Liraglutide and sitagliptin have no effect on intestinal microbiota composition: A 12-week randomized placebo-controlled trial in adults with type 2 diabetes

Mark M. Smits*, Kristina S. Fluitman, Hilde Herrema, Mark Davids, Mark H.H. Kramer, Albert K. Groen, Clara Belzer, Willem M. de Vos, Djuna L. Cahen, Max Nieuwdorp, Daniël H. van Raalte

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

25 Citations (Scopus)


Aim: Preclinical data suggest that treatment with either glucagon-like peptide (GLP)-1 receptor agonists or dipeptidyl peptidase (DPP)-4 inhibitors could change the intestinal microbiome and thereby contribute to their beneficial (cardio)metabolic effects. Therefore, our study aimed to investigate the effects of these agents on microbiota composition in adults with type 2 diabetes (T2D). Methods: A total of 51 adults with T2D (mean ± SD: age 62.8 ± 6.9 years, BMI 31.8 ± 4.1 kg/m2, HbA1c 7.3 ± 0.6%) treated with metformin and/or sulphonylureas were included in the 12-week randomized, double-blind trial. Patients were given the GLP-1 receptor agonist liraglutide (1.8 mg sc) or the DPP-4 inhibitor sitagliptin (100 mg), or matching placebos, once daily for 12 weeks. Faecal samples were collected at baseline and at 12 weeks after the start of the intervention. Microbiota analyses were performed by 16S rRNA gene-sequencing analysis. Bile acids were measured in faeces and plasma. Results: Liraglutide decreased HbA1c by 1.3% (95% CI: -1.7 to -0.9) and tended to reduce body weight (-1.7 kg, 95% CI: -3.6 to 0.3), but increased faecal secondary bile acid deoxycholic acid. Sitagliptin lowered HbA1c by 0.8% (95% CI: -1.4 to -0.4) while body weight remained stable (-0.8 kg, 95% CI: -2.7 to 1.0), but increased faecal levels of cholic acid, chenodeoxycholic acid and ursodeoxycholic acid. However, neither liraglutide nor sitagliptin affected either alpha or beta diversity of the intestinal microbiota, nor were changes in microbial composition related to clinical parameters. Conclusion: These data suggest that the beneficial effects of liraglutide and sitagliptin on glucose metabolism, body weight and bile acids, when used as add-on therapies to metformin or sulphonylureas, are not linked to changes in the intestinal microbiota (NCT01744236).

Original languageEnglish
Article number101223
JournalDiabetes and Metabolism
Issue number5
Publication statusPublished - Sept 2021

Bibliographical note

Funding Information:
Through M.H.H.K., the Amsterdam University Medical Centers, location VUmc, received research grants from AstraZeneca, Boehringer Ingelheim, Novo Nordisk and Sanofi-Aventis. D.H.v.R. serves on advisory boards for Sanofi-Aventis and Merck Sharp & Dohme. M.N. is supported by a ZONMW‐VIDI grant 2013 (016.146.327) and a Dutch Heart Foundation CVON IN CONTROL Young Talent Grant 2013. M.N. and W.M.d.V. are Scientific Advisory Board members of Caelus Pharmaceuticals, The Netherlands. All authors declare they have not received any fees personally in connection with the roles described above, as all honoraria were paid to their employer (Amsterdam University Medical Centers, location VUmc). No other potential conflicts of interest relevant to this article are reported.

Funding Information:
The research leading to the present results was funded by the Seventh Framework Programme ( FP7/2007–2013 ) of the European Commission under grant nº 282521 (the SAFEGUARD project). Also, Novo Nordisk kindly provided the prefilled liraglutide and matching placebo pens. All of the researchers are independent of the funders, who had no role in the study design; in the collection, analysis and interpretation of the data; in the writing of the report; or in the decision to submit this article for publication.

Publisher Copyright:
© 2021 The Authors


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