Efficacy and safety of mazdutide in adults with obesity or overweight: a US-based, multicentre, phase 2, randomised, placebo-controlled clinical trial.
Mazdutide showed significant weight reduction in adults with obesity or overweight, with higher doses leading to greater effects compared to placebo.
Where it sits
this study against the rest of the mazdutide (ibi362) corpusSummary and findings
This study evaluated the efficacy and safety of mazdutide in adults with obesity or overweight without type 2 diabetes. Participants received doses of mazdutide ranging from 3-16 mg weekly for 48 weeks. The study reported significant weight reductions compared to placebo.
Abstract
<h4>Background</h4>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.<h4>Methods</h4>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/m<sup>2</sup> and higher-or of 27 kg/m<sup>2</sup> to less than 30 kg/m<sup>2</sup> 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.<h4>Findings</h4>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.<h4>Interpretation</h4>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.<h4>Funding</h4>Eli Lilly and Company.
Background
This paper addresses the efficacy of mazdutide, a dual agonist of glucagon and GLP-1 receptors, in promoting weight loss among adults with obesity or overweight. Prior therapies targeting GLP-1 and GIP receptors have shown efficacy in weight reduction, but mazdutide may offer a differentiated mechanism. Understanding its efficacy and safety profile is crucial given the rising prevalence of obesity.
Methods
This was a multicenter, double-blind, placebo-controlled phase 2 trial conducted at 24 centers in the USA. The study included adults aged 18-75 years with a BMI of 30 kg/m² or higher, or 27 kg/m² to less than 30 kg/m² with at least one weight-related comorbidity. Participants were randomly assigned to receive subcutaneous injections of placebo or mazdutide (3-6 mg, 10 mg, or 16 mg) for 48 weeks, with the primary outcome being the percentage change in body weight from baseline to 32 weeks.
Results
At 32 weeks, the least-squares mean percentage change in body weight was -7.3% (SE 0.9) for the 3-6 mg group, -15.6% (0.7) for the 10 mg group, and -18.1% (1.0) for the 16 mg group, compared to -0.9% (0.8) for the placebo group. All treatment comparisons to placebo were statistically significant (p<0.0001). Adverse events were primarily gastrointestinal and mostly mild to moderate in severity.
Interpretation
The findings suggest that mazdutide is associated with significant weight reduction compared to placebo, particularly at higher doses. While the statistical significance is clear, the clinical significance of the weight changes should be considered in the context of individual patient goals and potential side effects. Limitations include the study's funding source and the relatively short follow-up period, which may not reflect long-term outcomes.
Key findings
- -7.3% bodyweight change with 3-6 mg mazdutide at 32 weeks, n=32, p<0.0001.
- -15.6% bodyweight change with 10 mg mazdutide at 32 weeks, n=48, p<0.0001.
- -18.1% bodyweight change with 16 mg mazdutide at 32 weeks, n=51, p<0.0001.
- -0.9% bodyweight change with placebo at 32 weeks, n=48.
- 20% discontinuation rate due to adverse events with 16 mg mazdutide.
Limitations
- funded by Eli Lilly and Company
- short follow-up duration of 48 weeks
- small sample sizes for some dosage groups
- potential for industry bias