JAMA Publishes Companion Phase 3 Trials of Mazdutide in Obesity and Orforglipron Added to Insulin in Type 2 Diabetes

JAMA published two Phase 3 randomized clinical trials on August 4, 2026, one testing the GLP-1/glucagon dual agonist mazdutide for weight loss in Chinese adults with obesity and the other testing the oral GLP-1 agonist orforglipron added to insulin therapy in adults with type 2 diabetes. The journal ran the two trials alongside a joint editorial, "Mazdutide and Orforglipron-New Evidence in Obesity and Diabetes," by researchers from the University of California, Irvine and the Pennington Biomedical Research Center.

GLORY-2, sponsored by Innovent Biologics, was a double-blind, placebo-controlled trial conducted at 27 hospitals in China between December 2023 and November 2025. It randomized 461 adults with obesity (body mass index of 30 or higher), 2:1, to a once-weekly, 9-mg subcutaneous dose of mazdutide or placebo, added to a reduced-calorie diet and increased physical activity, for 60 weeks. At week 60, the mazdutide group had lost an average of 16.65% of body weight, compared with 1.50% in the placebo group, a between-group difference of 15.15 percentage points (95% CI, 13.09 to 17.22; p<.001). Among participants on mazdutide, 84.3% achieved a weight reduction of 5% or more, versus 33.1% on placebo (p<.001).

Adverse events leading to discontinuation of study treatment occurred in 2.9% of the mazdutide group and none of the placebo group. The most common adverse events with mazdutide were gastrointestinal: vomiting (53.1% versus 1.3% on placebo), nausea (46.9% versus 3.2%) and diarrhea (39.4% versus 6.5%). The trial authors described most adverse events as mild to moderate in severity. The study is registered as ClinicalTrials.gov identifier NCT06164873.

ACHIEVE-5, sponsored by Eli Lilly and Company, was a randomized, double-blind trial at 72 sites across the United States, Brazil, China, Japan and Romania, enrolling adults with type 2 diabetes and inadequate glycemic control on insulin glargine, with or without metformin or an SGLT2 inhibitor, between November 2023 and September 2025. The 546 participants were randomized 1:1:1:1 to once-daily oral orforglipron at 3 mg, 12 mg or 36 mg, or placebo, added to titrated insulin glargine, for 40 weeks. At week 40, mean A1C fell by 1.58, 1.88 and 1.82 percentage points at the three doses respectively, compared with 0.79 points on placebo; each dose was statistically superior to placebo (estimated treatment differences of -0.78 to -1.08 percentage points, p<.001 for all). Body weight fell by 2.6% to 5.4% across the orforglipron doses versus a 0.2% increase on placebo, and orforglipron did not increase the risk of clinically significant hypoglycemia. The trial is registered as ClinicalTrials.gov identifier NCT06109311.

Neither trial result changes current regulatory status. Mazdutide was approved by China's National Medical Products Administration in 2025 for chronic weight management and, subsequently, for glycemic control in type 2 diabetes, but it is not approved by the FDA, the European Medicines Agency or Australia's Therapeutic Goods Administration, where it remains investigational. Orforglipron was approved by the FDA in April 2026, under the brand name Foundayo, for chronic weight management in adults with obesity or overweight with weight-related conditions, but it is not yet approved for type 2 diabetes, the indication ACHIEVE-5 tested; it is also not yet authorized by the EMA or TGA. The trial results describe study outcomes in the populations tested and do not constitute treatment or dosing guidance.