The Reporting of Estimated Glucose with Hemoglobin A1c

Hemoglobin A1c (Hb A1c) 2 is a key parameter for understanding glycemic control in diabetes. It is used by both clinicians and patients to trigger adjustments in behavior and treatment. In general, clinicians understand Hb A1c and its limitations well, but evidence suggests that patients have difficulty understanding what Hb A1c means and how it relates to glucose. This situation may be particularly applicable for patients who regularly monitor their own glucose. We know a relationship exists between Hb A1c levels and average glucose concentrations over approximately 4 months, and it seems intuitive that it should be possible to express Hb A1c in terms of average glucose to provide a measure that patients more easily understand. Therefore, following completion and publication of the A1cDerived Average Glucose (ADAG) study (1 ), a proposal was made to report Hb A1c as estimated average glucose (eAG) concentration by means of an equation derived from the ADAG study data set, as well as in conventional units (percent and millimoles per mole hemoglobin) (2 ). Although all clinicians and laboratory specialists will support the desire to promote understanding of Hb A1c, many have challenged whether converting Hb A1c to eAG is scientifically justified from the available evidence and whether it is likely to be helpful in practice. This Counterpoint summarizes the case against eAG. No single relationship exists between average glucose and Hb A1c; therefore, it is not possible to have a single equation that expresses Hb A1c as eAG and is applicable to all patients. The proposal to express Hb A1c as eAG is underpinned by a number of assumptions. For such an approach to be valid, a consistent mathematical relationship between glucose concentration and the extent of glycation is necessary, so that if 2 individuals have identical glucose profiles over a period of several months, they should have identical Hb A1c levels. A wealth of evidence shows that this is not the case. The extent to which glycation of hemoglobin occurs at a given glucose concentration is likely to be influenced by a variety of environmental parameters, including, for instance, lipid peroxidation. In addition, glycated proteins (including hemoglobin) may undergo further reactions that lead to deglycation (3 ), a process that is likely to vary between individuals. Glycation potentially affects all proteins, both intracellular and extracellular, and the term “glycation gap” refers to the difference that exists between the glycation of hemoglobin and glycation of extracellular proteins (4 ). Glycation of extracellular proteins is generally determined simply by exposure to glucose, but in the case of hemoglobin, additional factors come into play, including the extent to which glucose enters red blood cells, the half-life of the red blood cell, and the extent of competing glycating and deglycating reactions. Studies of twins have shown that approximately 70% of the glycation gap is hereditary and cannot be explained by differences in average glucose concentrations (4 ). The authors concluded that there are gene(s) that preferentially affect erythrocyte life span, glucose, and/or nonenzymatic glycation or deglycation in the intracellular, rather than the extracellular, compartment. Variation in these genes will lead to between-individual differences in Hb A1c levels and the glycation gap when patients are exposed to similar glucose concentrations. In keeping with the concept that there are important genetic determinants of Hb A1c levels that are independent of the glucose concentration, a number of large studies have shown Hb A1c differences among ethnic groups after adjusting for both fasting and postprandial glucose, as well as for other demographic and clinical features. Herman et al. assessed various measures of glycemic control in 2000 patients with type 2 diabetes from several racial groups (5 ) and found differences in Hb A1c levels, but not in mean plasma glucose concentrations, among racial/ethnic groups. Mean (SD) levels of Hb A1c were higher in Hispanics [9.4% (1.4%)], Asians [9.2% (1.4%)], and patients of other racial/ethnic groups [9.7% (1.5%)], compared with Caucasians [8.9% (1.2%)]. In the Diabetes Prevention Program, which involved 3000 patients with impaired glucose tolerance, the mean Hb A1c level in non-Hispanic whites was 5.78%, whereas the corre1 Centre for Public Health, Queen’s University Belfast, Belfast, Northern Ireland. * Address correspondence to the author at: First Floor ICS B Block, Royal Victoria Hospital, Grosvenor Rd., Belfast BT12 6BJ, Northern Ireland, UK. Fax 442890-235900; e-mail [email protected]. Received January 17, 2010; accepted January 29, 2010. Previously published online at DOI: 10.1373/clinchem.2009.138677 2 Nonstandard abbreviations: Hb A1c, hemoglobin A1c; ADAG, A1c-Derived Average Glucose; eAG, estimated average glucose; DCCT, Diabetes Control and Complications Trial. Clinical Chemistry 56:4 547–549 (2010) Point/Counterpoint