Retatrutide
Human RCTLY3437943 · triple agonist · GIP/GLP-1/glucagon receptor agonist
Highest available evidence among curated papers: Human RCT (as of 2026-06-04).
Chemical & identity
- Molecular formula
- C221H342N46O68
- Molecular weight
- 4731 g/mol · PubChem
- PubChem CID
- 171390338 · PubChem
- SMILES
- CC[C@H](C)C(C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(=O)O)C(=O)NCC(=O)NCC(=O)N2CCC[C@H]2C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](C)C(=O)N3CCC[C@H]3C(=O)N4CCC[C@H]4C(=O)N5CCC[C@H]5C(=O)N[C@@H](CO)C(=O)N)NC(=O)[C@H](CC6=CC=CC=C6)NC(=O)[C@H](C)NC(=O)C(C)(C)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](C)NC(=O)[C@H](CCCCNC(=O)COCCOCCNC(=O)CC[C@@H](C(=O)O)NC(=O)CCCCCCCCCCCCCCCCCCC(=O)O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@](C)(CC(C)C)NC(=O)C([C@@H](C)CC)NC(=O)[C@H](CO)NC(=O)[C@H](CC7=CC=C(C=C7)O)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CC8=CC=CC=C8)NC(=O)[C@H]([C@@H](C)O)NC(=O)CNC(=O)[C@H](CCC(=O)N)NC(=O)C(C)(C)NC(=O)[C@H](CC9=CC=C(C=C9)O)N
- InChIKey
- MLOLQJNKXBNWFW-SAGGEDDASA-N
- ChEMBL ID
- CHEMBL5095485 · ChEMBL
- Category
- Metabolic/GLP-1
Chemical/structural fields are auto-pulled and source-linked. ChEMBL data: ChEMBL_36, CC BY-SA 3.0.
Mechanism (curated)
Triple receptor agonist activating the glucagon, glucose-dependent insulinotropic polypeptide (GIP), and glucagon-like peptide-1 (GLP-1) receptors.
Pharmacology & handling
- Half-life
- Approximately 6 days, supporting once-weekly subcutaneous dosing.
Research
Abdrabou Abouelmagd A et al. · Proceedings (Baylor University. Medical Center) · 2025 · Meta-analysis
A systematic review and meta-analysis of three randomized controlled trials in 878 obese patients (with or without diabetes) evaluated retatrutide, a triple agonist of GLP-1, GIP, and glucagon receptors. Retatrutide significantly reduced body weight (−14.33%), BMI (−5.38), waist circumference (−10.51 cm), fasting plasma glucose (−23.51 mg/dL), hemoglobin A1c (−0.91%), and systolic/diastolic blood pressure (−9.88 and −3.88 mm Hg, respectively), all with P < 0.00001. No significant difference in adverse events was observed between retatrutide and placebo groups. The authors conclude retatrutide showed significant metabolic improvements with an appropriate safety profile but emphasize that larger, long-term trials are needed.
Jastreboff AM et al. · The New England journal of medicine · 2023 · RCT
This phase 2 randomized controlled trial enrolled 338 adults with obesity and tested retatrutide (LY3437943), a triple-hormone-receptor agonist targeting glucose-dependent insulinotropic polypeptide, glucagon-like peptide 1, and glucagon receptors, at doses of 1, 4, 8, or 12 mg weekly versus placebo for 48 weeks. At 24 weeks, retatrutide produced dose-dependent body weight reductions of -7.2% (1 mg), -12.9% (4 mg), -17.3% (8 mg), and -17.5% (12 mg) compared to -1.6% placebo; at 48 weeks, reductions were -8.7%, -17.1%, -22.8%, and -24.2% respectively. The most common adverse events were gastrointestinal and dose-related, mostly mild to moderate in severity and partially mitigated by lower starting doses; dose-dependent increases in heart rate peaked at 24 weeks then declined. The trial concluded that retatrutide treatment resulted in substantial body weight reductions in adults with obesity.
Sanyal AJ et al. · Nature medicine · 2024 · RCT
Retatrutide is a triple agonist of glucose-dependent insulinotropic polypeptide, glucagon-like peptide 1, and glucagon receptors. This randomized, double-blind, placebo-controlled phase 2a trial enrolled 98 participants with metabolic dysfunction-associated steatotic liver disease and ≥10% liver fat, randomized to 48 weeks of once-weekly retatrutide (1, 4, 8, or 12 mg) or placebo. At 24 weeks, retatrutide produced dose-dependent reductions in liver fat (−42.9% to −82.4% across doses) compared to placebo (+0.3%), with 79–86% of participants in the 8 and 12 mg groups achieving normal liver fat levels (<5%). Liver fat reductions correlated with improvements in body weight, abdominal fat, and metabolic markers of insulin sensitivity and lipid metabolism.
Giblin K et al. · Diabetes, obesity & metabolism · 2026 · RCT
TRIUMPH is a Phase 3 clinical development program evaluating retatrutide, a triple agonist of glucose-dependent insulinotropic polypeptide, glucagon-like peptide-1, and glucagon receptors. The program consists of four randomized, double-blind, placebo-controlled trials enrolling over 5,800 participants to assess safety and efficacy of weekly subcutaneous retatrutide for obesity, obstructive sleep apnea, and knee osteoarthritis. Two trials use a basket design with nested protocols for OSA and/or OA within weight management studies, one trial evaluates weight management in participants with cardiovascular disease, and one is a stand-alone OA trial. Primary endpoints include percent change in body weight, change in Apnea-Hypopnea Index, and change in knee pain scores.
Tewari J et al. · Expert review of clinical pharmacology · 2025 · Meta-analysis
This systematic review and meta-analysis pooled results from four RCTs comparing retatrutide, a novel triple hormone receptor agonist, versus placebo for obesity treatment. Retatrutide showed a dose-dependent relationship with the 12 mg dose producing maximum reductions across measured outcomes. The safety profile of retatrutide was comparable to control groups. The analysis concluded retatrutide was clinically and statistically superior to placebo, though the authors note that further trials are needed for more robust results.
Pasqualotto E et al. · Metabolism open · 2024 · Meta-analysis
This systematic review and meta-analysis examined three placebo-controlled randomized clinical trials (640 patients total, 510 receiving retatrutide) to assess the effects of once-weekly subcutaneous retatrutide on weight and metabolic outcomes in patients with overweight, obesity, and/or type 2 diabetes. Compared with placebo, retatrutide significantly reduced body weight (−10.66 kg), body mass index (−4.53 kg/m²), and waist circumference (−6.61 cm), and substantially increased the proportion of patients achieving weight reductions of ≥5%, ≥10%, ≥15%, and ≥20%. The treatment was associated with increased non-severe gastrointestinal and hypersensitivity adverse events. The authors note that longer-term Phase 3 RCTs are needed to further evaluate the long-term efficacy and safety of retatrutide.
Coskun T et al. · Cell metabolism · 2022 · Other
LY3437943 is a novel triple receptor agonist peptide targeting the glucagon receptor (GCGR), glucose-dependent insulinotropic polypeptide receptor (GIPR), and glucagon-like peptide-1 receptor (GLP-1R). In vitro studies showed balanced GCGR and GLP-1R activity with higher GIPR activity. In obese mice, LY3437943 decreased body weight and improved glycemic control through GCGR-mediated increases in energy expenditure combined with GIPR- and GLP-1R-driven reductions in calorie intake. A phase 1 single ascending dose study in humans demonstrated a safety and tolerability profile similar to other incretins, supported once-weekly dosing, and showed body weight reduction persisting up to day 43 after a single dose.
Rosenstock J et al. · Lancet (London, England) · 2023 · RCT
This phase 2 randomized controlled trial evaluated retatrutide, a triple agonist at GIP, GLP-1, and glucagon receptors, in 281 adults with type 2 diabetes in the USA. Retatrutide doses from 0.5 to 12 mg administered once weekly produced dose-dependent reductions in HbA1c (ranging from -0.43% to -2.02% at 24 weeks) and bodyweight (ranging from -3.19% to -16.94% at 36 weeks) compared to placebo and the active comparator dulaglutide 1.5 mg. The most common adverse events were mild-to-moderate gastrointestinal symptoms (nausea, diarrhea, vomiting, constipation), reported in 35% of retatrutide-treated participants, with no severe hypoglycemia or deaths observed. The study was double-blind, placebo- and active-controlled, and included 275 participants in the efficacy analysis.
Urva S et al. · Lancet (London, England) · 2022 · RCT
LY3437943 is a single peptide agonist for glucagon, GIP, and GLP-1 receptors tested in a phase 1b randomized, double-blind, placebo-controlled trial in 72 adults with type 2 diabetes over 12 weeks. The compound showed dose-proportional pharmacokinetics with a half-life of approximately 6 days, supporting once-weekly dosing. At the three highest doses (3 mg, 3/6 mg, and 3/6/9/12 mg), LY3437943 significantly reduced placebo-adjusted mean daily plasma glucose (by 2.8–3.1 mmol/L), HbA1c (by 1.2–1.6%), and bodyweight (up to 8.96 kg), with gastrointestinal disorders as the most common treatment-emergent adverse events (63% incidence across LY3437943 arms). The safety profile was deemed acceptable, supporting progression to phase 2 development.
Neumann J et al. · Naunyn-Schmiedeberg's archives of pharmacology · 2026 · In-vitro study
Retatrutide, a synthetic peptide agonist of glucagon, GIP, and GLP-1 receptors, increased force of contraction in isolated human right atrial preparations obtained from cardiac surgery patients in a concentration- and time-dependent manner (10–100 nM). The inotropic effect was enhanced by a phosphodiesterase III inhibitor and operated through cAMP signaling, as demonstrated by antagonist studies blocking each of the three receptors and by modulators of calcium handling and adenosine signaling. The effect was independent of β-adrenergic signaling.
Incretin triple agonist retatrutide (LY3437943) alleviates obesity-associated cancer progression.
Animal-onlyMarathe SJ et al. · npj metabolic health and disease · 2025 · Animal study
This pre-clinical study reports that retatrutide (RETA, LY3437943), an incretin triple agonist, reduced pancreatic and lung tumor engraftment, delayed tumor onset, and attenuated progression in animal models. Retatrutide produced a 14-fold reduction in pancreatic tumor volume and a 17-fold reduction in lung tumor volume compared to controls, with greater anti-tumor effects than single agonist semaglutide in pancreatic cancer. The anti-tumor benefits persisted despite weight regain after treatment withdrawal. Retatrutide also induced systemic immune reprogramming, including increased antigen-presenting cells, reduced immunosuppressive cells, and elevated circulating IL-6. The authors suggest that patients receiving retatrutide for weight loss may benefit from reduced cancer risk and improved outcomes, though this conclusion exceeds the scope of the pre-clinical findings presented.
Viebahn GK et al. · American journal of physiology. Gastrointestinal and liver physiology · 2025 · Animal study
Retatrutide, a triple receptor agonist, was tested in a new 31-day mouse model of diet-induced steatohepatitis combining Western diet, fructose, sucrose, and a final fructose binge. The study found that female mice developed more severe liver injury from a single fructose binge than males, and the 31-day model induced robust steatohepatitis with hepatic gene expression correlating to human MASH. Retatrutide intervention over the final 2 weeks significantly reduced body weight, ALT levels, hepatic triglycerides and cholesterol, and hepatic inflammatory markers in female mice compared to vehicle controls. The findings support the model's utility for testing pharmacological interventions for steatohepatitis.
Heerspink HJL et al. · Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association · 2026 · RCT
TRANSCEND-CKD is a Phase 2b double-blind, placebo-controlled randomized trial evaluating retatrutide, a glucose-dependent insulinotropic polypeptide/glucagon-like peptide-1/glucagon receptor agonist, in 146 adults with chronic kidney disease and overweight/obesity, with and without type 2 diabetes. The trial's primary objective is to assess the effect of retatrutide (up to 12 mg once-weekly) versus placebo on measured glomerular filtration rate change by iohexol clearance at Week 24, with secondary objectives including kidney hemodynamic and volumetric measurements by MRI. Baseline characteristics show a mean age of 65.1 years, mean weight 101.1 kg, mean measured glomerular filtration rate 49.3 mL/min/1.73 m², and 37.7% of participants with type 2 diabetes. The trial is designed to provide mechanistic insights on retatrutide's effects on kidney function and structure.
Pearson MJ et al. · The Journal of clinical endocrinology and metabolism · 2026 · Other
This post-hoc exploratory metabolomics and lipidomics analysis examined fasting plasma samples from two randomized, placebo-controlled phase 2 trials of retatrutide in 282 participants with obesity and 213 with type 2 diabetes (treatment duration 36–48 weeks). Higher doses of retatrutide were associated with changes in metabolites related to fatty acid oxidation (3-hydroxybutyrate, acetylcarnitine, free carnitine, and long-chain acylcarnitines), with mediation analyses suggesting these changes accounted for 23.2% of weight reduction in non-diabetic participants and 12.7% in diabetic participants. Retatrutide also altered metabolites linked to insulin resistance, including branched-chain amino acids and related products, in both populations. The authors concluded that retatrutide-induced metabolic changes in these two clusters were associated with improved metabolic health and reduced cardiovascular risk.
Summaries are our own; we link to originals (PubMed / DOI) and never rehost full text.
Regulatory status
- FDA approved
- No
- WADA prohibited
- No
- Compounding status
- Investigational; not approved. In phase 3 clinical development.
- Notes
- Not FDA-approved as of 2026-06-04; investigational (Eli Lilly LY3437943), in phase 3 trials for obesity and type 2 diabetes. Not listed on the WADA prohibited list.
Legal/regulatory status varies by jurisdiction and changes over time — accurate as of last review (2026-06-04).
Data sources: Curated IDs (PubChem/UniProt/ChEMBL) + Europe PMC + ClinicalTrials.gov (2026-06-04).
Last reviewed 2026-06-04