Factors That Influence HbA1c Levels
HbA1c levels are influenced by two major categories: factors affecting average glycemia (the primary determinant) and factors affecting red blood cell turnover, hemoglobin glycation, or hemoglobin structure (which can falsely alter results independent of glucose control).
Primary Determinant: Average Blood Glucose
- HbA1c reflects average glycemia over the preceding 2-3 months, corresponding to the lifespan of red blood cells 1, 2.
- The test is not significantly affected by acute fluctuations in blood glucose, such as those occurring with illness or after meals 1.
- Mean glucose levels directly correlate with HbA1c values, with each percentage point representing a specific average glucose range 1.
Red Blood Cell Turnover Factors
Conditions That Falsely Lower HbA1c
Any condition that shortens RBC survival or decreases mean RBC age will falsely lower HbA1c results regardless of the assay method used 1, 3:
- Hemolytic anemia (including autoimmune hemolytic anemia) 1, 3, 4
- Recent acute blood loss or blood transfusion 1
- Erythropoietin therapy - can decrease HbA1c by approximately 0.6% per 10,000 IU weekly dose 1, 5
- Iron supplementation (when correcting iron deficiency) 1
- Vitamin B12 supplementation (when correcting deficiency) 1
- Chronic liver disease 1
- Splenomegaly 1
- Pregnancy (second and third trimesters) - due to increased red blood cell turnover 1
- Hemodialysis 1, 6
- G6PD deficiency - can lower HbA1c by approximately 0.7-0.8% 3
- Hereditary macrocytosis (frequently associated with hemolytic conditions) 3
Conditions That Falsely Elevate HbA1c
Conditions that prolong erythrocyte lifespan or decrease red cell production will falsely elevate HbA1c 1, 3:
Hemoglobin Variants and Structural Factors
- Hemoglobin variants (hemoglobinopathies) can interfere with HbA1c measurement depending on the assay method used 1.
- Sickle cell disease - HbA1c cannot be measured in homozygous variants like HbSS 1.
- Other hemoglobin variants (HbEE, etc.) may cause assay interference 1.
- Marked discordance between measured HbA1c and plasma glucose levels should raise suspicion of hemoglobin variant interference 1, 3.
Age and Race
- Age: HbA1c increases approximately 0.1% per decade after age 30 years in people without diabetes 1.
- Race: Black individuals have mean HbA1c values approximately 0.4% higher than White individuals at similar glucose levels, though this does not modify cardiovascular risk associations 1.
- Hispanic populations also show relatively higher HbA1c compared to White populations at the same glycemia level 1.
Other Interfering Substances
- Vitamins C and E may falsely lower HbA1c by inhibiting hemoglobin glycation 1.
- Hypertriglyceridemia, hyperbilirubinemia, uremia, and chronic alcoholism can affect results 1.
Chronic Kidney Disease
- CKD significantly weakens the correlation between HbA1c and glucose levels, particularly when combined with anemia 6.
- In patients with both severe CKD (eGFR <30 mL/min) and anemia, the correlation coefficient between HbA1c and fasting glucose drops from r=0.70 to r=0.35 6.
- Anemia in CKD represents a catabolic state affecting both red cell and plasma protein turnover, compromising both HbA1c and alternative markers like fructosamine 6.
Critical Clinical Pitfall
When conditions affecting red blood cell turnover, hemoglobin variants, or other interfering factors are present, HbA1c should not be used for diagnosis or monitoring 1, 3. In these situations:
- Use plasma glucose criteria only (fasting glucose, 2-hour OGTT) for diagnosis and monitoring 1, 3.
- Consider alternative glycated proteins (fructosamine or glycated albumin) that reflect 2-4 weeks of glycemic control 1, 3.
- Utilize self-monitoring of blood glucose or continuous glucose monitoring for direct glucose assessment 3, 6.