TRIUMPH-2 is a phase 3 trial of retatrutide in 1152 adults with obesity and type 2 diabetes, published in The Lancet. After 80 weeks, participants on the highest dose (12 mg per week) lost an average of 18.8% of their body weight, compared with 5.1% on placebo. Gastrointestinal complaints were the most common side effects. Retatrutide has not yet been approved as a medicine.
What is retatrutide?
Retatrutide (development code LY3437943) is a synthetic peptide that activates three hormone receptors at once: those for GIP, GLP-1 and glucagon. That's why it is called a triple agonist. Well-known drugs such as semaglutide act only on the GLP-1 receptor; tirzepatide acts on GIP and GLP-1.
Manufacturer Eli Lilly is studying retatrutide in obesity, type 2 diabetes and related conditions, such as knee osteoarthritis and obstructive sleep apnoea. TRIUMPH-2 is one of the phase 3 trials in that programme.
How was the trial designed?
TRIUMPH-2 was a double-blind, randomised, placebo-controlled, parallel-group trial. This means that participants and researchers did not know who received which treatment, and that each group was compared with placebo at the same time.
- Sites: 92 medical centres, research centres and hospitals in eight countries.
- Inclusion: adults with a BMI of 27 or higher, type 2 diabetes (HbA1c 6.5–10.5%) with stable treatment for at least 90 days, and at least one unsuccessful attempt to lose weight through diet.
- Groups: participants were assigned in equal numbers (1:1:1:1) to placebo or retatrutide 4 mg, 9 mg or 12 mg, given once weekly by subcutaneous injection.
- Primary endpoint: the percentage change in body weight after 80 weeks for 9 mg and 12 mg compared with placebo. The comparison of 4 mg with placebo was a key secondary endpoint.
- Registration: ClinicalTrials.gov NCT05929079 (completed).
Who took part?
Between 11 July 2023 and 1 November 2024, 2047 people were screened. Of these, 1152 were assigned: 292 to 4 mg, 284 to 9 mg, 287 to 12 mg and 289 to placebo.
| Mean age | 55.1 years (SD 10.8) |
|---|---|
| Female / male | 48% / 52% |
| Mean BMI | 38.2 kg/m² (SD 7.4) |
| Mean HbA1c | 7.71% (SD 1.07) |
| Median duration of obesity | 21 years |
| Median duration of diabetes | 5.6 years |
| Oral diabetes medication used | 92% |
Of all participants, 84% completed treatment with the study drug.
Results: how much weight did participants lose?
After 80 weeks, weight loss with all three doses of retatrutide was clearly greater than with placebo. The higher the dose, the greater the average loss. All differences from placebo were statistically significant (p < 0.0001).
| Group | Change | Difference from placebo (95% CI) |
|---|---|---|
| Placebo | −5,1% | – |
| Retatrutide 4 mg | −11,9% | −6.9% (−8.7 to −5.1) |
| Retatrutide 9 mg | −16,8% | −11.8% (−13.7 to −9.8) |
| Retatrutide 12 mg | −18,8% | −13.8% (−15.8 to −11.8) |
The researchers also report better blood sugar control (glycaemic control) with retatrutide. The study abstract gives no exact figures for this.
Which side effects occurred?
The most frequently reported side effects were gastrointestinal, and they occurred more often with retatrutide than with placebo. According to the researchers, the safety profile is largely in line with that of other drugs that act on the GLP-1 receptor.
| Side effect | Placebo | 4 mg | 9 mg | 12 mg |
|---|---|---|---|---|
| Diarrhoea | 13% | 27% | 34% | 34% |
| Nausea | 8% | 14% | 21% | 28% |
| Low blood pressure (hypotension) | <1% | 1% | 5% | 6% |
| Dysaesthesia (abnormal skin sensation) | 1% | 4% | 6% | 7% |
| Permanently discontinued due to side effects or death | 5% | 4% | 12% | 8% |
Seven participants died during the trial: two in the 4 mg group, three in the 9 mg group, one in the 12 mg group and one in the placebo group. According to the investigator, none of these deaths were related to the study treatment.
What does this mean, and what doesn't it?
TRIUMPH-2 shows that retatrutide led to large, dose-dependent weight loss in people with obesity and type 2 diabetes, within the controlled setting of a clinical trial with medical supervision. A few caveats apply:
- Not approved. Retatrutide is an investigational drug. It has not been authorised by the European Medicines Agency (EMA) or the US FDA.
- Specific group. The results apply to adults with obesity and type 2 diabetes, and say nothing about other groups.
- Funded by the manufacturer. The trial was paid for by Eli Lilly and Company, the developer of retatrutide.
- Abstract only. This article is based on the abstract of the publication in The Lancet. Details such as the exact reduction in HbA1c are in the full article.
Frequently asked questions about TRIUMPH-2
Is retatrutide approved as a medicine?
No. Retatrutide is still being studied in phase 3 trials and has not been approved by the EMA or the FDA. It is therefore not available as a medicine.
How much weight did participants lose in TRIUMPH-2?
After 80 weeks, an average of 11.9% with 4 mg, 16.8% with 9 mg and 18.8% with 12 mg, compared with 5.1% with placebo.
What were the most common side effects?
Gastrointestinal complaints, especially diarrhoea (27–34%) and nausea (14–28%). Low blood pressure and abnormal skin sensation were also more common than with placebo.
Who funded the trial?
Eli Lilly and Company, the manufacturer of retatrutide.
