Adults with obesity who took the highest tested dose of Eli Lilly’s experimental drug retatrutide lost an average of 25% of their body weight over 80 weeks, according to Phase 3 trial results published Sept. 29 in the New England Journal of Medicine.

The trial, called TRIUMPH-1, randomly assigned 2,339 adults with obesity or overweight to receive weekly injections of retatrutide at 4, 9 or 12 milligrams, or a placebo, for 80 weeks. Weight loss reached 17.6% on the 4-mg dose, 23.7% on 9 mg and 25.0% on 12 mg, compared with 3.9% for placebo, according to the study, led by Ania Jastreboff of Yale School of Medicine and funded by Lilly. The differences were statistically significant, the researchers reported.

Retatrutide is designed to act on three hormones involved in appetite and metabolism at once: GLP-1, GIP and glucagon. Lilly’s already-approved tirzepatide, sold as Zepbound for obesity and Mounjaro for type 2 diabetes, targets only GLP-1 and GIP. Novo Nordisk’s semaglutide, sold as Wegovy and Ozempic, targets GLP-1 alone.

GIP stimulates insulin release after meals, slows the breakdown of fats in the blood and signals fullness in the brain; it can also prompt a rise in glucagon when blood sugar falls too low. Glucagon itself is best known for releasing glucose and fatty acids into the bloodstream during low blood sugar, but after meals it also appears to help regulate insulin production, slow stomach emptying and control lipid levels. GLP-1 increases insulin release, delays stomach emptying and signals fullness in the brain.

A prespecified extension of the trial followed a subgroup of participants with a body mass index of at least 35 to 104 weeks. Those who had been assigned to the 12-mg dose lost an average of 85 pounds, or 30.3% of their starting weight, by that point, according to the published results.

TRIUMPH-1 also included two nested groups of participants with weight-related conditions. Among those with knee osteoarthritis, pain scores on a standard scale fell by as much as 73.1%. Among those with moderate-to-severe obstructive sleep apnea, the number of breathing interruptions per hour fell by as much as 60.6%, the study found.

In adults with obesity, retatrutide resulted in significant weight reduction, reduced pain in participants with knee osteoarthritis, and reduced apnea–hypopnea events in participants with obstructive sleep apnea.

Side effects were mostly gastrointestinal and grew more common at higher doses. Nausea was reported by 42.4% of participants on the 12-mg dose, versus 14.8% on placebo, and diarrhea by 32.0%, versus 13.5% on placebo, according to the trial data. Discontinuations due to adverse events rose with dose, from 4.1% on the 4-mg arm to 11.3% on the 12-mg arm, compared with 4.9% on placebo.

Lilly has reported similar results from four other Phase 3 trials in the TRIUMPH program this year, including one in patients with type 2 diabetes and obesity and another in patients with severe obesity and established cardiovascular disease, according to the company’s investor announcements. Lilly’s chief scientific and product officer, Dan Skovronsky, has said the extension-trial weight loss of 30% put retatrutide in territory previously reached only through bariatric surgery.

Lilly said in July it would submit a biologics license application to the Food and Drug Administration in the first quarter of 2027, having pushed back an earlier target of filing by the end of 2026 so it could complete manufacturing and quality-control data, according to reporting by CNBC. Retatrutide has not been approved by the FDA for any use.

The trial is registered with the U.S. National Institutes of Health under the identifier NCT05929066.