Retatrutide Improves Weight Loss, Knee Osteoarthritis Pain, Sleep Apnea Versus Placebo

Retatrutide treatment results in substantial weight loss among patients with obesity, as well as reduced pain in patients with knee osteoarthritis and reduced apnea-hypopnea events in patients with obstructive sleep apnea, according to the TRIUMPH-1 study.1

Earlier phase 2 trials including patients with obesity have indicated that once-weekly subcutaneous retatrutide resulted in substantial weight reductions and improved cardiometabolic measures, such as systolic and diastolic blood pressure, glycated hemoglobin, waist circumference, and lipid levels. Another substudy examining the same dosing regimen saw a significant reduction in liver fat.1

“Recent studies of these medications have shown prevention and mitigation of cardiometabolic complications of obesity, including type 2 diabetes, cardiovascular disease, and metabolic dysfunction-associated steatohepatitis, as well as reductions in other obesity-related diseases, including knee osteoarthritis and obstructive sleep apnea,” Ania Jastreboff, MD, PhD, the Harvey and Kate Cushing Professor of Medicine and Professor of Pediatrics at the Yale School of Medicine, and colleagues wrote. “Because obesity is a heterogeneous disease, medications that act through multiple mechanisms may provide the possibility of greater weight reduction and improved health outcomes.”1

TRIUMPH-1 was a multicenter, randomized, placebo-controlled, double-blind trial conducted across 131 sites in 11 countries. Jastreboff and colleagues screened potential patients for 5 weeks, followed by 80 weeks of treatment and 4 weeks of follow-up. After concluding treatment, eligible participants were entered into a 24-week extension period.1

Patients were eligible for inclusion if they were ≥18 years old and had obesity without diabetes. For this trial, obesity was defined as a body mass index (BMI) ≥30, or a BMI between 27 to <30 and ≥1 obesity-related complication. Patients with moderate or severe knee osteoarthritis or obstructive sleep apnea were eligible for 1 of 2 basket trials and were included as subpopulations of the broader population with obesity. After enrollment, patients were randomly assigned in a 1:1:1:1 ratio to either retatrutide 4 mg, 9 mg, or 12 mg, or placebo, for 80 weeks.1,2

The primary endpoints were the percent change in body weight for the main population, the change in score on the pain subscale on the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) for the knee osteoarthritis basket, and the change in the apnea-hypopnea index (AHI) for the sleep apnea basket. These endpoints were measured for retatrutide 9 mg, 12 mg, or both, compared with placebo, at week 80. The primary endpoint for the extension study was percent change in body weight at week 104, comparing retatrutide 12 mg (80 weeks) followed by retatrutide ≤12 mg (24 weeks) versus placebo (80 weeks) followed by retatrutide ≤12 mg (24 weeks).1,2

A total of 2339 patients were enrolled; of these, 84.7% completed the trial. In the retatrutide group, investigators saw a mean percent change in body weight from baseline of -17.6% with the 4 mg dose, -23.7% with the 9 mg dose, and -25% with the 12 mg dose, compared with -3.9% with placebo. Between-group differences were -13.7 with the 4 mg dose, -19.8 with the 9 mg dose, and -21 with the 12 mg dose (P <.001 for all comparisons).1

Among patients with knee osteoarthritis, the retatrutide groups saw changes in WOMAC score of -3.2, -3.5, and -3.6, respectively, versus -1.9 with placebo (differences, -1.6 and -1.8 points; both P <.001), and corresponding ITT estimand changes were -3.4, -3.9, and -4.1 versus -2.5 with placebo (differences, -1.4 and -1.6 points; both P <.001). Patients with obstructive sleep apnea saw changes in events per hour of -22.9, -34.3, and -31.7 versus -9.9 with placebo (differences, -24.4 and -21.9; both P <.001).1

Ultimately, Jastreboff and colleagues concluded that treatment with retatrutide directly resulted in substantial reductions in all 3 main endpoints. The safety of retatrutide was generally the same as was seen in earlier phase 2 trials. The most common adverse events were gastrointestinal and were mild to moderate in severity, which is consistent with existing GLP-1 medications. Additionally, although symptoms of hypotension were reported, the team concluded that these were dose-dependent and more common among patients who were receiving concurrent antihypertensive therapy.1

“It has been hypothesized that treating obesity with therapies that target multiple nutrient-stimulated hormone pathways may facilitate greater weight reduction and broader health improvement,” Jastreboff and colleagues wrote. “Given the degree of weight reduction in response to retatrutide, these data support the possibility of treating to a defined target as is done for other diseases (e.g., a glycated hemoglobin target of <6.5% for type 2 diabetes), rather than to a relative percent change in weight.”1

References

1. Jastreboff A, Kaplan L, Davies M, et al. Retatrutide, a Triple Hormone Receptor Agonist, for Treatment of Obesity. NEJM. September 29, 2026. Accessed September 29, 2026. https://www.nejm.org/doi/full/10.1056/NEJMoa2604169

2. Eli Lilly. A Study of Retatrutide (LY3437943) in Participants Who Have Obesity or Overweight (TRIUMPH-1). ClinicalTrials.gov Identifier: NCT05929066. Updated August 21, 2026. Accessed September 29, 2026. https://clinicaltrials.gov/study/NCT05929066