The use of mazdutide among adults with obesity results in a clinically significant weight reduction and improvements in cardiometabolic risk factors, with an acceptable safety profile, as shown in the phase 3 GLORY-2 trial presented at ADA 2026.
“Mazdutide provided clinically meaningful weight reduction in Chinese adults with moderate to severe obesity compared with placebo, but participants receiving the drug experienced gastrointestinal adverse reactions compared with those receiving placebo,” said the investigators led by Dr Linong Ji, Department of Endocrinoloy and Metabolism, Peking University People’s Hospital, Beijing, China. [JAMA 2026;doi:10.1001/jama.2026.8142]
GLORY-2 is a randomized, double-blind, placebo-controlled trial including 462 Chinese adults with obesity (BMI ≥30 kg/m2; 16.0 percent with type 2 diabetes [T2D]) that was conducted at 27 hospitals from December 2023 to November 2025. Participants were randomly allocated 2:1 to receive once-weekly, subcutaneous mazdutide 9 mg (n=308) or placebo for 60 weeks (n=154).
The primary endpoints were the percentage change in weight from baseline and a weight reduction of at least 5 percent at week 60.
The mean body weight of participants at baseline was 94.0 kg, while their mean BMI was 34.3 kg/m2. Those treated with mazdutide met all the primary endpoints. [ADA 2026, abstract 1225-OR]
Weight loss
Mazdutide-treated participants achieved a percentage change in body weight of ‒18.5 percent at week 60 from baseline, while those on placebo only had ‒3.0 percent (treatment difference, ‒15.5 percent, 95 percent confidence interval [CI], ‒17.6 to ‒13.4).
Furthermore, 85.7 percent of participants in the mazdutide group achieved a weight reduction of ≥5 percent compared with 33.2 percent in the placebo group. The proportion of individuals who had a weight reduction of ≥20 percent was also greater in the mazdutide group (44.0 percent vs 2.6 percent).
For participants without T2D, those who received mazdutide had a percentage change in body weight of ‒20.1 percent at week 60 from baseline compared with ‒2.8 percent with placebo (treatment difference, ‒17.3 percent, 95 percent CI, ‒19.6 to ‒15.0).
Nearly all participants in the mazdutide group (88.2 percent) achieved a weight reduction of ≥5 percent, while only a third (32.3 percent) did in the placebo group. Moreover, almost half (48.7 percent) of those treated with mazdutide achieved a weight loss of ≥20 percent relative to just 3.1 percent with placebo (p<0.001 for all comparisons).
“[W]eight loss in the mazdutide group was primarily attributable to a decrease in total fat mass compared with a decrease in total lean mass,” Ji and colleagues said. “Although overall body composition and body fat distribution improved, any loss of total lean mass (with a possible negative effect on muscle content and function) warrants further consideration.”
Safety profile
Numerically more participants on mazdutide reported treatment-emergent adverse events (AEs) than those on placebo (98.7 percent vs 93.5 percent). Serious AEs occurred in 22 individuals in the mazdutide group and in eight in the placebo group (7.2 percent vs 5.2 percent). No participant died during the trial.
Notably, nine (2.9 percent) individuals who received mazdutide discontinued treatment due to AEs and none (0 percent) with placebo. The most common AEs were gastrointestinal events, which were mostly mild to moderate in severity.
Additionally, “[p]atient-reported outcomes on physical function improved slightly in both the mazdutide and placebo groups,” Ji and colleagues said.
“Further studies are warranted to assess the effects of weight loss with mazdutide on muscle function and the concomitant use of a muscle-preserving lifestyle intervention,” they added.
“Mazdutide is a synthetic peptide analog of mammalian oxyntomodulin and a once-weekly glucagon and GLP-1 receptor dual agonist for the treatment of overweight or obesity and type 2 diabetes,” according to the investigators. [Nature 2026;652:181-188; N Engl J Med 2025;392:2215-2225]