Retatrutide The triple agonist peptide that is revolutionizing obesity research
Retatrutide (LY3437943) is the first triple GLP-1/GIP/glucagon agonist approached in a phase 3 clinical trial. With a reduction in body weight reaching 24% in phase 2 studies, it surpasses in efficacy all molecules known to date in obesity research.
What is Retatrutide?
Le Retatrutide (designation INN, development code LY3437943) is a molecule developed by Eli Lilly that belongs to the new class of multi-receptor incretin agonistsUnlike Semaglutide (GLP-1 monoagonist) or Tirzepatide (GLP-1/GIP dual agonist), Retatrutide acts simultaneously three distinct receptors :
- GLP-1 Receiver (Glucagon-Like Peptide-1) — regulation of appetite, slowing of gastric emptying, stimulation of insulin
- GIP Receiver (Glucose-Dependent Insulinotropic Polypeptide) — potentiation of the insulinotropic effect, reduction of postprandial glucagon levels
- Glucagon receptor — increased energy expenditure, increased hepatic lipolysis, reduced de novo lipogenesis
It is this triple simultaneous action which fundamentally distinguishes Retatrutide and explains its superior efficacy on fat mass compared to previous generations of GLP-1 peptides.
Retatrutide is a 39-amino-acid peptide conjugated to a C18 fatty acid chain via a spacer, giving it a prolonged half-life of approximately 6 days (allowing for weekly administration in a clinical protocol). Its molecular mass is approximately 4,720 Da.
Mechanism of action: how Retatrutide affects weight
Action on the GLP-1 receptor — appetite control
Activation of the GLP-1 receptor (GLP-1R) in the hypothalamus and the nucleus of the solitary tract induces a reduction in food intake through several channels:
- Reduction of circulating ghrelin (the hunger hormone)
- Increased satiety signals (peptide YY, CCK)
- Slowing of gastric emptying (increased feeling of prolonged satiety)
- Activation of POMC/CART neurons and inhibition of NPY/AgRP neurons in the hypothalamus
Action on the GIP receptor — metabolic potentiation
GIP (formerly known as "gastric inhibitory hormone") plays a complex role in lipid and glucose metabolism. Activation of the GIP receptor (GIPR) by Retatrutide:
- Potentiates the glucose-dependent insulinotropic effect (insulin sensitizer)
- Reduces insulin resistance in adipose tissue
- Modulates lipogenesis in adipocytes
- Improves bone metabolism (effect observed in research)
Action on the glucagon receptor — the differentiating novelty
This is where Retatrutide differs radically from Tirzepatide. Activation of the glucagon receptor (GCGR):
- Increase the basal energy expenditure (hepatic thermogenesis and adipose tissue)
- Stimulates the hepatic lipolysis — mobilization of fats stored in the liver (NAFLD/NASH)
- Reduces de novo lipogenesis in the liver
- Promotes the mild ketogenesispreferential use of fatty acids as an energy substrate
This glucagon component explains why Retatrutide shows a particularly marked reduction in liver fat in studies, in addition to overall fat mass loss.
Results of clinical trials
Phase 2 — Results published (NEJM 2023)
The phase 2 multicenter, randomized, double-blind, placebo-controlled study, published in the New England Journal of Medicine in 2023, included 338 adults with obesity (BMI ≥ 30) over a period of 48 weeks.
| Tested dose | Average weight loss | % of participants ≥ 15% loss | % of participants ≥ 20% loss |
|---|---|---|---|
| Placebo | -2,1% | 1% | 0% |
| Retatrutide 1 mg | -7,2% | 18% | 6% |
| Retatrutide 4 mg | -17,5% | 53% | 32% |
| Retatrutide 8 mg | -22,8% | 73% | 50% |
| Retatrutide 12 mg | -24,2% | 83% | 62% |
For comparison, Semaglutide 2.4 mg (Wegovy) achieved -15% in 68 weeks in the STEP-1 study, and Tirzepatide 15 mg (Mounjaro) achieved -22.5% in 72 weeks in the SURMOUNT-1 study. Retatrutide 12 mg achieved -24.2% in only 48 weeks.
Side effects observed in phase 2
The adverse effect profile is consistent with the class of GLP-1 agonists:
- Nausea: 40-60% (dose-dependent, usually transient during the titration phase)
- Vomiting: 15-30%
- Diarrhea : 20-35%
- Constipation : 15-25%
- Mild tachycardia: observed with high doses (glucagon component)
- Discontinuation due to adverse effects: ~7% of participants (12 mg dose)
Phase 3 — ongoing (TRIUMPH-1, TRIUMPH-2, TRIUMPH-3)
Eli Lilly launched the TRIUMPH program in 2024 for phase 3 studies of Retatrutide in obesity, with three major trials:
- TRIUMPH-1: obesity without comorbidity (n ≈ 2000, 72 weeks)
- TRIUMPH-2: obesity + type 2 diabetes (n ≈ 1500)
- TRIUMPH-3: obesity + high cardiovascular risk (MACE)
Retatrutide vs Semaglutide vs Tirzepatide — Comparative Table
| Criteria | Semaglutide | Tirzepatide | Retatrutide |
|---|---|---|---|
| Mechanism | GLP-1 monoagonist | GLP-1 + GIP | GLP-1 + GIP + GCG |
| Maximum weight loss (trials) | ~15% (68 weeks) | ~22.5% (72 weeks) | ~24.2% (48 weeks) |
| Liver fat reduction | Moderate | High | Very high |
| Basal energy expenditure | Slightly modified | Slightly modified | Augmented (GCG) |
| Stage of development | Marketed | Marketed | Phase 3 |
| Availability search | Available | Available | Available |
| Half-life | ~7 days | ~5 days | ~6 days |
The role of the glucagon receptor in fat loss
The glucagonergic component is the key element that differentiates Retatrutide and justifies the particular scientific interest in this molecule in research protocols on body composition.
Historically, researchers feared that activating the glucagon receptor would induce problematic hyperglycemia. Eli Lilly resolved this tension by balancing the relative activities: strong GLP-1/GIP activation sufficiently stimulates insulin secretion to counteract the hyperglycemic effect of glucagon, while preserving the metabolic benefits (thermogenesis, lipolysis) of GCGR activation.
Phase 2 data show that Retatrutide preferentially reduces the visceral fat mass (the most metabolically damaging adipose tissue) and hepatic adipose tissue, while preserving more lean mass compared to Semaglutide alone. Follow-up studies with DEXA are underway in the TRIUMPH program.
Retatrutide and NASH/NAFLD: an additional benefit
Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are major comorbidities of obesity. Phase 2 data show a reduction in liver fat content of -82% with Retatrutide 12 mg vs -34% with placebo, measured by MRI-PDFF.
Eli Lilly is also conducting specific trials of Retatrutide in NASH, where the glucagon component (direct hepatic lipolysis) represents a specific mechanistic advantage.
Applications in preclinical research
In a laboratory research setting, Retatrutide is being studied for:
- La experimental modeling of obesity and its metabolic comorbidities
- The study of incretin signaling pathways (GLP-1R, GIPR, GCGR) and their synergistic interactions
- Research on the gut microbiota and its interaction with GLP-1 agonists
- The investigation of neuroendocrine effects on food reward circuits
- The models of hepatic steatosis and metabolic inflammation
Order Retatrutide for your research
MyPeptide offers research-grade Retatrutide certified HPLC 99%+, with a Janoshik COA available before purchase. Discreet shipping within 48-72 hours from the European Union.
Key points to remember
- Retatrutide is a triple GLP-1/GIP/glucagon agonist — the first molecule of its class in phase 3
- Average weight loss of -24,2% over 48 weeks at a dose of 12 mg (phase 2)
- The glucagon component increases basal energy expenditure and hepatic lipolysis — a mechanism absent in Semaglutide and Tirzepatide
- Tolerance profile similar to GLP-1 class (nausea mainly during the titration phase)
- Of particular interest for NAFLD/NASH research due to the combined hepatoprotective effect
- Phase 3 (TRIUMPH program) underway since 2024
Scientific sources: Jastreboff et al., NEJM 2023 — Retatrutide Phase 2 · NCT04881760 — Phase 3 Clinical Trial
📦 Buy Retatrutide in Europe
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Scientific sources
- Triple hormone receptor agonist retatrutide for obesity — a phase 2 trial — Jastreboff AM et al. (2023)
- Retatrutide improves steatohepatitis in murine MASH models — Briand F et al. (2026)
- Triple agonist peptides — mechanistic overview — Ganamurali N et al. (2026)
- Retatrutide Phase 3b — Weight Loss Maintenance (TRIUMPH-1) — ClinicalTrials.gov (2024)
To compare with other GLP-1 molecules, see our comparison Retatrutide vs Tirzepatide vs Semaglutide.