How HbA1c Measures Blood Glucose Over Months
HbA1c reflects average blood glucose levels over approximately 2-3 months because it measures the irreversible glycation of hemoglobin on red blood cells, which have a lifespan of approximately 120 days. 1
The Biochemical Mechanism
Glucose attaches irreversibly to the N-terminal valine residue of the hemoglobin β-chain through a stable ketoamine formation (Amadori rearrangement), creating glycated hemoglobin (HbA1c). 2
The amount of HbA1c formed is directly proportional to the concentration of glucose in the blood, making it an integrated measure of glycemia over the red blood cell's lifespan. 3, 4
Since red blood cells (erythrocytes) have a life span of approximately 120 days, HbA1c accumulates glucose exposure throughout this entire period. 1
The Time-Weighted Average
Recent glycemia has greater influence on the HbA1c value: approximately 50% of the HbA1c level reflects glucose from the past month, 25% from 30-60 days prior, and 25% from 60-120 days prior. 2
This weighted contribution means that while HbA1c represents a 2-3 month average, changes in glucose control will begin to show in HbA1c measurements within weeks, with the most recent month having the strongest impact. 1
Clinical Correlation with Blood Glucose
Each 1% increase in HbA1c corresponds to approximately 28.7 mg/dL increase in mean plasma glucose, based on the ADAG (A1C-Derived Average Glucose) study. 2, 5
The ADAG study demonstrated a strong correlation (r = 0.92) between HbA1c and average glucose levels derived from approximately 2,700 glucose measurements over 3 months per patient. 1
This relationship allows HbA1c to be reported as an estimated average glucose (eAG), making it more understandable to patients in the same units (mg/dL or mmol/L) used for daily glucose monitoring. 5
Important Clinical Limitations
Conditions affecting red blood cell turnover can falsely alter HbA1c independent of actual glycemic control:
Shortened RBC lifespan (hemolytic anemia, blood loss, kidney disease, pregnancy) decreases HbA1c, causing falsely low readings. 1, 2
Prolonged RBC lifespan (iron deficiency anemia, aplastic anemia) increases HbA1c, causing falsely elevated readings. 2, 3
Hemoglobin variants (HbS, HbC, HbEE) can interfere with HbA1c assays, and HbA1c cannot be measured at all in individuals with sickle cell disease (HbSS) who lack HbA. 1, 2
Alternative Measures When HbA1c Is Unreliable
Fructosamine and glycated serum albumin reflect glycemia over only 1-2 weeks (based on albumin's half-life of 14-20 days rather than the 120-day RBC lifespan), making them useful alternatives when HbA1c is unreliable. 1
These glycated serum protein assays correlate well with HbA1c but require more frequent testing (monthly) to provide equivalent information to quarterly HbA1c measurements. 1
Monitoring Frequency
HbA1c should be measured approximately every 3 months to determine whether glycemic goals have been reached and maintained, as this timeframe aligns with the test's reflection of 2-3 months of glucose control. 1
Patients meeting treatment goals with stable glycemic control may only require testing twice yearly, while those with therapy changes or not meeting goals require quarterly assessment. 1