Validation of a hemoglobin A1c model in patients with type 1 and type 2 diabetes and its use to go beyond the averaged relationship of hemoglobin A1c and mean glucose level

Background: Glycated hemoglobin A(1c) (HbA(1c)) has been used as an index of glycemic control in the management, guidance, and clinical trials of diabetic patients for the past 35 years. The aim of this study was to validate the HbA(1c) model in patients with type 1 and type 2 diabetes and to use it to support interpretation of HbA(1c) in different clinical situations. Methods: The HbA1c model was identified in 30 patients (15 with type 1 diabetes and 15 with type 2 diabetes) by estimating the overall glycation rate constant (k), based on results of continuous glucose monitoring. The model was validated by assessing its ability to predict HbA(1c) changes in cultures of erythrocytes in vitro and to reproduce results of the A1C-Derived Average Glucose (ADAG) study. The model was used to simulate the influence of different glucose profiles on HbA(1c). Results: The mean k was equal to 1.296 +/- 0.216 x 10(-9) vertical bar mmol(-1) s(-1) with no difference between type 1 and type 2 diabetes. The mean coefficient of variation of k was equal to 16.7%. The model predicted HbA(1c) levels in vitro with a mean absolute difference less than 0.3% (3.3 mmol/mol). It reproduced the linear relationship of HbA(1c) and mean glucose levels established in the ADAG study. The simulation experiments demonstrated that during periods of unstable glycemic control, glycemic profiles with the same mean glucose might result in much different HbA(1c) levels. Conclusions: Patients with type 1 and type 2 diabetes are characterized by the same mean value of k, but there is considerable interindividual variation in the relationship of HbA(1c) and mean glucose level. Results suggest that reciprocal changes in glycation rate and the life span of erythrocytes exist in a wide range of HbA(1c) values. Thus, for an average patient with diabetes, no modifications of parameters of the glycation model are required to obtain meaningful HbA(1c) predictions. Interpreting HbA(1c) as a measure of the mean glucose is fully justified only in the case of stable glycemia. The model and more frequent tests of HbA(1c) might be used to decrease ambiguity of interpreting HbA(1c) in terms of glycemic control.