Glepaglutide
A once- or twice-weekly GLP-2 analogue for short bowel syndrome, built to cut the injections teduglutide needs daily
People with short bowel syndrome have too little intestine to absorb what they eat and depend on intravenous nutrition. GLP-2 makes the remaining gut absorb more. Glepaglutide is a long-acting version tested in a phase 3 trial that met its primary endpoint on the twice-weekly dose.
What is it?
Short bowel syndrome follows surgery that removes much of the small intestine. What remains cannot absorb enough fluid and nutrients, so many patients depend on parenteral support, nutrition delivered into a vein for several nights a week. GLP-2 is the gut hormone that drives the remaining intestine to adapt, growing its lining and absorbing more.
Teduglutide, the approved GLP-2 analogue, works but is injected daily. Glepaglutide was designed to last long enough for once- or twice-weekly dosing: nine amino-acid substitutions and a six-lysine tail make it stable enough for a ready-to-use liquid. In healthy volunteers given 5 or 10 mg weekly for six weeks, the pharmacokinetics supported that schedule, and severe kidney impairment did not change exposure.
The phase 3 trial randomised 106 patients with intestinal failure to 10 mg twice weekly, 10 mg once weekly or placebo for 24 weeks. The twice-weekly dose cut weekly parenteral support by 5.13 litres against 2.85 on placebo, meeting the primary endpoint; 65.7% had at least a 20% reduction against 38.9%, and 5 patients came off parenteral support entirely. The once-weekly dose did not differ significantly from placebo on any primary or key secondary endpoint.
Earlier work explains the mechanism in patients: three weeks of daily glepaglutide in a phase 2 crossover trial reduced faecal output and improved absorption, with changes in the intestinal lining and its blood flow. It also slowed the passage of food through the stomach and small bowel, giving the remaining gut more time. Effects on the liver were mixed, with better excretory function but higher stiffness, and the gut microbiome did not change.
It is not approved anywhere, and no application appears in Drugs@FDA.
Mechanism of Action
Glepaglutide is a stabilised, long-acting analogue of GLP-2, the gut hormone that makes the intestinal lining grow and absorb more.
Intestinal growth
Activates the GLP-2 receptor, increasing mucosal growth; biopsies showed changes in the lining and its blood flow.
Slower transit
At 10 mg it delayed gastric emptying and small-bowel emptying, giving more time for absorption.
Bile acid axis
Raised the after-meal FGF19 response and lowered C4, a marker of bile acid synthesis.
Published Research
These are the trials that describe glepaglutide, read from their PubMed abstracts: the phase 3, two phase 2 analyses and a pharmacokinetic study.
The phase 3
106 patients with intestinal failure needing parenteral support at least three days a week took 10 mg twice weekly, once weekly or placebo for 24 weeks. Twice weekly cut weekly support by 5.13 litres against 2.85 on placebo, meeting the primary endpoint.
The phase 2 crossover
Adults with high faecal output took daily glepaglutide at 0.1, 1 or 10 mg for three weeks in sequence, separated by a washout. The trial measured faecal output and intestinal absorption, the effects that justified moving to phase 3.
What changes in the gut
In 18 patients from the phase 2 trial, biopsies and perfusion imaging before and after three weeks of treatment tracked changes in intestinal morphology, absorption-related gene expression and blood flow, the adaptation GLP-2 is meant to drive.
The dosing interval
Healthy adults took 5 or 10 mg once weekly for six weeks or a single 1 mg intravenous dose. The pharmacokinetics of the drug and its two main metabolites supported weekly subcutaneous dosing.
Absorption and parenteral support
In short bowel syndrome, glepaglutide raised energy absorption by about 1,038 kJ/day at 24 weeks, and by week 52 parenteral support volume had fallen by 800 mL/day, with stable body weight.
Severe kidney impairment
A single 10 mg dose gave similar exposure in people with severe kidney impairment or end-stage disease as in people with normal kidneys, suggesting no dose adjustment is needed.
Slower transit
In 18 patients from the phase 2 trial, 10 mg slowed gastric emptying of solids by 27 minutes and of fluids by 40 minutes, and small-bowel emptying of solids by 21 minutes.
Liver markers
In the phase 2 trial, glepaglutide improved a marker of liver excretory function but raised liver stiffness and, at 10 mg, a marker of liver macrophage activation; transaminases did not change.
Bile acid signalling
At 10 mg, the after-meal FGF19 response rose and C4, a marker of bile acid synthesis, fell, suggesting it may temper the excess bile acid production linked to intestinal failure liver disease.
Gut bacteria unchanged
In 10 patients treated weekly for 24 weeks in an open-label study, intestinal wet weight and energy absorption rose but stool bacterial load and composition did not change; anatomy, especially whether the colon remained, determined the microbiome.
How it was designed
Native GLP-2 is short-lived and unstable; glepaglutide carries nine amino-acid substitutions and a six-lysine tail that improve stability, potency and half-life, making a ready-to-use liquid injection possible.
Inflamed rat intestine
In a rat model of small-intestinal inflammation, glepaglutide given during or after the injury reduced inflammation and increased intestinal mass, without needing pre-treatment.
Dosing Data
There is no approved dose. The phase 3 trial gave 10 mg under the skin twice weekly or once weekly; only twice weekly met its endpoints.
Educational information, not medical advice. Each dose above is tagged with its source: an approved label, a published human study, animal data, or amounts reported by users. None is a recommendation for you. An unapproved compound has no established safe or effective human dose, and products sold for “research use only” are not made or tested for people. Talk to a doctor before acting on anything on this site, including before you start, stop or change any medicine or dose. Full medical disclaimer.
Side Effects & Contraindications
Reported Side Effects
From the trials above; there is no approved label.
Contraindications & Cautions
An investigational drug for a rare condition.
Legal Status
Glepaglutide is investigational everywhere.
Frequently Asked Questions
?What is glepaglutide?
A long-acting analogue of GLP-2, the gut hormone that makes the intestine grow and absorb more, developed for short bowel syndrome.
?How is it different from teduglutide?
Teduglutide is approved and injected daily. Glepaglutide was designed for once- or twice-weekly dosing.
?Did the phase 3 work?
The twice-weekly dose met the primary endpoint, cutting weekly parenteral support by 5.13 litres against 2.85 on placebo.
?Is it approved?
No. It is investigational, and no application appears in Drugs@FDA.
?Once or twice a week?
Twice. In the phase 3 trial, 10 mg twice weekly reduced parenteral support significantly; 10 mg once weekly did not differ from placebo on the primary or key secondary endpoints.
References
- [pubmed] Jeppesen PB, et al. "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;168(4):701-713.e6. PMID: 39708985.
- [pubmed] Naimi RM, et al. "Glepaglutide, a novel long-acting glucagon-like peptide-2 analogue, for patients with short bowel syndrome: a randomised phase 2 trial." Lancet Gastroenterol Hepatol, 2019;4(5):354-363. PMID: 30880176.
- [pubmed] Naimi RM, et al. "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 J Parenter Enteral Nutr, 2023;47(1):140-150. PMID: 35511704.
- [pubmed] Agersnap MA, et al. "Pharmacokinetics of Glepaglutide, A Long-Acting Glucagon-Like Peptide-2 Analogue: A Study in Healthy Subjects." Clin Drug Investig, 2022;42(12):1093-1100. PMID: 36323988.
- [other] US FDA, Drugs@FDA (openFDA): no application for glepaglutide. Read September 30, 2026.
- [clinicaltrials] ClinicalTrials.gov NCT03690206: EASE SBS 1, the phase 3 efficacy and safety trial of glepaglutide in short bowel syndrome, completed (registry record read September 30, 2026).
- [pubmed] Pinar I, et al. "Outcomes of glepaglutide on intestinal absorption and parenteral support in patients with short bowel syndrome." Clin Nutr ESPEN, 2025;69:590-598. PMID: 40774623.
- [pubmed] Agersnap MA, et al. "Pharmacokinetics, Safety, and Tolerability of Glepaglutide, a Long-Acting GLP-2 Analog, in Subjects with Renal Impairment." Clin Pharmacokinet, 2023;62(4):645-651. PMID: 36811175.
- [pubmed] Hvistendahl MK, et al. "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 J Parenter Enteral Nutr, 2020;44(8):1535-1544. PMID: 32022286.
- [pubmed] Naimi RM, et al. "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;46:444-451. PMID: 31326433.
- [pubmed] Hvistendahl MK, et al. "Bile acid-farnesoid X receptor-fibroblast growth factor 19 axis in patients with short bowel syndrome: The randomized, glepaglutide phase 2 trial." JPEN J Parenter Enteral Nutr, 2022;46(4):923-935. PMID: 34287979.
- [pubmed] Pinar I, et al. "Investigation of the stool microbiome of short bowel syndrome patients before and after a 24-week treatment with the glucagon-like peptide 2 analog glepaglutide." Clin Nutr ESPEN, 2026;73:102989. PMID: 41759957.
- [pubmed] Larsen BD, et al. "Creating Glepaglutide, the First Long-Acting GLP-2 Analogue to Enable a Ready-to-Use Injection." J Med Chem, 2025;68(3):3134-3145. PMID: 39851172.
- [pubmed] Skarbaliene J, et al. "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 Gastroenterol, 2023;23(1):79. PMID: 36944922.
Sources & Citations
Studies were read from their PubMed abstracts; no label exists. Read October 6, 2026.
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