High‐Density Lipoprotein Particle Concentration and Size Predict Incident Coronary Artery Disease Events in a Cohort With Type 1 Diabetes

Background The cholesterol efflux capacity of high density lipoprotein (HDL) is negatively associated with cardiovascular risk. Small HDL particles account almost quantitatively for cholesterol efflux capacity, perhaps mediated through efflux of cholesterol and outer leaflet plasma membrane phospholipids by ABCA1 (ATP binding cassette subfamily A member 1). People with type 1 diabetes are at increased coronary artery disease (CAD) risk despite normal HDL‐cholesterol concentrations. We therefore tested the hypothesis that small HDL particles (HDL‐P)—rather than HDL‐cholesterol—predict incident CAD in type 1 diabetes. Methods and Results Incident CAD (CAD death, myocardial infarction, or coronary revascularization) was determined in 550 individuals with childhood‐onset type 1 diabetes. HDL‐P was quantified by calibrated ion mobility analysis and cholesterol efflux capacity was quantified with validated assays. During a median follow‐up of 26 years, 36.5% of the participants developed incident CAD, for an incidence density of 181.3 per 10 000 person‐years. In multivariable Cox models, neither HDL‐cholesterol nor apolipoprotein A1 concentration was significantly associated with CAD risk. In contrast, higher extra‐small HDL‐P concentrations were significantly associated with decreased CAD risk (hazard ratio [HR], 0.26 [95% CI, 0.14–0.50]). Weaker associations were observed for total HDL‐P (HR, 0.88 [95% CI, 0.83–0.93]), small HDL (HR, 0.83 [95% CI, 0.68–1.02]), medium HDL (HR, 0.79 [95% CI, 0.71–0.89]), and large HDL (HR, 0.72 [95% CI, 0.59–0.89]). Although cholesterol efflux capacity was negatively associated with incident CAD, this association was no longer significant after adjustment for total HDL‐P. Conclusions Lower concentrations of total HDL‐P and HDL subpopulations were positively associated with incident CAD independently of HDL‐cholesterol, apolipoprotein A1, and other common CVD risk factors. Extra‐small HDL was a much stronger predictor of risk than the other HDLs. Our data are consistent with the proposal that extra‐small HDL plays a critical role in cardioprotection in type 1 diabetes, mediated by macrophage cholesterol efflux by the ABCA1 pathway.