Research Article: Hemoglobin glycation index as a useful predictor of therapeutic responses to dipeptidyl peptidase-4 inhibitors in patients with type 2 diabetes

Date Published: February 9, 2017

Publisher: Public Library of Science

Author(s): Yu-Wei Chen, Jun-Sing Wang, Wayne H-H Sheu, Shih-Yi Lin, I-Te Lee, Yuh-Min Song, Chia-Po Fu, Chia-Lin Lee, Stephen L. Atkin.


A high hemoglobin glycation index (HGI) and glycated hemoglobin (HbA1c) level are associated with greater inflammatory status, and dipeptidyl peptidase-4 (DPP-4) inhibitors can suppress inflammation. We aimed to evaluate the relationship between HGI and the therapeutic effect of DPP-4 inhibitors.

This retrospective cohort study followed 468 patients with type 2 diabetes receiving DPP-4 inhibitor treatment for 1 year. Estimated HbA1c was calculated using a linear regression equation derived from another 2969 randomly extracted patients with type 2 diabetes based on fasting plasma glucose (FPG) level. The subjects were divided into two groups based on HGI (HGI = observed HbA1c – estimated HbA1c). Mixed model repeated measures were used to compare the treatment efficacy after 1 year in patients with a low (HGI<0, n = 199) and high HGI (HGI≧0, n = 269). There were no significant group differences in mean changes of FPG after 1 year (-12.8 and -13.4 mg/dL in the low and high HGI groups, respectively). However, the patients with a high HGI had a significantly greater reduction in HbA1c from baseline compared to those with a low HGI (-1.9 versus -0.3% [-20.8 versus -3.3 mmol/mol]). Improvements in glycemic control were statistically significantly associated with the tested DPP-4 inhibitors in the high HGI group (-2.4, -1.4, -1.2 and -2.2% [-26.2, -15.3, -13.1 and -24.0 mmol/mol] for vildagliptin, linagliptin, saxagliptin and sitagliptin, respectively) but not in the low HGI group. The HGI index derived from FPG and HbA1c may be able to identify who will have a better response to DPP-4 inhibitors.

Partial Text

The prevalence of type 2 diabetes mellitus is increasing worldwide, especially in Asian countries, and this is a major challenge for health care systems [1]. The current management of diabetes aims to lower the glycosylated hemoglobin (HbA1c) level to decrease the risk of diabetes complications. However, the HbA1c level varies considerably even in individuals who have similar preceding mean blood glucose (MBG) levels. Between-person biological variations in HbA1c have been studied in healthy individuals without diabetes [2–4], and it has been suggested that between-patient differences in HbA1c are greater than within-subject variations in HbA1c, and that there is a tendency for some individuals to have persistently higher or lower HbA1c levels than expected [3]. Several investigators have also identified this phenomenon in patients with type 1 and type 2 diabetes using the hemoglobin glycation index (HGI) [5, 6]. The HGI is calculated as the difference between an individual’s observed HbA1c and estimated HbA1c (HGI = observed HbA1c – estimated HbA1c). An estimated HbA1c level is calculated from a linear regression equation and describes the relationship between HbA1c and blood glucose by including observed MBG or fasting plasma glucose (FPG) into the equation [5–7].

A total of 468 (268 men) patients were analyzed. Baseline demographic, biochemical, and clinical characteristics as well as concomitant background therapies were compared between the two HGI groups (Table 1). Compared with the low HGI group, the high HGI group was younger with a higher initial mean HbA1c value but similar FPG level. In addition, the high HGI group was more likely to have used insulin before the start of the study.

Our results demonstrate that patients with type 2 diabetes with a high HGI managed by DPP-4 inhibitors had significant improvements in glycemic control compared with those with a low HGI. To the best of our knowledge, this is the first study to evaluate the efficacy of DPP-4 inhibitor treatment on glycemic control stratified by HGI. In this study, the patients with a high HGI were more likely to use insulin for sugar control, which may be because they tended to have a persistently high HbA1c level, which is consistent with previous studies [6, 9]. In addition, our finding of a markedly distinct HbA1c response in different HGI subgroups is also consistent with a former study, which suggested that baseline HbA1c was an important predictor of HbA1c response to DPP-4 inhibitors in patients with type 2 diabetes [27]. However, we divided our patients into tertiles according to baseline HbA1c level, and the results still showed between-subgroup differences in the HbA1c lowering effect, which may suggest that both baseline HbA1c and also HGI are major determinants of improvements in HbA1c.

In summary, we found that the administration of DPP-4 inhibitors in patients with a high HGI resulted in a significant reduction in HbA1c after 1 year of follow-up. This supports that the choice of diabetes therapy should be individualized. When starting therapy with a DPP-4 inhibitor, the HGI may help to quantify individual differences in daily clinical practice. Additional studies are needed to verify the results of this study and further investigate the use of HGI in other anti-diabetes medications.