Type 2 Diabetes and Glycated Hemoglobin (HbA1c)
Where Have We Been and Where Are We Going?
December 2020
Volume 1, Issue 1


Welcome from W. Patrick Zeller, MD

In this edition of EndoScan, we will focus on glycated hemoglobin (HbA1c) goals in the non-pregnant type 2 diabetic.  We have included seven abstracts that address the implications of tight glycemic control, as well as the current controversy around HbA1c. Treatment to goal HbA1c is less than 7%.

To begin, I’d like to set the stage by quickly reviewing the development of HbA1c as a tool in diabetes treatment. HbA1c has been used now for over a half century.

HbA1c History

Glycated hemoglobin (also called hemoglobin A1c, or abbreviated as HbA1c or simply A1c) has achieved importance in diabetes because of its value in the evaluation of glucose control and its relation to long-term microvascular complications.  This was shown in the Diabetes Control and Complications Trial (DCCT) for people with type 1 diabetes; for type 2 diabetes, it was demonstrated in the UK Prospective Diabetes Study (UKPDS).

Glycosylation is a non-enzymatic, post-translational event in which glucose condenses and forms a stable ketoamine linkage.  This is mainly at the n-terminal valine of the beta chain of the adult hemoglobin molecule, as was shown in 1976 by Haney and Bunn (Haney D and Bunn HF. Glycosylation of hemoglobin in vitro: affinity labeling of hemoglobin by glucosee-6-phospate. Proc Natl Acad Sci USA. 1976;73(10):3534-3538).

HbA1c was first separated as a fast hemoglobin in 1958 using a column chromatographic technique.  HbA1C was called a “fast hemoglobin” because it eluted off the chromatography column more rapidly than adult hemoglobin (Huisman TH, Martis EA, Dozy A. Chromatography of hemoglobin types on carboxymethylcellulose. J Lab Clin Med. 1958;52(2):312-327).

Ten years later, HbA1c was determined to be a glycoprotein, and in the following year—1969—an increase in HbA1c was reported in diabetes patients (Rahbar S, Blumenfeld O, Ranney HM. Studies of an unusual hemoglobin in patients with diabetes mellitus. Biochem Biophys Res Commun. 1969 ;22;36(5):838-843).

The use of HbA1c for monitoring diabetic patients’ glucose control was first postulated in 1976 (Koenig RJ, Peterson CM, Jones RL et al.  Correlation of glucose regulation and hemoglobin A1c in diabetes mellitus. N Engl J Med.  1976;295(8):417-420).

It was noted that the post-translational modification of HbA1c is a stable form and reflects the glucose concentration over the previous 4 to 8 weeks (Koenig RJ, Peterson CM , Kilo C et al. Hemoglobin A1 as an indicator of the degree of glucose intolerance in diabetes. Diabetes. 1976;25(3):230-232).

However, it’s important to remember that HbA1c only reflects glucose concentrations over 4 to 8 weeks if there is a normal hemoglobin concentration and normal red blood cell survival.  That’s because the concentration of HbA1c is dependent on a normal red cell survival rate; therefore, anything that will shorten red cell survival will lower HbA1c.

Low results of HbA1c are rare and may indicate substantial amounts of fetal hemoglobin, or the patient may have a decreased red blood cell life span, such as hemolytic anemia or polycythemia.

Over the past 30 years, HbA1c measurement has become automated, and it’s now possible to have a long-term measurement of glucose control in a matter of minutes.  This point-of-service testing is now readily available in our offices.

HbA1c gives clinicians and researchers a measuring device of glucose control. The clinicians can then inform their patients that the changes in medication, diet, and exercise prescribed for diabetes treatment are making the average blood sugar more near normal.

Why These Articles Were Chosen

The use of HbA1c was essential as a laboratory marker to group (categorize) glucose control and to prove the contribution of glucose concentrations to the microvascular complications that can occur with diabetes, as you will see in the following landmark articles.

The seven articles that we present here—five abstracts and two summaries of editorials—give an effective overview of current thinking on HbA1c and our treatment to goal.

Take Home Message

Glycated hemoglobin (HbA1c) is a valuable tool in diabetes management. It is a yardstick to measure glucose management and help make management decisions. When deciding on treatment for a patient, we must keep our recommendations in mind: HbA1c of 7% or less with good clinical judgment to stave off or prevent microvascular complications in type 1 and 2 diabetes.

Simultaneously, we must use HbA1c wisely in conjunction with home glucose monitoring, lifestyle change (exercise, diet, and tobacco cessation), vigorous use of blood pressure, lipid and hyper coagulation therapy.

In conclusion, HbA1c goals should be set:

  • as rationally as possible
  • as early as possible
  • as safely as possible
  • as low as possible
  • as long as possible
First Article:
Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34)
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