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GLP-1 Receptor Agonists in Obese Patients with Inflammatory Bowel Disease: from Molecular Mechanisms to Clinical Considerations and Practical Recommendations for Safe and Effective Use

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Abstract

Purpose of Review

To discuss current literature and provide practical recommendations for the safe and effective use of glucagon-like peptide 1 receptor agonists (GLP-1 RA) in people with inflammatory bowel disease (IBD) and type 2 diabetes (T2D) and/or obesity. The molecular mechanisms that justify the potential benefits of GLP-1 RA in IBD and the links between IBD, obesity, and cardiovascular disease are also discussed.

Recent Findings

Preliminary data suggest that GLP-1 RA can modulate crucial pathways in the pathogenesis of IBD, such as chronic inflammation circuits, intestinal tight junctions, and gut microbiome dysbiosis, setting the stage for human trials to investigate the role of these agents in the treatment of IBD among people with or without diabetes and obesity. However, gastrointestinal side effects related to GLP-1 RA need appropriate clinical management to mitigate risks and maximize the benefits of therapy in people with IBD.

Summary

GLP-1 RA originally emerged as drugs for the treatment of hyperglycemia and are currently licensed for the management of T2D and/or overweight/obesity. However, their wealth of pleiotropic actions soon raised expectations that they might confer benefits on non-metabolic disorders. Future studies are expected to clarify whether GLP-1 RA deserve an adjunct place in the arsenal of drugs against IBD.

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Data Availability

Not applicable.

Abbreviations

IBD:

Inflammatory bowel disease

GI:

Gastrointestinal

CD:

Crohn’s disease

UC:

Ulcerative colitis

T2D:

Type 2 diabetes

CVD:

Cardiovascular disease

GLP-1 RA:

Glucagon-like peptide 1 receptor agonists

CVOT:

Cardiovascular outcome trial

HF:

Heart failure

NAFLD:

Nonalcoholic fatty liver disease

HCC:

Hepatocellular carcinoma

EEC:

Enteroendocrine cell

GIP:

Glucose-dependent insulinotropic polypeptide

TNF:

Tumor necrosis factor

IL:

Interleukin

JAK:

Janus kinase

CCL:

C-C motif ligand

TGF:

Tumor growth factor

EGF:

Epidermal growth factor

KGF:

Keratinocyte growth factor

HGF:

Hepatocyte growth factor

cAMP:

Cyclic adenosine monophosphate

NF-kB:

Nuclear factor-kB

TCA:

T cell activation gene

SDF:

Stromal cell–derived factor

M-CSF:

Macrophage colony stimulating factor

CSMC:

Colon smooth muscle cell

SSM:

Stabilized phospholipid micelles

DDS:

Dextran sodium sulfate

DRA:

Downregulated in adenoma

BLG:

Ban-Lan-Gen

ACE:

Angiotensin-converting enzyme

GPBAR:

G protein–coupled bile acid receptor

iNKT:

Invariant natural killer T cells

DPP-4:

Dipeptidyl peptidase-4

GLP1/2-Fc:

GLP1/2-Fc fusion

SCID:

Severe combined immunodeficiency disease

Ex-4:

Exendin-4

IRR:

Incidence rate ratio

BMI:

Body mass index

APN:

Adiponectin

MAT:

Mesenteric adipose tissue

HFD:

High-fat diet

TLR:

Toll-like receptor

NASH:

Nonalcoholic steatohepatitis

HDL:

High-density lipoprotein

LDL:

Low-density lipoprotein

CRP:

C-reactive protein

PPI:

Proton pump inhibitor

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Authors and Affiliations

  1. Division of Gastroenterology and Hepatology, First Department of Internal Medicine, AHEPA University Hospital, Aristotle University of Thessaloniki, St. Kiriakidi 1, 54636, Thessaloniki, Greece

    Konstantinos Arvanitakis & Georgios Germanidis

  2. Basic and Translational Research Unit, Special Unit for Biomedical Research and Education, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, 54636, Thessaloniki, Greece

    Konstantinos Arvanitakis & Georgios Germanidis

  3. Division of Endocrinology and Metabolism and Diabetes Centre, First Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, AHEPA University Hospital, Thessaloniki, Greece

    Theocharis Koufakis & Kalliopi Kotsa

  4. Clinic for Endocrinology, Diabetes and Metabolic Disorders, Clinical Centre of Vojvodina, Medical Faculty, University of Novi Sad, Novi Sad, Serbia

    Djordje Popovic

  5. Department of Diabetes and Endocrinology, Epsom & St Helier University Hospitals, Surrey, SM5 1AA, UK

    Giuseppe Maltese

  6. Unit for Metabolic Medicine, Cardiovascular Division, Faculty of Life Sciences & Medicine, King’s College, London, UK

    Giuseppe Maltese

  7. Department of Diabetes, King’s College Hospital NHS Foundation Trust, Denmark Hill, London, UK

    Omar Mustafa

  8. King’s College London, London, UK

    Omar Mustafa

  9. Second Propedeutic Department of Internal Medicine, Hippokration General Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece

    Michael Doumas & Olga Giouleme

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Contributions

KA and TK reviewed the literature and drafted the first version of the manuscript. DSP, GM, OM, MD, OG, KK, and GG reviewed the literature and edited the manuscript. All authors have read and approved the final version of the manuscript.

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Correspondence to Georgios Germanidis.

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TK has received honoraria for lectures from AstraZeneca, Boehringer Ingelheim, Pharmaserve Lilly, and Novo Nordisk, for advisory boards from Novo Nordisk, and has participated in sponsored studies by Eli-Lilly and Novo Nordisk. DSP declares associations to Abbott, Alkaloid, AstraZeneca, Boehringer Ingelheim, Berlin-Chemie, Eli Lilly, Galenika, Krka, Merck, Novo Nordisk, PharmaSwiss, Sanofi-Aventis, Servier, Viatris, and Worwag Pharma. GM has received honoraria for lectures from AstraZeneca and Novo Nordisk. OM received speaker’s honoraria from NovoNordisk, Eli Lilly, Sanofi, and Boehringer Ingelheim. KK has received honoraria for lectures/advisory boards and research support from AstraZeneca, Boehringer Ingelheim, Pharmaserve Lilly, Sanofi-Aventis, ELPEN, MSD, and Novo Nordisk. Other authors report no conflict of interest.

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Arvanitakis, K., Koufakis, T., Popovic, D. et al. GLP-1 Receptor Agonists in Obese Patients with Inflammatory Bowel Disease: from Molecular Mechanisms to Clinical Considerations and Practical Recommendations for Safe and Effective Use. Curr Obes Rep 12, 61–74 (2023). https://doi.org/10.1007/s13679-023-00506-3

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