What is hemoglobin A1c (HbA1c)?

What is HbA1c?

HbA1c (hemoglobin A1c) is a blood test that measures the percentage of hemoglobin molecules that have glucose permanently attached to them, reflecting your average blood sugar levels over the past 2-3 months. 1

How HbA1c Forms

HbA1c forms through a specific biochemical process: 1

• Glucose in your bloodstream binds to the N-terminal valine amino acid on the β-chain of hemoglobin through a nonenzymatic reaction
• This initially creates an unstable compound called a Schiff base (aldamine)
• The Schiff base then undergoes an irreversible Amadori rearrangement to form a stable ketoamine structure
• This glycation process occurs continuously throughout the 120-day lifespan of red blood cells 1
• The rate of HbA1c formation is directly proportional to the ambient glucose concentration in your blood 1

What the Time Window Actually Means

The 2-3 month reflection is not evenly weighted—recent blood sugar levels contribute more to your HbA1c value: 1

• Approximately 50% of your HbA1c reflects glucose levels from the most recent month
• About 25% reflects glucose from 30-60 days prior
• The remaining 25% reflects glucose from 60-120 days before measurement

Clinical Uses of HbA1c

For Diabetes Diagnosis

• HbA1c ≥6.5% can be used as a supplementary diagnostic criterion for diabetes (must use NGSP-certified laboratory methods) 1
• Normal range: below 5.7% 2
• Prediabetes range: 5.7% to 6.4% 2
• Diabetes: 6.5% or higher 2

For Monitoring Glycemic Control

HbA1c serves as the gold standard for assessing long-term diabetes management: 1, 2

• Test every 3 months when initiating treatment or when not meeting glycemic targets 1, 2
• Test every 6 months once HbA1c goals are achieved and diabetes is stable 1, 2
• Target HbA1c for most people with diabetes is below 7% 2

Relationship to Average Blood Glucose

Each 1% change in HbA1c corresponds to approximately a 29-35 mg/dL change in average blood glucose: 1, 2

• HbA1c of 6% = average glucose of approximately 126-135 mg/dL
• HbA1c of 7% = average glucose of approximately 154 mg/dL
• Each 1% increase adds roughly 35 mg/dL to average glucose 1

Key Advantages Over Daily Glucose Testing

HbA1c provides unique clinical benefits that point-in-time glucose measurements cannot: 1

• Not affected by short-term factors like recent meals, exercise, stress, or illness
• Does not require fasting before the blood draw
• Provides a stable, objective measure of overall glycemic control
• Strongly correlates with risk of diabetes complications (retinopathy, nephropathy, neuropathy, cardiovascular disease) 1, 2
• Very stable chemical with minimal day-to-day variability 1

Important Limitations and Confounders

Certain conditions can make HbA1c results inaccurate—in these situations, rely on daily glucose monitoring instead: 2

Conditions That Falsely Elevate HbA1c

• Iron deficiency anemia 1
• Vitamin B12 deficiency 1
• Splenectomy (prolonged red blood cell lifespan) 1

Conditions That Falsely Lower HbA1c

• Hemolytic anemia 1, 2
• Recent blood loss or transfusion 1, 2
• Chronic liver disease 1
• Splenomegaly 1
• Pregnancy (due to increased red blood cell turnover) 1
• Use of erythropoietin or iron supplementation 1, 2
• End-stage kidney disease 2

Hemoglobin Variants

• Hemoglobin S, C, and other variants can unpredictably interfere with HbA1c measurements 1
• May cause spuriously high or low results depending on the assay method used 1

Measurement Standardization

Use only NGSP-certified or IFCC-certified laboratory methods to ensure accurate, comparable results: 1

Common Measurement Methods

Two main categories of HbA1c testing exist: 1

1. Charge-based methods: Ion exchange HPLC, capillary electrophoresis
2. Structure-based methods: Boronate affinity HPLC, immunoassays

Why Standardization Matters

• The National Glycohemoglobin Standardization Program (NGSP) in the U.S. ensures 99% of laboratories use methods traceable to the Diabetes Control and Complications Trial reference 1
• The IFCC developed a reference measurement system using mass spectrometry that measures the specific analyte: hemoglobin with glucose attached to the N-terminal valine of the β-chain 1
• Laboratories should participate in external quality assessment programs 1

Common Pitfalls to Avoid

• Do not use HbA1c alone in patients with conditions affecting red blood cell turnover—verify with fasting glucose or continuous glucose monitoring 1, 2
• Do not assume HbA1c reflects recent glycemic changes—it takes 8-12 weeks for changes in glucose control to fully manifest in HbA1c 1
• Do not use non-certified point-of-care HbA1c devices for diagnosis—diagnostic decisions require NGSP-certified laboratory methods 1
• Do not ignore hemoglobin variants—they can cause significant measurement errors depending on the assay method 1