Dapiglutide, a dual GLP-1 and GLP-2 receptor agonist, for obesity: a randomised, double-blind, placebo-controlled...

Dapiglutide, a dual glucagon-like peptide (GLP)-1 and GLP-2 receptor agonist, is under clinical development for bodyweight reduction in obesity, capitalising on GLP-1 receptor-mediated food intake-reducing effect leading to bodyweight loss and GLP-2 receptor-mediated improvement of gut barrier function and anti-inflammatory properties.

In this 12-week, investigator-initiated, phase IIa, proof-of-concept, double-blind, placebo-controlled trial in Denmark, adults (18-75 years) with obesity (BMI ≥30 kg/m²) were randomised to once-weekly subcutaneous dapiglutide (4 or 6 mg) or placebo (1:1:1; stratified by sex) without concurrent lifestyle intervention. Exclusion criteria included HbA_1c ≥48 mmol/mol and recent ≥5% bodyweight change. The primary endpoint was percentage bodyweight change from baseline to week 12. The effects of 6 mg and 4 mg dapiglutide were tested hierarchically against first placebo, next each other in efficacy analyses with missing data replaced by standard multiple imputation. The study is registered with EU (trial no. 2022-501649-54-00) and ClinicalTrials.gov (NCT05788601).

Between April 27, 2023, and April 24, 2024, 54 adults living with obesity (63% women; mean bodyweight 101·3 kg; mean BMI 35·2 kg/m²) were randomised. In the primary efficacy analysis, 6 mg dapiglutide led to a mean bodyweight change of -2·1% [95% CI -4·3 to 0·2; p = 0·076] compared to placebo. Dapiglutide appeared safe and well-tolerated, with common adverse events including reduced appetite and nausea. No participants discontinued due to drug-induced adverse events, and in general, dropout rates were low, i.e. 0% (placebo), 11% (4 mg), and 6% (6 mg).

Dapiglutide (4 mg or 6 mg) for 12 weeks did not result in a statistically significant difference in bodyweight change compared with placebo in persons with obesity. The safety profile was favourable, and the findings support further investigation of higher doses in larger and longer studies to evaluate the weight-lowering potential of dapiglutide.

Unrestricted grant from Zealand Pharma.