Next-generation weight-loss drugs just hit a new milestone: In a phase 3 clinical trial, retatrutide helped people with type 2 diabetes lose an average of up to 49.6 pounds, or more than 20 percent of body weight—a first for the field—according to the drug’s maker, Eli Lilly.
Importantly, trial participants also saw significant reductions in blood sugar, as well as lower cholesterol and blood pressure—both of which are risk factors for cardiovascular disease.
“We achieved a new high-water mark for what’s possible in terms of weight loss,” says Daniel Skovronsky, chief scientific and product officer at Eli Lilly.
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Retatrutide is one of several experimental weight-loss drugs informally called GLP-3s. Existing glucagonlike peptide 1 (GLP-1) receptor agonist drugs such as semaglutide, sold as Ozempic and Wegovy, bind to GLP-1 hormone receptors in the brain, where the receptors help regulate hunger. Drugs such as tirzepatide, sold as Mounjaro and Zepbound, target two receptors: GLP-1 and glucose-dependent insulinotropic polypeptide (GIP). Retatrutide targets three: GLP-1, GIP and glucagon. It’s the first such “triple agonist” to be put to the test in a phase 3 clinical trial—the gold standard test needed for the U.S. Food and Drug Administration to consider a drug for approval.
The trial, called TRIUMPH-2, took place over the course of 80 weeks and included 1,152 people with obesity and type 2 diabetes. Participants were given four milligrams, 9 mg, or 12 mg of retatrutide or a placebo. In the 4-mg group, participants lost an average of 29.8 pounds (13.5 kilograms); participants who took 9 mg lost an average of 45.4 pounds (20.6 kg); and those who were on the highest dose, 12 mg, lost an average of 49.6 pounds (22.5 kg), Eli Lilly said in a statement. The placebo group lost 9.3 pounds (4.2 kg) on average over the course of the study.
Strikingly, at the end of 80 weeks, about six out of 10 participants in the 12-mg group were no longer considered to have obesity based on their body mass index, according to Eli Lilly. Between 28.4 and 40 percent of participants who received retatrutide saw normalized blood sugar levels by the study’s end, depending on the dose. These findings, as well as a broader statistical analysis of the trial, were published in the Lancet.
The results are particularly impressive because, in general, people with type 2 diabetes tend to lose less weight on GLP-1 drugs than people without diabetes do, says Randy Seeley, a professor of surgery, internal medicine and nutritional sciences at the University of Michigan. (Seeley has worked as a paid consultant in the past for Eli Lilly and other weight-loss drug makers but was not involved in TRIUMPH-2.)
A separate clinical trial, also funded by Eli Lilly, found that participants with obesity who were not diabetic saw an up to 25 percent loss in body weight over the course of 80 weeks when they received the same doses of retatrutide. The results of that trial, TRIUMPH-1, were published on Tuesday in the New England Journal of Medicine.
Retatrutide is not side-effect-free, however. Dosed participants in TRIUMPH-2 have reported diarrhea, constipation, nausea and vomiting. (Seven people died during the course of the study, the Lancet paper notes, but their deaths were determined to be unrelated to the treatment.)
Anonymous study participants on retatrutide have also reported skipping doses as a result of side effects, as well as concerns about rapid rates of weight loss, according to reporting by STAT.
Intense weight loss can increase the risk of gallstones, as well as micronutrient deficiencies, Seeley says. “If you’re eating very few calories, it’s harder and harder to get all of the other things you need from your food,” he says.
If retatrutide, or reta, becomes widely available, people should work with their physicians to determine what dose—and which drug, if any—is right for them, Seeley says. “Particularly for reta, I think, a lot of these patients aren’t going to need to get to the maximum dose,” he says.
Retatrutide is a sign of things to come—drugs targeting four and even five hormone receptors are in the works, too.
“The science is moving very, very fast,” Seeley says.
Eli Lilly plans to submit the trial data to the FDA and to other health agencies around the world for approval “early next year,” Skovronsky says.