Retatrutide and Osteoarthritis: TRIUMPH-4 Results

Overview

Knee osteoarthritis is one of the most common and disabling complications of obesity. Extra body weight puts constant mechanical stress on weight-bearing joints, speeds up cartilage breakdown and drives body-wide inflammation that adds to joint pain and loss of function. Weight loss has been a first-line treatment for knee osteoarthritis for decades, but lifestyle changes alone often cannot produce enough weight loss to bring real relief.

TRIUMPH-4, the first Phase 3 trial of retatrutide to report results, was designed to test the drug in adults with obesity and knee osteoarthritis. The results, announced by Eli Lilly in December 2025, showed record weight loss and clinically significant improvements in knee pain and function.

TRIUMPH-4: Trial Design

TRIUMPH-4 was a randomized, double-blind, placebo-controlled Phase 3 trial with the following parameters:

• Participants: 445 adults randomized 1:1:1
• Population: Adults with obesity or overweight and knee osteoarthritis; no type 2 diabetes
• Baseline BMI: 40.4 kg/m2 (mean); 84% of participants had BMI of 35 or above
• Duration: 68 weeks
• Doses: Retatrutide 9 mg and 12 mg (with dose escalation) vs. placebo
• Co-primary endpoints: Percentage change in body weight and change in WOMAC pain score from baseline
• Source: Eli Lilly press release, December 11, 2025. Full data expected to be submitted for peer-reviewed publication; TRIUMPH program design described by Giblin et al. in Diabetes, Obesity and Metabolism (2026).

Weight Loss Results

The 28.7% mean weight loss at the 12 mg dose is the largest mean weight reduction reported for any pharmacological agent in a Phase 3 clinical trial. At a mean baseline body weight of approximately 112 kg, this translates to an average loss of 71.2 lbs (32.3 kg).

Weight Loss Thresholds

The share of participants reaching clinically meaningful weight loss thresholds shows how consistent the response was:

Nearly 60% of participants at the 12 mg dose lost at least a quarter of their body weight, and nearly 40% lost 30% or more. Weight loss on this scale approaches what is usually seen with bariatric surgery.

Knee Pain and Function Outcomes

WOMAC Pain Scores

The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) is the standard validated instrument for assessing osteoarthritis symptoms. WOMAC pain scores range from 0 (no pain) to higher values indicating more severe pain.

The drops in pain scores were clinically and statistically significant. A 75.8% reduction in pain is a large improvement in daily function and quality of life.

Complete Pain Freedom

Approximately one in eight participants treated with retatrutide achieved complete freedom from knee pain by the end of the trial.

Pain Reduction Thresholds

Nearly three-quarters of participants at the 9 mg dose had their pain cut by 70% or more, so most people on treatment got substantial relief.

WOMAC Physical Function

Function improved alongside pain, and treated participants had much better physical function at 68 weeks. This fits the idea that weight loss eases the mechanical load on the knee and reduces obesity-related inflammation, improving both symptoms and function.

Cardiovascular Biomarkers

TRIUMPH-4 also reported improvements in cardiometabolic parameters:

• Systolic blood pressure: Reduced by up to 14.0 mmHg at the 12 mg dose
• Non-HDL cholesterol, triglycerides, and hsCRP: Reduced across active treatment groups

These findings are consistent with the cardiometabolic benefits reported for retatrutide in Phase 2 and are clinically relevant given that obesity and osteoarthritis frequently co-occur with hypertension, dyslipidemia, and systemic inflammation.

Safety Profile in TRIUMPH-4

Side effects in TRIUMPH-4 were typical of the GLP-1 receptor agonist class, though some findings deserve particular attention.

Gastrointestinal Adverse Events

Dysesthesia

Dysesthesia, an altered sense of touch that can include tingling, burning, numbness or heightened skin sensitivity, was reported in 8.8% (9 mg) and 20.9% (12 mg) of participants, compared with 0.7% on placebo. This side effect was not seen in Phase 2 trials and is a new safety signal for retatrutide. It was generally described as mild and self-limiting.

Discontinuation Rates

Discontinuation rates were higher in participants with lower baseline BMI, attributed in part to perceived excessive weight loss. In the subgroup with BMI of 35 or above (84% of the trial population), discontinuation rates were lower and comparable to those observed with other injectable incretin therapies. Eli Lilly has noted that this BMI-dependent pattern may influence prescribing guidance.

Clinical Significance

Weight Loss and Joint Health

The link between weight loss and better osteoarthritis symptoms is well established. Each kilogram of weight lost takes about 4 kg of load off the knee during walking. With 32.3 kg of mean weight loss (12 mg group), that adds up to a large reduction in joint stress.

Weight loss alone may not fully explain the drop in pain, though. The placebo group lost only 2.1% of body weight yet saw a 40.3% reduction in WOMAC pain scores, likely because of the placebo effect, the natural course of the disease and the effect of being in a trial. The extra benefit of retatrutide (about 35 more percentage points of pain reduction than placebo) comes from large weight loss, less body-wide inflammation and possibly direct metabolic effects of triple receptor agonism working together.

Comparison with Other Obesity Therapies in OA

No head-to-head trials have compared retatrutide against other obesity therapies in an osteoarthritis population. In cross-trial comparisons, retatrutide’s WOMAC pain reduction of 75.8% numerically exceeds the approximately 42% reduction reported for semaglutide in osteoarthritis trials, though differences in trial design, populations, and duration preclude direct comparison. Retatrutide’s much greater weight loss (28.7% vs. approximately 15%) is the most likely explanation for any difference in pain outcomes.

Regulatory Implications

Eli Lilly has stated plans to include osteoarthritis of the knee among the initial proposed indications when it submits the TRIUMPH program data to the FDA (Lilly’s July 23 and August 5, 2026 statements), which it plans to do no later than the first quarter of 2027. If approved, retatrutide would be one of few pharmacological agents with a specific indication for obesity-related knee osteoarthritis.

Frequently Asked Questions

How much knee pain improvement can be expected with retatrutide?

In TRIUMPH-4, WOMAC pain scores improved by 74-76% on average at the 9 mg and 12 mg doses over 68 weeks. Approximately 12-14% of participants achieved complete freedom from knee pain, and roughly 68-73% achieved 70% or greater pain reduction. These are mean values; individual responses varied. These results are from a press release (Eli Lilly, December 2025); full published data are pending.

Does retatrutide work directly on joints, or only through weight loss?

The clinical data do not separate the contributions of weight loss, reduced inflammation, and any direct effects on joint tissue. The main mechanism is almost certainly weight loss and the lighter load it puts on the joints. The drop in inflammatory markers (hsCRP) seen in TRIUMPH-4 may also help with joint symptoms. There is no evidence of a direct effect of retatrutide on cartilage or joint tissue.

Who was eligible for the TRIUMPH-4 trial?

Participants were adults with obesity or overweight (baseline BMI averaged 40.4 kg/m2; 84% had BMI of 35 or above) and diagnosed knee osteoarthritis. Individuals with type 2 diabetes were excluded. The population was relatively homogeneous in terms of obesity severity, which should be considered when extrapolating results to individuals with lower BMI.

What about the dysesthesia side effect?

Dysesthesia (altered skin sensation) was reported in up to 20.9% of participants at the 12 mg dose, a rate not observed in Phase 2 trials. It was generally described as mild and self-limiting and did not lead to significant treatment discontinuations. This is a novel safety signal; the later TRIUMPH trials reported lower rates at 12 mg (12.5% in TRIUMPH-1, 7.3% in TRIUMPH-2 and 6.4% in TRIUMPH-3). The mechanism is not established.

Will retatrutide be approved specifically for osteoarthritis?

Eli Lilly has stated plans to submit the TRIUMPH program data to the FDA no later than the first quarter of 2027, with osteoarthritis of the knee listed among the proposed initial indications alongside obesity/overweight and obstructive sleep apnea. On October 2, 2026 the FDA ruled that retatrutide is a drug, not a biologic, so the application must be a New Drug Application (NDA); Lilly disputes the FDA ruling in court and has not said which pathway it will use. On our estimate, the earliest FDA decision would be late 2027. Approval is not guaranteed and will depend on the totality of safety and efficacy data across the TRIUMPH program.

How does the weight loss in TRIUMPH-4 compare to Phase 2?

TRIUMPH-4 reported -28.7% weight loss at 12 mg over 68 weeks, exceeding the -24.2% observed at the same dose over 48 weeks in the Phase 2 obesity trial (Jastreboff et al., NEJM 2023). The extra weight loss reflects the longer treatment period and confirms that weight loss continues beyond 48 weeks. In Phase 2, weight was still falling at 48 weeks, and the Phase 3 data show that continued treatment brings further weight loss.

Summary

TRIUMPH-4 showed that retatrutide produces both record weight loss (-28.7% at 12 mg, 68 weeks) and clinically significant improvements in knee osteoarthritis symptoms (-75.8% WOMAC pain reduction at 9 mg) in adults with obesity and knee osteoarthritis. Approximately one in eight treated participants achieved complete freedom from knee pain. Cardiovascular risk markers also improved, including a 14.0 mmHg reduction in systolic blood pressure. The safety profile included notable rates of gastrointestinal adverse events and a dysesthesia signal affecting up to 20.9% at the highest dose. These are the first Phase 3 results for retatrutide, reported via Eli Lilly press release in December 2025. Full peer-reviewed publication is pending.