Lixisenatide reduces postprandial hyperglycaemia via gastrostatic and insulinotropic effects

Abstract

BackgroundLixisenatide 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.MethodsTwenty 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.ResultsAfter 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.ConclusionsLixisenatide 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.

A meta‐analysis comparing clinical effects of short‐ or long‐acting GLP‐1 receptor agonists versus insulin treatment from head‐to‐head studies in type 2 diabetic patients

“…The difference in fasting glucose concentrations was more pronounced when short‐acting GLP‐1 RAs were compared to insulin treatment. The likely reason is the low exposure to effective drug levels overnight with short‐acting GLP‐1 RAs . Nevertheless, even compared to long‐acting GLP‐1 RAs, insulin was superior in controlling fasting glycaemia (Figure ).…”

“…In addition, recent findings point to differences in the mode of action of short‐acting GLP‐1 RAs injected once or twice daily (exenatide b.i.d . and lixisenatide, characterized by a typical intermittent exposure to active drug concentrations with approved injection schedules) and long‐acting GLP‐1 RAs, injected once daily or once weekly (liraglutide, exenatide once weekly, dulaglutide, albiglutide, characterized by relatively constant elevations in drug concentrations without intermittent troughs). While long‐acting GLP‐1 RAs reduce fasting plasma glucose more effectively, because of overnight exposure to significant drug concentrations, short‐acting GLP‐1 RAs have greater effects on preventing post‐meal glycaemic excursions, because they maintain the ability to decrease gastric emptying with long‐term treatment, which typically is lost as a result of tachyphylaxis in the case of long‐acting GLP‐1 RAs Given the number of novel compounds in the class of GLP‐1 RAs and publications on their clinical effectiveness from head‐to‐head comparisons vs. insulin treatment (Table ), as well as an opportunity to explore differences between short‐acting and long‐acting GLP‐1 RAs, we performed an updated meta‐analysis.…”

Lixisenatide, a Once‐Daily Prandial Glucagon‐Like Peptide‐1 Receptor Agonist for the Treatment of Adults with Type 2 Diabetes

“…It presents an approximately 4‐fold higher affinity for the GLP‐1 receptor than native human GLP‐1 and enhances glycemic control through potentiation of glucose‐induced insulin secretion . In addition, lixisenatide reduces postprandial glucagon release and PPG levels by slowing gastric emptying …”

“…The pharmacokinetic and pharmacodynamic characteristics of lixisenatide are summarized in Table . A pharmacokinetic analysis in healthy adults showed an increase in maximum concentration ( C max ) of 0.77 times with ascending single doses of lixisenatide (2.5–20 μg) administered before an oral glucose challenge, with a terminal half‐life ( t 1/2 ) of 2.0 hours for a 20‐μg dose . Two additional single‐dose, placebo‐controlled studies showed a value for time to reach C max ( T max ) of 2.0 hours for healthy subjects and patients with T2D after administration of lixisenatide 20 μg .…”

“…The GetGoal‐O trial evaluated the effects of lixisenatide in nonfrail, elderly patients (≥ 70 years old) uncontrolled on their current regimens and showed significant reductions from baseline to week 24 in Hb A1c and weight without affecting nutritional status (Table ) . A pooled analysis of six GetGoal studies showed that lixisenatide was effective in decreasing Hb A1c levels across age groups, with a similar safety profile . Moreover, a meta‐analysis of data on patients aged ≥ 65 years from five GetGoal trials showed that lixisenatide as an add‐on therapy to OADs resulted in significant reductions in Hb A1c and PPG levels (both p<0.0001), FPG levels (p=0.0005), and weight (p=0.0021) compared with placebo …”