What is glycated hemoglobin (HbA1c)?

What is HbA1c?

HbA1c (glycated hemoglobin) is a stable chemical compound formed by the nonenzymatic binding of glucose to the N-terminal valine residue of the β-chain of hemoglobin A, reflecting average blood glucose levels over the preceding 2-3 months and serving as the gold standard for assessing long-term glycemic control in diabetes. 1

Biochemical Formation

• Glucose attaches to hemoglobin through a two-step process: First, glucose forms an unstable Schiff base (aldamine) with the N-terminal valine on the β-chain of hemoglobin, which then undergoes an irreversible Amadori rearrangement to form a stable ketoamine structure. 1

• The glycation process is continuous and proportional: Throughout the 120-day lifespan of red blood cells, hemoglobin molecules are continuously glycated at a rate directly proportional to the ambient glucose concentration in the blood. 1

• Recent glucose levels contribute more heavily: Approximately 50% of the HbA1c value reflects glycemia during the most recent month, 25% from 30-60 days prior, and 25% from 60-120 days before measurement. 1, 2

Clinical Significance

• HbA1c represents time-averaged glycemia: The measurement provides an integrated assessment of mean blood glucose over 2-3 months, making it superior to single-point glucose measurements for evaluating overall glycemic control. 1

• Strong correlation with mean glucose: In the Diabetes Control and Complications Trial, an HbA1c of 6% corresponded to a mean plasma glucose of 135 mg/dL (7.5 mmol/L), with each 1% increase in HbA1c corresponding to approximately a 35 mg/dL (2 mmol/L) increase in mean glucose. 1, 3

• Diagnostic utility: HbA1c ≥6.5% is an established diagnostic criterion for diabetes, while values of 5.7-6.4% indicate prediabetes, and <5.7% is considered normal. 2

Key Advantages

• Stability and convenience: HbA1c is a very stable chemical with minimal day-to-day variability, and testing does not require fasting or specific timing, allowing blood samples to be drawn at any time. 1

• Unaffected by acute factors: Unlike capillary glucose measurements, HbA1c results are not influenced by short-term diet, exercise, stress, or recent lifestyle modifications. 1

• Standardized measurement: The National Glycohemoglobin Standardization Program (NGSP) and International Federation of Clinical Chemistry (IFCC) have established reference systems ensuring reliable inter-laboratory comparison of results. 1

Important Limitations

• Conditions affecting red blood cell lifespan alter results: Any factor that shortens erythrocyte survival (hemolytic anemia, recent blood loss, transfusion) produces falsely low HbA1c values, while conditions prolonging red cell lifespan (iron deficiency anemia) cause falsely elevated results. 2, 3

• Hemoglobinopathies interfere with measurement: Hemoglobin variants (HbS, HbC, HbE) can cause spuriously high or low results depending on the assay method used; African Americans with sickle cell trait may have HbA1c values approximately 0.3% lower than those without the trait for the same mean glycemia. 2, 3

• Pregnancy affects accuracy: During the second and third trimesters, HbA1c values tend to be lower due to increased red cell turnover. 2

• Chronic kidney disease complicates interpretation: In patients with advanced kidney disease, factors including reduced red cell lifespan, transfusions, hemolysis, and carbamylation of hemoglobin can produce unreliable HbA1c values. 3

Recommended Testing Frequency

• Before achieving glycemic targets: People with diabetes should measure HbA1c every 3 months when HbA1c is above target to guide treatment adjustments. 1

• After achieving glycemic targets: Once the HbA1c goal is met, testing can be reduced to every 6 months for ongoing monitoring. 1

Alternative Markers When HbA1c is Unreliable

• Glycated albumin (GA): Reflects glycemic exposure over the preceding 2-3 weeks and is independent of red cell turnover, making it accurate in the presence of hemoglobinopathies, hemolytic anemia, or recent transfusion. 3

• Fructosamine: Represents average glucose over 1-2 weeks and is not influenced by red cell lifespan, providing an alternative when HbA1c reliability is in doubt. 2

• Continuous glucose monitoring (CGM): Provides 24-hour glucose profiles that can uncover patterns missed by HbA1c or isolated glucose measurements, particularly useful when HbA1c values are discordant with clinical presentation. 3, 4