Lipids and apolipoproteins and the risk of vascular disease and mortality outcomes in women and men with type 2 diabetes in the ADVANCE study

Aim: Whether apolipoproteins (apolipoprotein A1, apolipoprotein B, apolipoprotein B/apolipoprotein A1 [ApoB/ApoA1] ratio) or very-low-density lipoprotein (VLDL) cholesterol are better risk predictors than established lipid risk markers, and whether there are sex differences, is uncertain, both in general populations and in patients with diabetes. The aim of this study was to assess the association between established risk markers, apolipoproteins and the risk of macro- and microvascular disease and death in a large study of women and men with diabetes and to assess the potential sex differences in the associations. Materials and Methods: Established lipid risk markers were studied in 11 140 individuals with type 2 diabetes from the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified-Release Controlled Evaluation (ADVANCE) trial, and apolipoproteins (A1, B, ApoB/ApoA1 ratio) and VLDL cholesterol from nuclear magnetic resonance (NMR) lipid analyses in biobanked samples from 3586 individuals included in the ADVANCE case-cohort study (ADVANCE CC). Primary outcomes were major macro- and microvascular events and death. Cox proportional hazards models adjusted for confounders were used to quantify the associations (hazard ratio [HR] and 95% confidence intervals [CIs]) between established lipid risk markers and apolipoproteins with study outcomes. To address potential effect modification by sex, we investigated the association between the lipid risk markers and outcomes in subgroup analyses by sex. Results: There was a lower risk of macrovascular complications for high-density lipoprotein (HDL) cholesterol (HR [95%CI] 0.88 [0.82-0.95]), a higher risk for total cholesterol (1.10 [1.04-1.17]), low-density lipoprotein (LDL) cholesterol (1.15 [1.08-1.22]), non-HDL cholesterol (1.13 [1.07-1.20]) and the total cholesterol/HDL ratio (1.20 [1.14-1.27]) but no significant associations with triglycerides from ADVANCE. There was a higher risk of macrovascular complications for the ApoB/ApoA1 ratio (1.13 [1.03-1.24]) from the ADVANCE CC. Only the ApoB/ApoA1 ratio (1.19 [1.06-1.34]), but none of the established lipid risk markers, was associated with a higher risk of microvascular complications. There were no statistically significant sex differences for any of the established lipid risk markers or apolipoproteins with any outcome. Using C-statistics and net reclassification improvement (NRI) did not detect significant improvement in predicting all outcomes by adding lipids or apolipoproteins to the models with confounding factors only. Conclusions/Interpretation: All established lipid risk markers, except triglycerides, were predictors of macrovascular complications, but not microvascular complications, in patients with type 2 diabetes. The ApoB/ApoA1 ratio was associated with major macro- and microvascular complications, but there was no evidence that apolipoproteins are better than established lipid risk markers in predicting cardiovascular complications in patients with type 2 diabetes.