In this article entitled "Predictive factors for efficacy of dipeptidyl peptidase-4 inhibitors in patients with type 2 diabetes mellitus," Yagi et al. [5] evaluated the predictive factors for the efficacy of DPP-4 inhibitors based on the change of glycosylated hemoglobin (HbA1c) after 12 months of treatment. They described the predictors to be a decrease in HbA1c level after 3 months of treatment, a high baseline HbA1c level, a low baseline body mass index, and no history of coronary artery disease (CAD). This article is interesting, especially in that the long-term effects of DPP-4 inhibitors on glycemic control could be predicted by the short term response, which might make it easier to identify the good responders to DPP-4 inhibitors. Although there are some clinical significances, some points need to be clarified.

First, the criteria for DPP-4 inhibitor add-on therapy needs to be clarified better in this study. The study patients aged 68.3±35.8 years old, and baseline HbA1c were 7.5%±1.3%. Initially, 36.6% of patients already had HbA1c <7% when DPP-4 inhibitors are added on. Considering that the patients were relatively old with mild elevated HbA1c level, the reason for additional DPP-4 inhibitors might be helpful to understand and validate the efficacy of DPP-4 inhibitors. In addition, a majority of patients have already been treated with other anti-diabetic drugs. Forty-four percent of patients used α-glucosidase inhibitors, 32.5% for sulfonylurea, and 15.2% for biguanides. In these patients, the reason for additional DPP-4 inhibitor instead of the dose increment of baseline drugs could be informative.

Second, combination therapy of other anti-diabetic drugs might affect glucose metabolism and exert confounding effects. A previous study has reported that combination treatment of alogliptin and voglibose increased plasma active glucagon-like peptide-1 (GLP-1) levels and pancreatic insulin content synergistically in db/db mice [6]. Another study showed that a combination of miglitol and sitagliptin effectively attenuate postprandial hyperglycemia with various patterns of insulin, glucagon, and GLP-1 release, suggesting that individual hormone-related glycemic responses to the DPP-4 inhibitors and α-glucosidase inhibitor are complex and multifactorial [7]. Synergistic effect of sulfonylurea and DPP-4 inhibitor has been suggested, because some patients showed dramatic glycemic improvement after this combination therapy [8]. Sulfonylurea added to DPP-4 inhibitor might potentiate insulin secretion by activating exchange protein activated by cyclic AMP 2 (Epac2) [9]. There are substantial synergistic or heterogenous responses to combination therapy of DPP-4 inhibitor with other anti-diabetic drugs. Analyzing the patients with similar baseline anti-diabetic drugs could be more appropriate to evaluate the predictive factors for the efficacy of DPP-4 inhibitors.

Third, duration of diabetes is one of the substantial predictors for the response to DPP-4 inhibitors. Several studies have shown that shorter duration of diabetes is associated with greater reduction in HbA1c after DPP-4 inhibitor add-on [123]. Further information including duration of diabetes could support the interesting findings in this study. In addition, incidence rate of CAD increases with longer duration of diabetes [10]. As shown in this study, absence of CAD itself could be one of the predictors of DPP-4 inhibitor response, otherwise, shorter duration of diabetes might be the unrevealed connection link of good response for DPP-4 inhibitors.

Lastly, the authors evaluated the predictive factors based on the change of HbA1c after 12 months of treatment. Baseline HbA1c, however, is an important factor that affects the change of glycemic control [4]. In this study, as baseline HbA1c was high, the change of HbA1c would also appear to be more significant. Identifying the predictive factors with reference to the baseline HbA1c could be more interesting if individual responses to DPP-4 inhibitors were considered. Based on the results of this study, short-term follow-up studies with a large patient population are warranted to investigate the predictors of DPP-4 inhibitor response.