New GLP-1/Glucagon Dual Agonist Mazdutide Cuts Body Weight Up to 18% in 32 Weeks
Phase 2 trial finds once-weekly mazdutide drives up to 18% weight loss in adults with obesity, rivaling top GLP-1 agents.
Summary
Mazdutide is a novel drug that activates both GLP-1 and glucagon receptors — a different mechanism than semaglutide or tirzepatide. In this US-based phase 2 trial of 179 adults with obesity or overweight (no type 2 diabetes), participants received weekly injections of mazdutide at 3–6 mg, 10 mg, or 16 mg, or placebo for 48 weeks. At 32 weeks, the 10 mg dose produced 15.6% average weight loss and the 16 mg dose produced 18.1%, compared to just 0.9% with placebo. Side effects were mostly mild-to-moderate gastrointestinal symptoms. The 16 mg group had the highest dropout rate at 20% due to GI issues. These results position mazdutide as a potentially competitive obesity therapy with a distinct receptor profile that may offer metabolic advantages beyond weight loss alone.
Detailed Summary
Obesity is a central driver of metabolic aging, cardiovascular disease, and reduced healthspan. The GLP-1 receptor agonist class has transformed obesity treatment, but a new dual-target approach — hitting both GLP-1 and glucagon receptors simultaneously — may push outcomes further and offer distinct metabolic benefits.
This US-based, multicentre, randomised, double-blind, placebo-controlled phase 2 trial evaluated mazdutide — an Eli Lilly compound activating both glucagon and GLP-1 receptors — across three dose levels (3–6 mg, 10 mg, and 16 mg once weekly subcutaneously) versus placebo. The 179 enrolled adults were aged 18–75, had a BMI of 30 or higher (or 27+ with a weight-related comorbidity), and had no type 2 diabetes. The trial ran for 48 weeks, with the primary endpoint assessed at 32 weeks.
Results were striking. At 32 weeks, mazdutide produced least-squares mean weight reductions of 7.3% (3 mg), 15.6% (10 mg), and 18.1% (16 mg) versus 0.9% for placebo — treatment differences of 6.5% to 17.2% (p<0.0001 for all). Weight loss continued to accrue through 48 weeks. The participant population was 66% female and 34% male, with a mean age of 47.7 years.
The safety profile mirrored that of GLP-1 class drugs: gastrointestinal side effects dominated, were mostly mild to moderate, and drove the highest discontinuation rate in the 16 mg arm (20%). Lower doses were better tolerated.
For clinicians and health-optimizers, the 10 mg dose stands out as offering near-maximum efficacy with a more manageable tolerability profile. The glucagon receptor component may provide additive metabolic benefits — including effects on lipid metabolism and energy expenditure — that pure GLP-1 agonism does not. Mazdutide now advances toward phase 3 trials, and this data positions it as a serious competitor in the rapidly evolving obesity-pharmacology landscape.
Key Findings
- Mazdutide 16 mg produced 18.1% mean weight loss at 32 weeks vs. 0.9% for placebo (p<0.0001).
- Mazdutide 10 mg achieved 15.6% weight loss with a lower discontinuation rate than the 16 mg dose.
- Weight loss continued to increase beyond 32 weeks, with further reductions observed at 48 weeks.
- GI side effects were the most common adverse events; 20% of the 16 mg group discontinued due to them.
- Mazdutide targets both GLP-1 and glucagon receptors — a mechanistically distinct profile from semaglutide or tirzepatide.
Methodology
Randomised, double-blind, placebo-controlled phase 2 trial at 24 US centres enrolling 179 adults without type 2 diabetes, allocated 3:2:3:3 to placebo or mazdutide (3–6 mg, 10 mg, 16 mg) for 48 weeks. Primary endpoint was percentage bodyweight change at 32 weeks using an efficacy (hypothetical) estimand. The trial is completed and registered at ClinicalTrials.gov (NCT06124807).
Study Limitations
This summary is based on the abstract only, as the full paper is not open access. The trial was phase 2 with a relatively small sample (179 participants), limiting power for subgroup analyses. The study was funded by Eli Lilly, with multiple authors being company employees and stockholders, introducing potential bias. Long-term cardiometabolic outcomes, body composition data (lean vs. fat mass), and comparative efficacy against approved agents like semaglutide or tirzepatide were not reported in the abstract.
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