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Randomized Controlled Trial
. 2024 Aug 5;191(2):192-203.
doi: 10.1093/ejendo/lvae095.

The role of glucagon-like peptide 1 in the postprandial effects of metformin in type 2 diabetes: a randomized crossover trial

Laura S Hansen  1 , Lærke S Gasbjerg  1   2 , Andreas Brønden  1   3 , Niels B Dalsgaard  1 , Emilie Bahne  1   4 , Signe Stensen  1 , Pernille H Hellmann  1 , Jens F Rehfeld  5 , Bolette Hartmann  2 , Nicolai J Wewer Albrechtsen  6 , Jens J Holst  2   7 , Tina Vilsbøll  4   8 , Filip K Knop  1   4   8
Affiliations
Randomized Controlled Trial

The role of glucagon-like peptide 1 in the postprandial effects of metformin in type 2 diabetes: a randomized crossover trial

Laura S Hansen et al. Eur J Endocrinol. .

Abstract

Aims: Although metformin is widely used for treatment of type 2 diabetes (T2D), its glucose-lowering mechanism remains unclear. Using the glucagon-like peptide 1 (GLP-1) receptor (GLP-1R) antagonist exendin(9-39)NH2, we tested the hypothesis that postprandial GLP-1-mediated effects contribute to the glucose-lowering potential of metformin in T2D.

Methods: In a randomized, placebo-controlled, double-blind, crossover study, 15 individuals with T2D (median HbA1c 50 mmol/mol [6.7%], body mass index 30.1 kg/m2, age 71 years) underwent, in randomized order, 14 days of metformin and placebo treatment, respectively. Each treatment period was preceded by 14 days without any glucose-lowering medicine and concluded by two 4 h mixed meal tests performed in randomized order and separated by >24 h with either continuous intravenous exendin(9-39)NH2 or saline infusion.

Results: Compared to placebo, metformin treatment lowered fasting plasma glucose (mean of differences [MD] 1.4 mmol/L × min [95% CI 0.8-2.0]) as well as postprandial plasma glucose excursions during both saline infusion (MD 186 mmol/L × min [95% CI 64-307]) and exendin(9-39)NH2 infusion (MD 268 mmol/L × min [95% CI 108-427]). The metformin-induced improvement in postprandial glucose tolerance was unaffected by GLP-1R antagonization (MD 82 mmol/L × min [95% CI -6564-170]). Metformin treatment increased fasting plasma GLP-1 (MD 1.7 pmol/L × min [95% CI 0.39-2.9]) but did not affect postprandial GLP-1 responses (MD 820 pmol/L × min [95% CI -1750-111]).

Conclusions: Using GLP-1R antagonization, we could not detect GLP-1-mediated postprandial glucose-lowering effect of metformin in individuals with T2D. We show that 2 weeks of metformin treatment increases fasting plasma GLP-1, which may contribute to metformin's beneficial effect on fasting plasma glucose in T2D. Trial registration: Clinicaltrials.gov NCT03246451.

Keywords: GLP-1; exendin(9-39)NH2; metformin; randomized controlled trial; type 2 diabetes.

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Conflict of interest statement

Conflict of interest: L.S.H., A.B., N.B.D., E.B., S.S., P.H.H., and J.F.R. have nothing to disclose. L.S.G. is a minority shareholder of Antag Therapeutics ApS. B.H. is a board member and cofounder of Bainan Biotech. N.J.W.A. has received funding from and served on scientific advisory panels and/or speakers bureaus for Boehringer Ingelheim, MSD/MERCK, Novo Nordisk, and Mercodia. J.J.H. has served on scientific advisory panels and/or speaker for Novo Nordisk, Eli Lilly, and Zealand Pharma. He has given lectures and received financial support for travel from Novo Nordisk. He has served as a consultant for AlphaSights, Eli Lilly, Structure Therapeutics, and Zealand Pharma. He is currently consulting for GV Management L.L.C. He is a cofounder and on the board of directors of Antag Therapeutics and Bainan Biotech. He is supported by grants from Arla Foods, ERC Advanced Grants, and the Novo Nordisk Foundation Center for Basic Metabolic Research Faculty of Health and Medical Sciences University of Copenhagen Denmark. He serves as an investigator for Boehringer Ingelheim and Scohia. T.V. has served on scientific advisory panels, been part of speakers bureaus, and served as a consultant to and/or received research support from Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, GSK, Mundipharma, Novo Nordisk, Sanofi, Zealand Pharma, and Sun Pharmaceuticals. All authors declare that the study was conducted without financial or conflicts of interest. F.K.K. has been on the advisory panel of, a consultant for, in the speakers bureau of, owns shares in, and/or has received research support from 89bio, AstraZeneca, Boehringer Ingelheim, Cytoki Pharma, Eli Lilly, Gubra, Novo Nordisk, Merck Sharp & Dohme, Sanofi, Structure Therapeutics, Zealand Pharma, and Zucara and is cofounder of and a minority shareholder in Antag Therapeutics. F.K.K. is currently employed at Novo Nordisk A/S, Bagsværd, Denmark; the present work was done independent of Novo Nordisk A/S. F.K.K. is on the editorial board of EJE. He was not involved in the review or editorial process for this paper, on which he is listed as author.

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