The Obesity Drug That Might Actually Be an Osteoarthritis Drug

Eli Lilly calls retatrutide an obesity drug. The trial data suggests it might be something more useful: a knee pain drug.

The drug landed headlines in December 2025 when Lilly announced that participants in the TRIUMPH-4 trial lost an average of 28.7 percent of their body weight — 71 pounds — after 68 weeks on the highest dose [Eli Lilly Press Release]. That is a large number. It is also not the most interesting number in the trial.

TRIUMPH-4 (ClinicalTrials.gov NCT05931367) was a 68-week Phase 3 study in 445 adults with obesity and knee osteoarthritis. The coprimary endpoints were weight loss and change in WOMAC pain score. WOMAC — the Western Ontario and McMaster Universities Osteoarthritis Index — is a standard 0-to-10 scale for knee pain and function. Participants at baseline had a mean WOMAC pain score of approximately 6.0. After 68 weeks on retatrutide 12mg, that score fell by 4.4 points, a 75.8 percent reduction from baseline. Placebo fell 2.4 points. Fourteen percent of patients on the highest dose were completely free of knee pain at week 68, compared to 4.2 percent on placebo [Eli Lilly Press Release].

The pain reduction held even as 18.2 percent of participants on the 12mg dose quit the trial because of adverse events — roughly four times the placebo rate [Eli Lilly Press Release]. The signal survived the attrition. STAT News noted that when including all participants — including those who discontinued — overall efficacy was closer to 25 percent [STAT News].

How retatrutide reduces pain is not yet established. The leading hypothesis is mechanical: less weight means less load on the knee joint, which means less pain. But GLP-1 receptors are expressed in pain pathways outside the joint, and animal models suggest a direct analgesic effect is biologically plausible. The press release does not resolve which mechanism is driving the effect — and neither does the trial design, since weight loss and pain reduction were co-primary endpoints run simultaneously. Separating the two will require a dedicated pain-indication trial.

That is the regulatory problem. TRIUMPH-4 was designed primarily as an obesity study with knee osteoarthritis as an enrolled population. For Lilly to file for a standalone chronic osteoarthritis pain indication, the FDA would typically want a trial where pain reduction is the primary — not co-primary — endpoint, enrolled specifically in an OA population without obesity as an inclusion criterion. Whether the agency would accept the existing coprimary endpoint design is an open question. FDA precedent on co-primary endpoints in obesity-plus-comorbidity trials is limited, and the current acting commissioner has no clinical medicine background.

No other triple agonist has a late-stage osteoarthritis pain program. Vertex Pharmaceuticals won FDA approval in January 2025 for Journavx (suzetrigine), the first non-opioid analgesic for moderate-to-severe acute pain. But Journavx is approved for short-term use, up to 14 days, and targets a different mechanism than what retatrutide appears to be hitting. No other GLP-1 or triple-agonist drug has announced a chronic osteoarthritis pain indication, according to a review of clinical trial registries and public pipeline announcements.

Osteoarthritis affects more than 32 million Americans in some form. Knee osteoarthritis — the specific condition TRIUMPH-4 studied — is the most common location, accounting for roughly 40 percent of OA cases. The standard pharmacologic playbook is NSAIDs, which carry GI bleeding risk, or opioids, which carry dependence risk. Joint replacement is the endgame for many. A drug that reduces pain by two points on a ten-point scale without either liability would be a significant shift in how that disease is managed — if it reaches patients.

Lilly has seven more Phase 3 retatrutide readouts expected in 2026 [Eli Lilly Press Release]. Whether any of them test a pain endpoint in osteoarthritis is the question worth watching. The company has not explicitly said it will pursue an OA pain indication. But it announced the pain data in the same press release as the weight data, called it a coprimary endpoint, and framed the results as clinically meaningful. The door is open.

The FDA will have to evaluate whatever Lilly decides to file. The agency is not in its strongest state to do that. Commissioner Martin Makary was ousted May 12, 2026 after 13 months in the job [Politico]. Acting commissioner Kyle Diamantas comes from the food division and does not have a medical degree [Politico]. The agency has absorbed 3,500 DOGE-driven layoffs under RFK Jr. [Politico]. Whether that institutional thinning affects review quality for a novel drug with a novel pain endpoint is not a theoretical concern — it is a current fact about the regulatory environment retatrutide will navigate.

Endpoints News reported that biotech companies including Biohaven ran a covert campaign to push out Commissioner Makary [Endpoints News].

The weight-loss headline is real. The dropout rate is a legitimate caveat. But the knee pain signal in the same trial is what nobody else has written about, and it reframes what this drug actually is: not just a way to get smaller, but potentially a way to manage a condition that makes life unbearable for tens of millions of people who have run out of options that do not require surgery.