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How to Optimize Antidiabetic Pharmacotherapy Using the Clinical Significance of HbA1c Variations

Nov 20, 2015

Very elevated HbA1c associated with fasting blood glucose levels.

Huisman and Meyering were the first to separate Hemoglobin A1c from other forms of hemoglobin. (Hb A1a and A1b were also recognized then.) While A1c was identified as a glycoprotein in 1968 by Bookchin and Gallop, the distinction of describing its increase in people with diabetes rests with Samuel Rahbar and his colleagues. Koenig and coworkers were responsible for the inclusion of A1c in monitoring the control over glucose metabolism, especially in people with diabetes. Thus, the clinical significance of HbA1c came into play.


Glycosylated Hemoglobin count (Hb A molecules), a form of the hemoglobin compound, is used by doctors to identify the average level of plasma glucose concentration over an extended period of time. In the process called glycosylation, the hemoglobin’s normal exposure to high blood sugar levels usually takes place in a controlled environment i.e. it is overseen by enzymes. But the A1c subtype of hemoglobin is formed in a non-enzymatic pathway (in the absence of these regulating enzymes). Thus the process of A1c formation is called non-enzymatic glycosylation or “glycation.”

However, not all hemoglobin is converted to HbA1c. The conversion rate depends heavily on the concentration of glucose that the hemoglobin is exposed to (i.e. the average plasma glucose) and the duration of such exposure.

Monitoring the HbA1c levels of a person with diabetes tremendously aids the patient’s treatment. By observing long-term serum glucose regulation, the effectiveness of diabetes treatment can be estimated. Nevertheless, certain important details need to be kept in mind while decoding the HbA1c values.

While the HbA1c counter is proportionate to average blood sugar levels over the past 4 weeks to 3 months, a major portion of the final reading actually reflects only the value of, at most, the past 2–4 weeks.

Some people have persistently elevated blood glucose, e.g. patients with diabetes mellitus or whose red blood cell lifespan is longer (due to deficiency of Vitamin B12 or folate).

Readings can also be lower than normal in patients with reduced red blood cell lifespan (due to sickle cell disease, glucose-6-phosphate, hemolytic anemia, or dehydrogenase deficiency) or any condition resulting in the premature death of RBCs.

There is always bound to be a mixture of old RBCs (exposed to recent and past blood glucose levels) and new RBCs (exposed to recent blood glucose levels). Therefore, it is thought that half of an HbA1c value can be attributed to the previous month, a quarter to the month preceding that and the final quarter to two months before.

The commonly used diabetes marker HbA1c deserves more analysis. The American Association for Clinical Chemistry recently held a free, informative webinar about HbA1c. Dr. Randie R. Little of University of Missouri and Dr. Steven D. Wittlin of University of Rochester Medical Center spoke at the American Association for Clinical Chemistry and covered different factors affecting HbA1c, including the natural variants of it, factors affecting it, and the clinical significance of HbA1c (A1c).

Dr. Little reminded that there are four common hemoglobin variants: A, S, C, E, and F. Hemoglobin A is the most common form, and the majority of people are homozygous for it. Hemoglobin F is the fetal variant, which typically decreases after infancy. Hemoglobin F is probably clinically benign. Cation-exchange high performance liquid chromatography tests usually can distinguish between hemoglobins F and A, allowing for accurate HbA1c results. This is because hemoglobin F is sufficiently structurally distinct from hemoglobin A. Hemoglobin S is the most common of the variants, found in those with North African, Middle Eastern, and Indian descent. It gives falsely elevated HbA1c results. Hemoglobin C is most commonly found in people with West African and Caribbean heritage. Its impact on HbA1c readings is less clear than the impact of the other variants, but it is suggested that it results in elevated HbA1c, similar to hemoglobin S. Hemoglobin E, most prevalent among Asian populations, skews HbA1c lower, especially with high performance liquid chromatography tests versus affinity chromatography.

Aside from genetic variations in hemoglobin, HbA1c can be altered by other factors. Chronic kidney disease can result in increased carbamylated hemoglobin, which can interfere with some assays as well. Other factors affecting HbA1c readings are alcohol abuse and chronic opioid use. In addition, the impact of these genetic variants or external factors on HbA1c readings differs based upon the method used to read HbA1c. Examples of methods to read HbA1c are immunoassay, capillary electrophoresis, ion-exchange chromatography, and affinity binding.

Dr. Wittlin then went over the clinical importance of Hba1c. Despite the potential for skewed results, HbA1c is still a clinically valuable tool. According to various landmark trials, such as UKPDS and DCCT, lowering HbA1c results in decreased retinopathy, proteinuria, and neuropathy. One of the most interesting and important points Dr. Wittlin made was about goal HbA1c for diabetic patients. Dr. Wittlin said that the evidence suggests that an ideal goal of HbA1c is essentially as low as possible as long as the risk of hypoglycemia does not interfere with this goal. Less stringent HbA1c goals (e.g. < 8% or so) should be reserved for those with limited life expectancy, advanced comorbidities, or risk of hypoglycemia. (See publisher’s note.)

It is important to know that at very elevated HbA1c levels, reductions in fasting plasma glucose are more closely associated with reductions in HbA1c. As HbA1c becomes lower and closer to 8% or 7%, then post-prandial blood glucose is more important. This knowledge, combined with accurate blood glucose records from patients, can help guide clinicians on how to optimize antidiabetic pharmacotherapy for their patients who are having trouble reducing HbA1c at all levels.

Another important point about HbA1c is that there is controversy over the commercially available point-of-care testing. It may not be as accurate as results from a blood draw sent to a lab for HPLC or another method.

Practice Pearls:

  • HbA1c readings can be skewed by many factors, such as genetic variants of hemoglobin and disease states.
  • Very elevated HbA1c is associated with fasting blood glucose levels.
  • HbA1c closer to goal is associated with postprandial blood glucose levels.
  • Point-of-care HbA1c testing may not be as accurate as results from a blood draw sent to a lab for HPLC or another method.

Publisher’s Note:  It is important that patients understand the importance of what their HbA1c test results are.  It can determine your potential risk for not just diabetes and cardiovascular death, but your increased risk for every disease known to man, as blood sugars attached to every red blood cell can decrease your resistance to diseases.

Little RR, Wittlin SD. “American Association for Clinical Chemistry (AACC). Using HbA1c Wisely – An AACC Webinar.” Presented:November 11, 2015.