Limitations of A1c Interpretation

Jessica G. Shepard, PharmD; Anita Airee, PharmD, BCPS; Andrew W. Dake, MD; M. Shawn McFarland, PharmD; Amit Vora, MD


South Med J. 2015;108(12):724-729. 

In This Article

Alternative Markers for A1c

Alternative markers for diabetic control, including fructosamine, glycated albumin, and 1,5 anhydroglucitol (1,5-AG),[48–51] have been evaluated in recent years. These tests can be considered in clinical practice in situations in which hemoglobin A1c may be unreliable, such as hemoglobinopathies and conditions with a reduced red blood cell lifespan. They also can be considered to assess glycemic control in patients with follow-up less than 1 month apart;[52,53] however, there are no guidelines recommending their use because of a lack of standardization, limited outcome data for diabetic complications, and a lack of consensus target values for glycemic control.[54,55]

Fructosamine is formed when fructose binds to serum proteins, mostly albumin. Glycated albumin is formed by the glycation reaction of serum albumin. The half-life of albumin is 2 to 3 weeks. As such, fructosamine and glycated albumin reflect the average glucose in the last 2 to 3 weeks, as opposed to hemoglobin A1c, which is reflective of the previous 3 months. This difference makes these tests useful in shorter follow-up.[48] Some studies suggest glycated albumin, in particular, could be more reliable than A1c in CKD 4 and 5.[18,56] Like hemoglobin A1c, fructosamine and glycated albumin are not without pitfalls in their interpretation. Liver failure, nephrotic syndrome, and protein-losing enteropathy can lead to falsely low fructosamine and glycated albumin levels caused by hypoalbuminemia. Some studies have looked at correcting for hypoalbuminemia as is done with calcium, but there is no consensus for this.[56a,56b] Conditions with increased protein metabolism, such as hyperthyroidism, hyperuricemia, and hypertriglyceridemia, also can cause falsely low levels. In contrast, conditions with decreased protein metabolism, such as hypothyroidism and cirrhosis, can lead to falsely high levels.[57,58]

1,5-AG is a dietary polyol, structurally similar to glucose, that is normally filtered and completely reabsorbed by the kidneys. Glucose is a competitive inhibitor of 1,5-AG for reabsorption in the kidneys. When glucose levels increase beyond 180 mg/dL (the renal threshold for glucose), glucose is reabsorbed preferentially over 1,5-AG, leading to rapid reductions in 1,5-AG levels. As such, patients with elevated glucose levels will have lower 1,5-AG levels. 1,5-AG does not reflect glycemic variability or hypoglycemia; therefore, it is less useful to assess overall glycemic control. 1,5-AG may be useful in the evaluation for postprandial hyperglycemia, however. Patients with impaired renal function may have falsely low levels of 1,5-AG, so this test would be unhelpful in that situation.[51,59]