Retatrutide
LY3437943 / Reta
Retatrutide (LY3437943) is a novel triple-hormone receptor agonist developed by Eli Lilly that simultaneously activates GIP (glucose-dependent insulinotropic polypeptide), GLP-1 (glucagon-like peptide-1), and glucagon receptors. In Phase 2 clinical trials, it produced unprecedented weight loss of up to 24.2% of body weight at 48 weeks, surpassing all other incretin-based therapies including semaglutide and tirzepatide. The addition of glucagon receptor agonism to the established GIP/GLP-1 dual agonist framework is hypothesized to provide additive metabolic benefits through increased energy expenditure, enhanced lipid oxidation, and hepatic fat reduction.
Mechanism of Action
Triple agonist targeting GIP, GLP-1, and glucagon receptors simultaneously. The glucagon receptor activation increases energy expenditure and hepatic fat oxidation.
Research Protocols
For research purposes only. Not medical advice.
Phase 2 research protocols ranged from 1mg to 12mg weekly with dose escalation over 24 weeks.
Research Notes
Clinical Research Status
Retatrutide is in Phase 3 clinical trials (TRIUMPH program) initiated by Eli Lilly in 2023, with multiple trials evaluating efficacy in obesity, type 2 diabetes, and metabolic-associated steatohepatitis (MASH/NASH). The Phase 2 trial (published in NEJM, June 2023) enrolled 338 adults with obesity and demonstrated dose-dependent weight loss reaching 24.2% at the highest dose (12 mg) over 48 weeks. FDA breakthrough therapy or fast track designation has not been publicly confirmed as of early 2025. Eli Lilly targets potential regulatory submission pending Phase 3 results, with market launch potentially in 2026-2027.
Key Published Findings
The pivotal Phase 2 study published in the New England Journal of Medicine (Jastreboff et al., 2023) showed 24.2% mean body weight reduction at 48 weeks with the 12 mg dose, with 100% of participants in the highest dose group achieving at least 5% weight loss. A companion Phase 2 trial in type 2 diabetes patients (Rosenstock et al., Lancet 2023) demonstrated HbA1c reductions of up to 2.02% alongside significant weight loss. Glucagon receptor agonism contributes an estimated 5-7% additional weight loss through increased resting energy expenditure and hepatic lipid mobilization versus GIP/GLP-1 alone. Liver fat reduction of approximately 82% was observed at the highest dose, suggesting potent MASH/NASH therapeutic potential.
Safety Profile
The most common adverse events in Phase 2 trials were gastrointestinal (nausea, diarrhea, vomiting, constipation), occurring primarily during dose escalation and diminishing over time. GI adverse event rates were comparable to other incretin-based therapies despite the superior weight loss efficacy. Glucagon receptor agonism raised theoretical concerns about hyperglycemia, but glucose levels remained well-controlled in both diabetic and non-diabetic participants. Heart rate increases of 2-4 bpm were observed, consistent with other GLP-1 receptor agonists, and no serious cardiovascular signals emerged. Phase 3 trials will provide larger safety datasets needed for regulatory evaluation.
Drug Interactions & Contraindications
As with other GLP-1 receptor agonists, retatrutide slows gastric emptying and may affect absorption of oral medications requiring precise timing (oral contraceptives, levothyroxine, narrow therapeutic index drugs). Concurrent use with insulin or sulfonylureas carries increased hypoglycemia risk and requires dose reduction of the concomitant agent. Contraindicated in patients with personal or family history of medullary thyroid carcinoma or Multiple Endocrine Neoplasia syndrome type 2 (class effect of GLP-1 agonists based on rodent thyroid C-cell findings). Patients with a history of pancreatitis should use with caution given the GLP-1 class label concern, though causal evidence remains debated.
Comparison to Related Compounds
Retatrutide's 24.2% weight loss at 48 weeks exceeds tirzepatide (22.5% at 72 weeks in SURMOUNT-1) and semaglutide 2.4 mg (15.3% at 68 weeks in STEP-1) in cross-trial comparison, though direct head-to-head data is not yet available. The addition of glucagon receptor agonism provides metabolic benefits absent from tirzepatide (GIP/GLP-1 only) including increased energy expenditure and enhanced hepatic fat clearance. Compared to survodutide (Boehringer's GLP-1/glucagon dual agonist), retatrutide adds GIP agonism which may improve tolerability and provide additional anabolic signaling. If Phase 3 confirms Phase 2 results, retatrutide could represent the most effective pharmacological obesity treatment ever developed.
Community Observations
Retatrutide is not yet commercially available, and community access has been limited to clinical trial participants and gray market research peptide sources of uncertain quality. Early reports from trial participants align with published data describing dramatic weight loss with manageable GI side effects during dose titration. The peptide community closely tracks Eli Lilly's Phase 3 TRIUMPH trial results as a potential successor to tirzepatide (Mounjaro/Zepbound). Given its investigational status, most practitioners recommend tirzepatide or semaglutide as established alternatives until retatrutide receives regulatory approval and quality-controlled manufacturing.
Half-Life
~6 days
Reconstitution
Bacteriostatic water (BAC)
Storage
Lyophilized
Refrigerate 2-8C. Protect from light.
Reconstituted
Refrigerate 2-8C. Use within 28 days.
US Legal Status
Also Known As
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