Progression of Nephropathy in Type 2 Diabetes: The Glycation Gap Is a Significant Predictor After Adjustment for Glycohemoglobin (Hb A1c)

BACKGROUND: The glycation gap has been proposed as an index of nonglycemic determinants of glycated hemoglobin (Hb A1c). We investigated whether it predicts progression of nephropathy in type 2 diabetic patients. METHODS: We recorded albumin excretion rate, Hb A1c, and serum fructosamine in 2314 patients over an average of 6.5 years. Hb A1c was regressed on fructosamine by using a repeated-measures longitudinal regression model and data for all visits of all patients; the raw glycation gap gg was calculated at each visit, as measured by Hb A1c minus the value predicted by the regression; and the mean glycation gap (GG) was defined for each patient as the mean of the values for the raw glycation gap (gg) calculated at each visit. The study group was divided into high-, medium- and low-GG groups of equal sizes, which were compared for progression of nephropathy by Cox regression analyses controlling for age, sex, duration of diabetes, initial nephropathy status, therapy, baseline Hb A1c, mean Hb A1c, and mean fructosamine. The design of the study was a retrospective cohort study with follow-up for 6.5 (SD 4.2) years. RESULTS: The gg exhibited considerable stability over time. In the high- and medium-GG groups, the risk of progression of nephropathy was respectively 2.5 and 1.6 times that of the low-GG group ( P < 0.0001 and P = 0.001, respectively) after adjustment as described above. CONCLUSIONS: GG predicts the progression of nephropathy in type 2 diabetic patients independently of fructosamine and even after adjustment for Hb A1c. The joint use of the glycation gap and fructosamine as measures of nonglycemic and glycemic determinants of glycation, respectively, may improve evaluation of the risk of nephropathy and of the glycemic control desirable for the individual patient.