Consistent Reduction of Postprandial Glucagon and Insulin by Lixisenatide in the GetGoal Clinical Trial Program

Abstract

To evaluate 2-hour glucose, glucagon and insulin changes following a standardized mixed-meal tolerance test before and after 24 weeks of treatment with the once-daily prandial glucagon-like peptide-1 receptor agonist lixisenatide* in patients with type 2 diabetes mellitus (T2DM). This was a meta-analysis of data from 6 randomized, placebo-controlled studies within the lixisenatide phase III GetGoal program. Studies included: lixisenatide in patients insufficiently controlled on diet and exercise (GetGoal-Mono), lixisenatide in combination with oral antihyperglycemic agents (GetGoal-M and GetGoal-S) and lixisenatide in combination with basal insulin ± oral antihyperglycemic agents (GetGoal-Duo 1, GetGoal-L and GetGoal-L-Asia). Meta-analysis was performed (lixisenatide n=1124 vs. placebo n=707) combining ANCOVA least squares (LS) mean values using an inverse variance weighted analysis. Lixisenatide significantly reduced 2-hour postprandial glucose from baseline (LS mean difference vs. placebo: –4.9 mmol/L, p<0.0001, Figure) and glucose excursions (LS mean difference vs. placebo: –4.5 mmol/L, p<0.0001). As measured in 2 studies, lixisenatide also reduced postprandial glucagon (LS mean difference vs. placebo: –19.0 ng/L, p<0.0001) and insulin (LS mean difference vs. placebo: –64.8 pmol/L, p<0.0001), although the glucagon/insulin ratio was increased (LS mean difference vs. placebo: 0.15, p=0.02) vs. placebo. In subjects with T2DM, lixisenatide potently reduces the glucose excursion after meal ingestion in association with marked reductions in glucagon and insulin levels. It is suggested that diminished glucagon secretion and slower gastric emptying contribute to reduced hepatic glucose production and delayed glucose absorption, enabling postprandial glycemia to be controlled with less demand on beta-cell insulin secretion.