Combined GLP-1 and GLP-2 treatment appears safe but does not beat placebo for obesity

Can combining two gut hormone pathways unlock better obesity treatments? In the first human trial of dapiglutide, researchers found encouraging metabolic signals but no statistically significant edge over placebo, highlighting both the promise and the limits of next-generation dual agonists.

Trial: Dapiglutide, a dual GLP-1 and GLP-2 receptor agonist, for obesity: a randomised, double-blind, placebo-controlled parallel-group, proof-of-concept trial. Image Credit: Alones / Shutterstock

In a recent proof-of-concept study published in the journal eClinicalMedicine, researchers in Denmark describe the safety and efficacy outcomes of the first human trial of Dapiglutide, a novel drug that targets both the glucagon-like peptide-1 (GLP-1) and glucagon-like peptide-2 (GLP-2) receptors.

The study included 54 adults with clinically diagnosed obesity, who were randomized in a 1:1:1 ratio (18 per group) to receive weekly injections of Dapiglutide at either 4 mg or 6 mg over 12 weeks, while the remaining participants received an equivalent volume of placebo. Study findings revealed that, while the drug was safe and showed physiologically beneficial metabolic signals, it failed to achieve a statistically significant weight reduction compared with the placebo group at the tested doses.

Obesity Burden and Limitations of Lifestyle Interventions

Obesity is a complex and increasingly prevalent global metabolic condition characterized by excessive and unwanted fat accumulation. The condition is reported to be the fifth leading cause of premature death worldwide. It has been clinically linked to several potentially lethal diseases, including type 2 diabetes (T2D), stroke, heart disease, and certain cancers.

Traditional anti-obesity interventions aimed to leverage behavioral modifications, such as dietary and physical exercise, to promote weight loss. Unfortunately, these interventions have demonstrated limited long-term efficacy and often result in rapid weight regain upon withdrawal.

GLP-1 Agonists and Emergence of Dual-Receptor Therapies

The recent development of long-acting GLP-1 receptor agonists, such as semaglutide, has revolutionized the field of weight loss. Several studies have demonstrated these drugs’ substantial weight-loss efficacy by mimicking natural hormones that signal fullness.

Researchers hypothesize that dual or triple agonists that simultaneously target multiple receptors may yield better weight-loss outcomes than single-receptor agonists. Dapiglutide is one of the first agents in this emerging generation of weight-loss drugs.

The drug’s mechanism of action first exploits the GLP-1 pathway to restrict hunger, thereby reducing food intake. It also incorporates GLP-2, a hormone previously found to promote intestinal growth and hypothesized to influence gut barrier integrity, intestinal permeability, and inflammatory pathways. However, its role in human obesity remains uncertain and controversial. Despite positive preclinical outcomes, Dapiglutide’s safety and efficacy had not previously been validated in patients with obesity.

Phase IIa Randomized Trial Design in Denmark

The present study aimed to address this knowledge gap and inform future Dapiglutide-based weight-loss interventions by reporting the outcomes of an investigator-initiated, 12-week, Phase IIa trial conducted at a single center in Denmark.

The study cohort comprised 54 adults with clinically diagnosed obesity (body mass index, BMI > 30 kg/m2). Participants were randomized into three equal groups: 4 mg dapiglutide (n = 18), 6 mg dapiglutide (n = 18), or placebo (n = 18).

To ensure tolerability and minimize adverse effects, Dapiglutide injections were administered using a gradual up-titration regimen, starting at a low dose that was increased every 3 weeks unless safety concerns were reported. Participants were instructed to maintain their usual diet and physical activity levels to isolate the drug’s biological effects.

Primary and Secondary Study Endpoints

The primary endpoint was the percentage change in body weight from baseline to week 12. Secondary and exploratory outcomes included changes in waist circumference, body composition, and glycated hemoglobin (HbA1c), a validated marker of long-term glycemic control.

Weight Loss Outcomes and Placebo Effect Context

Participants receiving 6 mg Dapiglutide experienced an estimated −2.1% greater reduction in body weight compared with placebo (p = 0.076). While suggestive of a treatment signal, the result did not reach statistical significance.

Within-group analyses showed that over 12 weeks, the placebo group lost 2.2% of body weight, the 4 mg group lost 2.9%, and the 6 mg group lost 4.3%. Investigators noted the relatively substantial placebo-associated weight loss as an important contextual factor when interpreting efficacy.

Glycemic and Anthropometric Secondary Outcomes

Participants in the 6 mg group demonstrated a 2.4 mmol/mol reduction in HbA1c compared with a 0.1 mmol/mol reduction in the placebo group (p = 0.006). No meaningful changes in circulating lipid levels were observed.

Reductions in BMI and waist circumference were observed in the high-dose group; however, these outcomes did not remain statistically significant after adjustment for multiple testing.

Safety Profile and Adverse Events

Dapiglutide at 4 mg and 6 mg weekly doses was generally well tolerated, with no participants discontinuing due to drug-related adverse effects. The most frequently reported adverse events were gastrointestinal, including reduced appetite (61%) and nausea (56%). Vomiting occurred in 11% of participants and was similar between the drug and placebo groups. One fatal, serious adverse event, small cell lung carcinoma with dissemination, occurred in the 6 mg group but was deemed unrelated to trial participation.

Clinical Implications and Future Research Directions

This study represents the first randomized controlled trial evaluating Dapiglutide in adults with obesity. While 12 weeks of treatment at 4 mg or 6 mg was safe, it was insufficient to produce a statistically significant difference in weight loss compared with placebo. The findings may reflect limitations in dose or treatment duration rather than a definitive lack of efficacy.

The potential role of the GLP-2 pathway in modulating intestinal barrier function and metabolic physiology remains an active area of investigation. Larger trials with higher doses and longer treatment durations will be required to determine the clinical utility of this dual-receptor approach.

• Nielsen, C. K., et al. (2026). Dapiglutide, a dual GLP-1 and GLP-2 receptor agonist, for obesity: a randomised, double-blind, placebo-controlled parallel-group, proof-of-concept trial. eClinicalMedicine, 93, 103801. DOI: 10.1016/j.eclinm.2026.103801, https://www.thelancet.com/journals/eclinm/article/PIIS2589-5370(26)00048-9/fulltext