What Is Glepaglutide?

1. What is glepaglutide, and how does it work?

Glepaglutide copies GLP-2, a 33-amino-acid hormone released from the gut after meals. GLP-2 acts on its own receptor, mostly in the intestine, where it promotes growth of the lining, increases blood flow and improves absorption. It shares a precursor protein and the same hormone-making cells with GLP-1, but not a receptor. The teduglutide page covers the hormone’s biology in more depth.

What sets glepaglutide apart is how long it lasts. In a pharmacokinetic study in 45 healthy volunteers by Agersnap and colleagues, injections under the skin formed a depot from which two active metabolites, shortened forms of the molecule, were slowly released. At steady state on weekly dosing, those two metabolites made up more than 98% of total exposure and the original molecule less than 1%.

Citrulline is an amino acid made by intestinal lining cells, used as a marker of how much working gut a person has. For comparison, teduglutide’s half-life is about 2 hours in healthy people (Gattex label). Zealand also describes glepaglutide as stable in a ready-to-use liquid, delivered by a single-dose autoinjector (Zealand, September 2026), whereas teduglutide is a powder that must be mixed before each dose.

2. What did the phase 2 trial show?

Naimi and colleagues’ phase 2 trial treated 18 adults with short bowel syndrome and high stool or stoma output, 1,500 g a day or more. Each person received two of three doses, 0.1, 1 or 10 mg, daily for 3 weeks, with a washout in between.

The same patients showed rises in citrulline of about 15 µmol/L at the 1 mg and 10 mg doses, with trends toward taller villi and deeper crypts in biopsies (Naimi et al., 2023). Exploratory analyses found changes in liver tests and bile acid signaling. Alkaline phosphatase fell, but liver stiffness and a marker of liver immune-cell activation rose, which the authors said called for attention in later trials (Naimi et al., 2019; Hvistendahl et al., 2022).

Side effects judged related to treatment were common in this small trial: stoma complications in 72%, injection site reactions in 61% and leg swelling in 56%. No one died.

3. What did the EASE-1 phase 3 trial find?

EASE SBS 1 was the pivotal trial (Jeppesen et al., 2025). It enrolled 106 adults with short bowel syndrome and intestinal failure who needed parenteral support at least 3 days a week, and randomized them equally to 10 mg twice weekly, 10 mg once weekly (with a placebo shot for the second weekly injection) or placebo, for 24 weeks. IV volumes were cut whenever 48-hour urine volume rose more than 10% above baseline, a sign that the gut was absorbing more.

The once-weekly figure comes from the results posted on ClinicalTrials.gov. Results were similar whether or not patients still had their colon connected. Zealand reports that 9 glepaglutide-treated patients in total reached enteral autonomy, meaning no IV support at all, against none on placebo, and that 102 of 106 completed the trial (Zealand, September 2026).

Patient-reported change was also better on glepaglutide. In exit interviews with 30 participants, 16 of 22 on glepaglutide and 2 of 8 on placebo described a better quality of life, though the authors cautioned about the small numbers.

As in the teduglutide trials, the placebo response was large because the protocol itself pushed clinicians to reduce IV support. The twice-weekly arm cut weekly volume by about 2.3 L more than placebo.

4. Why did the FDA reject glepaglutide?

On December 19, 2024, Zealand announced that the FDA had issued a complete response letter, the agency’s formal “not approved in its current form” decision. According to Zealand’s release, the FDA found the application “did not meet the full requirements for substantial evidence to establish the efficacy and safety” of the dose to be marketed, and recommended an additional clinical trial.

The core problem was a single positive pivotal trial in which only one of two tested regimens worked. The release noted that once-weekly dosing reduced IV support numerically but did not reach statistical significance.

Zealand’s response was a new trial. EASE SBS 5 is a double-blind, placebo-controlled phase 3 trial of 10 mg twice weekly in short bowel syndrome with intestinal failure, followed by a long-term open-label safety phase.

On that timeline, a US resubmission would come after the trial reads out. Zealand has not given a submission date.

5. What is happening in Europe?

In the same release, Zealand said it would go ahead with an EU application in 2025. On September 17, 2026, the EMA’s Committee for Medicinal Products for Human Use adopted a positive opinion recommending Zeydovio “for the treatment of adults with Short Bowel Syndrome,” in patients stable after a period of intestinal adaptation following surgery (EMA summary). The product would be a 10 mg solution in a pre-filled pen, started under a clinician experienced in short bowel syndrome.

The opinion is a recommendation. The European Commission makes the legally binding decision, which Zealand said was expected within about 67 days (Zealand, September 2026). When we checked on November 8, 2026, the EMA page still showed the decision as pending, and we found no announcement of authorization. Detailed dosing instructions will be published in the product information after authorization.

Zealand also said it was in partnership discussions for global commercialization and had not named a partner.

6. What do the extension trials add?

Several longer studies followed EASE-1:

Zealand reported that an interim EASE-2 analysis after at least 6 months showed efficacy maintained or improved, with more patients weaning off IV support, and that full EASE-2 and EASE-3 results are expected at meetings in 2027. For EASE-4, it reported a 398 g a day rise in fluid absorption at week 24, which narrowly missed statistical significance (P = .0585), a 1,038 kJ a day rise in energy absorption, and an 800 mL a day drop in IV volume at week 52 (Zealand, September 2026). These are company-reported, uncontrolled results that have not all been published in journals.

A study of stool samples from EASE-4 found no major change in gut bacteria after 24 weeks, even though absorption improved.

7. What are the side effects?

The EMA summary lists the most common side effects as injection site reactions, gastrointestinal stoma complications in people with a stoma, abdominal pain, abdominal swelling, nausea, fluid retention or overload, and vomiting.

The EASE-1 results posted on ClinicalTrials.gov give the numbers:

Swelling of the stoma and the legs fits what GLP-2 drugs do: the gut lining grows, and more fluid is absorbed. That is why IV volumes are reduced step by step, and why fluid overload is a warning on the teduglutide label.

Cancer and polyp questions

Because GLP-2 drugs make intestinal tissue grow, regulators require colon checks for teduglutide, and the same question applies to glepaglutide. A systematic review by Ring and colleagues found no increased risk of intestinal neoplasia in humans treated with GLP-2 for up to 30 months without existing cancer, but called the data too limited to be conclusive, and in animals GLP-2 could promote growth of tumors that were already present. The monitoring rules for glepaglutide will be set out in its product information once it is authorized.

8. How does glepaglutide compare with teduglutide and apraglutide?

No trial has compared these drugs directly, so this table compares their programs rather than their effects.

Cross-trial comparisons are unreliable here. The pivotal teduglutide and glepaglutide trials used similar rules for cutting IV volumes, but they enrolled different patients a decade apart.

9. Does glepaglutide matter for people on GLP-1 drugs?

Directly, not much. Glepaglutide does not act on the GLP-1 receptor, is not a glucose-lowering drug and is not a weight-loss drug. It is meant for a rare condition in which people need help absorbing more, not eating less.

Some points of overlap are worth knowing:

• Side effects. Nausea, vomiting and abdominal pain were more common on glepaglutide than on placebo in EASE-1, and they are also common on semaglutide and tirzepatide.
• Opposite goals. A GLP-1 drug reduces food intake. For someone trying to wean off IV nutrition, appetite loss could work against that goal. No published study has tested glepaglutide with a GLP-1 drug.
• Combined molecules. Zealand also tested dapiglutide, a single molecule that activates both GLP-1 and GLP-2 receptors, as a weight-loss drug. It is a different drug from glepaglutide, and its development was paused in November 2025.

Anyone with short bowel syndrome who is also prescribed a GLP-1 drug for diabetes or weight should have the intestinal failure team involved in that decision.

10. What can be tracked in a glepaglutide trial or program?

The trials measured response in IV volume and IV days, so those are the core records:

• IV support. Weekly volume and infusion days, with the date of each change.
• Fluid balance. Urine volume, stoma or stool output, body weight, and leg or stoma swelling.
• Dose log. Injection days for a once- or twice-weekly schedule, injection sites and any skin reactions.
• Lab results. Citrulline if measured, electrolytes, kidney and liver tests, with dates.
• Symptoms. Nausea, vomiting, abdominal pain and any change in other medicines.

A peptide tracker or spreadsheet can keep that history together. It cannot judge whether the drug is working, which depends on the specialist team’s review of IV needs over months. Glepaglutide is only available through trials or, once authorized, through prescription in the countries that approve it.

11. Glepaglutide FAQ

• Is glepaglutide FDA approved?

  No. The FDA issued a complete response letter on December 19, 2024, saying the application lacked substantial evidence for the dose to be marketed and recommending another trial. Zealand started that trial, EASE-5, in February 2026, with primary completion estimated for October 2028. As of November 2026 it has not been resubmitted to the FDA.

• Is Zeydovio approved in Europe?

  The EMA's Committee for Medicinal Products for Human Use adopted a positive opinion on September 17, 2026, recommending Zeydovio for adults with short bowel syndrome. The final decision belongs to the European Commission. When we checked in November 2026, the EMA page still listed the decision as pending.

• How is glepaglutide different from teduglutide?

  Both copy the gut hormone GLP-2. Teduglutide clears in about 2 hours and is injected daily. Glepaglutide forms a depot under the skin that slowly releases active forms of the drug, giving an effective half-life of several days, so it was tested once and twice weekly. No head-to-head trial has compared them.

• What dose of glepaglutide was studied?

  The phase 3 trials used 10 mg by injection under the skin, either twice weekly or once weekly. Only twice-weekly dosing beat placebo on the main outcome in EASE-1, and EASE-5 is testing 10 mg twice weekly. The EU product is a 10 mg pre-filled pen; its full dosing instructions will appear in the product information once authorized.

• What are the side effects of glepaglutide?

  The EMA lists injection site reactions, stoma complications in people with a stoma, abdominal pain and swelling, nausea, fluid retention or overload, and vomiting as the most common. In EASE-1, injection site reactions were reported in 9 of 35 people on twice-weekly dosing and 1 of 36 on placebo.

• Does glepaglutide cause weight loss like GLP-1 drugs?

  No. It acts on the GLP-2 receptor, which helps the gut absorb more fluid and nutrients. It is meant to reduce IV nutrition in people whose bowel cannot absorb enough, not to reduce appetite or body weight.

• Can glepaglutide be used with semaglutide or tirzepatide?

  There are no published data on the combination. Both drug types can cause nausea and abdominal symptoms, and GLP-1 drugs reduce food intake, which could work against weaning off IV nutrition. Zealand also tested a separate molecule, dapiglutide, that activates both GLP-1 and GLP-2 receptors, but paused its development in November 2025.

12. Sources