Retatrutide in phase 3 TRIUMPH-1: weight loss of up to 25.0% over 80 weeks in adults with obesity

In the phase 3 trial TRIUMPH-1, adults with obesity who received retatrutide lost significantly more weight than those on placebo, according to results published in the New England Journal of Medicine and summarized by endocrinologyadvisor.com. At 80 weeks, mean body weight decreased by 17.6%, 23.7%, and 25.0% with retatrutide 4, 9, and 12 mg, respectively, vs 3.9% with placebo endocrinologyadvisor.comendocrinologyadvisor.comendocrinologyadvisor.comOpen source ↗. Treatment differences for the 9 and 12 mg doses were -19.8 and -21.0 percentage points (both P<.001).

Retatrutide is a triple agonist of the glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), and glucagon receptors. The trial assessed its efficacy and safety in adults with obesity and without diabetes, as well as its effect on knee osteoarthritis and obstructive sleep apnea (OSA) outcomes.

Trial design

Participants had a body mass index (BMI) of at least 30, or 27 to less than 30 with at least one complication of obesity. They were enrolled at 131 sites in 11 countries between July 2023 and April 2026. They were randomly assigned 1:1:1:1 to weekly subcutaneous retatrutide (4, 9, or 12 mg) or placebo for 80 weeks, with lifestyle counseling and no prescribed caloric restriction. The primary outcomes were change in body weight, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score in participants with knee osteoarthritis, and apnea–hypopnea index (AHI) in those with OSA.

Osteoarthritis pain and sleep apnea results

Under the hybrid-treatment estimand, WOMAC pain scores fell by 3.2, 3.5, and 3.6 points with retatrutide vs 1.9 with placebo. Under the intention-to-treat (ITT) estimand, they fell by 3.4, 3.9, and 4.1 vs 2.5 points. Differences for 9 and 12 mg were -1.6 and -1.8 points (hybrid) and -1.4 and -1.6 points (ITT), all P<.001 endocrinologyadvisor.comendocrinologyadvisor.comendocrinologyadvisor.comOpen source ↗.

In OSA, AHI decreased by 22.9, 34.3, and 31.7 events per hour with retatrutide vs 9.9 with placebo under the hybrid-treatment estimand, and by 22.8, 34.3, and 32.1 vs 9.6 under ITT. Differences for 9 and 12 mg were -24.4 and -21.9 events per hour (hybrid) and -24.7 and -22.5 (ITT), all P<.001.

At 80 weeks, about 60% or more of participants on 12 mg reached a BMI below 30, and more than 25% reached a BMI below 25.

The authors noted limitations: no active comparator, which may have contributed to higher placebo-group attrition; limited generalizability to people with a baseline BMI below 30 (2% of participants); and the trial was not powered to assess cardiovascular safety. They wrote that the degree of weight reduction supports the possibility of treating to a defined target rather than to a relative percent change in weight.