Lilly says retatrutide delivered 28.3% average weight loss in phase 3 obesity trial

Eli Lilly said on May 21 that its investigational drug retatrutide helped adults with obesity lose an average of 28.3% of their body weight — about 70.3 pounds — over 80 weeks in a phase 3 trial, more than analysts have expected from the company's approved obesity drug Zepbound ^[1][2].

TRIUMPH-1 randomized 2,339 adults who had obesity or overweight plus at least one weight-related condition, and who did not have diabetes, to retatrutide 4 mg, 9 mg, 12 mg or placebo ^[1]. CNBC reported the trial enrolled roughly 2,500 patients ^[2]. Participants' average starting weight was 248.5 pounds, with an average starting BMI of 40.0 — the threshold for class 3 obesity ^[1].

Average weight loss at 80 weeks, by dose ^[1]:

• 12 mg: 70.3 pounds (28.3%)
• 9 mg: 64.4 pounds (25.9%)
• 4 mg: 47.2 pounds (19.0%)
• Placebo: 5.5 pounds (2.2%)

At the 12 mg dose, 45.3% of participants lost at least 30% of their body weight, compared with 37.9% at 9 mg, 15.3% at 4 mg and 0.5% on placebo ^[1]. Lilly said 65.3% of those on 12 mg reached a BMI below 30, the threshold for obesity, including 37.5% of participants who began the trial with class 3 obesity ^[1].

In a pre-specified extension, 532 participants who started with a BMI of 35 or higher and completed the main 80 weeks continued treatment to 104 weeks. Those on the 12 mg dose who reached a maximum tolerated dose lost an average of 85.0 pounds (30.3%) ^[1].

"People with severe obesity on the highest dose lost on average 30% of their body weight over two years," said lead investigator Ania Jastreboff, M.D., Ph.D., a professor of medicine and pediatrics at Yale School of Medicine ^[1]. Dan Skovronsky, Lilly's chief scientific and product officer, told CNBC, "We haven't seen that level of weight loss before with these kinds of medicines" ^[2].

The most common side effects were gastrointestinal and rose with dose. Nausea occurred in 42.4% of the 12 mg group versus 14.8% on placebo, diarrhea in 32.0% versus 13.5%, and constipation in 26.1% versus 10.9% ^[1]. Discontinuation because of adverse events was 4.1% at 4 mg, 6.9% at 9 mg and 11.3% at 12 mg, compared with 4.9% on placebo ^[1]. Dysesthesia, an unpleasant nerve sensation, occurred in 12.5% of the 12 mg group versus 0.9% on placebo, and urinary tract infections in 8.4% versus 5.3%; Lilly said these were generally mild to moderate and mostly resolved during treatment ^[1]. Lilly said it did not observe cardiac or liver issues ^[2].

For comparison, CNBC reported that ahead of the results analysts expected weight loss above the roughly 20% to 22% seen with Zepbound, which contains tirzepatide and targets GLP-1 and GIP. Semaglutide, the ingredient in Ozempic, Wegovy and Rybelsus, targets only GLP-1. Retatrutide targets GLP-1, GIP and glucagon ^[2]. Neither source reports a head-to-head trial comparing retatrutide with semaglutide or tirzepatide.

Why it matters for patients

Retatrutide is not approved. Lilly says it is legally available only to participants in its clinical trials, so it does not change what is prescribed today ^[1]. The reported averages come from a trial in which participants were assigned to different doses or placebo, not from a direct comparison with any marketed drug; neither source provides such a comparison ^[1][2].

The highest dose also had the highest dropout rate due to side effects, while the 4 mg dose — reached with a single escalation step — produced 19.0% average weight loss with a discontinuation rate slightly below placebo ^[1][2]. Skovronsky told CNBC that dose had "a really excellent tolerability profile" and said, "not everyone will go up to the highest dose level and stay on it for two years" ^[2]. How much retatrutide would cost, and whether insurers would cover it, has not been disclosed ^[1][2].

Lilly also reported a more conservative set of results that counts all randomized participants regardless of whether they stayed on treatment: 25.0% average weight loss at 80 weeks for the 12 mg dose ^[1].

What happens next

Additional TRIUMPH-1 results will be presented at the 86th annual American Diabetes Association Scientific Sessions; the sources do not give a date ^[1]. Lilly said more results from the TRIUMPH program will be shared later this year, including TRIUMPH-2 in adults with obesity or overweight and type 2 diabetes, and TRIUMPH-3 in adults with obesity or overweight and established cardiovascular disease ^[1]. Lilly has not disclosed when it plans to file retatrutide for approval ^[1][2].