What Is Glepaglutide? Definition and What Research Reports

Definition

Glepaglutide is a synthetic, long-acting analogue of glucagon-like peptide-2 (GLP-2), a peptide hormone secreted by enteroendocrine L-cells of the distal small intestine and colon that acts on the intestinal epithelium. Native GLP-2 is rapidly degraded in circulation, so medicinal chemists modified the sequence to resist enzymatic breakdown and extend exposure; a 2025 medicinal chemistry paper described the design work behind glepaglutide as the first long-acting GLP-2 analogue formulated to enable a ready-to-use injection (PMID 39851172). In research settings the term refers specifically to this investigational compound, not to GLP-2 itself, and not to the GLP-1 class of metabolic peptides with which it is sometimes confused.

This page is for educational purposes only and is not medical advice; consult a licensed physician for any question about a medical condition or treatment. Nothing here describes a protocol or endorses use of any compound.

What Class of Molecule Is It?

Glepaglutide sits in the GLP-2 receptor agonist class. GLP-2 receptors are expressed in the gastrointestinal tract, and receptor activation is associated in the literature with intestinal epithelial growth and adaptation. Because glepaglutide is a modified peptide rather than a small molecule, it has been studied as a subcutaneous injectable. The chemistry paper describing its creation emphasised a formulation goal — a stable, ready-to-use liquid rather than a powder requiring reconstitution (PMID 39851172).

How the term is used in peptide research

In published work, "glepaglutide" almost always appears in one of three contexts:

• Short bowel syndrome (SBS) trials — the primary clinical research programme, where the outcome of interest has been reliance on parenteral support (intravenous fluids and nutrition).
• Pharmacokinetic studies — characterising how the analogue behaves in healthy subjects and in people with reduced kidney function.
• Preclinical models of intestinal inflammation — animal and formulation work exploring mucosal effects beyond SBS.

What the Published Literature Reports

Phase 2 work in short bowel syndrome

A randomised phase 2 trial in patients with short bowel syndrome, published in 2019, evaluated glepaglutide and reported reductions in the need for parenteral support (PMID 30880176). Substudies from the same phase 2 programme examined more specific physiology: researchers reported effects of glepaglutide on gastrointestinal transit time and motility in patients with short bowel syndrome (PMID 32022286), and a separate analysis reported findings on intestinal morphology and perfusion in the same trial population (PMID 35511704).

Two further phase 2 analyses looked at systems downstream of intestinal adaptation. One examined markers of liver status in patients with short bowel syndrome receiving glepaglutide (PMID 31326433); another investigated the bile acid–farnesoid X receptor–fibroblast growth factor 19 axis in the same randomised phase 2 setting (PMID 34287979). Together these reports illustrate how a single trial cohort can generate multiple mechanistic publications.

Phase 3 results

The pivotal evidence comes from a phase 3 randomised controlled trial published in Gastroenterology in 2025, in which researchers reported that glepaglutide reduced parenteral support in patients with short bowel syndrome (PMID 39708985). A 2025 report in Clinical Nutrition ESPEN described outcomes of glepaglutide on intestinal absorption and parenteral support in this patient population (PMID 40774623). Readers interested in effect sizes, dosing regimens and statistical detail should consult those primary publications directly rather than relying on summaries.

Pharmacokinetics

A study in healthy subjects characterised the pharmacokinetics of glepaglutide as a long-acting GLP-2 analogue (PMID 36323988). Because GLP-2 analogues are cleared in part by the kidney, a separate investigation reported pharmacokinetics, safety and tolerability in subjects with renal impairment (PMID 36811175). Renal-impairment studies of this kind are standard regulatory-facing work and are not, on their own, statements about clinical benefit.

Preclinical and formulation research

Outside short bowel syndrome, researchers reported that glepaglutide had anti-inflammatory and mucosal regenerative effects in an experimental rat model of inflammatory bowel disease (PMID 36944922). A 2025 materials-science paper described a glepaglutide-loaded foam developed for the induction of mucosal healing in inflammatory bowel disease models (PMID 39905897). These are exploratory, non-clinical lines of work; animal and device findings do not establish outcomes in people.

Where Glepaglutide Has Been Studied: At a Glance

Tolerability: What Studies Report

Safety and tolerability were assessed alongside pharmacokinetics in subjects with renal impairment, and the study reported on tolerability in that population (PMID 36811175). Adverse-event profiles were also reported within the randomised phase 2 trial in short bowel syndrome (PMID 30880176) and the phase 3 randomised controlled trial (PMID 39708985). The specific event categories, frequencies and severity gradings are listed in those publications; this glossary entry does not reproduce or estimate them.

Common Points of Confusion

• GLP-2 is not GLP-1. Both are cleaved from proglucagon, but GLP-2 analogues such as glepaglutide were studied for intestinal outcomes in short bowel syndrome (PMID 39708985), not for glycaemic or weight endpoints.
• "Long-acting" describes chemistry, not superiority. The descriptor refers to design intent and formulation, as set out in the paper on creating the analogue (PMID 39851172).
• Animal findings are not clinical findings. Mucosal regeneration reported in a rat inflammatory bowel disease model (PMID 36944922) has not been shown to translate to human disease in the papers listed here.

Regulatory Context

Glepaglutide has been developed through randomised clinical trials, including the phase 3 study published in 2025 (PMID 39708985). Approval status differs by jurisdiction and changes over time, and readers should check current regulator databases rather than secondary sources. Research-grade peptide material labelled "research use only" is not a medicine and is not intended for human administration. This entry is definitional and does not address selection, administration or comparison of treatments.

References

• Glepaglutide, a Long-Acting Glucagon-like Peptide-2 Analogue, Reduces Parenteral Support in Patients With Short Bowel Syndrome: A Phase 3 Randomized Controlled Trial (Gastroenterology, 2025)
• Outcomes of glepaglutide on intestinal absorption and parenteral support in patients with short bowel syndrome (Clinical Nutrition ESPEN, 2025)
• Pharmacokinetics, Safety, and Tolerability of Glepaglutide, a Long-Acting GLP-2 Analog, in Subjects with Renal Impairment (Clinical Pharmacokinetics, 2023)
• Bile acid-farnesoid X receptor-fibroblast growth factor 19 axis in patients with short bowel syndrome: The randomized, glepaglutide phase 2 trial (JPEN, 2022)
• Effect of Glepaglutide, a Long-Acting Glucagon-Like Peptide-2 Analog, on Gastrointestinal Transit Time and Motility in Patients With Short Bowel Syndrome: Findings From a Randomized Trial (JPEN, 2020)
• Glepaglutide-Loaded Foam for the Induction of Mucosal Healing in the Treatment of Inflammatory Bowel Disease (Advanced Healthcare Materials, 2025)
• Glepaglutide, a novel glucagon-like peptide-2 agonist, has anti-inflammatory and mucosal regenerative effects in an experimental model of inflammatory bowel disease in rats (BMC Gastroenterology, 2023)
• Glepaglutide, a novel long-acting glucagon-like peptide-2 analogue, for patients with short bowel syndrome: a randomised phase 2 trial (The Lancet Gastroenterology & Hepatology, 2019)
• Pharmacokinetics of Glepaglutide, A Long-Acting Glucagon-Like Peptide-2 Analogue: A Study in Healthy Subjects (Clinical Drug Investigation, 2022)
• Effects of glepaglutide, a long-acting glucagon-like peptide-2 analog, on intestinal morphology and perfusion in patients with short bowel syndrome: Findings from a randomized phase 2 trial (JPEN, 2023)
• Creating Glepaglutide, the First Long-Acting GLP-2 Analogue to Enable a Ready-to-Use Injection (Journal of Medicinal Chemistry, 2025)
• Effects of glepaglutide, a novel long-acting glucagon-like peptide-2 analogue, on markers of liver status in patients with short bowel syndrome: findings from a randomised phase 2 trial (EBioMedicine, 2019)