Retatrutide effects greatest Weight Loss in TRIUMPH-4 trial, bests Tirzepatide
USA: A first-in-class triple hormone receptor agonist, retatrutide, has demonstrated striking reductions in body weight along with meaningful improvement in knee osteoarthritis symptoms in the first successful Phase 3 trial under the TRIUMPH programme.
The investigational treatment, which activates GIP, GLP-1, and glucagon receptors, was evaluated in adults with obesity or overweight and knee osteoarthritis without diabetes, and achieved all primary and key secondary endpoints at 68 weeks.
The TRIUMPH-4 trial showed that participants receiving the highest dose of 12 mg lost an average of 28.7% of their body weight, equivalent to 71.2 pounds. Significant improvements in joint pain and physical functioning were also observed. More than 84% of the trial population had a baseline BMI of at least 35 kg/m², highlighting the effectiveness of retatrutide in individuals with severe obesity.
Key findings from the trial were as follows:
- Eli Lilly and Company, the developer of retatrutide, noted that both the 9 mg and 12 mg doses of retatrutide consistently outperformed placebo across all main efficacy measures.
- Knee pain, measured using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), improved by up to 4.5 points, representing a 75.8% reduction from baseline.
- More than one in eight participants on retatrutide were completely free from knee pain at week 68, compared with 4.2% in the placebo group.
- With the 12 mg dose, 58.6% of participants achieved at least 25% weight loss.
- With the 12 mg dose, 39.4% of participants achieved at least 30% weight loss.
- Improvements in physical function mirrored pain results, with WOMAC physical function scores improving by more than 70% in retatrutide-treated participants.
- Retatrutide demonstrated favorable effects on cardiometabolic markers, including reductions in non-HDL cholesterol, triglycerides, and high-sensitivity C-reactive protein (hsCRP).
- The highest dose of retatrutide lowered systolic blood pressure by 14 mmHg.
- The safety profile aligned with typical incretin-based therapies.
- Common adverse events included nausea, diarrhea, constipation, and vomiting.
- Dysesthesia occurred more frequently in retatrutide-treated participants but was generally mild and rarely led to treatment discontinuation.
- Overall treatment discontinuation rates were similar between retatrutide and placebo.
- Some participants discontinued therapy due to perceived excessive weight loss.
Kenneth Custer, PhD, executive vice president and president of Lilly Cardiometabolic Health at Eli Lilly, highlighted the importance of these findings, noting that individuals with obesity and knee osteoarthritis often face declining mobility and may eventually require joint replacement. The strong results from TRIUMPH-4, he said, support the potential of retatrutide as a meaningful therapeutic option.
Comprehensive results from TRIUMPH-4 will be presented at a future medical meeting and submitted for peer review. Meanwhile, seven additional Phase 3 trials evaluating retatrutide in obesity, type 2 diabetes, obstructive sleep apnoea, metabolic liver disease and other weight-related conditions are expected to report in 2026.
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