Retatrutide Cuts Knee OA Pain, With Philip Conaghan, MBBS, PhD

In adults with painful knee osteoarthritis (OA) and obesity, once-weekly retatrutide significantly reduced knee pain and body weight compared with placebo over 68 weeks in the randomized, double-blind, placebo-controlled phase 3 TRIUMPH-4 trial.¹

Philip G. Conaghan, MBBS, PhD, director of the National Institute for Health and Care Research (NIHR) Leeds Biomedical Research Centre and professor of musculoskeletal medicine at the University of Leeds, presented the data in a plenary session at the American College of Rheumatology (ACR) Convergence 2026 in Orlando, Florida.² The trial was published at the same time in the New England Journal of Medicine. Conaghan described the pain and function gains as both statistically superior and clinically meaningful in an interview with HCPLive, and said they are notable in a field that has gone a long time without effective therapies.

Weight Loss as a Long-Standing Target in Knee Osteoarthritis

Guidelines have long recommended weight loss for patients with knee OA who have overweight or obesity.⁴ Still, few patients reach or keep enough weight loss to change their symptoms.

“We’ve always known that obesity plays a role in knee pain and other joint pain. And we know from studies of dieting that losing about 5% to 10% of your body weight is an important amount that makes a clinically important difference to your knee pain,” Conaghan said. “Now, in reality, it’s really hard to get people to lose weight, and that probably is reflected in the popularity of effective weight loss drugs that we’ve seen in the last few years.”

The phase 3 STEP 9 trial showed that semaglutide-driven weight loss reduced knee OA pain in people with obesity.⁵ Retatrutide works through a different mechanism. It is an investigational agonist of 3 receptors: glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), and glucagon. TRIUMPH-4 is the only stand-alone OA trial in the TRIUMPH registrational program.⁶ Lilly announced topline TRIUMPH-4 results in December 2025.

TRIUMPH-4 Design: Retatrutide 9 mg and 12 mg vs Placebo

TRIUMPH-4 enrolled 445 adults without diabetes. All had a body mass index (BMI) ≥27 kg/m², Kellgren-Lawrence grade 2 or 3 knee OA on radiograph, and baseline Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain scores of 4 to 9.¹ Participants were randomized 1:1:1 to once-weekly subcutaneous retatrutide 9 mg, retatrutide 12 mg, or placebo. Retatrutide started at 2 mg and was increased every 4 weeks until participants reached their target dose.³

The co-primary endpoints were change in WOMAC pain score (range, 0 to 10) and percent change in body weight at week 68.¹ At baseline, mean BMI was 40.4 kg/m², 84.0% of participants had a BMI ≥35 kg/m², and mean WOMAC pain score was 6.0.³

Every participant received individualized lifestyle counseling. The counseling emphasized a healthy diet over caloric restriction and at least 150 minutes per week of moderate-intensity physical activity, including strength training.³

“Interesting for this trial design, which is a little different from some randomized trials, is that all participants were given advice on healthy eating and diet, and were mandated to do 150 minutes of exercise per week,” Conaghan said. “So even the control arm had some intervention going on.”

Retatrutide Results for WOMAC Pain, Physical Function, and Weight Loss

The NEJM paper’s primary analysis used the hybrid-treatment estimand. In that analysis, mean WOMAC pain scores fell by 3.96 points with 9 mg and 3.74 points with 12 mg, compared with 2.12 points with placebo.¹ The differences from placebo were −1.83 points (95% CI, −2.37 to −1.30) for 9 mg and −1.61 points (95% CI, −2.16 to −1.07) for 12 mg (P <.001 for both). Mean body weight fell by 20.0% and 23.7% with retatrutide, compared with 4.6% with placebo (P <.001 for both).

The efficacy estimand reflects participants who stayed on treatment as intended. In that analysis, WOMAC pain fell by 4.48 points with 9 mg and 4.41 points with 12 mg, compared with 2.43 points with placebo (P <.001 for both).² Weight loss was 26.4% with 9 mg and 28.7% with 12 mg, compared with 2.1% with placebo. With 12 mg, 58.6% of participants lost ≥25% of their body weight.³

Conaghan said pain and function had separated from placebo by week 16, the first WOMAC assessment, and kept improving through week 68. WOMAC physical function scores improved by 4.1 and 4.2 points with retatrutide, compared with 2.1 points with placebo.³ In a post hoc analysis, 14.1% of participants on 9 mg and 12.0% on 12 mg were free of knee pain at week 68, compared with 4.2% on placebo.

Investigators also reported reductions in triglycerides, non-HDL cholesterol, and high-sensitivity C-reactive protein (hsCRP), along with a 14.0 mm Hg reduction in systolic blood pressure with 12 mg. These analyses were not controlled for multiplicity.³ Conaghan said some OA researchers believe systemic inflammation may contribute to joint pain. Lower hsCRP could therefore help with pain beyond the effect of weight reduction, and could matter for long-term outcomes in patients with chronic low-grade inflammation.

Gastrointestinal events were the most common adverse events and occurred mainly during dose escalation.¹ Adverse events led to discontinuation in 12.8% of participants on 9 mg and 18.2% on 12 mg, compared with 4.0% on placebo. Dysesthesia occurred in 8.8% and 20.9% of the retatrutide groups, compared with 0.7% with placebo.³

Could Incretin Therapies Reduce Knee Replacement in Osteoarthritis?

TRIUMPH-4 excluded patients who needed knee replacement. It was not designed to assess OA structural progression or avoidance of joint replacement.¹ Conaghan said that because pain and loss of function drive many patients to seek joint replacement, clinicians would hope incretin-driven weight loss eventually leads to data showing fewer procedures.

“We’ve already seen observational data from other countries on the use of GLP-1s being associated with reduced rates of joint replacement,” Conaghan said. “So they’re not from clinical trials, but from registry and observational data. But it does make sense, I think, to clinicians.”

Retatrutide is investigational and has not been approved by the US Food and Drug Administration (FDA).

Editor’s Note: Conaghan reports relevant disclosures with Eli Lilly and other companies.

References

1. Schnitzer TJ, Hunter DJ, Conaghan PG, et al. Retatrutide once weekly in adults with knee osteoarthritis pain and obesity. N Engl J Med. Published online November 8, 2026. doi:10.1056/NEJMoa2610676

2. Conaghan P, Schnitzer T, Hunter D, et al. Retatrutide once weekly for the treatment of knee osteoarthritis pain and obesity: results from a 68-week phase 3 randomized clinical trial. Abstract 0871. Presented at: American College of Rheumatology Convergence 2026; November 6-11, 2026; Orlando, FL. Arthritis Rheumatol. 2026;78(suppl 9).

3. Eli Lilly and Company. 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. Published December 11, 2025. Accessed November 9, 2026.

4. Kolasinski SL, Neogi T, Hochberg MC, et al. 2019 American College of Rheumatology/Arthritis Foundation guideline for the management of osteoarthritis of the hand, hip, and knee. Arthritis Care Res (Hoboken). 2020;72(2):149-162. doi:10.1002/acr.24131

5. Bliddal H, Bays H, Czernichow S, et al. Once-weekly semaglutide in persons with obesity and knee osteoarthritis. N Engl J Med. 2024;391(17):1573-1583. doi:10.1056/NEJMoa2403664

6. Giblin K, Kaplan LM, Somers VK, et al. Retatrutide for the treatment of obesity, obstructive sleep apnea and knee osteoarthritis: rationale and design of the TRIUMPH registrational clinical trials. Diabetes Obes Metab. 2026;28(1):83-93. doi:10.1111/dom.70209