HDL cholesterol efflux normalised to apoA-I is associated with future development of type 2 diabetes: from the CORDIOPREV trial

Abstract

This prospective study evaluated whether baseline cholesterol efflux is associated with future development of type 2 diabetes (T2DM) in cardiovascular patients. We measured cholesterol efflux in all CORDIOPREV study (NCT00924937) participants free of T2DM at baseline (n = 462) and assessed its relationship with T2DM incidence during a 4.5 years of follow-up. Cholesterol efflux was quantified by incubation of cholesterol-loaded THP-1 cells with the participants' apoB-depleted plasma. Disposition index was estimated as beta-cell function indicator. During follow-up 106 individuals progressed to T2DM. The cholesterol efflux/apoA-1 ratio was inversely associated with T2DM development independently of traditional risk factors (model-1, OR: 0.647, 95%CI: 0.495-0.846), and after additional adjustment for glycaemic parameters (model-2, OR: 0.670, 95%CI: 0.511-0.878). When cumulative incidence of diabetes was analysed by quartiles of cholesterol efflux/apoA-I, incidence of T2DM was reduced by 54% in subjects who were in the higher cholesterol efflux/apoA-I quartile compared to subjects in the lowest quartile (p = 0.018 and p = 0.042 for model-1 and 2). Moreover, participants who were in the higher cholesterol efflux/apoA-I presented significantly higher disposition index (β = 0.056, SE = 0.026; p = 0.035). In conclusion, HDL-cholesterol efflux normalised to apoA-I was inversely associated with T2DM development in cardiovascular patients. This association was independent of several T2DM risk factors, and may be related to a preserved beta-cell function.

Figure 1

Cholesterol efflux and cholesterol efflux/apoA-I ratio by glycaemic status at the end of the follow-up period. Scatterplot showed raw data of cholesterol efflux in % (a) and cholesterol efflux normalised by apoA-I (b) in subjects who remained as non-diabetic and subjects that progressed to diabetes. Black bars indicated mean values in each group. *p < 0.005 between groups analysed by univariate model adjusted by age, sex BMI and batch number.

Figure 2

Odds ratio (95% CI) for T2DM. Odds ratio for continuous variables are per 1-SD increase. Logistic regression model 1 (●) adjusted by age, sex, BMI, smoking status, alcohol drinking, lipid-lowering treatment, hypertension, serum triglycerides and batch number (in case of cholesterol efflux). In model 2 (○) additional adjustment by HbA1c, HOMA-IR and Disposition Index was done.

Figure 3

Receiver operator characteristic (ROC) curves from logistic regression models predicting T2DM. Model 1 (red line, AUC = 0.620) included the variables age, sex, BMI, smoking status, alcohol drinking, lipid-lowering treatment, hypertension, serum triglycerides and batch number. Model 2 (green line, AUC = 0.704) included the variables in model 1 plus glucose metabolism variables (Disposition Index, HOMA-IR and HbA1c). When cholesterol efflux/apoA-I ratio was added to both model 1 (yellow line, AUC = 0.753) and model 2 (blue line, AUC = 0.785), the prediction of both models increased significantly (p < 0.001).

Figure 4

Cumulative T2DM free-survival by cholesterol efflux/apoA-I ratio quartiles. Cox regression models with outcome of T2DM are shown for quartiles of cholesterol efflux/apoA-I ratio, with the use of quartile 1 (subjects with the lowest cholesterol efflux capacity) as reference. Model 1 were adjusted by age, sex, BMI, smoking status, alcohol drinking, lipid-lowering treatment, hypertension, serum triglycerides and batch number. In Model 2, additional adjustment by Disposition Index, HOMA-IR and HbA1c were done. (*p < 0.05 quartile 4 vs quartile 1).