Biological Variation in HbA_1c Predicts Risk of Retinopathy and Nephropathy in Type 1 Diabetes

Response to Genuth, Lachin, and Nathan

Genuth, Lachin, and Nathan (1) pose several questions regarding the methodology and conclusions of our recent report (2). We are responding in order to clarify the validity of our approach, results, and conclusions regarding the important relationship between biological variation (BV) in HbA_1c and mean blood glucose (MBG) and the development of microvascular complications of diabetes.

A key consideration in our hypothesis is the existence of consistent between-patient directional differences over time in HbA_1c not accounted for by the associated MBG levels (2). BV in biochemical metabolites is a well-recognized phenomenon in clinical chemistry (3). BV in HbA_1c levels has been reported in individuals without diabetes (4), where MBG has little impact on HbA_1c levels. In patients with diabetes, the strong correlation between HbA_1c and MBG must be taken into account when assessing the impact of BV on HbA_1c levels. The hemoglobin glycation index (HGI) was devised for this purpose (2,5). We have used the HGI to demonstrate the presence of directional BV in HbA_1c in longitudinal data from patients with diabetes in our own clinic population (5) as well as participants in the Diabetes Control and Complications Trial (DCCT) (2). In repeated measures obtained over the course of both studies, we found that large numbers of patients had consistently nonrandom, large positive or negative deviations (high or low HGIs, respectively) of their observed HbA_{1c …}