GLP-3 R
Triple Incretin Receptor Agonism & Weight Reduction
Retatrutide (LY3437943) — GIP/GLP-1/Glucagon Triple Agonist
Last reviewed: August 2026
GLP-3 R (Retatrutide) is one of the newest and most discussed compounds in metabolic research. It's a triple-receptor agonist — meaning it activates three different hormone receptors simultaneously: GLP-1R, GIP-R, and glucagon receptor. This triple action is what makes it particularly interesting compared to existing GLP-1 drugs like Ozempic, which only target one receptor.
By hitting all three receptors at once, Retatrutide combines the appetite-suppressing, insulin-stimulating effects of GLP-1 with the additional metabolic benefits of GIP (which enhances insulin secretion and may improve GLP-1 receptor sensitivity) and glucagon (which increases energy expenditure and fat burning). In Phase 2 clinical trials published in the New England Journal of Medicine in 2023, Retatrutide produced weight loss of up to 24.2% of body weight over 48 weeks — the highest ever reported for a pharmacological agent in a clinical trial.
The 24% weight loss figure from the Phase 2 trial is genuinely unprecedented in pharmacology. For context, semaglutide (Wegovy) produces about 15% weight loss, and tirzepatide about 20%. Retatrutide's triple-receptor mechanism may represent the next generation of metabolic therapeutics. It's currently in Phase 3 trials, meaning it could reach clinical approval within the next few years.
Retatrutide is arguably the most scientifically exciting compound in this entire catalog right now. Its Phase 2 NEJM data showing 24% weight loss is unprecedented, and its triple-receptor mechanism is at the cutting edge of metabolic research. It is an investigational compound with no current regulatory approval, supplied for laboratory research use only.
What is GLP-3 R?
Retatrutide (LY3437943, GLP-3 R) is a novel triple agonist developed by Eli Lilly that simultaneously activates three incretin and metabolic hormone receptors: the glucose-dependent insulinotropic polypeptide receptor (GIPR), the glucagon-like peptide-1 receptor (GLP-1R), and the glucagon receptor (GCGR). This triple agonism represents the next generation of metabolic peptide therapeutics, building on the success of GLP-1 agonists (semaglutide) and dual GIP/GLP-1 agonists (tirzepatide).
Phase II clinical trial data published in the New England Journal of Medicine (2023) demonstrated that retatrutide produced up to 24.2% mean body weight reduction at 48 weeks — the largest weight loss observed for any pharmacological agent in a clinical trial to date, surpassing even tirzepatide's results.
- Retatrutide (LY3437943) is a triple agonist simultaneously activating GLP-1R (appetite suppression, insulin secretion), GIPR (enhanced insulin sensitivity), and GCGR (thermogenesis, hepatic fat oxidation).
- Phase 2 NEJM trial (Jastreboff et al., 2023) demonstrated 24.2% mean body weight reduction at 48 weeks — the largest weight loss reported for any pharmacological agent in a randomized controlled trial.
- GCGR agonism is the distinguishing feature vs tirzepatide (GLP-1R/GIPR dual agonist): glucagon receptor activation increases brown adipose thermogenesis and hepatic fatty acid oxidation.
- Currently in Phase 3 TRIUMPH trials (obesity, T2D, cardiovascular outcomes); no regulatory approval in any jurisdiction as of 2026.
- For comparison: semaglutide 2.4 mg (STEP-1) = 14.9% weight loss; tirzepatide 15 mg (SURMOUNT-1) = 22.5%; retatrutide 12 mg (Phase 2) = 24.2%.
Molecular Composition
Retatrutide is a 37-amino-acid peptide with a fatty acid modification that enables once-weekly subcutaneous dosing through albumin binding. The sequence is based on a glucagon backbone with modifications that enable simultaneous engagement of GIPR, GLP-1R, and GCGR. The molecular weight is 4,731.33 Daltons.
The triple receptor agonism is achieved through careful sequence engineering: the N-terminal region is optimized for GLP-1R and GCGR engagement, while specific residues in the mid-sequence region enable GIPR activation. The fatty acid modification (C18 fatty diacid) enables albumin binding for extended half-life.
How Does It Work?
Retatrutide drives the most potent weight loss observed in clinical trials by activating three receptors — GLP-1, GIP, and glucagon — simultaneously.
Retatrutide's mechanism of action involves simultaneous activation of three receptors with complementary metabolic effects. GLP-1R activation provides glucose-dependent insulin secretion, glucagon suppression, gastric emptying delay, and central appetite suppression. GIPR activation enhances insulin secretion and may contribute to the superior weight loss observed with dual/triple agonists compared to GLP-1R agonists alone.
GCGR activation is the distinguishing feature of retatrutide: glucagon receptor stimulation increases hepatic glucose production (which is counterbalanced by the GLP-1R-mediated insulin secretion), but more importantly, it increases energy expenditure through thermogenic effects in brown adipose tissue and hepatic fatty acid oxidation. This energy expenditure-increasing component may explain the superior weight loss efficacy of retatrutide compared to GLP-1/GIP dual agonists.
Key Research Pathways
GLP-1R Signaling
Glucose-dependent insulin secretion, glucagon suppression, gastric emptying delay, and central appetite suppression via hypothalamic GLP-1R.
GIPR Signaling
Enhances insulin secretion and may contribute to superior weight loss vs. GLP-1R agonists alone through complementary beta cell effects.
GCGR / Energy Expenditure
Glucagon receptor activation increases hepatic fatty acid oxidation and brown adipose thermogenesis, raising total energy expenditure.
Albumin Binding (Fatty Acid Modification)
C18 fatty diacid modification enables reversible albumin binding, extending half-life to support once-weekly dosing.
Key Findings from the Literature
- Up to 24.2% mean body weight reduction at 48 weeks in Phase II trial (Jastreboff et al., NEJM 2023)
- Triple agonism: GIPR + GLP-1R + GCGR — broadest incretin receptor coverage of any approved/investigational agent
- GCGR activation increases energy expenditure via brown adipose thermogenesis and hepatic FAO
- Significant reductions in HbA1c and fasting glucose in subjects with type 2 diabetes
- Once-weekly dosing enabled by C18 fatty diacid modification for albumin binding
- Currently in Phase III clinical trials (TRIUMPH program) as of 2025
Evidence by Claimed Outcome
Each outcome rated by the highest level of evidence available. Tiers follow our 5-tier methodology.
Study counts reflect peer-reviewed publications in the evidence database below. "Theoretical" outcomes have mechanistic rationale only. Learn about our evidence tiers →
Structured Evidence Table
1 cited study — model, sample size, outcome, and effect size from published literature.
| Study | Model | Sample | Outcome | Effect Size | Level |
|---|---|---|---|---|---|
Jastreboff AM, et al. (2023) Triple–Hormone-Receptor Agonist Retatrutide for Obesity — A Phase 2 Trial PubMed | Human — Phase II RCT | n=338 | 24.2% mean body weight reduction at 48 weeks (highest dose cohort) | 24.2% weight loss vs. 2.1% placebo; statistically significant (p<0.001) | Phase II |
Important Research Context
Research References
Peer-reviewed literature supporting the research profile of GLP-3 R
The following peer-reviewed studies form the primary evidence base for GLP-3 R's research profile. All references are sourced from PubMed, NCBI, and peer-reviewed scientific journals. Published research is available through PubMed, NCBI, and peer-reviewed biomedical journals.
- 1.
Jastreboff AM, et al. Triple-Hormone-Receptor Agonist Retatrutide for Obesity — A Phase 2 Trial. New England Journal of Medicine. 2023.PMID: 37366315
Retatrutide achieved up to 24.2% body weight reduction at 48 weeks — the highest reported for any pharmacological agent in Phase II.
- 2.
Coskun T, et al. LY3437943, a novel triple GIP, GLP-1, and glucagon receptor agonist for glycemic control and weight loss. Cell Metabolism. 2022.PMID: 35985340
Preclinical characterization of retatrutide's triple receptor agonism and metabolic effects.
GLP-3 R
Metabolic Research
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Technical Specifications
| Peptide Class | Triple incretin receptor agonist (37 amino acids) |
| Molecular Weight | 4,731.33 Da |
| Receptor Targets | GIPR + GLP-1R + GCGR (triple agonism) |
| Clinical Stage | Phase III (TRIUMPH program, 2025) |
| Peak Weight Loss (Ph. II) | Up to 24.2% at 48 weeks |
| Available Sizes | 5mg vials |
| Form | Lyophilized powder |
| Purity | ≥99% (third-party tested) |
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Other Compounds in This Guide
Related Research Guides
Supporting Research
Retatrutide has Phase 2 human trial data showing exceptional weight loss (24.2% at 48 weeks). Phase 3 is ongoing. It is investigational — not FDA-approved. Claims about weight loss efficacy can be stated with confidence when tied to the Phase 2 NEJM trial, but must be accompanied by the Phase 3 / not-approved caveat.
References
- Jastreboff AM, et al.[HUMAN Phase 2 RCT, n=338]Up to 24.2% mean body weight reduction at 48 weeks — highest reported for any pharmacological agent in a Phase 2 trial.
- Coskun T, et al.[PRECLINICAL + early human PK]Triple receptor agonism characterization; GIP/GLP-1/GCGR co-agonism mechanism.
Research Databases
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