The influence of the DPP-4 inhibitors vildagliptin (100 mg daily) and sitagliptin (50 mg daily) on blood glucose levels in patients with type 2 diabetes mellitus was investigated in this crossover study. Mean 24-h blood glucose level and MAGE were significantly lower in patients taking vildagliptin than patients taking sitagliptin.
Differences in drug efficacy between vildagliptin and sitagliptin have been investigated in a few studies. A comparison of the randomized trials conducted in Japan showed that vildagliptin 100 mg daily resulted in lower HbA1c levels (by approximately 0.3%) than sitagliptin 50 mg daily . A meta-analysis of studies using doses between 50 mg and 100 mg for both drugs found that the efficacy of vildagliptin and sitagliptin were comparable [14, 15].
Kishimoto et al. reported that sitagliptin effectively reduced postprandial blood glucose fluctuations and stabilized blood glucose levels . Sitagliptin may also work as a vasoprotective agent in diabetes by blocking the AGE-RAGE axis . Marfella et al. compared vildagliptin (100 mg daily) and sitagliptin (100 mg daily) using CGM, and reported a better MAGE in the vildagliptin group, although there was no difference in mean 24-h blood glucose level between the groups . Rizzo et al. reported recently that reductions in oxidative stress and markers of systemic inflammation were greater in patients with type 2 diabetes taking vildagliptin than those taking sitagliptin . These results were obtained in Caucasian patients, and it important to also compare the effects of these drugs in Asian patients, including Japanese patients, because there are differences in causes of diabetes, insulin secretion, and background characteristics between Caucasian and Japanese patients.
The reason for the differences in drug efficacy (mean blood glucose level and MAGE) observed in this study is considered to be that sitagliptin 50 mg daily results in less than 70% suppression of DPP-4 activity over 24 h  whereas vildagliptin 50 mg twice daily results in 80% or greater suppression of DPP-4 activity over 24 h . It is also possible that the different mode of binding with DPP-4 and the different frequency of drug administration results in a greater reduction in blood glucose level after supper and breakfast in patients taking vildagliptin .
For patients taking vildagliptin it is possible that suppression of glucagon secretion by the evening dose leads to a lower AUC (≥180 mg/dL) after breakfast, and suppression of glucagon secretion by the morning dose leads to a lower peak in blood glucose level after supper. These results seem to support a twice daily administration schedule for vildagliptin.
Postprandial hyperglycemia has been reported to trigger vascular disorders and cause cardiovascular events, and is more common in patients with high HbA1c levels . Selection of a DPP-4 inhibitor that effectively suppresses postprandial hyperglycemia contributes to the maintenance of ideal HbA1c levels.
It is interesting that urinary CPR level and variations in blood glucose level were higher in patients taking vildagliptin than patients taking sitagliptin. We postulate that the higher level of DPP-4 inhibition over 24 h in patients taking vildagliptin, compared with patients taking sitagliptin, inhibits the destruction of incretin, which enhances endogenous insulin secretion, thereby improving MAGE and achieving a more stable reduction in blood glucose levels. A relationship between MAGE and oxidation stress has also been reported , suggesting that improvement of MAGE by vildagliptin administration might suppress oxidation stress and decrease the incidence of adverse cardiovascular events in the long term. This possibility should be further elucidated in future studies.
As DPP-4 inhibitors are reported to lower BNP level , and vildagliptin is reported to suppress PAI-1 production , this study measured BNP and PAI-1 levels to evaluate cardiovascular parameters, but no differences were observed between patients taking vildagliptin and sitagliptin. Linagliptin, other DPP-4 inhibitor, has been reported to be beneficial in terms of cardiac protection and safety . Improvements in parameters might be due to the effects of the drugs, but results might also be affected by factors such as the number of subjects, short treatment period, and the blood glucose levels being within the normal range.
This study has limitations as a pilot study because of the small number of subjects and the sitagliptin dose of 50 mg. A randomized, double-blind, placebo-controlled study of sitagliptin performed in Japanese patients reported that HbA1c was reduced by 0.71% after oral administration of sitagliptin 50 mg daily for 12 weeks, and by 0.69% after oral administration of sitagliptin 100 mg daily for 12 weeks, which was not a significant difference . It is not known if using a dose of sitagliptin 100 mg daily in this study would have significantly affected the results. The results of larger clinical trials evaluating the cardiovascular protective effects and safety of DPP-4 inhibitors are awaited.