What it is
Retatrutide (LY3437943) is a synthetic peptide developed by Eli Lilly that activates three hormone receptors: GIP, GLP-1 and glucagon. Coskun et al. (2022) described its discovery, mouse pharmacology and first single-dose human study, and the TRIUMPH phase 3 program began reporting results in late 2025. In trials it is given by once-weekly subcutaneous injection.
Mechanism of action
Retatrutide is a single peptide with agonist activity at the GIP, GLP-1 and glucagon receptors. In the discovery work by Coskun et al. (2022), it showed balanced activity at the glucagon and GLP-1 receptors and stronger activity at the GIP receptor in vitro; in obese mice it lowered body weight and improved glucose control, and a phase 1 single-ascending-dose study found pharmacokinetics that supported once-weekly dosing. The GLP-1 and GIP components are thought to work as they do in tirzepatide, increasing glucose-dependent insulin secretion and reducing food intake. The added glucagon receptor activity is the distinguishing feature. Glucagon signaling is studied for its effects on energy expenditure and on fat handling in the liver, which is one reason researchers have measured liver fat directly in retatrutide trials. Because glucagon also raises blood glucose, the balance between the three activities was central to the design of the molecule.
What it’s most studied for
Retatrutide is most studied for body weight reduction in adults with obesity. The TRIUMPH phase 3 program tests it in obesity with and without related conditions, including knee osteoarthritis and obstructive sleep apnea, over 68 to 104 weeks. Because glucagon receptor activity is expected to act on the liver, researchers have also measured liver fat in a phase 2 substudy of people with metabolic dysfunction-associated steatotic liver disease (MASLD). Its weight results are often set beside tirzepatide and semaglutide trials, but such cross-trial comparisons differ in population, duration and analysis method.
Notable findings
Each finding carries the species or population it was observed in and the dose that study used. Doses are reported as research context, exactly as published. They are not guidance.
Weight reduction over 80 weeks (TRIUMPH-1)
Jastreboff et al. (2026) randomized 2,339 adults with obesity or overweight and without diabetes 1:1:1:1 to retatrutide 4 mg, 9 mg, 12 mg or placebo. In the treatment-regimen analysis, mean body-weight change at 80 weeks was −17.6%, −23.7% and −25.0% versus −3.9% with placebo; the sponsor's efficacy-estimand figures, which estimate the effect for participants who stayed on treatment, were −19.0%, −25.9% and −28.3% versus −2.2%. In a prespecified 104-week extension in participants with a BMI of 35 or more, the 12 mg arm reached a mean reduction of 30.3%.
- Dose studied
- Retatrutide 4 mg, 9 mg or 12 mg once weekly, subcutaneous injection, adults, 80 weeks (104 weeks in the extension)
[4] Jastreboff AM et al. · 2026 · DOI 10.1056/NEJMoa2604169 (NCT05929066, TRIUMPH-1) ↗
Knee osteoarthritis pain and weight (TRIUMPH-4)
Eli Lilly and Company (2025) reported topline results for this registered trial, in which 445 adults with obesity or overweight and knee osteoarthritis were randomized 1:1:1 to retatrutide 9 mg, 12 mg or placebo for 68 weeks. Mean weight reduction was 26.4% (9 mg) and 28.7% (12 mg) versus 2.1% with placebo, and WOMAC pain scores fell by 4.5 and 4.4 points versus 2.4 points. Discontinuation for adverse events was 12.2% and 18.2% versus 4.0%, and dysesthesia was reported in 8.8% and 20.9% versus 0.7%.
- Dose studied
- Retatrutide 9 mg or 12 mg once weekly, subcutaneous injection, adults, 68 weeks
[5] Eli Lilly and Company (sponsor) · 2025 · NCT05931367 ↗
Dose-ranging phase 2 trial over 48 weeks
Jastreboff et al. (2023) randomized 338 adults with obesity, or overweight with a weight-related condition, to retatrutide or placebo. At the 24-week primary endpoint, mean weight change ranged from −7.2% (1 mg) to −17.5% (12 mg) versus −1.6% with placebo; at 48 weeks it was −8.7% (1 mg), −17.1% (4 mg), −22.8% (8 mg) and −24.2% (12 mg) versus −2.1%. Gastrointestinal events were the most common adverse events, generally mild to moderate and mostly during the dose-escalation period.
- Dose studied
- Retatrutide 1 mg, 4 mg, 8 mg or 12 mg once weekly, subcutaneous injection, adults, 48 weeks (the 4 mg and 8 mg results combine arms with different starting doses)
[2] Jastreboff AM et al. · 2023 · PMID 37366315 (NCT04881760) ↗
Liver fat in MASLD (phase 2 substudy)
Sanyal et al. (2024) studied 98 participants with MASLD and at least 10% liver fat, drawn from the phase 2 obesity trial. At 24 weeks, mean relative change in liver fat was −42.9% (1 mg), −57.0% (4 mg), −81.4% (8 mg) and −82.4% (12 mg) versus +0.3% with placebo. Liver fat fell below the 5% threshold in 86% of the 12 mg group at 24 weeks (0% on placebo) and in 93% at 48 weeks.
- Dose studied
- Retatrutide 1 mg, 4 mg, 8 mg or 12 mg once weekly, subcutaneous injection, adults, 48 weeks
[3] Sanyal AJ et al. · 2024 · PMID 38858523 ↗
Study quality
The human evidence is strong for an investigational compound: a phase 2 dose-ranging trial, a phase 2a liver substudy, and phase 3 trials enrolling from several hundred to more than 2,000 participants, all randomized, double-blind and placebo-controlled. It is not approved, and the peer-reviewed record is still forming; TRIUMPH-1 was published in 2026, while the TRIUMPH-4 figures summarized here come from a company announcement. All of these trials were funded by Eli Lilly. Gastrointestinal events were the most frequent adverse events: in TRIUMPH-1, nausea occurred in 28.6% to 42.4% of retatrutide groups versus 14.8% on placebo, and discontinuation for adverse events was 4.1%, 6.9% and 11.3% at 4, 9 and 12 mg versus 4.9%. Dysesthesia (abnormal skin sensation) appeared as a dose-related signal in TRIUMPH-4, reported in 20.9% of the 12 mg group. Data beyond about two years of treatment were not available in the sources reviewed.
On the research desk
Recent records on Retatrutide from the Alpha Helix research feed, each with its evidence tier and citation.
References
- 1
- 2Triple–Hormone-Receptor Agonist Retatrutide for Obesity — A Phase 2 Trial. New England Journal of Medicine. PMID 37366315 (NCT04881760)
- 3
- 4Retatrutide, a Triple Hormone Receptor Agonist, for Treatment of Obesity. New England Journal of Medicine. DOI 10.1056/NEJMoa2604169 (NCT05929066, TRIUMPH-1)
- 5A Study of Retatrutide (LY3437943) Once Weekly in Participants Who Have Obesity or Overweight and Osteoarthritis of the Knee (TRIUMPH-4). ClinicalTrials.gov registration, with topline results announced December 2025. NCT05931367
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