Aims: to study the effects of a novel once-daily oral semaglutide, a glucagon-like peptide-1 analogue, on postprandial glucose (PPG) and lipid (PPL) metabolism, and gastric emptying (GE), in subjects with type 2 diabetes (T2D). Methods: a double-blind, crossover trial (NCT02773381) randomised subjects to 12-weeks’ oral semaglutide (dose-escalated to steady-state at 14 mg) followed by placebo (pbo), or vice versa, with 5-9 weeks’ washout in between. At the end of each treatment period, assessments included PPG metabolism after a standardised breakfast, PPG and PPL metabolism after a standardised fat-rich breakfast, and GE (by paracetamol absorption test) after a standardised lunch. Primary endpoint was serum glucose AUC from 0-5 hours after start of standardised breakfast. Results: fifteen subjects were randomised (13 males, mean age 58.2 years, HbA1c 6.9%, BMI 30.8 kg/m2); two withdrew prior to completion. After 12 weeks, fasting glucose levels were significantly lower and C-peptide levels significantly higher with oral semaglutide vs pbo. After standardised breakfast, postprandial glucose, mean postprandial increments in glucose and postprandial glucagon were significantly lower with oral semaglutide vs pbo (Table). No significant differences were seen in fasting or postprandial insulin levels. Glucose metabolism results were similar after standardised fat-rich breakfast. Fasting levels of total, LDL, and VLDL-cholesterol, triglycerides (TG) and apolipoprotein B48 were significantly lower with oral semaglutide vs pbo after 12 weeks. In addition, postprandial VLDL-cholesterol, apolipoprotein B48, TG and increments (iAUC) in TG were significantly lower for oral semaglutide vs pbo. During the first hour after a meal, GE was delayed (31% decrease in paracetamol AUC0-1h) with oral semaglutide vs pbo, which may explain at least part of the effect on PPG and PPL. Conclusions: oral semaglutide improved fasting and postprandial glucose and lipid metabolism, and delayed GE during the first postprandial hour, consistent with results seen with subcutaneous semaglutide.