

It has been hypothesized that lowering RC by 0.83 mmol/L could reduce major cardiac events by 20% (Langsted et al., 2020). Initial steps for RC reduction include moderation or cessation of alcohol intake, weight loss, avoidance of foods that are high in carbohydrates and fructose, and regular physical activity. Specifically, adherence to national recommendations for high intensity physical activity is associated with lower RC (Chen et al., 2024), and a randomized trial assessing the Mediterranean diet, the Low-Glycemic Index diet, and the Low-Glycemic Index Mediterranean diet demonstrated that all three diets had a direct effect on RC lowering over 6 months (Campanella et al., 2020).

With respect to the role of medications to lower RC, clinical trials of RC- and triglyceride-lowering agents have not consistently demonstrated a reduction in cardiovascular risk.

At present, guidelines for assessing risk of atherosclerotic cardiovascular disease do not account for RC. There are no recognized or recommended risk cutoffs for RC, and existing evidence suggests that the optimal cutoff may vary depending on ethnicity and other factors. However, existing data indicates a clear increased risk of cardiovascular events and mortality at RC concentrations ≥1.5 mmol/L, compared to concentrations <0.5 mmol/L (Varbo et al., 2015)(Wadström et al., 2022). Thresholds of 0.7-0.8 mmol/L have also been identified in individuals of east Asian descent and persons with type 2 diabetes (Proctor et al., 2024)(Huh et al., 2022).