Retatrutide Clinical Trial Results: Phase 2 to the TRIUMPH Phase 3 Programme

Lilly reports most Phase 3 results under two estimands:

• Efficacy estimand: participants who stayed on treatment (dose changes allowed) and did not start prohibited weight-management or pain treatments.
• Treatment-regimen estimand: the average effect in everyone randomised, whether or not they stayed on treatment.

In TRIUMPH-1 at 12 mg these give 28.3% and 25.0%. Headlines use the first. The second is closer to what a whole population would see.

Obesity, no diabetes (NEJM 2023, NCT04881760). 338 adults, 51.8% men, with a BMI of 30 or more, or 27 to under 30 with a weight-related condition. 48 weeks of weekly retatrutide or placebo.

• 12 mg: 24.2% weight loss at 48 weeks versus 2.1% on placebo. At 24 weeks (the primary endpoint): 17.5% versus 1.6%.
• At 48 weeks, weight loss of at least 5%, 10% and 15% was reached by 100%, 93% and 83% on 12 mg, versus 27%, 9% and 2% on placebo (summary).
• Weight had not plateaued when the trial ended.

Type 2 diabetes (Lancet 2023). 281 adults with HbA1c of 7.0% to 10.5% and a BMI of 25 to 50. Retatrutide was compared with placebo and dulaglutide 1.5 mg.

• HbA1c at 24 weeks, 12 mg: down 2.02%, versus 1.41% with dulaglutide and 0.01% with placebo.
• Weight at 36 weeks, 12 mg: down 16.94%, versus 2.02% with dulaglutide and 3.00% with placebo.
• No severe hypoglycaemia and no deaths were reported.

A liver-fat substudy is covered in the guide to how retatrutide works.

All doses started at 2 mg weekly and stepped up every 4 weeks to the assigned target.

TRIUMPH-1: the pivotal obesity trial

Lilly’s release gives the full dose range at 80 weeks:

• Efficacy estimand: 19.0% (4 mg), 25.9% (9 mg), 28.3% (12 mg), versus 2.2% on placebo.
• Treatment-regimen estimand: 17.6%, 23.7% and 25.0%, versus 3.9%.
• At 12 mg, 62.5% lost at least 25% of body weight, 45.3% at least 30%, and 27.2% at least 35%. On placebo the figures were 2.2%, 0.5% and 0.3%.
• 65.3% of the 12 mg group ended with a BMI below 30, including 37.5% of those who started at BMI 40 or more.
• Waist circumference fell 24.1 cm at 12 mg versus 3.6 cm on placebo.

A pre-specified extension followed 532 participants who had BMI 35 or more at baseline, had completed 80 weeks and tolerated their dose. At 104 weeks, those on 12 mg (moving to maximum tolerated dose) had lost 30.3% (38.5 kg) on the efficacy estimand and 29.9% on the treatment-regimen estimand. Participants switched from placebo lost 19.2% and 18.9% over the same extension. This subgroup is heavier and more tolerant of treatment than the whole trial, so 30.3% is not the trial average.

TRIUMPH-1 also contained knee osteoarthritis and sleep apnoea basket trials. Healio reports significant reductions in knee pain and in apnoea-hypopnoea events.

TRIUMPH-4: knee osteoarthritis

This was the first Phase 3 readout, in December 2025. Participants had a mean baseline weight of 112.7 kg and BMI 40.4. See Lilly’s release.

• Weight, efficacy estimand: 26.4% (9 mg) and 28.7% (12 mg, 32.3 kg), versus 2.1% on placebo.
• Weight, treatment-regimen estimand: 20.0% and 23.7%, versus 4.6%.
• Knee pain (WOMAC pain score): a fall of up to 4.5 points (75.8%) on retatrutide versus 2.4 points (40.3%) on placebo on the efficacy estimand. On the treatment-regimen estimand the reductions were 62% to 67% versus 35.1% (reported here).
• In a post hoc analysis, about 1 in 8 retatrutide participants was completely free of knee pain at week 68, versus just over 4% on placebo.
• Commentators noted a high placebo response on the pain measure.

TRIUMPH-2: type 2 diabetes

Baseline weight was 106.4 kg and baseline HbA1c 7.7%. Lilly’s release:

• Weight at 80 weeks: 12.7% (4 mg), 19.1% (9 mg), 20.8% (12 mg), versus 4.0% on placebo.
• HbA1c: down 1.4, 1.6 and 1.5 percentage points, versus 0.2 on placebo.

TRIUMPH-3: established cardiovascular disease

Baseline weight was 111.4 kg. At 80 weeks, 9 mg gave 21.6% and 12 mg gave 22.6%, versus 3.2% on placebo. At 12 mg:

• Triglycerides down 37.0% and non-HDL cholesterol down 16.5%.
• Systolic blood pressure down 9.3 mmHg and waist circumference down 19.0 cm.
• High-sensitivity C-reactive protein down 51.2%.

Cardiovascular events were tracked but the trial was not built to test them. Pooling both doses against placebo, the hazard ratio for the five-component MACE measure was 0.82 (95% CI 0.55 to 1.22) and for the three-component measure 1.12 (95% CI 0.64 to 1.96). Neither is statistically significant. A dedicated outcomes trial of about 10,000 participants is expected to finish in February 2029.

TRANSCEND: the type 2 diabetes programme

• TRANSCEND-T2D-1 (people on diet and exercise alone, 40 weeks): HbA1c down 1.7 to 2.0 points depending on dose, with weight down 11.5% to 16.8% (report).
• TRANSCEND-T2D-2 (1,298 adults on metformin, 80 weeks): HbA1c down 2.2 points on both 9 mg and 12 mg versus 1.8 on semaglutide 2 mg, and weight down 19.5% and 20.9% versus 9.4%. It is the first Phase 3 comparison with another incretin drug (Lilly).

A head-to-head trial against tirzepatide, TRIUMPH-5, is ongoing.

• Cardiovascular outcomes. Not before the outcomes trial reports.
• Phase 3 body composition. A DXA substudy is planned within TRIUMPH-3. It is not in the releases reviewed here.
• Durability. The 104-week extension is the longest data so far, and only in a BMI 35-plus subgroup.
• Maintenance dosing. The 4 mg arm in TRIUMPH-1 reached 19.0% with a single escalation step, but long-term maintenance strategies are still being studied.

Nordapep supplies retatrutide for laboratory research use only. These trials tested Lilly’s investigational medicine under clinical supervision. They say nothing about any other material and are not guidance for human use.