Remnant cholesterol in the era of precision prevention

This editorial refers to ‘Variations in remnant cholesterol and the risk of cardiovascular disease: a national longitudinal cohort study’, by X. Zhu et al., https://doi.org/10.1093/eurjpc/zwaf598. Cardiovascular disease (CVD) remains the leading global cause of morbidity and mortality,1 despite major advances in lipid-lowering therapies targeting LDL-cholesterol (LDL-C). Several therapies including statins, ezetimibe, fibrates, and omega-3 formulations are well characterized to lower lipids and significantly reduce atherosclerotic cardiovascular disease (ASCVD). After several years of successful interventional approaches, a substantial residual cardiovascular risk persists even in patients with well-controlled LDL-C, prompting a search for additional therapeutic targets. HDL-cholesterol (HDL-C) was once considered promising for therapeutic approaches, but these interventions failed to reduce ASCVD events. After extensive research, the focus is shifted to triglycerides (TG) and TG-rich lipoproteins (TRLs) in particular their remnants which are now associated as causal contributors to ASCVD.2 Remnant particles are partially lipolysed TRLs such as LDL remnants, intermediate-density lipoprotein (IDL), and chylomicron (Figure 1). They carry significant cholesterol loads and are small enough to penetrate the arterial intima, deposit cholesterol, promote foam cell formation, and trigger local inflammation which results in endothelial dysfunction.2 At a molecular levels, cholesterol is involved in the regulation of ion channels and transporters.3 The schematic illustrates the definition, clinical consequences, and the new merging treatments for remnant cholesterol. Remnant cholesterol as calculated by (total cholesterol)−LDL-cholesterol−HDL-cholesterol. Remnant cholesterol has been directly linked with increased risk cardiovascular disease, such as stroke, peripheral artery disease, aortic stenosis, and myocardial infarction. Remnant cholesterol >1 mmol/L has been linked with two-fold mortality in patients.9 Ongoing research is focusing on remnant cholesterol by investigating novel therapeutic approaches, specifically ANGPTL3 inhibitors and antisense/siRNA therapies. Mendelian randomization studies have established a direct link between remnant cholesterol (RC) and ischaemic heart disease (IHD), stroke, peripheral artery disease (PAD), and aortic valve stenosis.4 Remnant cholesterol is typically calculated as total cholesterol minus HDL-C minus LDL-C or directly measured using advanced lipid profiling. In addition to traditional therapies listed above, new approaches incorporating ANGPTL3 inhibitors, antisense/siRNA therapies, novel small molecules show large TGs as well as RC reductions in early trials and are active areas of investigation. However, outcome trials specifically demonstrating that lowering RC (independent of LDL-C or apoB change) prevents events are still limited, indicating that there is a need for specific clinical research in this field.5 In addition, quantifying RC remains difficult due to their metabolic heterogeneity and lack of definitive biomarkers. This underscores the urgent need for dedicated basic research to quantify RS, and clinical research to validate RC as a therapeutic target and to refine risk stratification strategies beyond traditional lipid metrics. In this issue of the European Journal of Preventive Cardiology, Zhu et al.,6 titled ‘Variations in remnant cholesterol and the risk of cardiovascular disease: a national longitudinal cohort study’, present a compelling longitudinal analysis of RC dynamics and their association with incident CVD in a nationally representative Chinese cohort. They have used data from the China Health and Retirement Longitudinal Study (CHARLS) on 3866 middle-aged and older adults (mean age of 57.5 years) over 5 years to evaluate baseline RC levels, quantified changes over time, cumulative exposure, and presented absolute differences (ΔRC). Their findings are clinically significant and mechanistically plausible for a causal link between RC levels and cardiovascular risks as well as outcomes (Figure 1). The results indicated that participants who had high baseline RC levels but reduced their RC during the period of the study had a 29–32% lower risk of incident CVD compared with those with persistently high RC. Conversely, individuals with low baseline RC who progressed to high levels had similar risks to those with stable high RC, underscoring the adverse impact of RC elevation over time. These associations remained robust after adjusting for LDL-C and other confounders in the given patient population, suggesting that RC contributes independently to cardiovascular risk. The study6 by Zhu et al. is methodologically rigorous; several limitations are noted. Prior studies have focused on static RC measurements. Zhu et al. advanced the field by demonstrating that RC is a marker of CVD risk and is also a dynamic target for early intervention.6 Their use of longitudinal data allows for an exquisite understanding of how RC trajectories influence cardiovascular outcomes. Remnant cholesterol values in the study were calculated using the Friedewald equation7 rather than directly measured, although sensitivity analyses using the Sampson–NIH equation yielded consistent results. Cardiovascular disease outcomes were ‘self-reported’, which may introduce recall bias. The cohort was exclusively Chinese and predominantly middle-aged to older adults, raising questions about generalizability to other populations. However, the current study supports similar findings in other patient populations.4,8 To further solidify the usage of RC as a therapeutic target, randomized controlled trials are needed. Lifestyle changes, such as modified diets and physical activities to reduce body mass index (BMI), can support therapeutic interventions to reduce RC levels. Notoriously, the associations between RC changes and CVD were more pronounced in men than in women. This observation suggests potential sex-specific mechanisms in RC metabolism or vascular response, warranting further investigation to identify high-risk groups. Notoriously, the associations between RC changes and CVD were more pronounced in men than in women. A direct link between RC and mortality was established by Wadstrom et al.,9 who demonstrated that RC levels above 1 mmol/L (39 mg/dL), present in 22% of the study population, are associated with a two-fold increase in mortality from cardiovascular and other causes, but not from cancer. Increased RC has also been directly linked to an increased risk of major adverse cardiovascular events (MACE), as shown by Castañer et al.10 Their data, derived from the PREDIMED trials, demonstrated that a 10 mg/dL increase in RC was associated with a 21% higher risk of MACE. The lowest MACE incidence was observed in the low RC groups, independent of LDL-C levels. Additionally, a prospective cohort study of the Danish general population11 concluded that a reduction in RC of 32 mg/dL (0.83 mmol/L) was estimated to decrease recurrent MACEs by 20% in secondary prevention. Zhu et al.6 deliver a timely and impactful contribution to the field of preventive cardiology and precision medicine. Their study affirms that RC is a dynamic, independent, and modifiable risk factor for CVDs. By demonstrating that RC reduction correlates with lower CVD risk, Zhu et al.6 open the door to new strategies for risk stratification and intervention (Figure 1). From the clinical perspective, clinicians should prioritize RC screening in individuals with metabolic syndrome and elevated inflammatory markers. Similarly, individuals with low RC should also be monitored over time, as progression to high RC confers increased risk. In short-term Phase IV PREVAIL US trial,12 patients with primary hyperlipidaemia or mixed dyslipidaemia took either pitavastatin 4 mg daily or pravastatin 40 mg daily. The study found that pitavastatin was more effective than pravastatin at reducing atherogenic lipid parameters, including RC. While these findings are promising, more clinical trials are needed to investigate further the effect of targeting RC on ASCVD. This work is supported by the National Center for Advancing Translational Sciences (TR004178, TR005313) and National Heart Lung and Blood Institute (HL157453 and HL179189). S.G.R. and H.S. are supported by American Heart Association (972077 and 965031).