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Randomized controlled trial

TRIUMPH-1: retatrutide for obesity without diabetes

At 80 weeks, weight changed by −17.6%, −23.7% and −25.0% with retatrutide 4, 9 and 12 mg, compared with −3.9% on placebo, using the treatment-regimen estimand (intention to treat); the differences versus placebo were −19.8 and −21.0 percentage points with 9 and 12 mg (p < 0.001).

Jastreboff AM et al. Retatrutide, a Triple Hormone Receptor Agonist, for Treatment of Obesity. New England Journal of Medicine, 2026. DOI: 10.1056/NEJMoa2604169

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Key facts

Drug
retatrutide
Design
Randomized controlled trial
Participants
2,339
Duration
80 weeks
Funding
Eli Lilly
Registry
NCT05929066
Population
2,339 adults with obesity and without diabetes (per the registry, a BMI of 30 or more, or 27 or more with high blood pressure, abnormal blood lipids, obstructive sleep apnea or cardiovascular disease). The trial included a subgroup of 574 participants with knee osteoarthritis and another of 243 with obstructive sleep apnea. The ClinicalTrials.gov registry lists 2,335 participants.
Primary outcome
Percentage change in weight at 80 weeks with retatrutide 9 and 12 mg once weekly versus placebo (a 4 mg dose was also studied); in the knee osteoarthritis subgroup, the change in WOMAC pain score, and in the obstructive sleep apnea subgroup, the change in the apnea-hypopnea index.

What it found

At 80 weeks, weight changed by −17.6%, −23.7% and −25.0% with retatrutide 4, 9 and 12 mg, compared with −3.9% on placebo, using the treatment-regimen estimand (intention to treat); the differences versus placebo were −19.8 and −21.0 percentage points with 9 and 12 mg (p < 0.001). In the knee osteoarthritis subgroup, WOMAC pain fell by 3.4, 3.9 and 4.1 points with the three doses, compared with 2.5 on placebo (intention to treat); with the hybrid estimand of the main analysis, the differences with 9 and 12 mg were −1.6 and −1.8 points. In the obstructive sleep apnea subgroup, the apnea-hypopnea index fell by 22.8, 34.3 and 32.1 events per hour, compared with 9.6 on placebo (intention to treat); with the hybrid estimand, the differences with 9 and 12 mg were −24.4 and −21.9 events per hour. The most common adverse effects were digestive; the paper’s abstract does not give their frequency or confidence intervals.

Limitations

Funded by Eli Lilly, which is developing retatrutide. The paper’s abstract does not give discontinuations due to adverse effects or the frequency of each adverse effect, dysesthesia included; the figures in Lilly’s press release use a different estimand (the efficacy estimand) and are not comparable with these. It was compared with placebo, not with other treatments. Retatrutide is an investigational drug, not approved in any country.

What it means for you

In adults with obesity without diabetes, weekly retatrutide 12 mg reduced weight by an average of 25.0% over 80 weeks, compared with 3.9% on placebo, counting every participant; it also reduced knee pain in those with osteoarthritis and breathing pauses in those with sleep apnea. Retatrutide is not yet approved in any country. These data help show where research is heading, but they are not a basis for choosing a treatment or a dose today.

Further reading

Related trials

  • retatrutide80 weeks

    TRIUMPH-2

    At 80 weeks, weight changed by −11.9%, −16.8% and −18.8% with retatrutide 4, 9 and 12 mg, compared with −5.1% on placebo, using the treatment-regimen estimand.

  • retatrutide40 weeks

    TRANSCEND-T2D-1

    At 40 weeks, HbA1c fell by 1.69, 1.86 and 1.94 points with retatrutide 4, 9 and 12 mg, compared with 0.81 on placebo.

  • retatrutide48 weeks

    Retatrutide phase 2 (obesity)

    In this phase 2 trial, retatrutide (a GIP, GLP-1 and glucagon receptor agonist) reduced weight at 48 weeks by 24.2% with 12 mg once weekly, 22.8% with 8 mg, 17.1% with 4 mg and 8.7% with 1 mg, compared with 2.1% on placebo.

  • orforglipronEvent-driven

    ACHIEVE-4

    Over a median follow-up of 2 years, a major adverse cardiovascular event (MACE-4) occurred in 4.2% on orforglipron and 5.0% on insulin glargine, which showed noninferiority, not a reduction in risk.

Sources

The original paper and the records consulted for this summary, with the date they were accessed.

  1. New England Journal of Medicine.Jastreboff AM, et al. Retatrutide, a Triple Hormone Receptor Agonist, for Treatment of Obesity (TRIUMPH-1). N Engl J Med. Published online September 29, 2026.accessed .
  2. National Library of Medicine (PubMed).PubMed record PMID 42814954 (abstract).accessed .
  3. ClinicalTrials.gov (National Library of Medicine).ClinicalTrials.gov record NCT05929066 (TRIUMPH-1: registration, eligibility and enrollment).accessed .