Potential Clinical Error Arising From Use of HbA1c in Diabetes: Effects of the Glycation Gap

The glycation gap (GGap) and the similar hemoglobin glycation index (HGI) define consistent differences between glycated hemoglobin and actual glycemia derived from fructosamine or mean blood glucose, respectively. Such a disparity may be found in a substantial proportion of people with diabetes, being >1 U of glycated HbA1c% or 7.2 mmol/mol in almost 40% of estimations. In this review we define these indices and explain how they can be calculated and that they are not spurious, being consistent in individuals over time. We evaluate the evidence that GGap and HGI are associated with variation in risk of complications and mortality and demonstrate the potential for clinical error in the unquestioning use of HbA1c. We explore the underlying etiology of the variation of HbA1c from mean glucose in blood plasma, including the potential role of enzymatic deglycation of hemoglobin by fructosamine-3-kinase. We conclude that measurement of GGap and HGI are important to diabetes clinicians and their patients in individualization of therapy and the avoidance of harm arising from consequent inappropriate assessment of glycemia and use of therapies.