An experimental Eli Lilly weight-loss drug delivered body-weight reductions comparable to bariatric surgery in a major new trial, while also driving down blood sugar, blood pressure and inflammation markers.
The 80-week phase 3 study of retatrutide enrolled 2,047 adults with type 2 diabetes across Argentina, Australia, Brazil, India, Mexico, Romania, Spain and the US, all with a BMI of 27 or above. Participants received weekly injections of placebo or the drug at 4 mg, 9 mg or 12 mg doses.
Those on the highest dose lost an average of 18.8% of their body weight, far outpacing the 5.1% seen with placebo. Among the 12 mg group, 47% shed at least 20% of their starting weight and nearly a third dropped at least a quarter. The 9 mg cohort averaged 16.8% loss, while the 4 mg group still hit 11.9%.
“Retatrutide demonstrated substantial reduction in body weight alongside glycaemic control and cardiometabolic risk factors, with a safety profile generally similar to other molecules with GLP-1 receptor agonist activity,” the researchers said.
The metabolic improvements extended well beyond the scale. Some 72% of participants across all retatrutide doses achieved an HbA1c of 6.5% or lower, the standard threshold for diagnosing type 2 diabetes, compared with just 29% in the placebo group. Investigators also recorded significant improvements in blood pressure and lipid profiles, plus reductions in hsCRP, a key marker of inflammation.
Retatrutide operates through a triple-hormone mechanism that distinguishes it from existing options. It mimics GLP-1, GIP and glucagon, the gut hormones governing appetite, blood sugar and metabolism. Wegovy targets only the GLP-1 pathway to suppress appetite, while Mounjaro combines GLP-1 with GIP for blood sugar control. The addition of glucagon receptor engagement in retatrutide helps increase energy expenditure, adding a third lever for weight loss.
The trial’s design was randomized, double-blind and placebo-controlled. It was funded by Eli Lilly, retatrutide’s maker, and published in the Lancet after presentation at the annual meeting of the European Association for the Study of Diabetes in Milan, Italy. The drug has not yet received approval from any regulatory agency.
Gastrointestinal issues dominated the side effect profile. Diarrhea struck 27% to 34% of those on retatrutide versus 13% on placebo, while nausea hit 14% to 28% compared with 8%. Seven deaths occurred during the trial, two in the 4 mg group, three at 9 mg, one at 12 mg and one with placebo, all judged unrelated to the study intervention by the investigator.
The same Milan conference hosted separate research on weight-loss drugs and pregnancy, published in the Lancet Obstetrics, Gynaecology & Women’s Health. That study found that in most cases these medications are not associated with adverse pregnancy outcomes in women with type 2 diabetes. Researchers emphasized that more work is urgently needed to close large evidence gaps and keep pace with the rising number of women of reproductive age using the drugs.