Efficacy and safety of mazdutide in adults with obesity or overweight: a US-based, multicentre, phase 2, randomised, placebo-controlled clinical trial.

BACKGROUND: Therapies targeting GLP-1 or glucose-dependent insulinotropic polypeptide (GIP) receptors have provided efficacious weight reduction in adults with obesity. Mazdutide, a glucagon and GLP-1 receptor dual agonist, presents a novel opportunity for differentiated weight reduction. We aimed to evaluate the efficacy, safety, and tolerability of once-weekly mazdutide across a dose range up to 16 mg in adults with obesity or overweight without type 2 diabetes in the USA. METHODS: In this randomised, double-blind, placebo-controlled phase 2 trial at 24 centres in the USA, adults aged 18-75 years without type 2 diabetes and with a BMI of 30 kg/m2 and higher-or of 27 kg/m2 to less than 30 kg/m2 with at least one weight-related comorbidity-were randomly allocated (3:2:3:3) to receive once-weekly subcutaneous injections of placebo or mazdutide (3-6 mg, 10 mg, or 16 mg) for 48 weeks. Participants assigned to 3-6 mg mazdutide maintained 3 mg from week 4 to week 32 before escalating to 6 mg at 32 weeks to assess 3 mg and 6 mg as potential maintenance doses. The primary endpoint was percentage change in bodyweight from baseline to 32 weeks, evaluated using the efficacy (hypothetical) estimand. Efficacy analyses included all randomly allocated participants, and safety analyses included all randomly allocated participants who received at least one treatment dose. This study is registered at ClinicalTrials.gov, NCT06124807, and is completed. FINDINGS: Between Nov 17, 2023, and July 9, 2025, 179 participants were randomly allocated to receive mazdutide (32 participants to 3-6 mg, 48 to 10 mg, and 51 to 16 mg) or placebo (48 participants). The mean age was 47·7 years (SD 12·3), and 118 (66%) participants were female and 61 (34%) were male. At 32 weeks, the least-squares mean percentage change from baseline in bodyweight was -7·3% (SE 0·9) with mazdutide 3-6 mg, -15·6% (0·7) with 10 mg, and -18·1% (1·0) with 16 mg, versus -0·9% (0·8) with placebo. Estimated treatment differences versus placebo ranged from -6·5% to -17·2% (p<0·0001, all comparisons). Additional bodyweight reductions were observed at 48 weeks. The most common adverse events with mazdutide were gastrointestinal-related and mostly mild to moderate in severity; discontinuation of study treatment due to adverse events occurred most frequently with 16 mg (20%), associated primarily with gastrointestinal disorders. INTERPRETATION: Once-weekly, subcutaneous mazdutide showed clinically meaningful bodyweight reduction in adults with obesity or overweight across all studied doses, with higher doses (10 mg and 16 mg) showing additional weight reduction. FUNDING: Eli Lilly and Company.