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

Abstract

Aims/hypothesis: Elevated remnant cholesterol is observationally and causally associated with increased risk of atherosclerotic cardiovascular disease (ASCVD) in the general population. This association is not well studied in individuals with diabetes, who are often included in clinical trials of remnant cholesterol-lowering therapy. We tested the hypothesis that elevated remnant cholesterol is associated with increased risk of ASCVD in individuals with diabetes. We also explored the fraction of excess risk conferred by diabetes which can be explained by elevated remnant cholesterol.

Methods: We included 4569 white Danish individuals with diabetes (58% statin users) nested within the Copenhagen General Population Study (2003-2015). The ASCVDs peripheral artery disease, myocardial infarction and ischaemic stroke were extracted from national Danish health registries without losses to follow-up. Remnant cholesterol was calculated from a standard lipid profile.

Results: During up to 15 years of follow-up, 236 individuals were diagnosed with peripheral artery disease, 234 with myocardial infarction, 226 with ischaemic stroke and 498 with any ASCVD. Multivariable adjusted HR (95% CI) per doubling of remnant cholesterol was 1.6 (1.1, 2.3; p=0.01) for peripheral artery disease, 1.8 (1.2, 2.5; p=0.002) for myocardial infarction, 1.5 (1.0, 2.1; p=0.04) for ischaemic stroke, and 1.6 (1.2, 2.0; p=0.0003) for any ASCVD. Excess risk conferred by diabetes was 2.5-fold for peripheral artery disease, 1.6-fold for myocardial infarction, 1.4-fold for ischaemic stroke and 1.6-fold for any ASCVD. Excess risk explained by elevated remnant cholesterol and low-grade inflammation was 14% and 8% for peripheral artery disease, 26% and 16% for myocardial infarction, 34% and 34% for ischaemic stroke, and 24% and 18% for any ASCVD, respectively. LDL-cholesterol did not explain excess risk, as it was not higher in individuals with diabetes. We also explored the fraction of excess risk conferred by diabetes which can be explained by elevated remnant cholesterol.

Conclusions/interpretation: Elevated remnant cholesterol was associated with increased risk of ASCVD in individuals with diabetes. Remnant cholesterol and low-grade inflammation explained substantial excess risk of ASCVD conferred by diabetes. Whether remnant cholesterol should be used as a treatment target remains to be determined in randomised controlled trials.

Keywords: Impaired glucose tolerance; Insulin resistance; Lower-extremity arterial disease; Triglyceride-rich lipoprotein; Very-low-density lipoprotein.

Fig. 1

Remnant cholesterol (a, b) and LDL-cholesterol (c, d) levels of individuals in the Copenhagen General Population Study grouped by diabetes status (a, c), and by statin use in individuals with diabetes within the study (b, d). Individuals with diabetes had higher levels of remnant cholesterol, but lower levels of LDL-cholesterol, compared to individuals without diabetes

Fig. 2

Risk of ASCVD per doubling of remnant cholesterol and LDL-cholesterol in individuals with diabetes from the Copenhagen General Population Study. Higher remnant cholesterol, but not LDL-cholesterol, was associated with increased risk of ASCVD and its components peripheral artery disease, myocardial infarction and ischaemic stroke in individuals with diabetes. Results are from Cox regression adjusted for age, sex, systolic BP, diastolic BP, smoking status, cumulative smoking, birth year, non-fasting plasma glucose and LDL-cholesterol (in remnant cholesterol analyses) or remnant cholesterol (in LDL-cholesterol analyses). The Bonferroni-corrected threshold equivalent to p=0.05 is 0.05/8=0.00625 due to eight statistical tests. Number of events per 1000 person-years is from unadjusted Poisson regression. No., number

Fig. 3

Excess risk of ASCVD in individuals with diabetes from the Copenhagen General Population Study. Individuals with diabetes had higher risk of ASCVD and its components peripheral artery disease, myocardial infarction and ischaemic stroke, compared to individuals without diabetes. Risk of peripheral artery disease was particularly increased. Results were similar when statin users and smokers were excluded. Results are from Cox regressions adjusted for age, sex, smoking status, cumulative smoking and birth year. The Bonferroni-corrected threshold equivalent to p=0.05 is 0.05/12= 0.0042 due to 12 statistical tests. No., number

Fig. 4

Explained excess risk of ASCVD in diabetes by remnant cholesterol, LDL-cholesterol and low-grade inflammation in the Copenhagen General Population Study. Excess risk of ASCVD and its components peripheral artery disease, myocardial infarction and ischaemic stroke in individuals with diabetes could be partly explained by elevated remnant cholesterol and low-grade inflammation measured as elevated high-sensitivity C-reactive protein, but not by elevated LDL-cholesterol. LDL-cholesterol was lower in individuals with diabetes than in individuals without diabetes and could therefore not explain excess risk. Results are from Cox regressions adjusted for age, sex, smoking status, cumulative smoking and birth year. The Bonferroni-corrected threshold equivalent to p=0.05 is 0.05/12= 0.0042 due to 12 statistical tests. NA, not applicable