- Excess weight, as well as increasing age, is a primary risk factor for knee osteoarthritis.
- Weight loss can greatly improve symptoms, relieve pain, and improve physical function and quality of life.
- In two late-stage clinical trials, retatrutide, an experimental weight-loss drug, not only led to significant weight loss but also reduced knee pain from osteoarthritis among participants.
The knee is the joint most commonly affected by osteoarthritis, a condition in which the cartilage in joints wears away, causing pain, swelling, stiffness, and impaired movement. According to the
Studies suggest that two-thirds of people with obesity have knee osteoarthritis, and the incidence of knee osteoarthritis increases with increasing body mass index (BMI).
Now, two phase 3 trials of retatrutide, published in The New England Journal of Medicine, have shown that the medication significantly improves pain symptoms in people with obesity and knee osteoarthritis.
Over 68 weeks, roughly two-thirds of participants treated with retatrutide lost at least 15% of their body weight and reported that their knee pain had been cut in half.
Timothy Gibson, MD, board certified orthopedic surgeon and medical director of the MemorialCare Joint Replacement Center at Orange Coast Medical Center in Fountain Valley, CA, who was not involved in the study, was enthusiastic about the findings:
“This study reinforces something orthopedic surgeons have recognized for years: weight management is an important component of treating knee osteoarthritis, particularly in patients who (have obesity or overweight). What is encouraging about retatrutide is the potential to help patients achieve a degree of weight loss that can significantly change how their knees feel and function.”
“For some patients, who could mean walking more comfortably, returning to activities they enjoy, or delaying the need for knee replacement,” Gibson told Medical News Today.
Retatrutide acts on 3 receptors to aid weight loss
Retatrutide is the latest weekly injectable weight loss medication, following on from semaglutide (Ozempic/Wegovy), a GLP-1 agonist, and tirzepatide (Mounjaro/Zepbound), a GLP-1/GIP agonist.
The medications were developed to control blood glucose levels in people with type 2 diabetes, but are increasingly prescribed for weight management as they help to decrease a person’s appetite.
Retatrutide is a triple agonist, which acts on the GLP-1, GIP, and glucagon receptors, and is currently in phase 3 clinical trials as a treatment for several conditions, including obesity, type 2 diabetes, knee osteoarthritis pain, and moderate-to-severe obstructive sleep apnea (OSA). It has not yet been licensed by the US Food and Drug Administration.
Significant improvements in knee osteoarthritis pain
To investigate the medication’s effect on knee osteoarthritis, researchers recruited just over 1,000 people without type 2 diabetes, who had both obesity and knee osteoarthritis, in two phase 3 trials of weekly retatrutide injections. Both trials were funded by the manufacturer, Eli Lilly.
In the first, TRIUMPH-4, 445 people were randomized to receive 9mg or 12mg (the maximum prescribed dose) of retatrutide, or placebo. In the second, TRIUMPH-1-OA, researchers randomized 574 participants to receive retatrutide at 4mg, 9mg, or 12mg, or placebo.
TRIUMPH-4 ran for 68 weeks, and the primary endpoints were the change in WOMAC pain score — a 0 to 10 scale where the lower the score the better — and the change in weight. TRIUMPH-1-OA ran for 80 weeks, and one of its primary endpoints was the change in WOMAC pain score.
In TRIUMPH-4, at 68 weeks, pain scores for people on retatrutide had decreased by 3.96 (9mg) and 3.74 (12mg), compared with a reduction of 2.12 with placebo. Those on retatrutide also lost around one-fifth of their body weight, whereas those on placebo lost, on average, just under 5%.
In the TRIUMPH-1-OA trial, participants’ pain scores at week 80 had decreased by 3.22 (4 mg), 3.48 (9 mg), and 3.64 (12 mg), whereas people on placebo saw a reduction of 1.87.
Weight loss is likely to drive pain reduction
“We know that every pound of body weight translates into approximately 2 to 5 pounds of force across the knee joint during certain activities, such as walking, climbing stairs, or standing from a seated position,” Gibson explained.
“Therefore, losing 20% or more of body weight can significantly reduce the mechanical stress placed on the knee. This reduction in joint loading can translate into less pain, improved mobility, and better overall function. While other metabolic or anti-inflammatory effects may contribute, the magnitude of weight loss achieved in this study is likely the primary driver of the improvement in symptoms,” he told MNT.
“Obesity is associated with chronic, low-grade inflammation, and excess adipose tissue produces inflammatory substances that may contribute to joint pain and disease progression. By reducing adipose tissue and improving metabolic health, medications such as retatrutide may indirectly decrease inflammatory signaling throughout the body, potentially benefiting patients with osteoarthritis.”
—Timothy Gibson MD
Anti-inflammatory effects may add to retatrutide’s benefits
Şebnem Ünlüişler, chief longevity officer and genetic engineer at the London Regenerative Institute, who was not involved in the study, attended, telling MNT:
“Weight loss alone may not fully explain the findings. The medication’s combined GLP-1, GIP and glucagon receptor activity could offer additional metabolic and anti-inflammatory benefits, although a direct effect on joint inflammation remains unproven.”
“Compared with conventional osteoarthritis medications, retatrutide has the potential advantage of addressing obesity, an important underlying contributor to symptoms, rather than primarily managing pain,” she added.
Gibson said that comparison to other weight-loss interventions was needed to investigate whether retatrutide offers these additional metabolic or anti-inflammatory advantages, and cautioned that it was not a direct treatment for osteoarthritis:
“Retatrutide is not an anti-inflammatory medication administered into the joint, and we do not yet have convincing clinical evidence that it directly repairs cartilage, reverses arthritis, or changes the structural progression of osteoarthritis.”
Further research needed into medication’s potential
While highlighting that retatrutide’s ability to help people achieve substantial weight loss could be very effective in reducing pain from knee osteoarthritis, Gibson emphasized the need for further longer-term studies to examine whether these improvements could be sustained after patients stop taking the medication or transition to a maintenance dose.
He also called for studies to determine whether retatrutide influences the structural progression of knee osteoarthritis and reduces the overall need for knee replacement surgery, and to investigate whether the medications might benefit people with knee osteoarthritis who do not have obesity or overweight.
Ünlüişler emphasized the importance of muscle strength for knee stability, joint protection and long-term mobility, adding that excessive muscle loss (that has been seen with some weight loss medications) could undermine some of the benefits.
She advised that “Future studies should therefore assess changes in muscle mass, strength and physical function, alongside inflammatory markers and structural joint changes.”
“Weight loss should be part of a comprehensive treatment strategy. Patients also need appropriate strengthening exercises, low-impact physical activity, proper nutrition, and efforts to preserve muscle mass as they lose weight. We should view medications like retatrutide as potentially valuable tools in managing osteoarthritis, rather than as a cure for the underlying joint disease. The ultimate goal is not simply to help patients lose weight, but to help them remain active, maintain their independence, and improve their quality of life.”
—Timothy Gibson MD
