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.

Effects of lixisenatide once daily on gastric emptying in type 2 diabetes--relationship to postprandial glycemia.

OBJECTIVES: To determine the effects of lixisenatide, a new once-daily (QD) glucagon-like peptide-1 receptor agonist, on postprandial glucose (PPG) and gastric emptying, and the relationship between these effects in patients with type 2 diabetes mellitus (T2DM). METHODS: Data were obtained from a randomized, double-blind, placebo-controlled, parallel-group study with treatment duration of 28 days in patients with T2DM receiving ≤2 oral antidiabetic drugs. Lixisenatide was injected subcutaneously using an ascending dose range (5-20 µg) increased every fifth day in increments of 2.5 µg. Blood glucose was determined before and after three standardized meals (breakfast, lunch, and dinner). Gastric emptying of the standardized breakfast was determined by a (13)C-octanoic acid breath test at baseline (Day-1) and at Day 28. RESULTS: A total of 21 and 22 patients were randomized to lixisenatide 20 µg QD and placebo, respectively. With lixisenatide 20 µg QD, there was a reduction in PPG when compared with placebo after breakfast (p<0.0001), lunch (p<0.001) and dinner (p<0.05). Hence, lixisenatide 20 µg administered in the morning exhibited a pharmacodynamic effect on blood glucose throughout the day. Gastric emptying (50% emptying time) increased substantially from baseline with lixisenatide 20 µg QD, but not with placebo (change from baseline ± SD: -24.1 ± 133.1 min for placebo and 211.5 ± 278.5 min for lixisenatide; p<0.01). There was an inverse relationship between PPG area under the curve after breakfast and gastric emptying with lixisenatide 20 µg QD (n=17, r(2)=0.51, p<0.05), but not with placebo. CONCLUSIONS: In this study, lixisenatide at a dose of 20 µg QD reduced postprandial glycemic excursions in patients with T2DM, possibly as a result of sustained slowing of gastric emptying.

The effect of smoking cessation and subsequent resumption on absorption of inhaled insulin.

OBJECTIVE: To assess the absorption profile of inhaled insulin in healthy, actively smoking subjects at baseline, after smoking cessation, and after smoking resumption and compare it with nonsmoking subjects. RESEARCH DESIGN AND METHODS: Insulin pharmacokinetics and glucodynamics were measured in 20 male smoking subjects (10-20 cigarettes/day) and 10 matched nonsmoking subjects after receiving inhaled insulin (1 mg) or the approximate subcutaneous insulin equivalent (3 units) in a randomized cross-over fashion. All smokers then received inhaled insulin 12 h, 3 days, and 7 days into a smoking cessation period. They then resumed smoking for 2-3 days before again receiving inhaled insulin 1 h after the last cigarette. RESULTS: Before smoking cessation, maximum insulin concentration (Cmax) and area under the curve (AUC) for insulin concentration time (AUC-Insulin(0-360)) with inhaled insulin were higher, and time to Cmax (t(max)) shorter, in smokers than nonsmokers (Cmax 26.8 vs. 9.7 microU/ml; AUC-Insulin(0-360) 2,583 vs. 1,645 microU x ml(-1) x min(-1); t(max) 20 vs. 53 min, respectively; all P < 0.05), whereas with subcutaneous insulin, systemic exposure was unchanged (AUC-Insulin(0-360) 2,324 vs. 2,269 microU x ml(-1) x min(-1); P = NS). After smoking cessation, AUC-Insulin(0-360) decreased with inhaled insulin by up to 50% within 1 week and approached nonsmoker levels. Cmax decreased and t(max) increased relative to baseline but were still not comparable with nonsmoker values. Smoking resumption completely reversed the effect of smoking cessation. Glucodynamics corroborated the observed findings in insulin pharmacokinetics. CONCLUSIONS: Cessation and resumption of smoking greatly altered the pharmacokinetics of inhaled insulin. As rapid changes in systemic insulin exposure increase hypoglycemia risk, inhaled insulin should not be used in people with diabetes who choose to continue smoking. This is consistent with recommendations that people with diabetes refrain from smoking altogether.