Elevated remnant cholesterol is estimated to mediate part of excess cardiovascular risk in the metabolic syndrome: two cohort studies of 537,885 individuals

Background Individuals with the metabolic syndrome have elevated remnant cholesterol and increased cardiovascular risk. We tested the hypothesis that elevated remnant cholesterol mediates part of the excess risk of myocardial infarction, atherosclerotic cardiovascular disease (ASCVD), and all-cause mortality in the metabolic syndrome. Methods We included 117,108 and 420,777 individuals from the 2003–2015 Copenhagen General Population Study and the 2006–2010 UK Biobank, of which 35,050 and 143,909 had the metabolic syndrome. All individuals were followed in national health registers until December 2021, during which time 3,187 and 9,166 developed myocardial infarctions and 11,275 and 39,860 ASCVD in the two studies, respectively. The main statistical analyses were Cox regression and mediation analysis, multivariable adjusted and stratified on lipid-lowering therapy use. Results In both studies, individuals with versus without the metabolic syndrome had higher remnant cholesterol. In individuals with the metabolic syndrome from the Copenhagen General Population Study, a 1 mmol/L (39 mg/dL) higher remnant cholesterol conferred a hazard ratio for myocardial infarction of 1.39 (95% CI: 1.15–1.69) and 1.21 (1.07–1.36) in those with and without lipid-lowering therapy. Corresponding values in the UK Biobank were 1.36 (1.13–1.63) and 1.25 (1.11–1.40), respectively. In the two cohorts, elevated remnant cholesterol was estimated to mediate 16–48% of the excess risk of myocardial infarction from the metabolic syndrome in those with lipid-lowering therapy use and 12–24% in those without lipid-lowering therapy. The corresponding results for ASCVD were similar, but with lower hazard ratios and a smaller fraction of the excess risk estimated to be mediated. For all-cause mortality, remnant cholesterol was estimated to mediate part of the excess risk from the metabolic syndrome in individuals using lipid-lowering therapy. Results were similar in women and men. Conclusions In individuals with the metabolic syndrome, elevated remnant cholesterol was estimated to mediate a part of the excess risk of myocardial infarction and ASCVD, and among lipid-lowering therapy users, part of the excess risk of all-cause mortality.