HbA1c is an imperfect diagnosis of diabetes

HbA1c is an imperfect diagnosis of diabetes

When diabetes is uncontrolled, a higher percentage of hemoglobin becomes glycated, causing elevated HbA1c and glucose levels in the body.

The purpose of HbA1c as a clinical marker for diabetes

Hemoglobin A1c (HbA1c) is an accepted measure for both diagnosis and chronic management of diabetes.1 Hemoglobin is the protein responsible for transporting oxygen throughout the body.

HbA1c estimates the percentage of hemoglobin proteins that are glycated, which is a direct measure of how well the body’s glucose levels are controlled.1 If insulin is not released properly in response to increased glucose levels, complications involving both the macro- and microvascular system can occur.

When diabetes is uncontrolled, higher percentages of hemoglobin become glycated, causing an elevated HbA1c and a rise in glucose levels in the body, leading to the above complications.1,2

HbA1c can measure trends in glycated hemoglobin over the previous 3 months because the average lifespan of red blood cells (erythrocytes) is approximately 90-120 days.1 While this lab test can be helpful in assessing diabetes control, it’s also important to consider conditions that can affect these readings.

Conditions affecting HbA1c values

There are some conditions that can cause HbA1c levels to rise despite the patient’s blood glucose (BGL) levels being well controlled. Some of the common conditions are listed in table 1. One of them is anemia caused by a lack of iron, which leads to a decrease in the production of red blood cells.3,4

Table 1: Conditions that cause falsely elevated HbA1c.5

As production decreases, the average age of erythrocytes increases, leading to higher HbA1c levels (Picture 1). In general, any condition that prolongs the life of erythrocytes can cause a falsely elevated HbA1c value.

Figure 1: Iron deficiency anemia and the mechanism of HbA1c.

In addition, there are conditions that can reduce the lifespan of erythrocytes, leading to an inaccurately reduced HbA1c value. Conditions that can falsely lower the HbA1c value are listed in Table 2.

Table 2: Conditions causing falsely low HbA1c.5

*Expect low HbA1c values ​​during the second trimester, but may increase during the third trimester

**Higher than lower HbA1c is more common

Note that red blood cell transfusions can increase or decrease HbA1c values. The change in HbA1c value depends on the blood glucose level of the donor, as they can have a diluting or concentrating effect. Higher HbA1c values ​​are seen more often because most blood transfusions are stored in dextrose solutions.6

Alternative methods for assessing glucose control

Alternative labs may be considered for cases where HbA1c accuracy is questionable – one option includes fructosamine. This is a measure of circulating proteins such as albumin, globulin and lipoprotein that have been glycated over the previous 7-21 days (Figure 2).7

Figure 2. Glycated albumin as a measure of fructosamine.

Ultimately, albumin will play the largest role in this value because it is the most abundant protein circulating in the body. Albumin levels can be affected by a number of conditions, such as nephrotic syndrome, advanced liver disease, and thyroid disease, adding further complexity when considering the use of fructosamine as a marker of diabetes control.8

In addition, there is no clear equation for interpreting fructosamine in relation to HbA1c. Situations in which it would be reasonable to measure fructosamine levels include discordant blood glucose and AbA1c levels, when waiting 3 months to measure HbA1c is not feasible, or if an inaccurate HbA1c value is suspected.

According to the 2022 ADA and 2017 AACE guidelines, there are limitations to fructosamine, such as no specific guidelines on when or how to use it in diabetes.9,10

How to proceed with regard to incorrect HbA1c

If inaccurate HbA1c is suspected, it would be reasonable to consider relying on blood glucose levels or continuous glucose monitoring (CGM) data to guide diabetes therapy adjustments. Before relying entirely on blood glucose readings, consider having the patient’s fingerstick meter provide accurate readings using a control solution.

An additional HbA1c value can be drawn in 3 months, if time permits and if it still seems inaccurate, then consider using CGM, glucose or fructosamine data.5,11

Although the exact deviations from actual HbA1c values ​​are unknown for each of these conditions, clinical judgment should be used to assess whether there are deviations in patients’ HbA1c and other clinical signs of diabetes control.

By: Micaela Den Hartog, Candidate of Pharmacy, University of Minnesota, Class of 2023.
Preceptor: Kristina Thurber, PharmD, Clinical Pharmacist, Department of Community Internal Medicine, Mayo Clinic


  1. Eyth E, Naik R. Hemoglobin A1C. [Updated 2022 Mar 15]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; January 2022. Available at: https://www.ncbi.nlm.nih.gov/books/NBK549816/
  2. Sherwani SI, Khan HA, Ekhzaimy A, Masood A, Sakharkar MK. Significance of the HbA1c test in the diagnosis and prognosis of diabetic patients. Biomark Insights. July 3, 2016; 11:95-104. doi: 10.4137/BMI.S38440. PMID: 27398023; PMCID: PMC4933534.
  3. Mehdi U, Toto RD. Anemia, diabetes and chronic kidney disease. Diabetes care. 2009 July;32(7):1320-6. doi: 10.2337/dc08-0779. PMID: 19564475; PMCID: PMC2699743.
  4. “Diabetes and chronic kidney disease.” Centers for Disease Control and Prevention, Centers for Disease Control and Prevention, 7 May 2021, https://www.cdc.gov/diabetes/managing/diabetes-kidney-disease.html.
  5. Radin, Michael S. “Pitfalls in Hemoglobin A1c Measurement: When Results Can Be Misleading.” Journal of general internal medicine vol. 29.2 (2014): 388-94. doi:10.1007/s11606-013-2595-x
  6. Sugimoto, Takeshi et al. “Changes in HbA1c as a result of autologous blood donation for elective surgery in patients with diabetes.” Blood transfusion = Trasfusione del sangue vol 12 Suppl 1, Suppl 1 (2014): s209-13. doi:10.2450/2013.0271-12
  7. Gounden V, Ngu M, Anastasopoulou C, et al. fructosamine. [Updated 2021 Aug 11]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; January 2022. Available at: https://www.ncbi.nlm.nih.gov/books/NBK470185/
  8. Danese, Elisa et al. “Advantages and pitfalls of fructosamine and glycated albumin in the diagnosis and treatment of diabetes.” Journal of diabetes science and technology vol. 9.2 (2015): 169-76. doi:10.1177/1932296814567227
  9. American Diabetes Association Committee on Professional Practice et al. “16. Diabetes Care in the Hospital: Standards of Medical Care for Diabetes-2022.” Diabetes care vol. 45, Suppl 1 (2022): S244-S253. doi:10.2337/dc22-S016
  10. Rodbard, Helena W et al. “American Association of Clinical Endocrinologists Medical Guidelines for Clinical Practice in the Management of Diabetes Mellitus.” Endocrine Practice: Official Journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists, Vol. 13 Suppl 1 (2007): 1-68. doi:10.4158/EP.13.S1.1
  11. Henderson, Wendy O et al. “How should you assess glycemic control if hemoglobin A1c is inaccurate or uninterpretable?” Cleveland Clinic journal of medicine vol. 88.2 81-85. February 1, 2021, doi:10.3949/ccjm.88a.19135


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