Managing remnant cholesterol: consider both accumulation and visit variability

Your login
Your password
Confirm your password
Your email
I agree to receive the R3i newsletter
Yes No

Focus on...

26 September 2023

According to this study from China, the combination of higher cumulative remnant cholesterol and greater remnant cholesterol variability exacerbates the independent risk of carotid atherosclerosis in the general population.

Wang J, Jin R, Jin X, et al. Separate and joint associations of remnant cholesterol accumulation and variability with carotid atherosclerosis: a prospective cohort study. J Am Heart Assoc 2023;12:e029352. DOI: 10.1161/. JAHA.122.029352

STUDY SUMMARY

Objective

To investigate the individual and joint associations of cumulative remnant cholesterol and remnant cholesterol variability with the subsequent risk of carotid atherosclerosis and to assess their predictive value for carotid atherosclerosis.

Study design

The BHMC (Beijing Health Management Cohort) study is an ongoing prospective cohort study in which subjects undergo comprehensive regular physical examination, including ultrasonography of the carotid arteries.

Study population

The study included 6,213 subjects (54% men and median age 46 years) with three successive visits with carotid ultrasonography.

Study outcomes

• Carotid atherosclerosis, defined as the presence of carotid plaque or abnormal carotid intima-media thickness (CIMT) as assessed by carotid ultrasonography.

Methods

Remnant cholesterol was estimated as fasting total cholesterol minus low-density lipoprotein cholesterol (LDL-C) minus high-density lipoprotein cholesterol (HDL-C). Cumulative remnant cholesterol was calculated as the summed average remnant cholesterol levels for each pair of consecutive visits multiplied by the time interval between these consecutive visits. Remnant cholesterol variability was assessed on the basis of successive variation, variability independent of the mean, average real variability, standard deviation (SD) and coefficient of variation.

Cox proportional hazards models were used to investigate the associations of cumulative remnant cholesterol and remnant cholesterol variability with the risk of incident carotid atherosclerosis and carotid plaque. The models adjusted for age, sex, smoking status, drinking status, physical activity, body mass index, hypertension, type 2 diabetes, use of lipid-lowering medications, serum uric acid, and estimated glomerular filtration rate (Model 1), and LDL-C (Model 2). Individual and joint associations of cumulative remnant cholesterol and remnant cholesterol variability with the risk of carotid atherosclerosis were evaluated. Subjects were categorized into 4 groups, according to the median of cumulative remnant cholesterol and remnant cholesterol variability (greater than or equal to the median and less than the median).

Results

Over a median 4-year follow-up, 2,613 (42.1%) subjects developed carotid atherosclerosis and 1327 (21.4%) developed carotid plaque. Higher cumulative remnant cholesterol or greater remnant cholesterol variability were associated with elevated risk of carotid atherosclerosis, independent of traditional cardiovascular risk factors and LDL-C, and risk was exacerbated in combination (Table 1). Using cumulative remnant cholesterol or remnant cholesterol variability instead of single-time-point measures of remnant cholesterol significantly improved predictive value for carotid atherosclerosis.

Table 1. Association of cumulative remnant cholesterol (cRC) and remnant cholesterol variability (RCV) with risk of carotid atherosclerosis.

Variable	Hazard ratio (95% CI)	p-value
cRC	1.33 (1.17–1.52)*
	1.16 (1.01–1.32**

RCV	1.22 (1.08–1.39)*
	1.16 (1.02–1.31)**

Joint association
Both variables higher than median	1.21 (1.09-1.34)**	<0.001
High cRC and low RCV	1.21 (1.06-1.37)**	0.081
Low cRC and high RCV	1.14 (1.00-1.30)**	0.057

* Quartile 4 vs. quartile 1 (reference), adjusted for age, sex, smoking status, drinking status, physical activity, body mass index, hypertension, type 2 diabetes, use of lipid-lowering medications, serum uric acid, and estimated glomerular filtration rate; ** and LDL-C

Joint association: Subjects were divided into 4 categories according to the median of cRC and RCV

Authors’ conclusion

Excessive cumulative remnant cholesterol levels and greater remnant cholesterol variability were each independently associated with higher incidence of carotid atherosclerosis, regardless of traditional cardiovascular risk factors including LDL-C, and their coexistence could further exacerbate the independent risk of carotid atherosclerosis in the general population.

COMMENT

Previous studies evaluating the association between remnant cholesterol and risk for atherosclerotic cardiovascular disease (ASCVD) have focused on levels of remnant cholesterol. The current study adds new evidence showing the relevance of both remnant cholesterol accumulation and visit-to-visit variability in remnant cholesterol levels to ASCVD risk. These findings align with other reports indicating that the long-term variability of risk factors, including blood pressure (1,2), LDL-C (3) and glycated haemoglobin (4) were associated with adverse cardiovascular outcomes. Additionally, a post hoc analysis of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial showed that using both remnant cholesterol levels and visit-to-visit variability in remnant cholesterol identified type 2 diabetes patients with higher cardiovascular risk (5). The current study, a prospective cohort analysis, provides further evidence of a longitudinal association between remnant cholesterol and ASCVD risk.

While the authors acknowledge the use of calculated rather than directly measured remnant cholesterol as a limitation of their study, the findings extend evidence that both higher remnant cholesterol accumulation and variability could further exacerbate ASCVD risk in the general population. Taken together, the implication from this report is that clinicians should not only manage absolute remnant cholesterol levels but also reduce the fluctuation to improve cardiovascular health outcomes.

References

1. Stevens SL, Wood S, Koshiaris C, et al. Blood pressure variability and cardiovascular disease: systematic review and meta-analysis. BMJ 2016;354:i4098.
2. Nuyujukian DS, Koska J, Bahn G, Reaven PD, Zhou JJ. Blood pressure variability and risk of heart failure in ACCORD and the VADT. Diabetes Care. 2020;43:1471–78.
3. Bangalore S, Fayyad R, Messerli FH, et al. Relation of variability of Low-Density lipoprotein cholesterol and blood pressure to events in patients with previous myocardial infarction from the IDEAL trial. Am J Cardiol 2017;119:379–87.
4. Segar MW, Patel KV, Vaduganathan M, et al. Association of long-term change and variability in glycemia with risk of incident heart failure among patients with type 2 diabetes: A secondary analysis of the ACCORD trial. Diabetes Care. 2020;43:1920–8.
5. Fu L, Tai S, Sun J, Zhang N, et al. Remnant cholesterol and its visit-to-visit variability predict cardiovascular outcomes in patients with type 2 diabetes: findings from the ACCORD cohort. Diabetes Care 2022;45:2136-43.

Key words

remnant cholesterol; carotid atherosclerosis; cumulative exposure; visit to visit variability