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Background: This study evaluated the effects of exenatide, a GLP-1 receptor agonist, and sitagliptin, a DPP-4 inhibitor, on 2-h postprandial glucose (PPG), insulin and glucagon secretion, gastric emptying, and caloric intake in T2D patients.Methods: This double-blind, randomized cross-over, multi-center study was conducted in metformin-treated T2D patients: 54% female; BMI: 33 ± 5 kg/m2; HbA1c: 8.5 ± 1.2%; 2-h PPG: 245 ± 65 mg/dL. Patients received exenatide (5 μg BID for 1 week, then 10 μg BID for 1 week) or sitagliptin (100 mg QAM) for 2 weeks. After 2 weeks, patients crossed-over to the alternate therapy. Postprandial glycemic measures were assessed via standard meal test; caloric intake assessed by ad libitum dinner (subset of patients). Gastric emptying was assessed by acetaminophen absorption (Clinicaltrials.gov Registry Number: NCT00477581).Results: After 2 weeks of therapy, 2-h PPG was lower with exenatide versus sitagliptin: 133 ± 6 mg/dL versus 208 ± 6 mg/dL, p < 0.0001 (evaluable, N = 61). Switching from exenatide to sitagliptin increased 2-h PPG by +73 ± 11 mg/dL, while switching from sitagliptin to exenatide further reduced 2-h PPG by −76 ± 10 mg/dL. Postprandial glucose parameters (AUC, Cave, Cmax) were lower with exenatide than sitagliptin (p < 0.0001). Reduction in fasting glucose was similar with exenatide and sitagliptin (−15 ± 4 mg/dL vs. −19 ± 4 mg/dL, p = 0.3234). Compared to sitagliptin, exenatide improved the insulinogenic index of insulin secretion (ratio exenatide to sitagliptin: 1.50 ± 0.26, p = 0.0239), reduced postprandial glucagon (AUC ratio exenatide to sitagliptin: 0.88 ± 0.03, p = 0.0011), reduced postprandial triglycerides (AUC ratio exenatide to sitagliptin: 0.90 ± 0.04, p = 0.0118), and slowed gastric emptying (acetaminophen AUC ratio exenatide to sitagliptin: 0.56 ± 0.05, p < 0.0001). Exenatide reduced total caloric intake compared to sitagliptin (−134 ± 97 kcal vs. +130 ± 97 kcal, p = 0.0227, N = 25). Common adverse events with both treatments were mild to moderate in intensity and gastrointestinal in nature.Conclusions: Although this study was limited by a 2-week duration of exposure, these data demonstrate that, exenatide had: (i) a greater effect than sitagliptin to lower postprandial glucose and (ii) a more potent effect to increase insulin secretion and reduce postprandial glucagon secretion in T2D patients. In contrast to sitagliptin, exenatide slowed gastric emptying and reduced caloric intake. These key findings differentiate the therapeutic actions of the two incretin-based approaches, and may have meaningful clinical implications. [ABSTRACT FROM AUTHOR]