Once-weekly retatrutide reduced body weight by up to 25% over 80 weeks and significantly reduced knee osteoarthritis pain and obstructive sleep apnea severity among patients with obesity without diabetes in the phase 3 TRIUMPH-1 trial. The triple-receptor agonist, which targets glucose-dependent insulinotropic polypeptide, glucagon-like peptide-1, and glucagon receptors, also improved several cardiometabolic measures, although adverse events were more frequent at higher doses.
Conducted at 131 sites in 11 countries between July 2023 and April 2026, the randomized, double-blind, placebo-controlled trial enrolled 2,339 adults with a body mass index (BMI) of at least 30 or a BMI of 27 to less than 30 with at least 1 obesity-related complication. Patients were randomly assigned to receive once-weekly subcutaneous retatrutide at doses of 4 mg, 9 mg, or 12 mg, or placebo, for 80 weeks. The mean baseline BMI was 40, and 77.4% of participants had a BMI of at least 35.
The primary outcomes included percentage change in body weight and changes in knee osteoarthritis pain and obstructive sleep apnea severity in prespecified subgroups. Knee pain was evaluated using the Western Ontario and McMaster Universities Osteoarthritis Index pain subscale (a 1-to-10 scale, with higher scores indicating greater pain severity), while sleep apnea severity was assessed using the apnea-hypopnea index (AHI). The primary comparisons involved retatrutide 9 mg and 12 mg vs placebo. Key secondary outcomes included weight-loss thresholds, cardiometabolic measures, and physical functioning. Weight outcomes were analyzed using a treatment-regimen approach that accounted for treatment discontinuation, while the primary knee osteoarthritis and sleep apnea analyses used a hybrid-treatment approach.
At week 80, mean body weight decreased by 17.6%, 23.7%, and 25% among patients receiving retatrutide 4 mg, 9 mg, and 12 mg, respectively, compared with 3.9% among those receiving placebo, with statistically significant reductions at all 3 doses.
Among patients receiving retatrutide 12 mg, 36.9% achieved weight loss of at least 30%, compared with 0.6% receiving placebo. At the same dose, 21.1% lost at least 35% of their body weight vs 0.2% with placebo, while 57.1% achieved a BMI below 30 vs 9.2% with placebo.
Among 574 patients with knee osteoarthritis, mean pain scores decreased by 3.5 points with retatrutide 9 mg and 3.6 points with 12 mg, compared with 1.9 points with placebo in the primary hybrid-treatment analysis. The researchers reported pain reductions of up to 61.6% with the higher doses.
In the obstructive sleep apnea subgroup of 243 patients, the mean AHI decreased by 34.3 events per hour with retatrutide 9 mg and 31.7 events per hour with 12 mg, compared with 9.9 events per hour with placebo. Researchers reported reductions in AHI of up to 57.3% with the higher doses.
Retatrutide also improved several cardiometabolic measures. At week 80, systolic blood pressure decreased by 10.4 mmHg with retatrutide 12 mg, compared with 1.9 mmHg with placebo. Triglyceride levels declined by 38% and non–high-density lipoprotein cholesterol by 20.6% with the same dose, compared with reductions of 3% and 4.6%, respectively, with placebo.
Among patients with prediabetes at baseline, 89.4% to 93.2% of those receiving retatrutide achieved normoglycemia by week 80, compared with 54.2% receiving placebo. Retatrutide recipients also reported greater improvements in physical functioning and psychosocial quality-of-life measures.
Prespecified subgroup analyses suggested greater weight reduction among women than men. At the 12 mg dose, mean weight loss was 26.3% among women compared with 22.3% among men. Among 532 participants in the 24-week extension, those initially assigned to retatrutide 12 mg achieved 29.9% mean weight loss by week 104. During the extension, participants received a maximum tolerated dose of 9 mg or 12 mg.
Gastrointestinal adverse events were the most frequent, particularly during dose escalation. Nausea occurred in 28.6% to 42.4% of patients receiving retatrutide, compared with 14.8% receiving placebo. Diarrhea occurred in 25.2% to 34.1% vs 13.5%, while constipation occurred in 23.8% to 26.1% vs 10.9%. Vomiting occurred in 10.6% to 25.3% of retatrutide recipients vs 4.8% receiving placebo. Most gastrointestinal events were mild or moderate and transient.
Treatment discontinuation because of adverse events occurred in 4.1%, 6.5%, and 11.1% of patients receiving retatrutide 4 mg, 9 mg, and 12 mg, respectively, compared with 4.6% receiving placebo. Serious adverse events occurred in 7.7% to 10.5% of retatrutide recipients and 5.5% of placebo recipients. Dysesthesia, injection-site reactions, and hypotension were also reported more frequently with retatrutide. Hypotension was more common among patients receiving antihypertensive medications. Urinary tract infections occurred in 7.5% to 8.7% of retatrutide recipients vs 5.3% receiving placebo; most occurred in women, were mild or moderate, and did not lead to treatment discontinuation.
The trial had several limitations. The absence of an active comparator prevented direct comparisons with established obesity medications and may have contributed to greater attrition in the placebo group. Only 2% of participants had a baseline BMI below 30, limiting generalizability to patients with less severe obesity. The trial was also not powered to assess cardiovascular safety, and longer-term studies are needed to evaluate cardiovascular outcomes.
The protocol permitted dose reductions for gastrointestinal adverse events, inadequate food or fluid intake, low BMI, or excessive weight loss, raising questions about whether the highest tolerated dose is always necessary. “We speculate that these observations highlight the need to reconsider the use of the maximum tolerated dose as the treatment strategy,” wrote lead study author Ania M. Jastreboff, PhD, of Yale University School of Medicine, New Haven, Connecticut, and colleagues.
The study was funded by Eli Lilly, which conducted trial monitoring and data collection and analysis. Several study authors were Eli Lilly employees. Additional disclosures are available with the published article.
Source: New England Journal of Medicine
