Let’s Not Sugar Coat It: HbA1c is the Imperfect Diabetes Diagnostic

Purpose of HbA1c as a clinical marker for diabetes

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

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

When diabetes is uncontrolled, higher percentages of hemoglobin become glycated, which causes elevated HbA1c and glucose levels to rise within the body, leading to the aforementioned complications.^1,2

HbA1c can measure trends in glycated hemoglobin over the previous 3 months because the average lifespan of a red blood cell (RBC) is approximately 90-120 days.¹ Although this laboratory test can be helpful in assessing control of diabetes, it is also important to consider conditions that may affect these readings.

Conditions affecting HbA1c values

There are some conditions that could cause a rise in HbA1c levels despite the patient’s blood glucose levels (BGL) being well controlled. Some of the more common conditions are outlined in Table 1. One of these is iron deficiency anemia which leads to a decrease in RBC production.^3,4

Table 1: Conditions causing falsely inflated HbA1c.⁵

As production decreases, the average age of the RBC increases, leading to higher HbA1c levels (Figure 1). In general, any condition that increases the lifespan of an RBC may cause a falsely elevated HbA1c value.

Figure 1: Iron deficiency anemia and HbA1c mechanism.

Additionally, there are conditions that can decrease the lifespan of an RBC, thus leading to an inaccurately decreased HbA1c value. Conditions that may falsely decrease the HbA1c value are outlined in Table 2.

Table 2: Conditions causing falsely low HbA1c.⁵

^{*Expect low HbA1c values through second trimester, but may rise during third trimester}

^{**More common to elevate than lower HbA1c}

Note that red blood cell transfusions can increase or decrease HbA1c values. The change in HbA1c values is dependent on the donor’s glucose levels within the blood, as they can have a dilutional or concentrating effect. Higher HbA1c values are seen more commonly as most blood transfusions are stored in dextrose solutions.⁶

Alternative methods for assessing glucose control

Alternate labs may be considered for instances in which the accuracy of the HbA1c is in question—one option includes fructosamine. This is a measure of circulating proteins such as albumin, globulins, and lipoproteins that are glycated over the preceding 7-21 days (Figure 2).⁷

Figure 2. Glycated albumin as a measure for fructosamine.

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

Additionally, there is no clear-cut equation for the interpretation of fructosamine as it relates to HbA1c. Situations in which it would be reasonable to measure a fructosamine level include discordant blood glucose and AbA1c levels, when waiting 3 months to measure HbA1c is not feasible, or if there is a suspected inaccurate HbA1c value.

Per the 2022 ADA and 2017 AACE guidelines, there are limitations to fructosamine, such as no specific guidance on when or how to utilize it in the instance of diabetes.^9,10

How to proceed given inaccurate HbA1c

If there is suspicion of an inaccurate HbA1c, it would be reasonable to consider relying on blood glucose levels or continuous glucose monitor (CGM) data to guide therapeutic adjustments for diabetes. Before relying completely on blood glucose values, consider ensuring a patient’s fingerstick glucometer provides accurate readings through use of control solution.

An additional HbA1c value may be drawn in 3 months, if time allows, and if still seemingly inaccurate, then consider using CGM data, glucose levels, or fructosamine.^5,11

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

Author: Micaela Den Hartog, PharmD Candidate, University of Minnesota, Class of 2023

Preceptor: Kristina Thurber, PharmD, Clinical Pharmacist, Division of Community Internal Medicine at Mayo Clinic

References

1. Eyth E, Naik R. Hemoglobin A1C. [Updated 2022 Mar 15]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK549816/
2. Sherwani SI, Khan HA, Ekhzaimy A, Masood A, Sakharkar MK. Significance of HbA1c Test in Diagnosis and Prognosis of Diabetic Patients. Biomark Insights. 2016 Jul 3; 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 Jul;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 may 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. “Alterations in HbA1c resulting from the donation of autologous blood for elective surgery in patients with diabetes mellitus.” 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; 2022 Jan-. Available from: 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 Professional Practice Committee et al. “16. Diabetes Care in the Hospital: Standards of Medical Care in 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 for 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 the hemoglobin A1c is inaccurate or uninterpretable?” Cleveland Clinic journal of medicine vol. 88,2 81-85. 1 Feb. 2021, doi:10.3949/ccjm.88a.19135