There is increasing evidence that glycemic disorders such as rapid glucose fluctuations over a daily period might play an important role on diabetic complications. We evaluated the efficacy of sitagliptin 100 mg once daily vs. vildagliptin 50 mg twice daily on daily blood glucose fluctuations in patients with type 2 diabetes that was inadequately controlled by metformin. Forty-eight-hour continuous subcutaneous glucose monitoring (CSGM) was performed in patients treated with metformin plus vildagliptin (n=18) or sitagliptin (n=20) over a period of 3 months. The mean amplitude of glycemic excursions (MAGE) was used for assessing glucose fluctuations during the day. During a standardized meal, glucagon-like peptide-1 (GLP-1), glucagon, and insulin were measured. CSGM shows large MAGE decrements in the vildagliptin group compared with the sitagliptin group (P<.01). A marked increase in GLP-1 occurred during interprandial period in vildagliptin bid-treated toward sitagliptin 100 mg once daily (P<.01). Glucagon was more suppressed during interprandial period in subjects receiving vildagliptin compared to those receiving sitagliptin (P<.01). Since MAGE is associated with an activation of oxidative stress, our data suggest that dipeptidyl peptidase IV inhibition therapy should target not only reducing HbA(1c) but also flattening acute glucose fluctuations over a daily period.