Dapiglutide: a GLP-1 and GLP-2 dual agonist

Dapiglutide is an investigational, long-acting peptide from Zealand Pharma that activates both the GLP-1 receptor and the GLP-2 receptor. It is given as a once weekly injection. It was developed for obesity, which makes it the only GLP-2-acting molecule aimed at weight rather than short bowel syndrome. It is not approved anywhere, and its development is paused.

Why combine the two

The weight loss logic is all GLP-1. GLP-2 has no appetite effect in healthy people: in a blinded study of 18 adults, a GLP-2 infusion did not change hunger or food intake (see GLP-2 vs GLP-1). The GLP-2 half was added for a different reason. Zealand described the aim as targeting intestinal barrier function and the low-grade inflammation linked to obesity-related disease.

The idea traces to animal work. In a 2009 study in obese ob/ob mice, a GLP-2 agonist reduced gut permeability and lowered systemic and liver inflammation, and blocking GLP-2 cancelled most of the benefit of a prebiotic diet. That is mouse data. Whether adding GLP-2 activity changes inflammation or outcomes in people with obesity has not been shown.

The human results

Part 1 enrolled 54 adults with a median age of 46 and a median BMI of 30.0, across three dose cohorts given 13 weekly doses. Mean weight loss on dapiglutide was up to 6.2%, while the placebo group gained 2.1%, which is how the placebo-adjusted figure reaches 8.3%. Part 2 then tested a single, longer escalation to 26 mg in 30 people, randomised 2:1, with dose steps every fourth week.

How to read those numbers

• They are small. Part 2 had 30 participants in a single dose cohort at a single centre.
• The population was unusual. Part 2 was about 93% male, with a median BMI of 28.8. Most obesity trials enrol mainly women with a BMI above 30.
• They are efficacy estimands. The 11.6% assumes people stayed on the drug, which makes it look better than a treatment-policy figure would.
• They are press releases. Topline results, not peer-reviewed papers.
• The doses mattered. At 6 mg the DREAM result did not reach significance; the higher Part 2 doses produced more weight loss.

For comparison, the phase 3 GLP-1 class trials ran for 68 to 72 weeks in thousands of people: semaglutide 2.4 mg in STEP 1 and tirzepatide in SURMOUNT-1. The GLP-1 clinical trials page has those numbers. A 28 week, 30 person trial cannot be put on the same chart.

Safety

Zealand reported no severe or serious treatment-emergent adverse events in Part 2. Most events were mild, and the most common were gastrointestinal, including nausea and vomiting, at rates it called consistent with other incretin-based drugs. Two participants withdrew because of adverse events. Long-term GLP-2 exposure carries the growth-related questions seen on the teduglutide label, such as polyps and colonoscopy monitoring. Trials this short cannot answer those.

Open questions the trials could not answer

• Does the GLP-2 half do anything measurable in people? No published human data show a change in gut permeability or inflammation markers attributable to the GLP-2 activity.
• What happens to the gut lining over years? GLP-2 analogues grow intestinal tissue. In short bowel syndrome that is the goal. In people with a normal gut, the long-term effect of extra growth is unknown, and the teduglutide experience suggests colonoscopy surveillance would be part of any long-term use.
• Is the weight loss any better than GLP-1 alone? Without a comparison against a GLP-1 drug at a matched dose, there is no way to say the GLP-2 activity adds anything to weight.

The pause

In November 2025, in its quarterly earnings report, Zealand said it had paused dapiglutide as part of "active portfolio management", to focus money on programmes with the greatest potential for clinical differentiation. Zealand had earlier planned a phase 2b trial. The company did not publish a safety reason, and none is implied here.

Zealand's obesity work now centres on other molecules: petrelintide, an amylin analogue partnered with Roche, and survodutide, a glucagon and GLP-1 dual agonist partnered with Boehringer Ingelheim. Neither acts on the GLP-2 receptor. Dapiglutide remains wholly owned by Zealand, so a restart, a partner or a quiet end are all possible. Until one of those is announced, the 28 week phase 1b remains the longest human data on a GLP-1 and GLP-2 combination.

Other GLP-1 and GLP-2 combinations

No other molecule combining GLP-1 and GLP-2 receptor activity has published human results at the time of writing. The combinations that did reach late-stage trials pair GLP-1 with GIP (tirzepatide) or with GIP and glucagon (retatrutide). Neither touches the GLP-2 receptor. The slang page explains why those are sometimes mislabelled "GLP-2" and "GLP-3".

What to log

If you are on any weekly injectable, the useful record is the dose, weight, side effects and labs on one timeline. Peptide AI's dose log, body scanner and bloodwork tracking keep them together.