Glepaglutide
Glepaglutide (ZP1848)
Glepaglutide is a novel long-acting glucagon-like peptide-2 (GLP-2) analogue developed by Zealand Pharma for the treatment of short bowel syndrome (SBS), with positive Phase 3 RCT results showing significant reduction in parenteral support requirements (PMID 39708985, NCT03690206).
Last updated: 2026-03-10
Safety Summary
Side effect frequencies from the Phase 2 trial (N=18): stoma complications 72%, injection site reactions 61%, peripheral edema 56%, nausea and abdominal pain 44% each, polyuria and fatigue 33% each, abdominal distention, vomiting, and dizziness 28% each, cough and decreased appetite 22% each (PMID 30880176). Related or possibly related serious adverse events included abdominal pain, stoma obstruction, catheter-related sepsis, and infection of unknown origin (PMID 30880176). In the Phase 3 trial, anti-drug antibodies developed in 87% (61/70) of glepaglutide-treated patients but did not appear to affect efficacy or safety; serious adverse events were often catheter- or device-related infections occurring in both active and placebo arms (PMID 39708985). The Phase 3b open-label study described safety across 52 weeks as manageable (PMID 40774623). No deaths occurred during the Phase 2 trial (PMID 30880176).
Known Side Effects
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Who Should NOT Use This
GLP-2 analogues stimulate intestinal epithelial cell proliferation and could theoretically promote growth of GI malignancies. The confirmatory Phase 3 protocol excluded patients with colorectal cancer or other cancer unless disease-free for at least 5 years (NCT07197944). This is a general concern for the GLP-2 analogue drug class (PMID 35343263, PMID 35933503).
Suspicion of hypersensitivity, intolerance, or allergy to glepaglutide was exclusionary in clinical trials (NCT04178447, NCT03279302). One patient in the Phase 2 trial experienced a generalized rash (PMID 30880176).
The confirmatory Phase 3 protocol excluded ongoing bowel obstruction, treating this as a major safety concern in late-stage development (NCT07197944).
Pregnant or breastfeeding participants were excluded from PK and extension studies, so human pregnancy safety is not established (NCT04178447, NCT07228403).
These agents were excluded in Phase 1 and extension protocols, likely to avoid overlapping biology and confounding of safety or efficacy assessments (NCT04178447, NCT07228403).
Talk to Your Doctor
Before considering Glepaglutide, discuss it with your healthcare provider. Ask about potential interactions with your current medications, whether it is appropriate for your health conditions, and what monitoring may be needed.
Sources: [1-14]
Evidence Assessment
Evidence tier 2 is assigned because glepaglutide has positive Phase 3 RCT data. The EASE SBS 1 trial (NCT03690206, PMID 39708985) was a randomized, double-blind, placebo-controlled Phase 3 trial in 106 patients demonstrating statistically significant reduction in parenteral support volumes with twice-weekly 10 mg dosing. This is supported by Phase 2 RCT data (NCT02690025, PMID 30880176) in 18 patients and a Phase 3b open-label study (NCT04991311, PMID 40774623) in 10 patients. However, glepaglutide is not yet approved by any regulatory authority (FDA, EMA), the once-weekly dosing arm in the Phase 3 trial did not achieve statistical significance versus placebo, and confirmatory Phase 3 and long-term extension studies are still ongoing (NCT07197944, NCT07228403).
1Glepaglutide, a Long-Acting Glucagon-like Peptide-2 Analogue, Reduces Parenteral Support in Patients With Short Bowel Syndrome: A Phase 3 Randomized Controlled Trial.NCT03690206PMID 39708985
Jeppesen PB et al. - Gastroenterology (2025) - Phase 3 RCT - N=106 randomized
Twice-weekly 10 mg glepaglutide significantly reduced PS volumes vs placebo (-5.13 vs -2.85 L/wk, P=0.0039). Clinical response (>=20% PS reduction) achieved by 65.7% vs 38.9% (P=0.0243). PS days reduction >=1 d/wk in 51.4% vs 19.4% (P=0.0043). Five patients (14%) achieved enteral autonomy vs 0 for placebo. Once-weekly 10 mg did not reach significance vs placebo. Anti-drug antibodies developed in 87% (61/70) of glepaglutide patients.
Limitations: Once-weekly arm failed to achieve significance. High rate of anti-drug antibody formation (87%). 24-week duration may not capture long-term outcomes. Sponsor-funded (Zealand Pharma). SBS patient population limits generalizability.
2Glepaglutide, a novel long-acting glucagon-like peptide-2 analogue, for patients with short bowel syndrome: a randomised phase 2 trial.NCT02690025PMID 30880176
Naimi RM et al. - The Lancet Gastroenterology & Hepatology (2019) - Phase 2 RCT (crossover) - N=18 randomized (16 completed)
1 mg and 10 mg glepaglutide significantly reduced fecal wet weight output: -592 g/day (P=0.002) and -833 g/day (P=0.0002). 0.1 mg was not effective. Common AEs: stoma complications (72%), injection site reactions (61%), peripheral edema (56%), nausea and abdominal pain (44% each). No deaths.
Limitations: Small sample size (N=18). Short treatment duration (3 weeks per period). Single-center. Crossover design with potential carryover effects despite washout. Manufacturer-funded (Zealand Pharma).
3Outcomes of glepaglutide on intestinal absorption and parenteral support in patients with short bowel syndrome.NCT04991311PMID 40774623
Pinar I et al. - Clinical Nutrition ESPEN (2025) - Phase 3b open-label study - N=10 patients
With 10 mg once weekly, intestinal wet weight absorption increased by 398 g/day at week 24, energy absorption increased by 1038 kJ/day, and mean PS volume was reduced by 800 mL/day at week 52 while body composition remained stable. Manageable safety profile.
Limitations: Single-center open-label study with only 10 patients and no placebo control. Manufacturer-funded.
4Effect 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.NCT02690025PMID 32022286
Hvistendahl MK et al. - JPEN (2020) - Phase 2 RCT (substudy) - N=18
10 mg glepaglutide significantly increased time to 10% gastric emptying of solids by 27 min, time to 50% gastric emptying of fluids by 40 min, and time to 10% small bowel emptying of solids by 21 min.
Limitations: Small sample. Substudy of Phase 2 trial. Manufacturer-funded.
5Effects 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.NCT02690025PMID 31326433
Naimi RM et al. - EBioMedicine (2019) - Phase 2 RCT (substudy) - N=18
10 mg glepaglutide increased sCD163 by 0.44 mg/mL (P=0.0498) and increased transient elastography and ICG elimination. ALP decreased in 1 mg group by 33 U/L (P=0.032). CAP, sMR, LBP, transaminases, and INR were not affected. Diverse effects on liver status suggest both beneficial and potentially concerning findings.
Limitations: Small sample. Exploratory endpoints. Short duration (3 weeks). Diverse liver findings difficult to interpret clinically. Manufacturer-funded.
6Bile acid-farnesoid X receptor-fibroblast growth factor 19 axis in patients with short bowel syndrome: the randomized, glepaglutide phase 2 trial.NCT02690025PMID 34287979
Hvistendahl MK et al. - JPEN (2022) - Phase 2 RCT (substudy) - N=18
10 mg glepaglutide increased postprandial FGF19 AUC by 150 h x ng/L (P=0.001) and decreased C4 by 82 h x ug/L (P=0.010). ALP significantly decreased. FXR gene expression did not change.
Limitations: Small sample. Exploratory analysis. Manufacturer-funded.
7Effects 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.NCT02690025PMID 35511704
Naimi RM et al. - JPEN (2023) - Phase 2 RCT (substudy) - N=18
Glepaglutide increased plasma citrulline by 15.3 and 15.6 umol/L (1 mg and 10 mg doses). Trends toward increased villus height, crypt depth, and epithelium height, though not all reached statistical significance. Perfusion and gene-expression endpoints not significantly changed.
Limitations: Small sample. Morphological trends did not all reach significance. Short treatment duration. Manufacturer-funded.
8Pharmacokinetics of Glepaglutide, A Long-Acting Glucagon-Like Peptide-2 Analogue: A Study in Healthy Subjects.NCT03279302PMID 36323988
Agersnap MA et al. - Clinical Drug Investigation (2022) - Phase 1 PK study (open-label, partially randomized) - N=45 healthy subjects analyzed (parent protocol enrolled 75)
Estimated mean effective half-life: 124 h (95% CI 73-185) for 5 mg SC and 88 h (95% CI 31-146) for 10 mg SC. Two main metabolites account for >98% of exposure at steady state; parent drug <1%. Citrulline increased at both SC dose levels.
Limitations: Healthy volunteer population, not SBS patients. Open-label. Manufacturer-funded (Zealand Pharma).
9Pharmacokinetics, Safety, and Tolerability of Glepaglutide, a Long-Acting GLP-2 Analog, in Subjects with Renal Impairment.NCT04178447PMID 36811175
Agersnap MA et al. - Clinical Pharmacokinetics (2023) - Phase 1 renal-impairment PK study - N=16 subjects
No clinically relevant pharmacokinetic differences between subjects with renal impairment and those with normal renal function. No dose adjustment needed for renal impairment.
Limitations: Single-dose, non-randomized study in non-SBS subjects with only 16 participants. Manufacturer-funded.
10Investigation of the stool microbiome of Short Bowel Syndrome patients before and after a 24-week treatment with the Glucagon-like Peptide 2 analog glepaglutide.NCT04991311PMID 41759957
Pinar A et al. - Clinical Nutrition ESPEN (2026) - Phase 3b exploratory microbiome study - N=10
Despite increased wet-weight and energy absorption in the parent Phase 3b trial, 24 weeks of glepaglutide did not produce major shifts in bacterial load or gut microbiota composition. Anatomy drove differences more than treatment.
Limitations: Very small exploratory 16S study nested inside an open-label trial with substantial anatomy-related heterogeneity.
11Pharmacological Characterization of Apraglutide, a Novel Long-Acting Peptidic Glucagon-Like Peptide-2 Agonist, for the Treatment of Short Bowel Syndrome.PMID 32075870
Hargrove DM et al. - Journal of Pharmacology and Experimental Therapeutics (2020) - Preclinical comparative study - Animal (rat, monkey, minipig)
Compared glepaglutide to apraglutide and teduglutide. Glepaglutide was less potent and less selective at the GLP-2 receptor. Rat IV half-life: hGLP-2 6.4 min, teduglutide 19 min, glepaglutide 16 min, apraglutide 159 min. Clearance: hGLP-2 25, teduglutide 9.9, glepaglutide 2.8, apraglutide 0.27 mL/kg/min.
Limitations: Authored by apraglutide developer (Therachon/VectivBio). Preclinical only. Rat PK may not translate directly to humans. Potential conflict of interest as competitor product.
12Anti-inflammatory effects of glepaglutide in a rat model of indomethacin-induced intestinal inflammation [PREPRINT]
Skarbaliene J et al. - Research Square (preprint) (2022) - Animal study - Rat model
Glepaglutide demonstrated anti-inflammatory effects in indomethacin-induced intestinal inflammation rat model. Reduced alpha-1-acid glycoprotein and myeloperoxidase. Reversed intestinal shortening. Increased small intestinal mass.
Limitations: Animal model only. Preprint. Funded by Zealand Pharma. Cannot directly extrapolate to human IBD.
13Network meta-analysis of GLP-2 analogues in short bowel syndromePMID 38663565
Sabra MM et al. - Journal of Gastrointestinal Surgery (2024) - Network meta-analysis - Multiple RCTs of GLP-2 analogues
Compared efficacy of GLP-2 analogues (teduglutide, glepaglutide, apraglutide) in SBS. Provides comparative effectiveness data across the drug class.
Limitations: Indirect comparisons inherent to network meta-analysis methodology. Different trial designs and patient populations across studies.
14Systematic review and meta-analysis of GLP-2 analogues for short bowel syndromePMID 41344401
Bastas MA et al. - Clinical Nutrition ESPEN (2026) - Systematic review and meta-analysis - Multiple studies
Systematic review and meta-analysis evaluating efficacy and safety of GLP-2 analogues including glepaglutide for the treatment of SBS.
Limitations: Combines heterogeneous studies. Publication bias possible.