The purpose of HbA1c as a clinical indicator of diabetes

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

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

If diabetes is not controlled, a high percentage of hemoglobin becomes glycated, which leads to higher HbA1c and glucose levels in the body, which leads to the mentioned problems.^{1, 2}

HbA1c can measure glycated hemoglobin trends over the past 3 months because the average lifespan of a red blood cell is about 90-120 days.¹ Although this laboratory test helps to control diabetes, it is important to consider the conditions that can affect these readings.

Factors affecting HbA1c values

Even if the patient’s blood glucose level (BGL) is well controlled, there are some conditions that can cause the HbA1c level to rise. Some of the most common conditions are listed in Table 1. One of them is iron deficiency anemia, which reduces RBC production.^{3, 4}

Table 1: Conditions that cause 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 RBC age can result in a falsely elevated HbA1c value.

Figure 1: Iron deficiency anemia and HbA1c method.

Additionally, there are conditions that shorten the lifespan of RBCs, thus leading to falsely low HbA1c values. Conditions that can cause falsely low HbA1c values ​​are listed. Table 2.

Table 2: Conditions that cause low HbA1c.⁵

^{* Expect lower HbA1c values ​​from the second trimester, but may rise in the third trimester.}

^{** It is very common to raise HbA1c below}

Note that red blood cell transfusions may increase or decrease HbA1c values. Changes in HbA1c values ​​depend on blood glucose levels in donors, as they may have diluting or concentrating effects. High HbA1c values ​​are often seen as most transfusions are concentrated in dextrose solutions.⁶

Alternative methods to assess glucose control

In cases where the accuracy of HbA1c is in question, alternative tests may be used – one option involves fructosamine. This measures circulating proteins such as albumin, globulin, and lipoproteins over the previous 7–21 days (Figure 2).⁷

Figure 2. Glycated albumin as a measure for fructosamine.

Finally, albumin plays a major role in this value because it is the most abundant protein circulating in the body. Albumin levels can be affected by several conditions, such as nephrotic syndrome, advanced liver disease, and thyroid disease, leading to additional complications when taking fructosamine as a marker for diabetes control.⁸

Furthermore, there is no clear equation for the interpretation of fructosamine in relation to HbA1c. Circumstances in which it is reasonable to measure fructosamine levels include blood glucose and AbA1c levels, if it is not possible to wait 3 months to measure HbA1c, or if an incorrect HbA1c value is suspected.

In the 2022 ADA and 2017 AACE guidelines, there are restrictions for fructosamine, such as no specific guidance on when and how to use it in diabetes.^{9, 10}

How to proceed when given an inaccurate HbA1c

If an inaccurate HbA1c is suspected, it is reasonable to consider relying on blood glucose or continuous glucose monitoring (CGM) data to guide diabetes treatment adjustments. Before relying entirely on blood glucose values, ensure that the patient’s fingerprint glucometer provides accurate readings using a control solution.

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

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

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

Preceptor: Christina Thurber, PharmD, Clinical Pharmacist, Department of Community Internal Medicine at Mayo Clinic

References

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2. Sherwani SI, Khan HA, Ekhzaimy A, Masood A, Sakharkar MK Importance of HbA1c test in diagnosis and prognosis of diabetic patients. Biomarker 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 Jul; 32 (7): 1320-6. doi: 10.2337/dc08-0779. PMID: 19564475; PMCID: PMC2699743
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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 from https://www.ncbi.nlm.nih.gov/books/NBK470185/
8. Denmark, Elisa et al. “Pros and cons 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 Clinical Endocrinologists’ Clinical Practice Guidelines 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 hemoglobin A1c is inaccurate or not interpretable?” Cleveland Clinic Journal of Medicine. 88, 2 81-85. 1 February 2021, doi:10.3949/ccjm.88a.19135