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A GLP-2 analogue with a six-lysine tail that forms a subcutaneous depot — more than 98% of its exposure comes from two metabolites released slowly from the injection site.
Also known as: ZP1848 · ZP-1848
Part of the Metabolic & GLP-1 peptides cluster
Overview
Glepaglutide (ZP1848) is a 39-amino-acid long-acting analogue of glucagon-like peptide-2 with a C-terminal hexa-lysine extension, developed for short bowel syndrome with intestinal failure. In a phase 3 trial, twice-weekly dosing reduced parenteral support volume by 5.13 L/week versus 2.85 L/week with placebo at 24 weeks. The US FDA declined to approve it in 2024; additional phase 3 trials are running as of September 2026.
Source & context
Biological / chemical source: Synthetic engineered peptide (Zealand Pharma)
Primary research or clinical context: Investigational — phase 3 for short bowel syndrome with intestinal failure; the US FDA declined approval in 2024 and further phase 3 trials are under way
What glepaglutide is
Glepaglutide is a long-acting analogue of glucagon-like peptide-2 (GLP-2), the 33-residue gut hormone that stimulates growth and absorptive capacity in the intestinal lining. It was developed by Zealand Pharma for short bowel syndrome with intestinal failure — patients who have lost so much intestine that they depend on intravenous parenteral support for fluids and nutrition. An approved GLP-2 analogue, teduglutide, already exists but requires daily injection; glepaglutide was designed for once- or twice-weekly dosing. It remains investigational: after phase 3 results, the US FDA declined to approve it in 2024, and further phase 3 trials were active as of September 2026.
Sequence and the hexa-lysine tail
The IUPHAR record gives the sequence HGEGTFSSELATILDALAARDFIAWLIATKITDKKKKKK — 39 residues. Set against native GLP-2 (HADGSFSDEMNTILDNLAARDFINWLIQTKITD), the first 33 positions carry substitutions that reduce enzymatic cleavage and renal clearance, and six lysines are appended at the C-terminus, the last of them amidated. That basic tail is the point: it drives the peptide to form a depot at the injection site rather than extending albumin binding as the fatty-acid strategy of semaglutide does. GLP-2 analogues generally are engineered to resist the same DPP-4 cleavage that inactivates GLP-1.
Pharmacokinetics: a depot, not a lipid
A study in healthy subjects dosed 5 or 10 mg subcutaneously once weekly for six weeks, or 1 mg intravenously. Comparing the two routes showed that glepaglutide's subcutaneous pharmacokinetics are governed by slow release of its two main metabolites from a subcutaneous depot: at steady state those metabolites accounted for more than 98% of exposure and the parent peptide for less than 1%. The estimated effective half-life was 124 hours at 5 mg and 88 hours at 10 mg, and citrulline — a marker of enterocyte mass — rose with both doses (Agersnap et al., Clinical Drug Investigation 2022). Renal impairment did not require dose adjustment in a follow-up study (Agersnap et al., Clinical Pharmacokinetics 2023).
Phase 2: fewer stools, more absorption
The first patient trial was a single-centre, double-blind, crossover phase 2 study in adults with short bowel syndrome and faecal wet-weight output of at least 1,500 g/day. Patients received daily subcutaneous glepaglutide at 0.1, 1 or 10 mg for three weeks in two of six dose sequences separated by a washout, with the primary endpoint being change in faecal wet weight measured by inpatient metabolic balance studies (Naimi et al., Lancet Gastroenterology & Hepatology 2019). A rat model of indomethacin-induced small-intestinal inflammation later showed anti-inflammatory and mucosal-regenerative effects (Skarbaliene et al., BMC Gastroenterology 2023).
Phase 3: parenteral support reduced
The pivotal international phase 3 trial randomised 106 patients with short bowel syndrome intestinal failure needing parenteral support at least three days a week to 24 weeks of glepaglutide 10 mg twice weekly, once weekly, or placebo. Twice-weekly glepaglutide reduced weekly parenteral support volume by a mean 5.13 L versus 2.85 L with placebo (primary endpoint). Clinical response of at least 20% volume reduction was reached by 65.7% versus 38.9%, at least one fewer day per week on support by 51.4% versus 19.4%, and five patients (14%) achieved full enteral autonomy versus none on placebo. The once-weekly arm did not separate significantly from placebo on the primary endpoint (Jeppesen et al., Gastroenterology 2025).
| Endpoint | Glepaglutide 10 mg twice weekly | Placebo |
|---|---|---|
| Mean change in parenteral support volume | −5.13 L/week | −2.85 L/week |
| ≥ 20% volume reduction (weeks 20 and 24) | 65.7% | 38.9% |
| ≥ 1 day/week off parenteral support | 51.4% | 19.4% |
| Full enteral autonomy | 5 patients (14%) | 0 |
Regulatory status as of September 2026
Despite the phase 3 result, the US FDA declined to approve glepaglutide in 2024, according to the IUPHAR record. ClinicalTrials.gov lists further phase 3 trials — one recruiting and several active but not recruiting, including long-term extension studies — so the programme continues. A single-centre open-label phase 3b study of once-weekly dosing reported effects on wet-weight and energy absorption over 24 weeks and parenteral support over 52 weeks (Pinar et al., Clinical Nutrition ESPEN 2025). Glepaglutide is not approved in any jurisdiction documented in the evidence for this profile.
Relation to GLP-2 and the incretin family
GLP-2 comes from the same proglucagon precursor as GLP-1, glucagon and oxyntomodulin, but its job is intestinal growth rather than glucose control, and its drugs treat malabsorption rather than obesity. Glepaglutide, apraglutide and the approved teduglutide are the three GLP-2 analogues with substantial clinical data. The GLP-2 profile covers the hormone; the “What is GLP-3?” guide explains why GLP-2's existence is one reason that nickname for retatrutide is wrong.
Sequence
One-letter sequence commonly cited for Glepaglutide (educational; isoforms and modifications may differ):
HGEGTFSSELATILDALAARDFIAWLIATKITDKKKKKK
Residues plotted ~100° apart around an α-helix — clustering of one color reveals an amphipathic face.
Structure & chemistry
Molecular identity & reference confidence
Source-supported reference
Reference values are taken from the cited molecular record or curated profile. A database match is not independent laboratory verification; modifications, counter-ions, and formulations can change the measured mass.
- Molecular form
- Human GLP-2 (33 residues; HADGSFSDEMNTILDNLAARDFINWLIQTKITD) with substitutions for enzymatic stability plus a C-terminal hexa-lysine (KKKKKK) extension; C-terminal lysine amidated
- Species
- Not established by this molecular identity audit
- Termini (N / C)
- Not specified / Not specified
Average reference mass
Reference policy updated: 2026-10-05
- IUPHAR/BPS source snapshot · 2026-10-01
- PubChem molecular record · 2026-10-01
- Molecular formula
- C197H325N53O55
- Average reference mass
- ≈ 4,316
- Plasma half-life
- Effective half-life ≈ 124 h (5 mg) and ≈ 88 h (10 mg) after subcutaneous dosing, driven by slow release of two active metabolites from a subcutaneous depot (Agersnap et al. 2022)
- Receptors
- GLP-2 receptor (GLP-2R)
- Backbone
- Human GLP-2 (33 residues; HADGSFSDEMNTILDNLAARDFINWLIQTKITD) with substitutions for enzymatic stability plus a C-terminal hexa-lysine (KKKKKK) extension; C-terminal lysine amidated
- Status
- Investigational (phase 3). US FDA declined approval in 2024; phase 3 trials recruiting and active as of September 2026
The C-terminal lysine is amidated. Compared with native GLP-2, the sequence carries multiple substitutions (Ala2→Gly among them) and a six-lysine C-terminal addition.
- PubChem CID: 146170995
- IUPHAR ligand: 10885
- CAS RN: 914009-86-2
- UNII: 4M3C1913N6
Chemistry values: curated profile, PubChem, IUPHAR/BPS Guide to Pharmacology · fetched 2026-10-01.
Clinical development snapshot
ClinicalTrials.gov lists 9 registered studies with “Glepaglutide” as an intervention (snapshot 2026-10-01). A registry footprint is not evidence of efficacy or approval.
| NCT | Title | Phase | Status | Updated |
|---|---|---|---|---|
| NCT07197944 | Efficacy And Safety Evaluation of Glepaglutide in Treatment of SBS | Phase 3 | recruiting | 2026-09-29 |
| NCT03905707 | Evaluation of Long Term Safety and Efficacy of Glepaglutide in Treatment of SBS | Phase 3 | completed | 2026-09-08 |
| NCT04881825 | Evaluation of Long Term Safety and Efficacy of Glepaglutide in Treatment of SBS - Extension Trial | Phase 3 | completed | 2026-09-08 |
| NCT07228403 | Efficacy and Safety Evaluation of Glepaglutide in Treatment of Short Bowel Syndrome | Phase 3 | active not recruiting | 2026-07-30 |
| NCT03690206 | Efficacy And Safety Evaluation of Glepaglutide in Treatment of Short Bowel Syndrome (SBS) | Phase 3 | completed | 2025-07-17 |
| NCT04991311 | The Long-term Effect on Intestinal Absorption and Safety of Treatment With Glepaglutide in Patients With Short | Phase 3 | completed | 2024-11-22 |
Glepaglutide — reconstitution calculator
Enter how much peptide is in the vial and how much diluent (e.g. bacteriostatic water) is added. The tool returns the resulting solution concentration — and, for any amount you type, the volume it corresponds to. This is educational arithmetic, not a dosing recommendation.
Reference form: Human GLP-2 (33 residues; HADGSFSDEMNTILDNLAARDFINWLIQTKITD) with substitutions for enzymatic stability plus a C-terminal hexa-lysine (KKKKKK) extension; C-terminal lysine amidatedAverage reference mass: 4,316 Da
Enter an amount to see the volume it corresponds to.
Educational concentration mathematics only. This tool does not recommend a dose, amount, or protocol, and nothing here is medical advice. Many peptides are not authorized by Health Canada for human use — see our reconstitution and bacteriostatic-water guides for context.
Change log
Dated observations from the data pipeline (registry flags, trial footprints, identifiers) and editorial reviews of this profile.
- IdentifiersCross-linked to IUPHAR ligand 10885 and PubChem CID 146170995.
- TrialsClinicalTrials.gov snapshot added: 9 registered studies, highest phase 3.
- EditorialProfile content reviewed and updated by the editorial team.
FAQ about Glepaglutide
What is Glepaglutide?+
Glepaglutide (ZP1848) is a 39-amino-acid long-acting analogue of glucagon-like peptide-2 with a C-terminal hexa-lysine extension, developed for short bowel syndrome with intestinal failure. In a phase 3 trial, twice-weekly dosing reduced parenteral support volume by 5.13 L/week versus 2.85 L/week with placebo at 24 weeks. The US FDA declined to approve it in 2024; additional phase 3 trials are running as of September 2026.
What Canadian product status is recorded for Glepaglutide?+
Canadian product status for Glepaglutide has not been verified in this profile. No verified record here does not mean no authorization exists. Status depends on the product, formulation and use; consult Health Canada's product records.
What is the typical length of Glepaglutide?+
Glepaglutide is commonly described as approximately 39 amino acids (GLP-2 analogue).
What is glepaglutide?+
A 39-amino-acid long-acting GLP-2 analogue (ZP1848) developed for short bowel syndrome with intestinal failure. In phase 3, twice-weekly dosing cut parenteral support by about 5 L/week. It is not yet approved.
Is glepaglutide FDA-approved?+
No. The US FDA declined approval in 2024; further phase 3 trials are ongoing as of September 2026.
How is glepaglutide different from teduglutide?+
Both are GLP-2 analogues, but teduglutide is approved and dosed daily, whereas glepaglutide's hexa-lysine tail creates a subcutaneous depot for once- or twice-weekly dosing.
What is glepaglutide's half-life?+
An effective half-life of about 124 hours at 5 mg and 88 hours at 10 mg, driven by slow release of two active metabolites from the injection-site depot.
What did the phase 3 trial show?+
At 24 weeks, twice-weekly glepaglutide reduced parenteral support volume by 5.13 L/week versus 2.85 L/week with placebo; 14% of patients came off parenteral support entirely.
Related peptides
References & further reading
- 1.Jeppesen PB et al. (2025). Glepaglutide, a Long-Acting Glucagon-like Peptide-2 Analogue, Reduces Parenteral Support in Patients With Short Bowel Syndrome. Gastroenterology
- 2.Naimi RM et al. (2019). Glepaglutide, a novel long-acting glucagon-like peptide-2 analogue, for patients with short bowel syndrome: a randomised phase 2 trial. Lancet Gastroenterology & Hepatology
- 3.Agersnap MA et al. (2022). Pharmacokinetics of Glepaglutide, A Long-Acting Glucagon-Like Peptide-2 Analogue: A Study in Healthy Subjects. Clinical Drug Investigation
- 4.Agersnap MA et al. (2023). Pharmacokinetics, Safety, and Tolerability of Glepaglutide in Subjects with Renal Impairment. Clinical Pharmacokinetics
- 5.Skarbaliene J et al. (2023). Glepaglutide has anti-inflammatory and mucosal regenerative effects in an experimental model of small intestinal inflammation. BMC Gastroenterology
- 6.Pinar I et al. (2025). Outcomes of glepaglutide on intestinal absorption and parenteral support in patients with short bowel syndrome. Clinical Nutrition ESPEN
- 7.PubChem — Glepaglutide (CID 146170995)