The association between time-weighted remnant cholesterol and cardiovascular and non-cardiovascular mortality: A population-based cohort study

Background: Remnant cholesterol (RC) have been suggested as a significant mediator of atherosclerotic cardiovascular diseases. However, the relationship between RC with cause-specific mortality in long-term remained uncertain. This study aimed to investigate the association between time-weighted RC and cause-specific mortality outcomes. Methods: This retrospective population-based study enrolled patients attending family medicine clinics in Hong Kong between 1st January 2000, to 31st December 2003 with at least three RC testing results during follow-up. The time-weighted RC was calculated by the products of the sums of two consecutive measurements and the time interval divided by the total time. The primary outcomes were all-cause mortality and cause-specific mortality outcomes. Cox regression and marginal effective plots were applied to identify associations between time-weighted RC and mortality. Results: A cohort of 75,342 patients (39.69% males, mean age: 61.3 years old) with at least three valid RC test were included. During up to 19 years of follow-up, in the multivariate model adjusted for demographics, comorbidities, medications, and time-weighted laboratory results, time-weighted RC was associated with all-cause mortality (Hazard ratio [HR]: 1.41; 95% Confidence Interval [CI]: 1.35-1.48) but not RC (HR: 0.99; 95% CI: 0.89-1.10). Time-weighted RC was also associated with increased risks of cardiovascular-related mortality (HR: 1.40; 95% CI: 1.27-1.54), cancer-related mortality (HR: 1.59; 95% CI: 1.43-1.77), and respiratory-related mortality (HR: 1.33; 95% CI: 1.20-1.47). The exploratory analysis of the cause of death demonstrated that time-weighted RC was associated with Ischaemic heart disease, cerebrovascular-related and pneumonia. Conclusions: Time-weighted RC was independently associated with all-cause mortality and cause-specific mortality outcomes amongst the general population. Keywords: Cause-specific mortality, Low-density lipoprotein, Very-low-density lipoprotein, Intermediate-density lipoprotein, Remnant cholesterol, Atherosclerosis, Cardiovascular disease ### Competing Interest Statement G.Y.H.L. is a consultant and speaker for BMS/Pfizer, Boehringer Ingelheim, Anthos and Daiichi-Sankyo. No fees are directly received personally. He is a National Institute for Health and Care Research (NIHR) Senior Investigator and co-principal investigator of the AFFIRMO project on multimorbidity in AF, which has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No 899871. The remaining authors have no disclosures to report. ### Funding Statement This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This study was approved by the Institutional Review Board of the University of Hong Kong/ Hospital Authority Hong Kong West Cluster (Reference No. UW 20-250). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The data that support the findings of this study were provided by the Hong Kong Hospital Authority, but restrictions apply to the availability of these data, which were used under license for the current study, and so are not publicly available. Data are however available from the authors upon reasonable request and with permission of Hong Kong Hospital Authority.