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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.
Diabetologia. 2020 Jul; 63(7):1285-1298.D

Abstract

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/m2) and 12 healthy control individuals (age 66.1 ± 7.6 years; BMI: 24.0 ± 2.9 kg/m2) underwent two 3 h liquid mixed-meal tests (with paracetamol for assessment of gastric emptying) after single-dose injection of 20 μg 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 × min, p < 0.001) and in the control group (-126 ± 12 vs 222 ± 51 mmol/l × 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 × min, p = 0.008) and in the control group (141 ± 100 vs 190 ± 100 pmol/l × 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 × 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.

TRIAL REGISTRATION

ClinicalTrials.gov NCT02640118.

FUNDING

This study was funded by an unrestricted investigator-initiated study grant from Sanofi. Support was also received from from the Novo Nordisk Foundation Center for Basic Metabolic Research, the A.P. Møller Foundation for the Advancement of Medical Science and the Faculty of Health and Medical Sciences, University of Copenhagen.

Authors+Show Affiliations

Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Gentofte Hospitalsvej 7, 3rd floor, DK-2900, Hellerup, Denmark.Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Gentofte Hospitalsvej 7, 3rd floor, DK-2900, Hellerup, Denmark.Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Gentofte Hospitalsvej 7, 3rd floor, DK-2900, Hellerup, Denmark.Department of Surgery and Transplantation, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.Department of Surgery and Transplantation, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.Department of Clinical Biochemistry, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.Department of Clinical Biochemistry, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark. Clinical Metabolomics Core Facility, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.Department of Clinical Biochemistry, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark. Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Gentofte Hospitalsvej 7, 3rd floor, DK-2900, Hellerup, Denmark. Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Gentofte Hospitalsvej 7, 3rd floor, DK-2900, Hellerup, Denmark. filip.krag.knop.01@regionh.dk. Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. filip.krag.knop.01@regionh.dk. Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. filip.krag.knop.01@regionh.dk. Steno Diabetes Center Copenhagen, Gentofte, Denmark. filip.krag.knop.01@regionh.dk.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32394228

Citation

Juel, Caroline T B., et al. "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." Diabetologia, vol. 63, no. 7, 2020, pp. 1285-1298.
Juel CTB, Lund A, Andersen MM, et al. 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. Diabetologia. 2020;63(7):1285-1298.
Juel, C. T. B., Lund, A., Andersen, M. M., Hansen, C. P., Storkholm, J. H., Rehfeld, J. F., van Hall, G., Hartmann, B., Wewer Albrechtsen, N. J., Holst, J. J., Vilsbøll, T., & Knop, F. K. (2020). 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. Diabetologia, 63(7), 1285-1298. https://doi.org/10.1007/s00125-020-05158-9
Juel CTB, et al. 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. Diabetologia. 2020;63(7):1285-1298. PubMed PMID: 32394228.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Juel,Caroline T B, AU - Lund,Asger, AU - Andersen,Maria M, AU - Hansen,Carsten P, AU - Storkholm,Jan H, AU - Rehfeld,Jens F, AU - van Hall,Gerrit, AU - Hartmann,Bolette, AU - Wewer Albrechtsen,Nicolai J, AU - Holst,Jens J, AU - Vilsbøll,Tina, AU - Knop,Filip K, Y1 - 2020/05/11/ PY - 2019/11/25/received PY - 2020/03/11/accepted PY - 2020/5/13/pubmed PY - 2020/5/13/medline PY - 2020/5/13/entrez KW - Extrapancreatic glucagon KW - GLP-1 KW - GLP-1 receptor agonist KW - Gastric emptying KW - Glucagon KW - Postprandial glucose metabolism KW - Secondary diabetes KW - Total pancreatectomy SP - 1285 EP - 1298 JF - Diabetologia JO - Diabetologia VL - 63 IS - 7 N2 - 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/m2) and 12 healthy control individuals (age 66.1 ± 7.6 years; BMI: 24.0 ± 2.9 kg/m2) underwent two 3 h liquid mixed-meal tests (with paracetamol for assessment of gastric emptying) after single-dose injection of 20 μg 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 × min, p < 0.001) and in the control group (-126 ± 12 vs 222 ± 51 mmol/l × 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 × min, p = 0.008) and in the control group (141 ± 100 vs 190 ± 100 pmol/l × 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 × 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. TRIAL REGISTRATION: ClinicalTrials.gov NCT02640118. FUNDING: This study was funded by an unrestricted investigator-initiated study grant from Sanofi. Support was also received from from the Novo Nordisk Foundation Center for Basic Metabolic Research, the A.P. Møller Foundation for the Advancement of Medical Science and the Faculty of Health and Medical Sciences, University of Copenhagen. SN - 1432-0428 UR - https://www.unboundmedicine.com/medline/citation/32394228/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 L2 - https://doi.org/10.1007/s00125-020-05158-9 DB - PRIME DP - Unbound Medicine ER -
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