Acute Administration of the GLP-1 Receptor Agonist Lixisenatide Diminishes Postprandial Insulin Secretion in Healthy Subjects But Not in Type 2 Diabetes, Associated with Slowing of Gastric Emptying

Published online 22 April 2022Introduction: It is uncertain whether lixisenatide has postprandial insulinotropic effects when its effect on slowing gastric emptying is considered, in healthy subjects and type 2 diabetes mellitus (T2DM). We evaluated the effects of single administration of 10 lg sc lixisenatide on glycaemia, insulin secretion and gastric emptying (GE), measured using the ‘gold standard’ technique of scintigraphy following an oral glucose load (75 g glucose). Methods: Fifteen healthy subjects (nine men, six women; age 67.2 ± 2.3 years) and 15 patients with T2DM (nine men, six women; age 61.9 ± 2.3 years) had measurements of GE, plasma glucose, insulin and C-peptide for 180 min after a radiolabeled 75 g glucose drink on two separate days. All subjects received lixisenatide (10 lg sc) or placebo in a randomised, double-blind, crossover fashion 30 min before the drink. Insulin secretory response (ISR) was determined using the C-peptide deconvolution method. Results: GE was markedly slowed by lixisenatide compared with placebo in both healthy subjects (1.45 ± 0.10 kcal/min for placebo vs. 0.60 ± 0.14 kcal/min for lixisenatide) and diabetes (1.57 ± 0.06 kcal/min for placebo vs. 0.75 ± 0.13 kcal/min for lixisenatide) (both P\0.001) with no difference between the two groups (P = 0.42). There was a moderate to strong inverse correlation between the early insulin secretory response calculated at 60 min and gastric retention at 60 min with lixisenatide treatment in healthy subjects (r = - 0.8, P = 0.0003) and a trend in type 2 diabetes (r = - 0.4, P = NS), compared with no relationships in the placebo arms (r = - 0.02, P = NS, healthy subjects) and (r = - 0.16, P = NS, type 2 diabetes). Conclusion: The marked slowing of GE of glucose induced by lixisenatide is associated with attenuation in the rise of postprandial glucose in both healthy subjects and diabetes and early insulin secretory response in healthy subjects.Chinmay S. Marathe . Hung Pham . Tongzhi Wu . Laurence G. Trahair . Rachael S. Rigda . Madeline D. M. Buttfield . Seva Hatzinikolas . Kylie Lange . Christopher K. Rayner . Andrea Mari . Michael Horowitz . Karen L. Jone

Effects of lixisenatide on postprandial blood pressure, gastric emptying and glycaemia in healthy people and people with type 2 diabetes

AIM:To evaluate the effects of the prandial glucagon-like peptide-1 receptor agonist lixisenatide on gastric emptying and blood pressure (BP) and superior mesenteric artery (SMA) blood flow, and the glycaemic responses to a 75-g oral glucose load in healthy people and those with type 2 diabetes (T2DM). MATERIALS AND METHODS:Fifteen healthy participants (nine men, six women; mean ± SEM age 67.2 ± 2.3 years) and 15 participants with T2DM (nine men, six women; mean ± SEM age 61.9 ± 2.3 years) underwent measurement of gastric emptying, BP, SMA flow and plasma glucose 180 minutes after a radiolabelled 75-g glucose drink on two separate days. All participants received lixisenatide (10 μg subcutaneously) or placebo in a randomized, double-blind, crossover fashion 30 minutes before the glucose drink. RESULTS:Lixisenatide slowed gastric emptying (retention at 120 minutes, P < 0.01), attenuated the rise in SMA flow (P < 0.01) and markedly attenuated the decrease in systolic BP (area under the curve [AUC] 0-120 minutes, P < 0.001) compared to placebo in healthy participants and those with T2DM. Plasma glucose (incremental AUC 0-120 minutes) was greater in participants with T2DM (P < 0.005) than in healthy participants, and lower after lixisenatide in both groups (P < 0.001). CONCLUSIONS:In healthy participants and those with T2DM, the marked slowing of gastric emptying of glucose induced by lixisenatide was associated with attenuation of the increments in glycaemia and SMA flow and decrease in systolic BP. Accordingly, lixisenatide may be useful in the management of postprandial hypotension.Karen L. Jones, Rachael S. Rigda, Madeline D.M. Buttfield, Seva Hatzinikolas, Hung T. Pham, Chinmay S. Marathe, Tongzhi Wu, Kylie Lange, Laurence G. Trahair, Christopher K. Rayner, Michael Horowit

Acute effects of the glucagon-like peptide-1 receptor agonist, exenatide, on blood pressure and heart rate responses to intraduodenal glucose infusion in type 2 diabetes

Aim: To evaluate the effects of the glucagon-like peptide-1 receptor agonist, exenatide, on blood pressure and heart rate during an intraduodenal glucose infusion in type 2 diabetes. Methods: Nine subjects with type 2 diabetes were randomised to receive intravenous exenatide or saline control in a crossover design. Glucose (3 kcal min−1) was infused via an intraduodenal manometry catheter for 60 min. Blood pressure, heart rate, and the frequency and amplitude of duodenal pressure waves were measured at regular intervals. Gastrointestinal symptoms were monitored using 100 mm visual analogue scales. Results: During intraduodenal glucose infusion (0–60 min), diastolic (p(0–60) = 0.03) and mean arterial (p(0–60) = 0.03) blood pressures and heart rate (p(0–60) = 0.06; p(0–120) = 0.03)) were higher with exenatide compared to placebo. The increase in the area under the curve for diastolic blood pressure and mean arterial blood pressure was related directly to the suppression of the duodenal motility index with exenatide compared to control (p = 0.007 and 0.04, respectively). Conclusion: In type 2 diabetes, intravenous exenatide increases mean arterial blood pressure and heart rate during an intraduodenal glucose infusion, supporting the need for further research with exenatide for its potential use in postprandial hypotension.Sony S Thazhath, Chinmay S Marathe, Tongzhi Wu, Jessica Chang, Joan Khoo, Paul Kuo, Helen L Checklin, Michelle J Bound, Rachael S Rigda, Michael Horowitz, Karen L Jones, and Christopher K Rayne

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

International audienceBackground 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

Exenatide once weekly slows gastric emptying of solids and liquids in healthy, overweight, subjects under steady-state concentrations

AIMS: To evaluate the effects of 8 weeks' administration of exenatide once-weekly (ExQW) on gastric emptying of solids and liquids (using the 'gold standard' technique, scintigraphy), glucose absorption and postprandial glycaemia in health. MATERIAL AND METHODS: Thirty two healthy participants were randomized to receive ExQW (2mg per week subcutaneously) (6M,10F; age: 59.9±0.9 yr; BMI: 29.6±0.6 kg/m2 ) or matching placebo (PLAC) (6M,10F; age: 60.6±1.2 yr; BMI: 29.5±1.0 kg/m2 ) for 8 weeks. Gastric emptying, nausea (visual analog scale), and plasma glucose, insulin, C-peptide and glucagon were measured for 120min after a solid/liquid meal, comprising 100g ground beef (radiolabelled with 20MBq 99m Tc-sulphur colloid) and 150ml 10% glucose (radiolabelled with 7MBq 67 Ga-EDTA), and containing 5g 3-O-methyl-glucose (3-OMG) as a marker of glucose absorption, at baseline and after 8 weeks' treatment. RESULTS: The studies were well tolerated. Scores for nausea were consistently low without any difference between ExQW and PLAC groups. ExQW slowed gastric emptying of solids (e.g. AUC 0-120min: P<0.05) and liquids (e.g. AUC 0-120min: P=0.01) substantially and attenuated glucose absorption (e.g. 3-OMG iAUC 0-30min: P=0.001) and the postprandial rise in plasma glucose (e.g. iAUC 0-30min: P=0.008). Plasma glucagon at 2h was reduced by ExQW (P=0.001). The magnitude of the reduction in plasma glucose at t=30min from baseline to 8 weeks with ExQW was related inversely to the 50% emptying time of the glucose drink (r=-0.55, P=0.03). CONCLUSIONS: In healthy subjects, 8 weeks administration of the 'long-acting' GLP-1RA, ExQW, slows gastric emptying of solids and liquids substantially, with consequent reductions in glucose absorption and postprandial glycaemia. Clinical Trials Registration Number: ACTRN 12616000955415 This article is protected by copyright. All rights reserved.Karen L. Jones, Christopher K. Rayner, Michael Horowitz, Tongzhi Wu, Rachael S. Rigda, iza K. Phillips ... et al

Acute effects of lixisenatide on intragastric meal distribution: impact on energy intake

International audienceBackground 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<0.001 for PLAC vs LIXI in all groups. LIXI decreased energy intake (P<0.001) in both health and T2DM (Figure). Energy intake was inversely related to the distal stomach content at 180 min in health on PLAC (r=-0.58, P=0.03), but not in T2DM (r=-0.31, P=0.27), nor after LIXI (health: r=-0.16, P=0.58 vs T2DM: r=-0.004, P=0.99). Conclusion: In healthy subjects and T2DM patients, LIXI (10mcg) decreases energy intake in the absence of nausea, slows GE and increases retention in the distal and proximal stomach. The acute reduction in energy intake by LIXI is unrelated to changes in GE/intragastric distribution, consistent with a centrally-mediated effect