Pronounced reduction of postprandial glucagon by lixisenatide: a meta‐analysis of randomized clinical trials

Aim Glucagon‐like peptide‐1 ( GLP ‐1) receptor agonists improve islet function and delay gastric emptying in patients with type 2 diabetes mellitus ( T2DM ). This meta‐analysis aimed to investigate the effects of the once‐daily prandial GLP ‐1 receptor agonist lixisenatide on postprandial plasma glucose ( PPG ), glucagon and insulin levels. Methods Six randomized, placebo‐controlled studies of lixisenatide 20 µg once daily were included in this analysis: lixisenatide as monotherapy ( GetGoal ‐Mono), as add‐on to oral antidiabetic drugs ( OADs ; GetGoal ‐M, GetGoal ‐S) or in combination with basal insulin ( GetGoal ‐L, GetGoal ‐Duo‐1 and GetGoal ‐L‐Asia). Change in 2‐h PPG and glucose excursion were evaluated across six studies. Change in 2‐h glucagon and postprandial insulin were evaluated across two studies. A meta‐analysis was performed on least square ( LS ) mean estimates obtained from analysis of covariance ( ANCOVA )‐based linear regression. Results Lixisenatide significantly reduced 2‐h PPG from baseline ( LS mean difference vs. placebo: −4.9 mmol/l, p < 0.001) and glucose excursion ( LS mean difference vs. placebo: −4.5 mmol/l, p < 0.001). As measured in two studies, lixisenatide also reduced postprandial glucagon ( LS mean difference vs. placebo: −19.0 ng/l, p < 0.001) and insulin ( LS mean difference vs. placebo: −64.8 pmol/l, p < 0.001). There was a stronger correlation between 2‐h postprandial glucagon and 2‐h PPG with lixisenatide than with placebo. Conclusions Lixisenatide significantly reduced 2‐h PPG and glucose excursion together with a marked reduction in postprandial glucagon and insulin; thus, lixisenatide appears to have biological effects on blood glucose that are independent of increased insulin secretion. These effects may be, in part, attributed to reduced glucagon secretion.