High-density lipoprotein cholesterol in diabetes: is higher always better?

BACKGROUND: Recent data suggest that highly elevated high-density lipoprotein cholesterol (HDL-C) may not always protect against cardiovascular disease. To what degree this is true in type 1 diabetes is unknown, although cardiovascular risk is increased despite elevated mean HDL-C.
OBJECTIVE: To reassess the association between HDL-C and its subfractions with coronary artery disease (CAD) in childhood-onset type 1 diabetes.
METHODS: Epidemiology of Diabetes Complications study participants free of CAD at baseline (301 men, 298 women; mean age, 27.1 and diabetes duration, 18.9 years) were studied. CAD was defined as angina, ischemic electrocardiogram changes, confirmed myocardial infarction, angiographic stenosis ≥50%, revascularization, or CAD death. Cholesterol in the HDL fraction and HDL3 cholesterol subfraction was measured enzymatically after precipitation with heparin/manganese and dextran sulfate, respectively.
RESULTS: During 18 years of follow-up, 29.5% of men and 25.5% of women developed CAD. Although a linear decrease in incidence was observed with increasing HDL-C concentration in men, incidence increased in women at less than 47 mg/dL and greater than 80 mg/dL. These patterns largely reflected the HDL3 cholesterol-CAD association. After multivariable adjustment, the linear, inverse, HDL-C/CAD association persisted in men (hazard ratio [HR] 0.97, 95% confidence interval [CI] 0.94-0.99); in women, the U-shaped relationship lost significance. HDL3 cholesterol remained multivariably associated with CAD in both men (linear association, P = .03) and women (HR 2.31 (95% CI 1.31-4.08) and HR 1.80 (95% CI 1.01-3.23) for the lowest and highest versus the middle quintiles, respectively).
CONCLUSION: The increased CAD risk in women for an HDL-C >80 mg/dL in type 1 diabetes merits further study. Gender specificity could not be determined as only two men had HDL-C >80 mg/dL.