Why HbA1c is Elevated Despite Optimal Blood Glucose Readings
When HbA1c appears elevated despite optimal blood glucose readings, the most likely explanation is a condition affecting red blood cell lifespan or turnover, with iron deficiency anemia being the most common culprit, followed by occult malignancies, chronic infections, or hemoglobin variants that interfere with the assay. 1, 2
Primary Mechanisms of HbA1c-Glucose Discordance
Red Blood Cell Lifespan Alterations
Iron deficiency anemia is the most frequent cause of falsely elevated HbA1c because it prolongs erythrocyte lifespan, exposing red blood cells to glucose for longer periods than normal. 1, 2 This creates a situation where HbA1c rises independently of actual glycemic control.
Any condition that slows erythropoiesis or extends red blood cell survival will increase HbA1c values regardless of true glucose control. 1 The key conditions include:
- Occult malignancies affecting bone marrow function alter red blood cell production and lifespan, leading to falsely elevated HbA1c that doesn't reflect actual glucose exposure. 1, 2
- Chronic infections trigger inflammatory responses that affect red blood cell turnover, potentially producing higher HbA1c values than blood glucose levels would predict. 1, 2
Hemoglobin Variants and Assay Interference
Hemoglobin variants (HbS, HbC) can produce falsely elevated or falsely lowered HbA1c depending on which specific assay method your laboratory uses. 2 Suspect a hemoglobin variant when the HbA1c reading is surprisingly high or low, or when it changes significantly after your laboratory switches methods. 1, 2
Individual Biological Variation
HbA1c may not accurately reflect mean glucose in individual patients because of wide biological variation—the same HbA1c level can correspond to substantially different mean glucose concentrations between individuals. 3 A real-world analysis found that only 11% of patients had HbA1c-GMI (glucose management indicator) discordance less than 0.1%, while 50% had differences of 0.5% or greater, and 22% had differences of 1% or greater. 4
Diagnostic Algorithm When HbA1c and Glucose Don't Match
Step 1: Obtain Complete Blood Count and Iron Studies
Order CBC to assess for anemia and iron studies to evaluate for iron deficiency, as these are the most common reversible causes of HbA1c elevation independent of glycemic control. 1, 2
Step 2: Consider Hemoglobin Variant Testing
If the HbA1c is surprisingly high relative to glucose readings, order hemoglobin electrophoresis or variant analysis to identify structural hemoglobin abnormalities. 2 The American Diabetes Association recommends using boronate affinity methods for HbA1c measurement when hemoglobin variants are suspected, as they are less susceptible to interference. 2
Step 3: Evaluate for Occult Disease
When initial testing doesn't explain the discordance, consider evaluation for occult malignancies or chronic infections that could be affecting red blood cell turnover. 1, 2
Step 4: Use Alternative Glycemic Measures
When HbA1c is suspected to be unreliable, switch to alternative measures of glycemic control such as fructosamine, glycated albumin measurements, or continuous glucose monitoring (CGM). 1, 2 These alternatives bypass the red blood cell lifespan issue entirely.
Race and Age Considerations
African Americans have HbA1c values approximately 0.4% higher than white persons for any given level of glycemia, unexplained by measured glycemic differences. 2 Additionally, HbA1c increases approximately 0.1% per decade after age 30 years in people without diabetes. 2
Critical Management Pitfalls to Avoid
Never intensify diabetes treatment based solely on an elevated HbA1c when it conflicts with blood glucose readings—this can lead to dangerous hypoglycemia. 1, 2 Relying on HbA1c without considering potential confounding factors leads to inappropriate treatment intensification. 1
Do not average discordant HbA1c results or dismiss the higher value as laboratory error without investigation. 2 Sequential HbA1c values within 0.5% do not statistically differ from one another unless the assay coefficient of variation is less than 3%. 5, 2
Avoid comparing HbA1c tests performed in different clinical laboratories, as this introduces additional measurement error. 5, 2 Point-of-care HbA1c testing is not subject to systematic quality oversight and may be less reliable than central laboratory testing. 2
Ongoing Monitoring Strategy
Once you identify the cause of HbA1c-glucose discordance, use the most reliable glycemic measure for that specific patient. 1, 2 If hemoglobin variants are confirmed, use boronate affinity HbA1c exclusively for ongoing monitoring. 2 Supplement HbA1c monitoring with self-monitoring of blood glucose and continuous glucose monitoring to capture glycemic patterns and variability. 2
In patients with disorders affecting red blood cell turnover, glucose testing will be necessary for screening, diagnosis, and management, as HbA1c may provide spurious results regardless of the method used. 2