Association of Glycation Gap With Mortality and Vascular Complications in Diabetes

OBJECTIVE: The “glycation gap” (G-gap), an essentially unproven concept, is an empiric measure of disagreement between HbA(1c) and fructosamine, the two indirect estimates of glycemic control. Its association with demographic features and key clinical outcomes in individuals with diabetes is uncertain. RESEARCH DESIGN AND METHODS: The G-gap was calculated as the difference between measured HbA(1c) and a fructosamine-derived standardized predicted HbA(1c) in 3,182 individuals with diabetes. The G-gap’s associations with demographics and clinical outcomes (retinopathy, nephropathy, macrovascular disease, and mortality) were determined. RESULTS: Demographics varied significantly with G-gap for age, sex, ethnic status, smoking status, type and duration of diabetes, insulin use, and obesity. A positive G-gap was associated with retinopathy (odds ratio 1.24 [95% CI 1.01–1.52], P = 0.039), nephropathy (1.55 [1.23–1.95], P < 0.001), and, in a subset, macrovascular disease (1.91 [1.18–3.09], P = 0.008). In Cox regression analysis, the G-gap had a “U”-shaped quadratic relationship with mortality, with both negative G-gap (1.96 [1.50–2.55], P < 0.001) and positive G-gap (2.02 [1.57–2.60], P < 0.001) being associated with a significantly higher mortality. CONCLUSIONS: We confirm published associations of G-gap with retinopathy and nephropathy. We newly demonstrate a relationship with macrovascular and mortality outcomes and potential links to distinct subpopulations of diabetes.