Caveats regarding the use of HbA1c for prediction of mean blood glucose.

To the Editor: In a recent article, Nathan et al. [1] confirm a strong linear relationship between mean blood glucose (MBG) derived from continuous glucose monitoring (CGM) and HbA1c in 25 selected individuals observed for 12 weeks. The published study was conducted using CGM to eliminate variation in the relationship between HbA1c and MBG that might be due to non-representative glucose sampling. Based on the strong association between CGMderived MBG and HbA1c, the authors advocate that an individual’s HbA1c level is interchangeable with and can be safely interpreted as the estimated MBG based on the population regression equation. They further imply that the high degree of correlation supports the idea that HbA1c should be ‘used universally to adjust therapy’. After carefully reviewing both the authors’ data and similar data presented at the European Association for the Study of Diabetes (EASD) annual meeting [2], we wish to offer an alternative perspective to this ‘one size fits all’ concept. The authors’ Fig. 1 is a scattergram depicting the relationship between CGM-derived MBG and HbA1c. A horizontal line across the graph at a MBG of 8 mmol/l identifies two patients with HbA1c of about 6.5 and 8.0%, respectively [1]. Two patients, same MBG, yet one has a near normal HbA1c while the other has an unacceptably high HbA1c. Other examples of between-patient variation in HbA1c at the same MBG are apparent elsewhere in the figure and in the data presented at the EASD meeting [2]. Nathan et al. had faulted prior studies [3, 4] of the relationship between MBG and HbA1c for inadequate glucose sampling protocols that may have led to overor underestimation of the patient’s true MBG. In the present study, Nathan et al. overcame the problem of non-representative glucose sampling by using a more intensive glucose sampling protocol over 12 weeks, which would have allowed them to achieve the best possible estimate of a patient’s true MBG. Thus, the between-patient variation in HbA1c at the same MBG found in the data of Nathan et al. is unlikely to be due to inaccurate MBG caused by inadequate sample size or sampling biased to certain times of day. In this respect, the authors’ data resemble those reported by the Diabetes Research in Children Network (DirecNet) investigators, who also used CGM and observed between-patient variation in HbA1c independent of MBG [5]. Between-patient differences in HbA1c not due to MBG have been well documented in the literature, using less sophisticated glucose sampling protocols but with similar results (citations in [3] and [6]). In longitudinal studies evaluating repeated measures of MBG and HbA1c within individuals over time, we have shown that between-patient differences are not due to random variation, but instead track consistently through time and with changes of MBG [3, 6]. Furthermore, these between-patient HbA1c differences appear to be unrelated to erythrocyte longevity [3]. The widely cited DCCT study followed more than 1400 patients with repeated measures of MBG and HbA1c every 3 months for up to 9 years [7]. Albeit with a simple glucose sampling protocol, the DCCT also reported an impressive linear association between HbA1c and MBG [4]. However, large, non-random, consistently repeatable between-patient differDiabetologia (2008) 51:903–904 DOI 10.1007/s00125-008-0968-1