A phase 3 trial shows that the dual GLP-1 and glucagon receptor agonist mazdutide drove substantial weight loss and cardiometabolic benefits, while highlighting gastrointestinal side effects that clinicians will need to manage.
Study: Treatment With 9-mg Mazdutide for Weight Reduction in Chinese Adults With Obesity. Image Credit: ZCOOL HelloRF / Shutterstock
In a recent JAMA study, researchers reported the outcomes of the Phase 3 GLORY-2 clinical trial. The trial investigated the efficacy of mazdutide (the synthetic peptide analog of the natural mammalian peptide oxyntomodulin) in a cohort of Chinese adults with obesity (BMI ≥ 30 kg/m²) between December 2023 and November 2025.
Study findings revealed that a once-weekly 9-milligram (9-mg) dose of mazdutide significantly reduced weight (-16.65%) in these Chinese adults with obesity, while also significantly improving key cardiometabolic markers, including systolic blood pressure, triglycerides, non-HDL cholesterol, and LDL cholesterol. Safety evaluations indicate that the drug was associated with frequent but mostly mild-to-moderate gastrointestinal adverse events, particularly during the trial’s initial titration phase.
Background
A growing body of regional and national evidence highlights that China is currently confronting an escalating adult obesity epidemic. Reports indicate that in the past three decades alone, the prevalence of obesity has surged more than fourfold. Furthermore, clinical data emphasize that individuals with a body mass index (BMI) of 30 or greater face a disproportionately higher prevalence of obesity-related cardiometabolic comorbidities and increased cardiovascular mortality.
The development of modern Glucagon-Like Peptide-1">GLP-1 receptor agonists and co-agonists has produced substantial weight reductions in Chinese adults with overweight or obesity, but few clinical trials have been specifically designed for adults with a BMI of 30 or greater. These evidence gaps underscore the need for more effective pharmacological options for individuals with moderate-to-severe obesity.
Emerging evidence suggests that oxyntomodulin, a natural peptide hormone that regulates appetite and energy metabolism, may help further alleviate the burden of obesity.
This has led researchers to develop mazdutide, the synthetic peptide analog of mammalian oxyntomodulin, which, unlike single-pathway pharmacological weight-loss interventions (e.g., GLP-1 receptor agonists), acts as a dual agonist that simultaneously activates both the GLP-1 receptor and the glucagon receptor.
About the Study
The present study aimed to evaluate the safety and clinical efficacy of mazdutide by analyzing data from the GLORY-2 clinical trial. GLORY-2 is a double-blind, placebo-controlled, randomized phase 3 clinical trial that was conducted across 27 hospitals in China from December 2023 to November 2025.
The trial’s primary analysis included Chinese adults (n = 461) with a BMI of 30 or higher. Furthermore, a subpopulation of the sample cohort (16.1%) was diagnosed with both obesity and type 2 diabetes (T2D). Study participants were randomized in a 2:1 ratio to receive either a weekly 9-mg subcutaneous dose of mazdutide (randomized n = 308; analyzed n = 307) or an equivalent placebo (control cohort n = 154), as an adjunct to a reduced-calorie diet and increased physical activity.
The study duration comprised a treatment period (60 weeks) followed by an off-treatment follow-up period (12 weeks). The analyses' coprimary endpoints were the percentage change in body weight from baseline to week 60 and the percentage of participants achieving a total weight reduction of at least 5%. The study also statistically evaluated changes in waist circumference, blood pressure, and blood lipid profiles.
Study Findings
Study findings revealed that participants in the active mazdutide group achieved a mean body weight reduction of 16.65% from baseline, compared with 1.50% in the placebo group (between-group difference of 15.15 percentage points in favor of mazdutide; p < 0.001). Furthermore, the analyses found that 84.3% of individuals taking mazdutide lost 5% or more of their body weight, compared to only 33.1% in the placebo cohort (p < 0.001).
When evaluating key secondary weight-loss thresholds, the study revealed that 69.9% of the mazdutide group shed at least 10% of their weight, compared with 14.4% in the placebo group; 57.3% lost 15% or more, compared with 6.5%; and 42.4% achieved a 20% or greater weight reduction, compared with 2.6% (p < 0.001 for all comparisons).
The analyses also demonstrated that beyond direct weight reductions, mazdutide significantly improved participants’ cardiometabolic risk markers from baseline. The waist circumference of mazdutide participants decreased by an average of 12.82 cm, compared with a nominal 2.00 cm decrease in the placebo group (p < 0.001).
Mazdutide was also associated with greater reductions in systolic blood pressure (-9.80 mm Hg vs -0.23 mm Hg), triglycerides (-21.06% vs +15.76%), non-HDL cholesterol (-14.58% vs +0.34%), and LDL cholesterol (-6.94% vs +3.15%) compared with placebo.
Safety evaluations demonstrated that gastrointestinal adverse events were highly prevalent among the active drug group. More than half of the mazdutide participants reported vomiting (53.1%) compared to 1.3% in the placebo group. Mazdutide participants also frequently reported nausea (46.9%) and diarrhea (39.4%). However, most of these events were classified as mild to moderate in severity and occurred primarily during the initial dose-escalation period.
The paper also reported treatment discontinuation due to adverse events in 2.9% of mazdutide participants, serious adverse events in 7.2% versus 5.2%, and no deaths. Additional safety findings included a transient heart rate increase, sinus tachycardia, four cases of acute gallbladder disease, two cases of papillary thyroid cancer reported in the mazdutide group, and no reported cases of acute pancreatitis.
Conclusions
This study’s analyses of the GLORY-2 trial support the 9-mg dose of mazdutide as an effective and clinically meaningful option for long-term weight management in Chinese adults with moderate-to-severe obesity.
However, the trial has a few notable limitations. First, it did not include a 6-mg dose comparison arm to evaluate dose-dependent safety differences. Second, it enrolled a small sub-cohort of 74 patients with type 2 diabetes, limiting the robustness of the conclusions regarding weight and glycemic control in this population. Finally, the trial focused exclusively on Chinese adults, limiting generalizability to other ethnic groups.
Moving forward, tailored dose titration schedules may be important for managing early gastrointestinal side effects if this dual agonist is incorporated into clinical practice.
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