Is HbA1c Affected by Glycemic Instability?
Will fluctuations in blood glucose readings effect the HbA1c ?
posted 10/02/03

Glycated Hemoglobin (A1c) is a standard clinical assessment of glycemia and the basis of most data relating glycemic control to complications. It remains unclear, however, whether HbA1c is affected by glycemic variation and mean glycemia.

To test this question, the statistical relationship between HbA1c levels and glycemic variability was analyzed as measured by self-monitoring of blood glucose (SMBG). The records of 256 subjects were studied. SMBG data for the preceding 3 months were downloaded, and HbA1c was measured by ion-exchange high-performance liquid chromatography. Simple- and random-effects linear regression models were used to assess the independent contributions of mean blood glucose (BG) and SD of BG to HbA1c, after adjusting for the mean BG.

The results reveled that the mean ± SD for HbA1c was 7.66 ± 1.11% and for BG was 8.5 ± 1.9 mmol/l (153.3 ± 34.9 mg/dl); SD of BG for individual subjects was 3.5 mmol/l (63.3 mg/dl), varying from 0.4 mmol/l (8.1 mg/dl; very stable glycemia) to 8.4 mmol/l (152.5 mg/dl; very unstable glycemia). A close correlation between mean BG and HbA1c was demonstrated (r = 0.62). Also, within-subject SD of BG correlated with HbA1c (r = 0.375), indicating that people with poorer glycemic control had higher BG variance. After adjusting for mean BG in a linear regression model, however, the effect of the within-subject SD of BG on the HbA1c was insignificant. Several further analyses confirmed the strength of the observation.

The strong relationship we have found between mean BG and HbA1c reconfirms what has been well established. Our finding that people with greater glycemic variance have poorer diabetic control is also expected, because patients with widely fluctuating BG will have periods of high glycemia that increase their mean BG, and less stable glycemia is more difficult to control well to a mean level approaching normal. Possible causal relationships between poor mean glycemia and labile glycemia are not addressed by our data. However, it is evident from our data that an assessment of whether glycemic lability affects HbA1c cannot ignore the relationship between mean glycemia and HbA1c.

Our data refute the hypothesis that glycemic lability has an important independent effect on HbA1c. In particular, we do not find that spikes of glycemia into high ranges increase HbA1c beyond their contribution to mean BG. Rather, the statistical relationship between glycemic variance and HbA1c is, for all practical purposes, entirely accounted for by the tendency of people with increased fluctuations in BG to have increased mean BG.

Hb is continuously glycated during the 120-day life span of the erythrocyte, such that the proportion of Hb that is in the form of HbA1c increases throughout the erythrocyte’s lifetime.

Our findings could have potentially important implications for understanding the development of long-term complications of diabetes. Because the major long-term studies of control and complications use HbA1c to assess glycemia, and because we have shown that HbA1c is not importantly affected by glycemic variability, our results could be interpreted as compatible with the hypothesis that glycemic variability has little independent role in causing microvascular complications. The DCCT found that although HbA1c was the predominant determinant of risk, it did not account for the entire risk of retinopathy progression; other unidentified factors contributed to a difference between the conventionally and the intensively treated groups. The question of whether lability, as such, contributes to incidence of complications would ultimately be settled only by large, long-term, prospective clinical trials, presumably using continuous glucose monitoring. Our data, however, indicate that lability of blood glucose does not, at least, contribute to complications by affecting glycation of the protein Hb.

In conclusion, we have found that variation in BG does not affect HbA1c. We have reconfirmed the strong correlation between mean BG and HbA1c and found a close correlation between glycemic variance and mean BG. When these associations are taken into account, we identified no contribution of glycemic variance to HbA1c.

Source: Diabetes In Control.com:Diabetes Care 26:2728-2733, 2003.

October News Article Index