In early 2025, Eli Lilly initiated the first results from its Phase 3 TRIUMPH program testing a new class of drug called a triple hormone receptor agonist. Retatrutide, an investigational once-weekly injection, demonstrated substantial weight loss and pain reduction in patients with obesity and knee osteoarthritis, marking a significant expansion of therapeutic targets beyond weight management alone.
The trial, called TRIUMPH-4, enrolled 445 adults with obesity or overweight and clinically symptomatic knee osteoarthritis. Participants randomized to the highest dose of retatrutide lost an average of 28.7% of their body weight and experienced marked pain relief. The finding is notable because it represents an early clinical demonstration that a single drug can address two distinct but often co-occurring conditions.
The finding in plain terms
Retatrutide is an agonist of three hormone receptors: GLP-1, GIP, and glucagon. These receptors are expressed throughout the body: in the pancreas and gut (where they regulate glucose and hunger), in the brain (where they influence appetite and satiety), and in metabolic tissues (where they affect fat and energy storage). By activating all three simultaneously, retatrutide has a more potent effect on weight loss than single or dual agonists.
The TRIUMPH-4 trial was specifically designed for patients with obesity and knee osteoarthritis, a population where excess weight directly worsens joint pain. Researchers randomized 445 participants 1:1:1 to receive retatrutide 9 mg once weekly, retatrutide 12 mg once weekly, or placebo by subcutaneous injection, over 68 weeks.
At the primary endpoint, participants receiving retatrutide 12 mg had lost an average of 71.2 lbs (32.4 kg), a reduction of 28.7% from baseline. Placebo participants lost 4.2 lbs (1.9 kg). The placebo-adjusted weight loss difference was 26.6 percentage points. Crucially, weight loss was accompanied by substantial pain relief: patients on retatrutide 12 mg reduced their WOMAC knee pain score (Western Ontario and McMaster Universities Osteoarthritis Index) by an average of 4.5 points on a 0–20 scale, a 75.8% reduction. More than one in eight retatrutide-treated participants became completely free from knee pain.
Secondary endpoints showed additional benefits. Retatrutide reduced non-HDL cholesterol, triglycerides, and high-sensitivity C-reactive protein (hsCRP), all markers of cardiovascular risk. Systolic blood pressure fell by 14.0 mmHg at the 12 mg dose.
Why it matters
Obesity and osteoarthritis are deeply intertwined. Each kilogram of excess weight places roughly 4 kg of additional force on the knee joint. Most people with obesity develop osteoarthritis earlier and more severely than lean individuals. Current treatment for obesity involves lifestyle intervention, weight loss medications (primarily GLP-1 agonists like semaglutide), and bariatric surgery. Osteoarthritis treatment typically focuses on pain management, physical therapy, and joint replacement for advanced disease.
These treatments address weight and pain largely independently. The TRIUMPH-4 trial tests whether a single medication can tackle both. If retatrutide can shrink the body and simultaneously quiet joint pain (potentially allowing people to exercise more comfortably), the synergy is clinically meaningful.
The weight loss magnitude (28.7%) is noteworthy in context. GLP-1 agonists alone (semaglutide, tirzepatide) typically achieve weight loss of 15–22% depending on dose. Retatrutide’s additional 6–10 percentage points suggests the triple-agonist mechanism offers a real advantage, though the long-term durability of weight loss (after stopping the drug) remains unknown.
The pain reduction is equally important. Osteoarthritis affects roughly 10% of men and 13% of women globally, affecting some 370 million people. Most current therapies are symptomatic (NSAIDs, joint injections, joint replacement); few modify disease progression. The degree of pain relief observed here (75.8% improvement in WOMAC scores) approaches or exceeds what is typically seen with knee replacement surgery.
How they did it
TRIUMPH-4 was a 68-week, double-blind, randomized, placebo-controlled Phase 3 trial. Participants were adults aged 18–75 with body mass index (BMI) of 30 or above (or 27 or above if they had comorbidities), and symptomatic knee osteoarthritis (WOMAC pain subscale score of 7 or above).
Participants received weekly subcutaneous injections of retatrutide 9 mg, retatrutide 12 mg, or placebo. The primary endpoint was the change in body weight from baseline to week 68. Secondary endpoints included change in WOMAC knee pain subscale, proportions of participants achieving defined weight loss thresholds, and cardiovascular metabolic markers.
The trial was well-powered; it had sufficient participants to detect the observed differences. Baseline characteristics were balanced across groups. Patient adherence appeared high, based on the consistent separation of weight loss curves between active drug and placebo over the 68-week period.
Limitations and caveats
Several important limitations shape interpretation of these findings:
Adverse event rates are non-trivial. Discontinuation rates due to adverse events were 12.2% in the 9 mg group and 18.2% in the 12 mg group, compared to 4% in placebo. This means roughly 1 in 5 people assigned to the highest dose stopped the drug because they couldn’t tolerate it. The most common adverse events were nausea, diarrhea, constipation, and decreased appetite, which are similar to side effects seen with other GLP-1 and dual agonists. These side effects often diminish over time, but some participants did not tolerate them.
The trial duration is 68 weeks, not a lifetime. This is the initial efficacy signal. Whether patients maintain the weight loss after discontinuing retatrutide, or what happens with longer-term use, is unknown. All three agonists showed sustained weight loss over the trial period, but most weight-loss medications result in weight regain after discontinuation.
Knee osteoarthritis was moderate, not end-stage. Participants had symptomatic knee pain but were ambulatory and able to complete the trial. The findings may not apply to people with severe, advanced osteoarthritis or those with multiple joint involvement.
Safety profile is not fully characterized. This is Phase 3, the stage before approval. The trial enrolled 445 participants; post-marketing surveillance after approval will inevitably identify rare adverse events. A signal of interest has emerged in early retatrutide trials regarding potential pancreatitis and other GI complications, though TRIUMPH-4 data on this endpoint were not highlighted in the topline announcement.
Full results remain unpublished. Eli Lilly released topline data in December 2025. The full peer-reviewed publication in a medical journal has not yet appeared. Peer review may raise methodological points or highlight limitations not apparent in the press release.
What this means in practice
For patients with obesity and symptomatic knee osteoarthritis, TRIUMPH-4 offers hope. A single injection that simultaneously shrinks the body and reduces pain is appealing, especially given the magnitude of both effects. For clinicians, the finding suggests that obesity should be treated aggressively in patients with osteoarthritis, because the weight loss itself may be as important as any other intervention.
That said, retatrutide is not yet approved for any indication. Regulatory review is ongoing. When (and if) approved, it will likely be indicated for weight loss, possibly with knee pain relief as a secondary benefit for certain patients.
The adverse event rate is important context: approximately 1 in 5 people discontinue due to nausea or GI side effects at the highest dose. This is higher than what is typically seen with GLP-1 agonists. For some patients, a lower dose of retatrutide or a step-down approach (starting low and titrating up slowly to improve tolerability) might be necessary.
The trial also highlights an underappreciated opportunity: weight loss medications might be evaluated not just for weight, but for comorbid conditions that improve with weight loss. Osteoarthritis is one; sleep apnea and hypertension are others. The TRIUMPH program is testing retatrutide in all three contexts, which suggests the field is moving toward whole-person health outcomes rather than single-biomarker endpoints.
Source and further reading
Primary trial results (topline announcement): Eli Lilly, “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,” December 2025.
Trial design publication: Giblin et al., “Retatrutide for the treatment of obesity, obstructive sleep apnea and knee osteoarthritis: Rationale and design of the TRIUMPH registrational clinical trials,” Diabetes, Obesity and Metabolism 28(1):83–93 (2026). https://doi.org/10.1111/dom.70209
Clinical trial registry: NCT05931367: A Study of Retatrutide (LY3437943) Once Weekly in Participants With Obesity or Overweight and Knee Osteoarthritis (TRIUMPH-4)
Full peer-reviewed results are expected to be published in 2026 following formal medical presentations.