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Therapeutic Potential of GLP-2 Analogs in Gastrointestinal Disorders: Current Knowledge, Nutritional Aspects, and Future Perspectives

Abstract

Purpose of Review

Although Glucagon-like peptide (GLP)-1 receptor agonists have been used for almost two decades in the treatment of diabetes mellitus type 2 and, lately, in obesity, recent years have seen an increasing interest in the pharmacological agonism of other proglucagon-derived peptides, including GLP-2. Herein, we aimed to review the available evidence on the effects of GLP-2 agonism from animal and clinical studies. Furthermore, we summarize the current clinical applications of GLP-2 agonists among patients with intestinal failure associated with short bowel syndrome (SBS-IF) as well as potential future expansion of their indications to other intestinal disorders.

Recent Findings

Evidence from preclinical studies has highlighted the cellular trophic and functional beneficial actions of GLP-2 on small intestinal and colonic mucosa. Subsequently, pharmacologic agonism of GLP-2 has gathered interest for the treatment of patients with conditions pertaining to the loss of intestinal anatomical and/or functional integrity to a degree requiring parenteral support, collectively referred to as intestinal failure. GLP-2 analogs positively influence nutrient absorption in animal models and humans, although continued therapy is likely needed for sustained effects. The degradation-resistant GLP-2-analog teduglutide has received approval for the treatment of SBS-IF, in which it may decisively reduce patient dependency on parenteral support and improve quality of life. Another two longer-acting analogs, glepaglutide and apraglutide, are currently undergoing phase III clinical trials.

Summary

The use of GLP-2 analogs is effective in the management of SBS-IF and may show promise in the treatment of other severe gastrointestinal disorders associated with loss of effective intestinal resorptive surface area.

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Abbreviations

Anti-TNFα:

Anti-tumor necrosis factor-α

Anti-IL12 and anti-IL23:

Anti-interleukin-12 and anti-interleukin-23

c-AMP:

Cyclic adenosine monophosphate

CD:

Crohn’s disease

CDAI:

Crohn’s Disease Activity Index

DNA:

Deoxy-ribonucleic acid

DPP-4:

Dipeptidyl peptidase-4

EGF:

Epidermal growth factor

ESPEN:

European Society for Clinical Nutrition and Metabolism

GE:

Gastric emptying

GI:

Gastrointestinal

GLP-2:

Glucagon-like peptide-2

GLP-2R:

Glucagon-like peptide 2 receptor

GIP:

Glucose-dependent insulinotropic polypeptide

GRPP:

Glicentin-related pancreatic peptide

IBD:

Inflammatory bowel disease

IGF-1:

Insulin-like growth factor-1

IVS:

Intravenous supplementation

KGF:

Keratinocyte growth factor

nNOS:

Neuronal nitric oxide synthase

PC:

Pro-hormone convertase

PGDP:

Pro-glucagon-derived peptide

PKA:

Protein kinase A

PS:

Parenteral support

QoL:

Quality of life

SBS-IF:

Short bowel syndrome-intestinal failure

SC:

Subcutaneous

SGLT-1:

Sodium-glucose transporter-1

T2DM:

Diabetes mellitus type 2

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All authors meet authorship criteria. N.G. Vallianou and M. Dalamaga developed the concept of the manuscript. Literature research was carried out by D. Kounatidis, N.G. Vallianou, and D. Tsilingiris. D. Kounatidis, N.G. Vallianou, D. Tsilingiris, G.S. Christodoulatos, and T. Stratigou wrote the draft. Artwork was prepared by G.S. Christodoulatos. E. Geladari, I. Karampela, and M. Dalamaga edited and reviewed the manuscript. All authors read and approved the final version of the manuscript.

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Correspondence to Natalia G. Vallianou or Maria Dalamaga.

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Kounatidis, D., Vallianou, N.G., Tsilingiris, D. et al. Therapeutic Potential of GLP-2 Analogs in Gastrointestinal Disorders: Current Knowledge, Nutritional Aspects, and Future Perspectives. Curr Nutr Rep (2022). https://doi.org/10.1007/s13668-022-00433-0

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Keywords

  • Apraglutide
  • Glepaglutide
  • Teduglutide
  • Glucagon-like peptide
  • GLP-2 analog
  • Intestinal failure
  • Short bowel syndrome