What conditions can cause artificially low A1C (Hemoglobin A1C) and fasting blood glucose readings in patients with suspected pre-diabetes or type 2 diabetes?

Conditions Causing Artificially Low A1C and Fasting Blood Glucose

When A1C and fasting glucose appear normal but diabetes may still be present, suspect conditions that increase red blood cell turnover or alter hemoglobin structure, and rely exclusively on plasma glucose testing (fasting, 2-hour post-load, or random) to diagnose diabetes in these situations. 1

Conditions That Falsely Lower A1C

Increased Red Blood Cell Turnover

These conditions shorten the lifespan of red blood cells, reducing the time available for glucose to bind to hemoglobin, resulting in artificially low A1C readings despite elevated blood glucose:

• Hemolytic anemias and blood loss: Recent blood loss or transfusion within the past 2-3 months 1
• Hemoglobinopathies: Sickle cell disease (not just trait), glucose-6-phosphate dehydrogenase (G6PD) deficiency 1
• Pregnancy: Second and third trimesters and the postpartum period 1
• Hemodialysis: Chronic kidney disease requiring dialysis 1
• Erythropoietin therapy: Treatment that stimulates red blood cell production 1

Hemoglobin Variants That Interfere With A1C Measurement

Certain genetic variants can cause A1C assays to produce falsely low readings:

• Sickle cell trait (HbS heterozygosity): African American individuals with this trait may have A1C values approximately 0.3% lower than those without the trait for the same level of mean glycemia 1
• G6PD G202A variant: This X-linked variant, carried by 11% of African Americans, is associated with A1C decreases of approximately 0.8% in homozygous men and 0.7% in homozygous women 1
• Other hemoglobin variants: Various hemoglobinopathies can interfere with specific A1C assays, though most U.S. assays are unaffected by the most common variants 1

Additional Conditions

• HIV infection treated with certain antiretroviral drugs: Specific medications can alter the A1C-glucose relationship 1
• Iron deficiency anemia: Can affect A1C reliability 1

Critical Diagnostic Approach

When to Suspect Falsely Low A1C

Marked discordance between measured A1C and plasma glucose levels should immediately raise suspicion of A1C assay interference or altered red blood cell turnover. 1 For example, if a patient has fasting glucose consistently ≥126 mg/dL or random glucose ≥200 mg/dL with symptoms, but A1C is <6.5%, investigate for the conditions listed above. 1

Alternative Testing Strategy

In all conditions listed above, use only plasma blood glucose criteria to diagnose diabetes—never rely on A1C alone: 1

• Fasting plasma glucose (FPG) ≥126 mg/dL (7.0 mmol/L) after at least 8 hours of no caloric intake 1
• 2-hour plasma glucose during oral glucose tolerance test (OGTT) ≥200 mg/dL (11.1 mmol/L) using 75g glucose load 1
• Random plasma glucose ≥200 mg/dL (11.1 mmol/L) in patients with classic hyperglycemia symptoms 1

The OGTT Advantage

The 2-hour post-load glucose test diagnoses more people with prediabetes and diabetes compared to fasting glucose or A1C cutpoints. 1 This is particularly important in cardiovascular disease populations, where OGTT reveals that two-thirds of patients without known diabetes have newly detected diabetes or prediabetes. 1

Important Caveats for Fasting Glucose Testing

Pre-Test Preparation

Ensure adequate carbohydrate intake of at least 150 g/day for 3 days prior to testing to avoid falsely low fasting glucose results from carbohydrate restriction. 1

Sample Handling

Glucose samples must be spun and separated immediately after collection—samples left at room temperature without prompt centrifugation will show falsely low glucose levels due to ongoing glycolysis by blood cells. 1

Racial and Ethnic Considerations

African American individuals may have A1C levels that are 0.3-0.8% higher than non-Hispanic White individuals with similar glucose levels (independent of hemoglobin variants), meaning they may appear to have worse glycemic control than they actually do. 1 Conversely, when hemoglobin variants are present, their A1C may be falsely low. 1, 2

Confirmation Requirements

In the absence of unequivocal hyperglycemia (symptoms plus random glucose ≥200 mg/dL), diagnosis requires two abnormal test results from either the same sample or two separate samples. 1 When A1C is unreliable due to the conditions above, obtain two separate plasma glucose measurements (fasting or 2-hour post-load) to confirm the diagnosis. 1

Assay Selection

For patients with hemoglobin variants but normal red blood cell turnover (such as sickle cell trait), use an A1C assay specifically validated to be free from interference with that particular hemoglobin variant. 1 An updated list of A1C assays and their interferences is available at ngsp.org/interf.asp. 1