Area-under-the-HbA1c-curve above the normal range and the prediction of microvascular outcomes: an analysis of data from the Diabetes Control and Complications Trial

Aims: In the Diabetes Control and Complications Trial, mean updated HbA1c accounted for most of the differential risk of microvascular complications between intensive and conventional insulin therapy. We hypothesized, however, that a more precise measure of chronic hyperglycaemic exposure may be the incremental area-under-the-HbA_1c-curve above the Diabetes Control and Complications Trial-standardized normal range for HbA_1c (iAUC_HbA1c>norm).

 

Methods: Using the Principal Diabetes Control and Complications Trial data set, we compared the following three measures of chronic glycaemic exposure for their capacity to predict retinopathy, nephropathy and neuropathy during the Diabetes Control and Complications Trial: mean updated HbA_1c, iAUC_HbA1c>norm, and total area-under-the-HbA_1c-curve (tAUC_HbA1c). For each outcome, models using each of these three glycaemic measures were compared in the following three ways: hazard or odds ratio, χ² statistic, and Akaike information criterion.

 

Results: The three glycaemic measures did not differ in their prediction of neuropathy. iAUC_HbA1c>norm was modestly superior to mean updated HbA_1c for predicting nephropathy (χ²P = 0.017, Akaike P = 0.032). In contrast, for predicting retinopathy, both iAUC_HbA1c>norm(χ²P = 0.0005, Akaike P = 0.0005) and tAUC_HbA1c (χ²P = 0.004, Akaike P = 0.004) were significantly better than mean updated HbA_1c. Varying its HbA_1c threshold incrementally between 37 and 53 mmol/mol (5.5–7.0%), inclusive, did not improve the prediction of retinopathy by iAUC_{HbA1c>threshold} beyond that of tAUC_HbA1c,consistent with the concept of a continuous relationship between glycaemia and retinopathy, with no glycaemic threshold.

 

Conclusions: Both iAUC_HbA1c>norm and tAUC_HbA1c were superior to mean updated HbA_1c for predicting retinopathy. Optimal assessment of chronic glycaemic exposure as a determinant of retinopathic risk may require consideration of both the degree of hyperglycaemia and its duration.