Introduction

The hemoglobin A1c test, also known as glycated hemoglobin, glycosylated hemoglobin, HbA1c, or simply A1c, is used to measure a person's level of glucose control. The test shows average blood sugar levels over the past 90 days, expressed as a percentage. The test can also be used to diagnose diabetes mellitus.[1]

Hemoglobin is a protein found exclusively in red blood cells, giving blood its bright red color. Since red blood cells have an average lifespan of about three months, the A1c test measures the hemoglobin levels in the bloodstream at the time of testing, which is why the A1c test serves as an indicator of blood sugar control.

The primary role of hemoglobin is to carry oxygen from the lungs to all the cells in the body. Hemoglobin becomes glycated or coated with glucose from the bloodstream. As blood glucose levels rise, more glucose attaches to the hemoglobin protein. Higher blood glucose levels result in more glycated hemoglobin, leading to a higher A1c level.[2]

Etiology and Epidemiology

The Diabetes Control and Complications Trial (DCCT) [3] was a landmark study that provided extensive data on A1c and its correlation to blood glucose levels, establishing specific treatments to target A1c goals. Following the completion of the trial, the National Glycohemoglobin Standardization Program (NGSP) was formed to define a standardized assay for A1c measurement across laboratories.

The DCCT trial reported that a higher mean A1c level was the dominant predictor of diabetic retinopathy progression. Tighter glucose control, indicated by HbA1c levels in the 7% range or lower, was correlated with a 35 to 76% decrease in microvascular complications, such as retinopathy, nephropathy, and neuropathy, in patients with type 1 diabetes. In addition to predicting the progression of microvascular complications through A1c levels, the DCCT extension into the EDIC study showed long-term benefits in cardiovascular risk and mortality for patients with lower HbA1c levels.[4][5][6]

Pathophysiology

People with diabetes mellitus need regular A1c testing to ensure their average blood glucose levels are within the target range. The American Diabetes Association (ADA) recommends checking HbA1c twice a year for patients who are stable and well-controlled and every 3 months for those with medication changes or who are not well-controlled.

Specimen Requirements and Procedure

The HbA1c test can be performed as a point of care (POC), a STAT test, or by sending a sample to a laboratory. The POC test uses a STAT analyzer to measure A1c from a capillary fingerstick. The laboratory test uses a teaspoon of blood drawn from a venous sample into a K₂ EDTA (lavender top) tube. The sample gets processed as whole blood.

Diagnostic Tests

The venous sample A1c test may be used as a diagnostic tool in clinical practice when determining diabetes risk or onset. Due to the variability of capillary POC testing, any A1c test conducted using a capillary sample should be confirmed with a venous sample before rendering a diagnosis.

An HbA1c value below 5.7% is considered normal or in the non-diabetic range. A value between 5.7% and 6.4% indicates prediabetes mellitus, whereas a 6.5% or higher level is diagnostic for diabetes mellitus.

Tests should be sent to a laboratory certified by the NGSP to ensure results are standardized.[7][8]

Testing Procedures

The HbA1c test performed using a POC machine in a clinic may be less accurate than one drawn from a venous sample and processed in a laboratory. Results can differ by as much as 0.5% between different laboratories.

The HbA1c test should be performed using an NGSP-approved method.

Interfering Factors

There are several conditions where the HbA1c test can produce inaccurate results. Individuals with sickle cell anemia, thalassemia, anemia, kidney failure, liver disease, or those receiving blood transfusions can experience altered results due to the longevity of the red blood cell. HbA1c measurement in these patients must be interpreted cautiously and confirmed with plasma glucose samples to diagnose diabetes mellitus.[9]

A falsely low HbA1c value can result from several conditions, including high altitude, pregnancy, hemorrhage, blood transfusion, erythropoietin administration, iron supplementation,[10] hemolytic anemia, chronic kidney failure, liver cirrhosis, alcoholism, sickle cell anemia,[11] and spherocytosis. Vitamin C supplementation can increase or decrease HbA1c levels depending on the method used.

Conversely, a falsely high HbA1c value can be due to insufficient iron in the blood. This condition can result from iron deficiency anemia,[12] infection-induced anemia, or tumor-induced anemia. In addition, hemoglobinopathies such as thalassemia and B12 deficiency [10][13] can cause a falsely high HbA1c value. Other causes of falsely high HbA1c levels include hypertriglyceridemia, organ transplantation, and hyperglycation in certain ethnic groups. Medications such as immunosuppressants and protease inhibitors can sometimes lead to a falsely high HbA1c value.[9][7][14][15]

Results, Reporting, and Critical Findings

Relationship Between A1c and Glucose Levels

The HbA1c percentage reflects the average glucose level in a patient's body over the past 90 days.[16][17][18]

Clinical Significance

Hemoglobin A1c serves as an indicator of overall glycemic control and a reflection of the average blood sugar over the past 3 months.[2]

Quality Control and Lab Safety

Laboratories use several methods to determine HbA1c, with high-performance liquid chromatography being one of the most popular methods due to its ability to eliminate labile components used by other methods, such as immunoassay or affinity chromatography.[19]

POC devices are widely used to measure HbA1c levels. However, the range of POC machines available can make selecting the most suitable one for a particular practice challenging. There is limited information comparing the different machines. When using POC testing, it is important to note that POC values are typically lower than those reported by laboratory tests, with the average difference being −0.5%.

Enhancing Healthcare Team Outcomes

All clinicians caring for diabetic patients need a clear understanding of HbA1c and its significance. In general, HbA1c reflects the average glucose concentration over 3 months.

Hemoglobin A1c is often used as an outcome measure to determine whether an intervention in a population is successful by showing a decrease in HbA1c by a certain percentage. There is a movement within the medical community to shift away from using HbA1c as an exclusive standard of care test to measure patient response to treatment. The newest proposed methods are the estimated average glucose and the glucose time in the range.[20] These methods use data obtained from continuous glucose monitors that record blood glucose levels around the clock. These methods can also give healthcare professionals a more accurate view of the blood sugar average and fluctuations, but these methods are not available to all patients on a widespread basis.

According to ADA guidelines, HA1c levels should be measured twice a year in stable patients and at least four times in patients with glucose fluctuations or those who have changed their diabetic treatment. Hemoglobin A1c is one of the preferred diabetes diagnostic tests today. The blood draw can occur anytime, and no special handling requirements exist. However, to ensure that the A1c value is correct, clinicians must be aware of the causes of false-positive and false-negative results.

Given that many diabetic patients are treated in outpatient settings, it is essential for diabetes care nurses to understand HbA1c results and know when to refer patients to an endocrinologist for further evaluation. Pharmacists must also fully understand and interpret this test, as they are involved in glycemic management medication, agent selection, dosing, and monitoring. The nurse and pharmacist must inform the treating clinician regarding any changes in hemoglobin A1c and verify patient medication compliance. Hemoglobin A1c is a valuable tool in managing diabetes mellitus and other glycemic control disorders, but to be effective, it functions best in an interprofessional healthcare team environment.