HbA1c and Estimated Average Glucose (eAG)
Why is relating HbA1c to glucose important?
We are frequently asked about the relationship between HbA1c and plasma glucose levels. Many patients with diabetes mellitus now perform self-monitoring of blood glucose (SMBG) in the home setting, and understanding the relationship between HbA1c and glucose can be useful in setting goals for day-to-day testing.
HbA1c: A "Weighted" Average
Many studies have shown that HbA1c is an index of average glucose (AG) over the preceding weeks-to-months. Erythrocyte (red blood cell) life-span averages about 120 days. The level of HbA1c at any point in time is contributed to by all circulating erythrocytes, from the oldest (120 days old) to the youngest. However, HbA1c is a "weighted" average of blood glucose levels during the preceding 120 days, meaning that glucose levels in the preceding 30 days contribute substantially more to the level of HbA1c than do glucose levels 90-120 days earlier. This explains why the level of HbA1c can increase or decrease relatively quickly with large changes in glucose; it does not take 120 days to detect a clinically meaningful change in HbA1c following a clinically significant change in AG.
How does HbA1c relate to average glucose (AG)?
In the Diabetes Control and Complications Trial or DCCT (New Engl J Med 1993;329:977-986) study of patients with Type 1 diabetes, quarterly HbA1c determinations were the principal measure of glycemic control; study subjects also performed quarterly 24-hour, 7-point capillary-blood glucose profiles. Blood specimens were obtained by subjects in the home setting, pre-meal, 90 minutes post-meal, and at bed-time. In an analysis of the DCCT glucose profile data (Diabetes Care 25:275-278, 2002), mean HbA1c and AG were calculated for each study subject (n= 1439). Results showed a linear relationship between HbA1c and AG (AG(mg/dL) = ( 35.6 x HbA1c ) - 77.3), with a Pearson correlation coefficient (r) of 0.82.
Data from the A1c-Derived Average Glucose (ADAG) Study:
A more recent study (2006-2008) sponsored by the ADA, EASD and IDF was designed to better define the mathematical relationship between HbA1c and AG. The study included 507 subjects with Type 1 and Type 2 diabetes and without diabetes from 10 international centers. Estimated AG (eAG) was calculated by combining weighted results from at least 2 days of continuous glucose monitoring performed four times, with seven-point daily self-monitoring of capillary glucose performed at least 3 days per week. The relationship between eAG and HbA1c based on linear regression analysis was:eAG(mg/dl)= (28.7*HbA1c)-46.7, r2=0.84 (Diabetes Care 2008;31:1-6). Table 1 depicts this relationship.
More information about eAG, including a calculator to covert eAG to HbA1c and vice-versa, can be found here.
The regression equation from the ADAG study provides lower eAG values compared with the widely used equation derived from the DCCT, and the scatter around the regression is less wide. The proposed explanation for the difference is in the frequency of glucose measurements used to calculate AG, with the ADAG estimate providing a more complete and representative measure of average glucose.
How does Fasting Glucose Relate to HbA1c?
Further analyses of the DCCT data showed that among single time-point measurements, post-lunch and bedtime glucose showed relationships to HbA1c that were the most similar to full 7-point profile glucose. Fasting glucose correlated less well and results showed that with increasing HbA1c, fasting glucose progressively underestimated the level of HbA1c and/or AG calculated from the 7-point profile.
What Does All of This Mean?
First, there is a very predictable relationship between HbA1c and AG. Understanding this relationship can help patients with diabetes and their health-care providers set day-to-day targets for AG based on HbA1c goals (e.g. American Diabetes Association recommendations). Second, fasting glucose should be used with caution as a surrogate measure of AG. Finally, it is important to remember that HbA1c is a weighted average of glucose levels during the preceding 4 months. Unless the patient’s glucose levels are very stable month after month, quarterly measurement is needed to insure that a patient's glycemic control remains within the target range.