Objective: To review recent literature on the limitations of hemoglobin A 1C (HbA 1C) as a marker of glycemic control.Methods: English-language literature published between 1985 and 2011 was reviewed specific to analyses of major trials relating glycemic control to complications of diabetes mellitus, as expressed through HbA 1C as a marker of glycemic control.Results: HbA 1C has been accepted as the most fundamental biomarker in diabetes, if not all of medicine, as it clearly predicts risk for diabetes-related complications. What is not generally appreciated is that HbA 1C is a crude marker of glycemia with many limitations. It is now accepted that HbA 1C does not reflect mean glucose for many people, and even for those it does, any level could represent a wide range of glycemia. While we have learned HbA 1C is not a perfect biomarker, we also know that in the Diabetes Control and Complications Trial, HbA 1C could only explain 11% of the variation in retinopathy risk between the conventional and intensive therapy groups. This important finding suggests that other glycemic and nonglycemic factors may be responsible for the pathogenesis of diabetes-related complications. One candidate is glycemic variability, which must be differentiated from postprandial hyperglycemia since hypoglycemia can also result in inflammatory activation. Importantly, although it is clear that in insulin-requiring patients glycemic variability is associated with hypoglycemia, we require a definitive prospective trial to confirm glycemic variability's association with one or more vascular complications.Conclusions: What is abundantly clear is that the Hb HbA 1C message, as we know it, is too simplistic. While certain wholesome concepts such as motherhood and apple pie are accepted by all, the Hb HbA 1C message may be more complex than originally appreciated, and it may be time to reevaluate our most basic premise in diabetes.
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