Cardiovascular risk: targeting residual cholesterol

Dr Jean-François Renucci, vascular physician at the Timone University Hospital in Marseille and expert ambassador for Agir pour le Cœur des Femmes, explains the importance of keeping our cholesterol levels and other associated cardiovascular risk factors perfectly under control, especially as some factors are currently beyond our control.

Residual cholesterol accounts for a third of total cholesterol! A Danish study of 100,000 subjects shows that if it could be reduced, cardiovascular risk could fall by 13-20% over 10 years.

But what is residual cholesterol?
Yet another "other cholesterol"?
Alongside the well-known LDL cholesterol (C. LDL -> the bad kind that seeps into the artery) and HDL (C.HDL -> the good kind that is metabolized by the body), there is - and it's not often talked about - Residual Cholesterol (RC). It corresponds to the fraction of cholesterol carried by other lipoproteins: those of very low density (VLDL) and intermediate density (IDL).
It is not measured directly in the standard lipid panel, and for good reason, as it can only be identified by nuclear magnetic resonance spectroscopy...!
In the absence of a test to measure it in clinical routine, its value can be estimated by a simple calculation: CR = Total Cholesterol - (C. LDL + C. HDL).
Studies show that CR represents around 33% of the body's total cholesterol. This fraction, particularly rich in triglycerides, constitutes an independent cardiovascular risk factor, even in patients whose LDL-cholesterol is well controlled.
The term residual cholesterol, moreover, refers to "residual risk", i.e. the risk of cardiovascular accident that persists even though everything has been controlled, i.e. all accessible parameters are at an optimal level.
The idea is that, in order to reduce this residual risk, we therefore need to tackle parameters that have not yet been treated. One example is Lipoprotein a, which we are currently unable to control, and whose elevation we "compensate" for by trying to achieve the lowest possible LDL cholesterol levels.
Several studies have shown that CR is associated with higher cardiovascular mortality [1,2] in patients already suffering from cardiovascular disease (CVD), i.e. patients already undergoing secondary prevention.
The authors highlight the value of calculating CR in certain at-risk populations: obese patients, type 2 diabetics, carriers of genetic predispositions, or patients on statins presenting a significant cardiovascular risk despite a "normalized" LDL cholesterol level.
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In Denmark, a team of researchers from the Department of Clinical Biochemistry (Copenhagen University Hospital) carried out a study testing the hypothesis that reducing CR would lead to a substantial reduction in CVD. Their results have just been published [3].
This prospective study included 100,374 subjects (56% men) with no history of CVD from the Copenhagen General Population Study. They were followed through national health registries until December 2021 for the detection of any event.

Reducing residual cholesterol would substantially reduce CVD
During a median follow-up of 12 years, 10,989 subjects (10.9% of the cohort) developed CVD, with a higher frequency in men (13.7%) than in women (8.8%).
This mathematical analysis using a theoretical model and this is an important limitation shows a very interesting therapeutic potential. Based on what is known about the reduction of LDL cholesterol and triglycerides, it was hypothesized that "if we reduced CR by x g/l then we could obtain a y% reduction in cardiovascular events".

In patients at very high cardiovascular risk, a 0.77 g/L reduction in CR from a baseline of 1.16 g/l - which is considered the normal value - could substantially reduce the 10-year risk of CVD. This reduction would reach 17% in women taking statins and 13% in those not, while in men the benefits would be 20% and 15% respectively. For a more modest reduction of 0.39 g/L, gains would be 10% and 7% in women, and 11% and 9% in men.
These results suggest that "aggressive" or rather "significant" CR lowering has the potential to substantially reduce CVD in both sexes once the right treatment is available. The superior efficacy observed in statin users is explained by a dual mechanism: these patients have a higher baseline risk, but more importantly, the prior reduction in LDL-cholesterol risk confers greater importance on CR.
This model has its limitations, notably the simplifying assumption that CR can be reduced without affecting the metabolism of other lipoproteins, which is not the case with current therapeutics, notably those used to construct the mathematical model, but these data provide a strong argument in favor of the development of therapies specifically targeting this lipid fraction for cardiovascular prevention.

Perspectives and therapeutic implications
CR is emerging as a major cardiovascular marker - one more... - long underestimated in risk assessment. Its demonstrated involvement in the onset of CVD, particularly in statin-treated patients with residual cardiovascular risk despite optimal LDL-cholesterol control, argues for its systematic integration into prevention strategies in high-risk subjects.
However, in the absence of a standardized test, the determination of CR relies on indirect or calculated methods. Several approaches exist, but their results remain debated, underlining the need for in-depth methodological studies.
In view of this significant potential benefit, new therapeutics, such as those for lipoprotein (a), are currently being studied. (Examples include apoprotein C 3 and ANGPTL3 inhibitors).

Conclusion:
The data from this Danish cohort place residual cholesterol as a relevant predictive marker of atherosclerosis and therefore cardiovascular disease particularly when LDL cholesterol is properly controlled. It therefore deserves special attention in people at high risk of CVD. The major challenge lies in the development of new, effective and specific therapeutic approaches currently under development for the management of patients with high residual cholesterol, for new perspectives in personalized cardiovascular prevention.

References:

[1]. Wadstrom B.N. et al: Elevated remnant cholesterol, plasma triglycerides, and cardiovascular and non-cardiovascular mortality Eur Heart J. 2023 Apr 21;44(16):1432-1445.

[2]. Nordestgaard A.T. et al. Remnant cholesterol lowering in cardiovascular disease risk reduction in statin, ezetimibe, and PCSK9 inhibitor trials: meta-regression analyses. Eur J Prev Cardiol. 2025 Jun 12:zwaf337.

[3]. Hvid K. et al : Remnant cholesterol reduction for atherosclerotic cardiovascular disease prevention: modelling in the Copenhagen General Population Study .European Journal of Preventive Cardiology, 2025, 32, (13), 1145-1154.

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