We conducted a pilot study on HbA1c variability and CGM indexes, and showed that SD HbA1c is associated with the hypoglycemic indexes of TBR and LBGI. Although the association between HbA1c and CGM indexes has been analyzed previously, this is the first study that dissected the association between HbA1c variability and CGM indexes. HbA1c variability is known to be associated with mortality due to vascular complications in diabetes patients [13], and hypoglycemia is considered a possible contributory factor.
Variations in blood glucose levels are known to be involved in the progression of diabetes vasculopathies, and several studies reported the association of fasting blood glucose variability and postprandial blood glucose with vascular complications.
HbA1c variability has also attracted attention in recent years, with SD and CV used as scales of HbA1c variability. Bouchi et al. [11] reported that SD HbA1c, which is independent of the common cardiovascular risk factors, is associated with the risk of onset of cardiovascular disease (CVD) in T2DM patients. Hirakawa et al. [12] reported that high SD HbA1c is associated with increased risk of onset of vascular events and increased mortality rate in patients of the ADVANCE trial intensive therapy group. Furthermore, Orsi et al. [13] reported that HbA1c variability in T2DM patients is a strong independent predictor of all-cause mortality in T2DM. Although these reports have shown that HbA1c variability is associated with mortality due to diabetes vasculopathies, the significance of HbA1c variability remains unknown. This study is the first to show that HbA1c variability is associated with CGM-based hypoglycemic indexes. Since HbA1c variability reflects the risk of hypoglycemia, it is possible that HbA1c variability is associated with diabetic vascular complications and the related mortality risk.
The objective of glycemic control is to normalize blood glucose level. The United Kingdom Prospective Diabetes Study (UKPDS) [16] obtained data that confirmed the so-called legacy effect associated with intensive glycemic control; therefore, if that state can be maintained, then a long-term prognosis can be expected. On the other hand, intensive glycemic control also increases the risk of hypoglycemia. Particularly severe hypoglycemia must be avoided, as it is associated with poor prognosis. HbA1c is a useful index for evaluating hyperglycemia; however, since HbA1c cannot be used to evaluate hypoglycemia, it is recommended to set a lower limit blood glucose for HbA1c according to the conditions and risk of hypoglycemia [17, 18]. Our study showed that high HbA1c variability increases the risk of hypoglycemia, and provided the cutoff value for SD HbA1c, above which the risk of hypoglycemia is increased. Our results call for evaluation of hypoglycemia in patients with high SD HbA1c.
As mentioned previously [3, 5], correction of HbA1c is required in order to prevent microangiopathies. In agreement with previous studies, our results showed that the mean HbA1c was associated with the CGM indexes of TIR [19], average glucose [6] and GMI [14]. Although the mean HbA1c was also associated with hyperglycemic indexes, such as maximum, TAR and HBGI, it was not associated with markers of hypoglycemia risk. It is not possible to determine the presence of hypoglycemia by HbA1c values alone; therefore, HbA1c target values should be set individually, taking into consideration the risk of hypoglycemia and support systems.
There were two limitations to this study. The first is we were unable to measure glucose density of ≥ 500 mg/dL in FGM; therefore, as per the decision of the primary physician, patients within the FGM range were recruited for this study. As such, our study did not include patients with poor glycemic control, and thus the results of such patients may be different to those obtained in this study. The second limitation is this was a cross-sectional study conducted at two facilities, and included a relatively small number of patients. Consequently, we were unable to examine the effect of each anti-diabetes agent on SD HbA1c. We need to proactively continue with our research on a larger scale in order to substantiate the results of this study.