Why do some patients with diabetes have a high Hemoglobin A1c (HbA1c) level despite having low fasting and postprandial glucose levels?

Why HbA1c Can Be High Despite Low Fasting and Postprandial Glucose

When HbA1c is elevated but fasting and postprandial glucose readings are low, the most likely explanation is a condition that artificially increases HbA1c by prolonging red blood cell lifespan or altering hemoglobin glycation independent of actual glycemia. 1

Primary Mechanisms Causing Falsely Elevated HbA1c

Conditions That Increase Red Blood Cell Lifespan

Iron deficiency anemia paradoxically elevates HbA1c by creating an older red blood cell cohort with more accumulated glycation time, despite normal glucose levels. 1, 2

• When red blood cells survive longer than the normal 120-day lifespan, they accumulate more glycation over time, artificially raising HbA1c 1
• This is the opposite effect of hemolytic conditions, which lower HbA1c 2

Racial and Genetic Factors

African Americans may have HbA1c levels 0.3-0.8% higher than non-Hispanic whites with identical fasting and postprandial glucose levels. 1

• This discordance occurs independently of actual glycemia and may reflect higher postprandial glycemic burden not captured by spot glucose measurements 1
• The X-linked glucose-6-phosphate dehydrogenase G202A variant can cause HbA1c differences of 0.7-0.8% in homozygous individuals 1
• Despite these differences, the association of HbA1c with complication risk appears similar across racial groups 1

Assay Interference

Marked discordance between HbA1c and plasma glucose should prompt consideration of HbA1c assay interference from hemoglobin variants. 1

• Certain hemoglobinopathies can interfere with HbA1c measurement depending on the assay method used 1
• An updated list of assays with known interferences is available at www.ngsp.org/interf.asp 1

The Postprandial Glucose Contribution

Postprandial glucose excursions contribute 70% to HbA1c when diabetes control is good (HbA1c <7.3%), but this contribution decreases to 30% as control worsens (HbA1c >10.2%). 3

Why Spot Glucose Measurements May Miss the Problem

• HbA1c reflects glucose exposure over 120 days, with 50% determined by the preceding month, 25% from 30-60 days prior, and 25% from 60-120 days prior 2
• Afternoon and evening glucose levels correlate better with HbA1c than prebreakfast and prelunch values 4
• If you are only checking fasting and immediate postprandial glucose (typically 2 hours after meals), you may be missing late postprandial peaks or afternoon/evening hyperglycemia that significantly contribute to HbA1c. 4, 3

Diagnostic Algorithm

Step 1: Verify Measurement Accuracy

• Repeat both HbA1c and glucose measurements to confirm the discordance 1
• Ensure glucose samples were collected properly (fasting state confirmed, samples processed immediately) 2

Step 2: Screen for Red Blood Cell Disorders

Check complete blood count with indices, reticulocyte count, and iron studies (ferritin, serum iron, TIBC). 1, 2

• Iron deficiency anemia will show low ferritin, low serum iron, high TIBC, and may artificially elevate HbA1c 1, 2
• Normal or elevated MCV with normal iron studies suggests other causes 2

Step 3: Consider Hemoglobinopathy Screening

In African American patients or those with family history, obtain hemoglobin electrophoresis or variant testing. 1

• Hemoglobin variants like HbS trait can affect HbA1c measurements depending on the assay 1
• Use an assay without interference if a variant is identified 1

Step 4: Expand Glucose Monitoring

Implement continuous glucose monitoring (CGM) or obtain glucose measurements at multiple time points throughout the day, particularly mid-morning (11 AM) and mid-afternoon (2 PM). 4, 3, 5

• CGM provides thousands of measurements and accounts for the vast majority of HbA1c variation 5
• If CGM is unavailable, obtain glucose measurements at 11 AM and 2 PM, which are better predictors of HbA1c than fasting values alone 3
• Post-meal thresholds >200 mg/dL at 11 AM or >160 mg/dL at 2 PM suggest inadequate glycemic control despite normal fasting/immediate postprandial values 3

Alternative Glycemic Markers When HbA1c Is Unreliable

When marked discordance exists between HbA1c and plasma glucose, use plasma glucose criteria alone for diagnosis and monitoring. 1

Consider Alternative Markers

• Fructosamine or glycated albumin reflect 2-4 weeks of glycemic control and are less affected by red cell turnover. 1, 2
• These markers may be particularly useful in iron deficiency anemia or other conditions affecting red blood cell lifespan 2
• However, fructosamine assay reliability is variable and has not consistently shown clinical utility 1

Critical Pitfalls to Avoid

Do not assume HbA1c is always the gold standard—it is an indirect measure of glycemia that can be affected by numerous non-glycemic factors. 1

• Never rely on fasting glucose alone to assess glycemic control when HbA1c is elevated 4, 3
• Do not dismiss an elevated HbA1c as "lab error" without systematic evaluation for the causes listed above 1
• Remember that two different tests above diagnostic thresholds (e.g., HbA1c ≥6.5% and fasting glucose ≥126 mg/dL) confirm diabetes diagnosis, but discordant results require the abnormal test to be repeated 1

In conditions with altered red blood cell turnover (iron deficiency, hemolytic anemia, pregnancy, hemodialysis, recent blood loss/transfusion, erythropoietin therapy), only plasma glucose criteria should be used for diagnosis and monitoring. 1, 2