Elevated remnant cholesterol in atherosclerotic cardiovascular disease in diabetes: a population-based prospective cohort study

Abstract

Abstract Background Elevated remnant cholesterol is observationally and causally associated with increased risk of atherosclerotic cardiovascular disease (ASCVD) in the general population; the association in individuals with diabetes is not known. Purpose We tested the hypothesis that elevated remnant cholesterol is associated with increased risk of peripheral artery disease, myocardial infarction, ischemic stroke, and any ASCVD in individuals with diabetes. Methods We studied 4,569 individuals with diabetes and 102,674 individuals without diabetes from the Copenhagen General Population Study (2003-2015). In those with diabetes, during up to 15 years of follow-up, 236 were diagnosed with peripheral artery disease, 234 with myocardial infarction, 226 with ischemic stroke, and 498 with any ASCVD in national Danish health registries. Remnant cholesterol was calculated from a standard lipid-profile as total cholesterol minus HDL cholesterol minus LDL cholesterol. Results Individuals with diabetes had higher levels of remnant cholesterol, but lower levels of LDL cholesterol, compared to individuals without diabetes (Figure 1). Statin use could explain the lower levels of LDL cholesterol but did not associate with levels of remnant cholesterol. Multivariable adjusted hazard ratios (95% confidence interval) per doubling of remnant cholesterol and LDL cholesterol were 1.8 (1.2-2.5) and 0.9 (0.6-1.2) for peripheral artery disease, 1.8 (1.3-2.6) and 1.0 (0.7-1.4) for myocardial infarction, 1.6 (1.1-2.3) and 1.1 (0.8-1.6) for ischemic stroke, and 1.7 (1.4-2.2) and 0.9 (0.7-1.1) for any ASCVD, respectively. Excess risk conferred by diabetes was 2.5-fold for peripheral artery disease, 1.6-fold for myocardial infarction, 1.4-fold for ischemic stroke, and 1.6-fold for any ASCVD. Elevated remnant cholesterol explained 14% (95% confidence interval: 6-23%) of excess risk of PAD; corresponding numbers were 26% (10-41%) for myocardial infarction, 34% (5-64%) for ischemic stroke, and 24% (12-36%) for any ASCVD (Figure 2). LDL cholesterol was lower in individuals with diabetes than in individuals without diabetes and could therefore not explain excess risk. Conclusions Elevated remnant cholesterol was associated with increased risk of ASCVD in individuals with diabetes and explained 24% of their excess risk of ASCVD. Clinical trials should determine if remnant cholesterol lowering can prevent ASCVD in individuals with diabetes.