Once-Weekly Retatrutide Reduces Weight and Knee Pain in Patients With Obesity and Osteoarthritis

In the 68-week, randomized, double-blind, placebo-controlled TRIUMPH-4 (NCT05931367) study, retatrutide (Eli Lilly and Company) met all primary and key secondary end points, achieving significant weight loss and improvements in pain and physical function at 68 weeks among individuals with obesity and knee osteoarthritis.

Retatrutide is a first-in-class glucagon-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 receptor agonist (GLP-1), and glucagon triple hormone used as a once-weekly triple hormone receptor agonist.^1,2

Does Obesity Increase the Risk of Knee Osteoarthritis?

Overweight and obesity are risk factors for developing osteoarthritis, which is the most common joint disorder that causes symptoms in the hands, knees, hips, back, and neck. Individuals with obesity experience an increased amount of weight on the joints, which could cause the breakdown of cartilage, especially in the knee. According to data from the Johns Hopkins Arthritis Center, women who are overweight have nearly 4 times the risk of knee osteoarthrosis, and men who are overweight have a 5 times greater risk. It was also estimated that individuals in the highest quintile of body weight have up to 10 times the risk of knee osteoarthritis compared to those in the lowest quintile.³

"[Individuals] with obesity and knee osteoarthritis often live with pain and restricted mobility and may eventually require total joint replacement," Kenneth Custer, PhD, executive vice president and president of Lilly Cardiometabolic Health, said in a news release.¹

What did the TRIUMPH Trial Demonstrate?

A total of 445 patients were included in the study, which assessed the safety and efficacy of retatrutide compared to placebo in adults with overweight, obesity, and knee osteoarthritis. The participants were randomly assigned to receive either retatrutide 9 mg, 12 mg, or placebo in a 1:1:1 ratio. Using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score, researchers aimed to demonstrate if retatrutide is superior to placebo in a subscale score reduction and in body weight reduction from baseline to week 68 among individuals with a body mass index greater than 27 kg/m²; however, 84% of participants had a baseline BMI greater than or equal to 35 kg. Individuals in the retatrutide group started treatment with 2 mg once weekly and increased the dose every 4 weeks until reaching the target dose of 9 mg or 12 mg.¹

Results demonstrated that the study met all primary and key secondary end points, as 9 mg and 12 mg of retatrutide achieved significant weight loss and improvements in pain and physical function at 68 weeks. Retatrutide also lowered weight by an average of 28.7% and reduced pain by an average of 4.5 points based on the WOMAC pain score.¹

Further secondary end points demonstrated that retatrutide reduced non-HDL cholesterol, triglycerides, and high-sensitivity C-reactive protein, along with lowering systolic blood pressure by 14.0 mmHg at the highest dose.¹

Findings from an additional post-hoc analysis revealed that 14.1% of patients on retatrutide 9 mg and 12% of patients on retatrutide 12 mg were free of knee pain at 68 weeks compared to 4.2% on placebo.¹

The most common adverse events reported among individuals treated with retatrutide included nausea, diarrhea, constipation, vomiting, and decreased appetite.¹

"We are encouraged by the results of TRIUMPH-4, which highlight the powerful effect of retatrutide, a first-in-class triple agonist, on body weight, pain and physical function. With seven additional Phase 3 readouts expected in 2026, we believe retatrutide could become an important option for patients with significant weight loss needs and certain complications, including knee osteoarthritis,” Custer said in the news release.¹

REFERENCES

1. Lilly's triple agonist, retatrutide, delivered weight loss of up to an average of 71.2 lbs along with substantial relief from osteoarthritis pain in first successful Phase 3 trial. News release. Eli Lilly and Company. December 11, 2025. Accessed December 15, 2025. https://investor.lilly.com/news-releases/news-release-details/lillys-triple-agonist-retatrutide-delivered-weight-loss-average

2. A Study of Retatrutide (LY3437943) Once Weekly in Participants Who Have Obesity or Overweight and Osteoarthritis of the Knee (TRIUMPH-4). Updated April 22, 2025. Accessed December 15, 2025. https://clinicaltrials.gov/study/NCT05931367

3. Role of Body Weight in Osteoarthritis. Johns Hopkins Arthritis Center. News release. Accessed December 15, 2025. https://www.hopkinsarthritis.org/patient-corner/disease-management/role-of-body-weight-in-osteoarthritis/#obesity