Lixisenatide reduces postprandial hyperglycaemia via gastrostatic and insulinotropic effects

Background Lixisenatide is a once‐daily, prandial, short‐acting glucagon‐like peptide‐1 receptor agonist. Its main antidiabetic effect is to delay gastric emptying to control postprandial plasma glucose excursions. The dose–response relationship of the integrated insulinotropic and gastrostatic response to lixisenatide in healthy volunteers after a standardized liquid meal was investigated. Methods Twenty healthy subjects received acetaminophen 1000 mg with a standardized liquid meal 60 min after a single subcutaneous injection of placebo or lixisenatide 2.5, 5, 10 or 20 µg in randomized order separated by a 2‐ to 7‐day washout. Acetaminophen pharmacokinetics served as a surrogate to assess rate of gastric emptying. Postprandial plasma glucose, insulin, C‐peptide and glucagon were assessed for 5 h after the meal test, and lixisenatide pharmacokinetics were determined for 6 h. Results After lixisenatide administration and prior to the standardized meal, insulin and C‐peptide transiently increased, while fasting plasma glucose decreased in a dose‐dependent manner. After the meal, postprandial plasma glucose, insulin and C‐peptide were dose proportionally reduced with lixisenatide versus placebo for up to 6 h. Compared with placebo, glucagon levels were transiently lower after any lixisenatide dose, with more sustained reductions after the meal and no apparent dose‐related trends. Acetaminophen absorption was significantly reduced and delayed compared with placebo for lixisenatide doses ≥5 µg and demonstrated dose‐dependent slowing of gastric emptying. Lixisenatide displayed near dose‐proportional exposure, with gastrointestinal events increasing with dose. Conclusions Lixisenatide reduced fasting plasma glucose via stimulation of glucose‐dependent insulin release and controlled postprandial plasma glucose by delaying gastric emptying, demonstrating it to be a valuable option for overall glycaemic control. Copyright © 2015 John Wiley & Sons, Ltd.