Retatrutide & Knee Osteoarthritis: TRIUMPH-4 Phase 3 Data

What is the TRIUMPH-4 trial?

TRIUMPH-4 is a Phase 3 randomised, double-blind, placebo-controlled trial evaluating retatrutide (LY3437943) in adults with overweight or obesity and knee osteoarthritis (OA). Eli Lilly announced topline results on 11 December 2025, reporting that the trial met all primary and key secondary endpoints.[1]

TRIUMPH-4 is part of the TRIUMPH Phase 3 programme, Eli Lilly’s broad clinical investigation of retatrutide across multiple metabolic and obesity-related disease states. Unusually for a GLP-1 class compound, TRIUMPH-4 included a musculoskeletal primary endpoint — the WOMAC (Western Ontario and McMaster Universities Osteoarthritis Index) pain score — alongside body weight, marking the first Phase 3 trial to test whether a GIP/GLP-1/glucagon triple agonist can improve validated joint-pain outcomes in addition to reducing adiposity.

Retatrutide (CAS 2381089-83-2) is a synthetic peptide developed by Eli Lilly that simultaneously activates three receptor pathways: the GLP-1 receptor (GLP-1R), the glucose-dependent insulinotropic polypeptide receptor (GIPR), and the glucagon receptor (GCGR). This triple-agonist profile distinguishes it from semaglutide (GLP-1 only) and tirzepatide (GLP-1/GIP dual agonist). For a full overview of retatrutide’s receptor pharmacology and preclinical data, see the Retatrutide Research Overview. For head-to-head mechanistic comparison, see the retatrutide vs tirzepatide vs semaglutide guide.

Velox Peptides supplies retatrutide as an HPLC-verified (≥99% purity) lyophilised reagent for in vitro research use only. View the Retatrutide product page →

Why study a triple agonist in knee osteoarthritis research?

The rationale for studying an incretin-class compound in osteoarthritis is grounded in the known intersection of metabolic dysfunction and joint pathology. Researchers have described this as “metabolic OA” — a distinct disease phenotype in which adipose tissue and systemic inflammatory mediators are thought to contribute to cartilage degradation independently of, and in addition to, the mechanical load imposed by excess body weight.[2]

Mechanical unloading as a research mechanism

The most straightforward hypothesis is biomechanical: each kilogram of body weight lost reduces the compressive force through the knee joint by approximately four kilograms during walking (based on published biomechanical models in the OA literature). Significant body-weight reduction therefore produces a proportionally larger reduction in joint loading. Researchers have observed that weight loss in OA populations is associated with reduced pain scores in observational data, though controlled Phase 3 evidence with a GLP-1 class compound achieving the weight-loss magnitude seen in TRIUMPH-4 had not previously existed.

Adipokine-mediated pathways as a research hypothesis

A second line of research interest concerns adipokines — signalling proteins secreted by adipose tissue including leptin, adiponectin, and resistin — which in preclinical models modulate chondrocyte function and synovial inflammation. GLP-1 receptors are expressed in chondrocytes and synovial cells in animal models, and in vitro studies have investigated GLP-1R agonism in models of cartilage catabolism.[3] Whether the glucagon receptor component of retatrutide’s triple-agonist profile contributes additional anti-inflammatory signalling in joint tissue remains an active question in the field — one that TRIUMPH-4 does not resolve mechanistically, but which its outcomes data make more relevant to investigate.

TRIUMPH-4 was designed to test whether the combined effect of retatrutide’s triple-receptor pharmacology could produce measurable improvements in a validated patient-reported pain scale, not to establish mechanism. The mechanistic questions remain open for preclinical and translational research.

How was TRIUMPH-4 designed?

TRIUMPH-4 enrolled 445 adults with overweight or obesity and knee osteoarthritis. Participants were randomised 1:1:1 to three arms:[1]

• Retatrutide 9 mg once weekly (subcutaneous injection)
• Retatrutide 12 mg once weekly
• Placebo

The trial ran for 68 weeks. Unlike TRIUMPH-1 (which tested 4 mg, 9 mg and 12 mg) and the Phase 2 programme, TRIUMPH-4 did not include the lower 4 mg arm, reflecting prior data suggesting the higher doses produce more robust outcomes on both body weight and cardiometabolic markers.

TRIUMPH-4 had dual primary endpoints:

1. Percentage change in body weight from baseline to week 68
2. Change in WOMAC pain score from baseline to week 68

Pre-specified key secondary endpoints included: physical function (WOMAC function subscale), proportion of participants achieving complete pain freedom at week 68, changes in LDL cholesterol, prediabetes-to-normoglycaemia reversal rate, and waist circumference.

What body-weight reduction did TRIUMPH-4 report?

At 68 weeks, retatrutide 12 mg produced a mean body-weight reduction of 28.7% from baseline, equivalent to up to an average of 71.2 lbs (approximately 32.3 kg).[1] Both the 9 mg and 12 mg doses met the body-weight primary endpoint versus placebo.

For context, this weight-reduction magnitude is consistent with TRIUMPH-1 (which reported 28.3% at 80 weeks on 12 mg in a non-diabetic, non-OA obesity population). The fact that comparable weight loss was observed in 68 weeks rather than 80 is noted in the topline release, though the two trials are not directly comparable due to differences in population and endpoint timing.

These figures are from a pharmaceutical Phase 3 clinical trial. They are not claims about Velox Peptides products, which are supplied as research reagents for in vitro laboratory use only.

What WOMAC pain results did TRIUMPH-4 report?

The WOMAC (Western Ontario and McMaster Universities Osteoarthritis Index) pain subscale is the standard validated patient-reported measure of OA pain severity. A score reduction of 4.5 points on an absolute basis, corresponding to a 75.8% reduction from baseline, represents a substantial effect size by the standards of Phase 3 OA trials.[1][4]

Notably, more than 1 in 8 participants on the 12 mg dose reported being completely pain-free at the end of the 68-week trial — an outcome that would be considered clinically meaningful in the OA field even absent weight-loss data.[5]

Both doses (9 mg and 12 mg) met the primary WOMAC pain endpoint versus placebo. Eli Lilly’s announcement did not provide the 9 mg arm absolute WOMAC figures in the topline release, but confirmed statistical superiority over placebo for both doses across all primary and key secondary endpoints.

What secondary endpoints did TRIUMPH-4 report?

Beyond the dual primary endpoints, TRIUMPH-4 reported a cluster of secondary outcomes that extend the trial’s relevance to cardiometabolic and glycaemic research contexts.[1]

The 72% prediabetes reversal rate in the TRIUMPH-4 population is particularly notable: the trial enrolled individuals with osteoarthritis and obesity rather than diabetes as primary criteria, yet a substantial proportion had prediabetes at baseline. The reversal rate reported is higher than some dedicated metabolic trials with shorter durations, though direct comparison across different trial populations is methodologically limited.

The ~20% LDL cholesterol reduction reported alongside the primary outcomes adds to the picture of retatrutide’s multi-system effects in this population, consistent with findings in TRIUMPH-1 and the earlier Phase 2 programme. As with all data on this page, these are pharmaceutical research findings from Eli Lilly’s clinical programme, not properties of any Velox Peptides research reagent.

Where does TRIUMPH-4 fit in the broader research programme?

TRIUMPH-4 is one of several Phase 3 trials in the TRIUMPH programme, each studying retatrutide in a distinct population or disease state. Eli Lilly has confirmed further trial readouts are expected in 2026 and beyond, covering sleep apnoea, metabolic dysfunction-associated steatotic liver disease (MASLD), chronic low back pain, and cardiovascular outcomes.[6]

The breadth of the TRIUMPH programme is relevant to researchers studying multi-receptor incretin pharmacology because it provides comparative data across distinct metabolic phenotypes in prospective, controlled settings — a dataset without precedent for a triple GIP/GLP-1/glucagon agonist. For a mechanistic explanation of how each receptor pathway contributes to the outcomes observed, see the retatrutide mechanism of action guide.

Velox Peptides supply information

Retatrutide is supplied as a research reagent only. It is not a medicine, and it has not been assessed or approved by the MHRA or FDA for any indication. Not for human or veterinary use. See our Research Use Policy and MHRA Statement.

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