Retatrutide Phase 3 Results: Up to 71.2 lbs Lost and Significant Osteoarthritis Pain Relief

Eli Lilly’s investigational triple agonist Retatrutide has delivered some of the most compelling weight loss data seen in a Phase 3 clinical trial to date “” with participants losing an average of 28.7% of body weight over 68 weeks, while simultaneously experiencing near-complete relief from knee osteoarthritis pain.

Once-weekly injectable peptides like retatrutide represent the next frontier in metabolic research.

What Is Retatrutide?

Retatrutide is a once-weekly injectable peptide that simultaneously activates three hormone receptors: GIP (glucose-dependent insulinotropic polypeptide), GLP-1 (glucagon-like peptide-1), and glucagon. This triple-receptor mechanism sets it apart from existing GLP-1 single agonists like semaglutide and dual agonists like tirzepatide “” making it the first-in-class triple hormone receptor agonist of its kind.

By targeting all three pathways simultaneously, retatrutide amplifies the body’s natural metabolic signaling: reducing appetite, improving insulin response, and increasing energy expenditure through glucagon receptor activation.

Structural visualization of retatrutide’s triple agonism at GLP-1R, GIPR, and GCGR receptors (Cell Discovery).

TRIUMPH-4 Trial: Overview

The TRIUMPH-4 trial (NCT05931367) enrolled 445 adults with obesity or overweight and knee osteoarthritis over 68 weeks. Participants had an average starting weight of 248.5 lbs (112.7 kg) and a BMI of 40.4 kg/m², with 84% having a BMI of 35 or above. Both the 9 mg and 12 mg doses of retatrutide met all primary and key secondary endpoints.

Weight Loss Outcomes

The proportion of participants achieving major weight loss thresholds on the 12 mg dose was remarkable:

• 58.6% of the 12 mg group lost ¥25% of body weight
• 39.4% lost ¥30% of body weight
• 23.7% lost ¥35% of body weight
• Only 0.8% of placebo participants reached ¥30% weight loss

Osteoarthritis Pain Relief

WOMAC pain scores “” a validated patient-reported measure where higher values indicate worse symptoms “” were reduced dramatically:

Physical function improved by over 71% in both dose groups. Notably, 14.1% of patients on the 9 mg dose were completely free of knee pain at week 68, compared to just 4.2% on placebo.

Cardiovascular and Metabolic Benefits

Beyond weight and pain, retatrutide also reduced cardiovascular risk markers including non-HDL cholesterol, triglycerides, and high-sensitivity C-reactive protein (hsCRP). The 12 mg dose lowered systolic blood pressure by an average of 14.0 mmHg.

Safety Profile

Adverse events were consistent with other incretin-based therapies. The most commonly reported side effects in the 9 mg and 12 mg groups respectively were:

Overall discontinuation rates due to adverse events were 12.2% (9 mg) and 18.2% (12 mg), compared to 4.0% on placebo, and were highly correlated with baseline BMI. Dysesthesia events were generally mild and rarely led to discontinuation.

What’s Next for Retatrutide?

Retatrutide’s 28.7% weight loss surpasses results seen with current GLP-1 and dual agonist therapies.

TRIUMPH-4 is the first of eight Phase 3 trials in the TRIUMPH program. Seven additional trials evaluating retatrutide across obesity, type 2 diabetes, obstructive sleep apnea, chronic low back pain, cardiovascular outcomes, and metabolic liver disease are expected to report results through 2026.

A maintenance dose of 4 mg is also being evaluated, and analysts have noted that TRIUMPH-1 “” the longest trial at 80 weeks “” could potentially exceed 30% average weight loss.