Search

International audience; Background and aims: Glucagon-like peptide-1 agonists (GLP-1RAs) induce weight loss in obese patients and, particularly with ‘short-acting’ GLP-1RAs, slow gastric emptying (GE). In healthy subjects, energy intake after a nutrient ‘preload’ is more strongly related to the content of the distal, than the total, stomach. The effect of GLP-1RAs on intragastric meal distribution has not been reported.We evaluated the acute effects of lixisenatide (LIXI) on intragastric distribution of a glucose drink and subsequent energy intake in health and type 2 diabetes (T2DM). Materials and methods: 15 healthy subjects (9M, 6F; age: 67.2 ± 2.3 yr; BMI: 25.4 ± 0.8 kg/m2) and 15 T2DMpatients managed by diet ormetformin (9M, 6F; age: 61.9 ± 2.3 yr; BMI: 30.3 ± 0.7 kg/m2; duration of known diabetes: 5.3 ± 1.2 yr; HbA1c: 6.9 ± 0.2%were studied. All subjects received LIXI (10mcg sc) or placebo (PLAC) on 2 separate days in a randomised, double-blind, crossover fashion 30 min before a 75g glucose drink labelled with 20MBq 99mTc-Calcium Phytate. A lower than usual dose of LIXI was used to maximise tolerability. GE was measured by scintigraphy for 180 min. A region-of-interest was drawn around the total stomach, which was divided into proximal and distal stomach regions. At 180 min each participant was offered a buffet meal and allowed to eat for 30 min to assess subsequent energy intake. Nausea was measured, using a visual analogue questionnaire, prior to receiving study drug, before the drink and at regular intervals during the study. Data are mean ± SEM and PResults: The studies were well tolerated; scores for nausea were uniformly lowwith no difference between PLAC and LIXI in either group. LIXI slowed GE (% total stomach retention at 180 min - health: PLAC 16.0 ± 11.1 vs LIXI 59.5 ± 24.6 ; T2DM: PLAC 14.5 ± 7.5 vs LIXI 54.4 ± 27.5) and increased retention in both the proximal stomach (health: PLAC 6.6 ± 3.5 vs LIXI 40.9 ± 24.6 ; T2DM: PLAC 6.3 ± 4.1 vs LIXI 34.8 ± 24.5) and distal stomach (health: PLAC 9.4 ± 9.1 vs LIXI 18.6 ± 11.1 ; T2DM: PLAC 8.2 ± 4.2 vs LIXI 19.6 ± 10.4); P

International audience; Background and aims: ‘Short-acting’ glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) lower postprandial glucose predominantly via their profound effect to slow gastric emptying (GE). It is generally assumed that ‘long-acting’ GLP-1RAs have little, if any, effect on GE with longer-term administration, reflecting ‘tachyphylaxis’ to slowing of GE as a result of sustained receptor exposure. However, information relating to the effect of ‘long-acting’ GLP-1RAs on GE is limited and previous studies have been compromised by the use of suboptimal methodology to quantify GE. We evaluated the effects of 8 weeks’ administration of exenatide once-weekly (ExQW) on GE of solids and liquids (using the ‘gold standard’ technique, scintigraphy), postprandial glycaemia and glucose absorption in health. Materials and methods: Thirty two healthy participants completed an 8-week double-blind, placebo-controlled, parallel-group designed study. Participants were randomised to receive either ExQW (2mg sc) (6M, 10F; mean age: 59.9 ± 0.9yr; BMI: 29.6 ± 0.6 kg/m2) or matched placebo (PLAC) (6M, 10F; mean age: 60.6 ± 1.2yr; BMI: 29.5 ± 1.0 kg/m2). GE, nausea (100mm visual analogue scale) and plasma glucose, insulin, C-peptide, glucagon were measured for 120 min after a mixed solid/liquid meal, comprising 100g minced beef radiolabelled with 20MBq 99mTc-sulphur colloid and 150ml 10% glucose radiolabelled with 7MBq 67Ga-EDTA and containing 5g 3-O-methyl-glucose (3-OMG) to assess oral glucose absorption, at baseline and after 8 weeks’ administration. Data are shown as mean values ± SEM and a PResults: The studies were well-tolerated. Scores for nausea were consistently very low and there was no difference between ExQW and PLAC groups at either baseline or after treatment. ExQW slowed GE of both solids (AUC0-120: P=0.05) and liquids (AUC0-120: P=0.01) substantially (Figure) and attenuated both the postprandial rise in plasma glucose (e.g. iAUC0-30: P=0.008) and glucose absorption (e.g. 3-OMG iAUC0-30: P=0.001). There were no differences in plasma insulin, C-peptide or glucagon between the two groups. The magnitude of the reduction in plasma glucose at t=30 min from baseline to 8 weeks with ExQW was inversely related to the 50% emptying time of the glucose drink (r=-0.55, P=0.03) i.e. postprandial glucose-lowering by ExQW was dependent on the magnitude of the slowing of GE. Conclusion: In healthy subjects, 8 weeks administration of the ‘long-acting’ GLP-1RA, ExQW, slows GE of solids and liquids with consequent reductions in glucose absorption and postprandial glycaemia.