Limitations of A1c Interpretation

Jessica G. Shepard, PharmD; Anita Airee, PharmD, BCPS; Andrew W. Dake, MD; M. Shawn McFarland, PharmD; Amit Vora, MD


South Med J. 2015;108(12):724-729. 

In This Article

Abstract and Introduction


Hemoglobin A1c is the measurement of glycated hemoglobin and can aid in both the diagnosis and continued management of diabetes mellitus. Accurate glycosylated hemoglobin A1c (A1c) measurements are an essential part of decision making in the diagnosis and treatment of type 2 diabetes mellitus. Although national standards exist to eliminate technical error with A1c testing, multiple patient conditions can falsely decrease or elevate the A1c. In this review, we discuss the methods to measure A1c and the corresponding conditions that can affect the clinical utility of the test. Conditions that affect the A1c can be either those that impair erythrocyte production or alter the normal process of glycation. Some variation also has been associated with patient ethnicity and even with normal aging. We describe alternatives to A1c testing for the above clinical scenarios in an effort to make the practicing clinician aware of alternatives for glucose evaluation.


In 2010 the American Diabetes Association (ADA) added the glycosylated hemoglobin A1c (A1c) to aid timely and appropriate diagnosis of diabetes mellitus.[1] In the United States alone, there are approximately 21 million people diagnosed as having diabetes mellitus and there are approximately 8.1 million who have it but are not diagnosed.[2] Recognizing this lost opportunity to diagnose and treat, the hemoglobin A1c was added to avoid cumbersome oral glucose tolerance tests and fasting glucose testing constraints for busy clinicians.[3] In 2009–2012, based on fasting glucose or A1c levels, 37% of US adults aged 20 years or older had prediabetes mellitus (51% of those aged 65 years or older). Applying this percentage to the entire US population in 2012 yields an estimated 86 million Americans aged 20 years or older with prediabetes mellitus.[2] The 2014 US Preventive Services Task Force recommendation calls for screening everyone beginning at age 45 years, as well as younger adults with risk factors including overweight or obesity, a first-degree relative with diabetes mellitus, women with a history of gestational diabetes or polycystic ovary syndrome, and certain racial/ethnic minority groups, including African Americans, American Indians/Alaskan Natives, Asian Americans, and Hispanics/Latinos.[4] The new proposed US Preventive Services Task Force recommendations are generally in line with diabetes mellitus screening recommendations previously made by other groups, including the ADA, the American Association of Clinical Endocrinologists, and the American Academy of Family Physicians.[5–7] In our opinion, the A1c test is already being used widely but is only going to be used more to help control the juggernaut of diabetes mellitus not just in the United States but also globally.

The A1c, however, may not always be accurate because of several limitations of the test itself. This creates a dilemma in that accurate A1c measurements are not only an essential part of decision making but also serve as standards for quality of care and reimbursement structures under accountable care models and pay-for-performance measures.[8] Although the National Glycohemoglobin Standardization Program (NGSP) was initiated in 1996 to eliminate many potential technical errors that can occur with A1c testing, various clinical conditions/patient dispositions can lead to falsely low or high A1c.[9] The conditions that may affect A1c values include changes in erythrocyte lifespan, hemoglobin variants, chemically modified hemoglobin, altered rate of glycation, ethnicity, and aging.[10–44]