The GLP-1 receptor agonist lixisenatide reduces postprandial glucose in patients with diabetes secondary to total pancreatectomy: a randomised, placebo-controlled, double-blinded crossover trial

Aims/hypothesis Treatment of diabetes secondary to total pancreatectomy remains a challenge and insulin constitutes the only glucose-lowering treatment for these patients. We hypothesised that the glucagon-like peptide 1 (GLP-1) receptor agonist lixisenatide would improve postprandial glucose tolerance in totally pancreatectomised patients. Methods In a double-blinded, randomised, crossover study, 12 totally pancreatectomised individuals (age: 65.0 +/- 9.5 mean +/- SD years; BMI: 22.9 +/- 3.9 kg/m(2)) and 12 healthy control individuals (age 66.1 +/- 7.6 years; BMI: 24.0 +/- 2.9 kg/m(2)) underwent two 3 h liquid mixed-meal tests (with paracetamol for assessment of gastric emptying) after single-dose injection of 20 mu g of lixisenatide or placebo. Basal insulin was given the night before each experimental day; no insulin was given during study days. Results Compared with placebo, lixisenatide reduced postprandial plasma glucose excursions in the pancreatectomy group (baseline-subtracted AUC [bsAUC] [mean +/- SEM]: 548 +/- 125 vs 1447 +/- 95 mmol/l x min, p < 0.001) and in the control group (-126 +/- 12 vs 222 +/- 51 mmol/l x min, p < 0.001). In the pancreatectomy group a mean peak glucose concentration of 23.3 +/- 1.0 mmol/l was reached at time point 134 +/- 11 min with placebo, compared with a mean peak glucose concentration of 18 +/- 1.4 mmol/l (p = 0.008) at time point 148 +/- 13 min (p = 0.375) with lixisenatide. In the control group a mean peak concentration of 8.2 +/- 0.4 mmol/l was reached at time point 70 +/- 13 min with placebo, compared with a mean peak concentration of 5.5 +/- 0.1 mmol/l (p < 0.001) at time point 8 +/- 25 min (p = 0.054) with lixisenatide. Lixisenatide also reduced gastric emptying and postprandial glucagon responses in the pancreatectomy group (66 +/- 84 vs 1190 +/- 311 pmol/l x min, p = 0.008) and in the control group (141 +/- 100 vs 190 +/- 100 pmol/l x min, p = 0.034). In the pancreatectomy group, C-peptide was undetectable in plasma. In the control group, postprandial plasma C-peptide responses were reduced with lixisenatide (18 +/- 17 vs 189 +/- 31 nmol/l x min, p < 0.001). Conclusions/interpretation The GLP-1 receptor agonist lixisenatide reduces postprandial plasma glucose excursions in totally pancreatectomised patients. The mode of action seems to involve deceleration of gastric emptying and reduced postprandial responses of gut-derived glucagon.