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Effect of exenatide once-weekly (QW) on gastric emptying in health: impact on glycaemia and glucose absorption

Abstract : 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 P<0.05 was considered significant. Results: 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.
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https://hal.inrae.fr/hal-02734914
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Submitted on : Tuesday, June 2, 2020 - 2:39:13 PM
Last modification on : Tuesday, September 7, 2021 - 3:36:25 PM

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K.L. Jones, L.Q. Huynh, S. Hatzinikolas, R.S. Rigda, L. Phillips, et al.. Effect of exenatide once-weekly (QW) on gastric emptying in health: impact on glycaemia and glucose absorption. 55. Annual Meeting of the European-Association-for-the-Study-of-Diabetes (EASD), Sep 2019, Barcelone, Spain. ⟨hal-02734914⟩

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