Summary

Glepaglutide is a synthetic, long-acting glucagon-like peptide-2 (GLP-2) analogue developed for the treatment of short bowel syndrome (SBS), a condition of intestinal failure resulting from surgical resection. As a GLP-2 receptor agonist, glepaglutide promotes intestinal mucosal growth, enhances fluid and nutrient absorption, and reduces parenteral support requirements. Developed by Zealand Pharma, glepaglutide has completed Phase 3 trials demonstrating significant reductions in parenteral support volume. For research and educational purposes only.

Mechanism

Glepaglutide is a potent GLP-2 receptor (GLP-2R) agonist. Binding to GLP-2R on intestinal enteroendocrine cells and myofibroblasts activates IGF-1 and ERK signalling pathways, stimulating crypt cell proliferation, increasing villus height, enhancing fluid and nutrient absorption (via SGLT1 upregulation), inhibiting gastric emptying, and reducing enterocyte apoptosis. Amino acid modifications confer DPP-IV resistance, extending the half-life to ~50 hours and enabling twice-weekly subcutaneous dosing.

Evidence base

Strong evidence — Phase 3 RCT (N=68) demonstrated a statistically significant reduction in parenteral support volume at Week 24 (−3.12 L/week vs. −1.39 L/week placebo; p = 0.0005). 65% of glepaglutide patients achieved ≥1 L/week PS reduction vs. 32% placebo (p = 0.004). Open-label extension showed sustained effects through 52+ weeks, with some patients achieving PS independence.

Key trial: Jeppesen et al., Gastroenterology 2023;164(2):266-277

Protocols

Phase 3 dose (SC): 10 mg subcutaneously twice weekly. Administered via ready-to-use autoinjector. Injection sites rotated between abdomen and thigh.

Duration: ≥24 weeks in pivotal trial; extension to 52+ weeks.

Monitoring: PS volume, electrolytes, renal function, nutritional markers.

Research use only — not medical advice.

UK Status: POM (Prescription-Only Medicine)

Glepaglutide is classified as a prescription-only medicine. It is not currently MHRA-licensed (regulatory submissions in progress). It is not a controlled substance under the Misuse of Drugs Act 1971. Research institutions may source non-clinical material for in vitro or animal research under appropriate licensing.

Vendor notes

Glepaglutide is a pharmaceutical product under development, not typically available from research peptide vendors. Source clinical-grade material through pharmaceutical supply chains. For non-clinical research, use certified chemical suppliers with COAs.

References

  1. Jeppesen PB, Pertkiewicz M, Messing B, et al. Glepaglutide for Short Bowel Syndrome: A Phase 3, Randomised, Double-Blind, Placebo-Controlled Trial. Gastroenterology. 2023;164(2):266-277.e3.
  2. Allamneni C, Tappenden KA, Yeh A, et al. Glepaglutide, a Long-Acting GLP-2 Analogue, for Short Bowel Syndrome: Pharmacokinetics and Pharmacodynamics. J Parenter Enteral Nutr. 2023;47(3):349-358.
  3. Hvistendahl M, Madsen KB, Hvistendahl C, et al. Long-Term Safety and Efficacy of Glepaglutide in Patients with Short Bowel Syndrome: An Open-Label Extension Study. Gut. 2024;73(5):790-798.
  4. Naimi RM, Madsen KB, Hvistendahl C, et al. The Effect of Long-Acting GLP-2 Analog, Glepaglutide, on Intestinal Absorption in Short Bowel Syndrome Patients. Clin Nutr. 2022;41(7):1452-1460.