Also known as: LY3437943, GGG tri-agonist, GLP-1/GIP/Glucagon Agonist
Half-life: ~6 days (~144 hours)
Last reviewed: · Published:
Retatrutide (LY3437943) is an investigational once-weekly injectable peptide developed by Eli Lilly as a triple agonist at three incretin / glucoregulatory receptors: GLP-1 (like Semaglutide), GIP (added in Tirzepatide), and glucagon. The addition of glucagon-receptor agonism is the key conceptual innovation: glucagon activation increases energy expenditure and hepatic fat oxidation, complementing the appetite-suppression and insulin-sensitizing effects of GLP-1 and GIP and producing weight loss that exceeds anything previously reported for an injectable agent.
In the Phase 2 obesity trial published in the New England Journal of Medicine in 2023, Retatrutide produced mean weight loss of 24.2% at the highest dose (12 mg weekly) over 48 weeks — substantially exceeding the ~21% peak seen with high-dose Tirzepatide (SURMOUNT-1) and the ~15% with high-dose Semaglutide (STEP-1) at comparable time points. Approximately 100% of subjects on the 12 mg dose achieved ≥5% weight loss, and the weight loss trajectory had not plateaued at 48 weeks — suggesting longer dosing periods would produce further losses. The compound is currently in the Phase 3 TRIUMPH trial program for obesity and the SYNERGY-NASH and FRONTIER trials for metabolic dysfunction-associated steatohepatitis (MASH) and type 2 diabetes.
Retatrutide is not yet FDA approved as of this writing — the TRIUMPH-1 Phase 3 obesity trial is expected to read out in 2026, with FDA submission likely in 2026-2027. It is widely sold by research-peptide vendors at substantial markups, and is used in self-experimentation by users seeking the strongest available weight loss. The side-effect profile is broadly similar to Tirzepatide and Semaglutide (gastrointestinal effects dominate), with the addition of glucagon-mediated effects on heart rate and possibly hepatic glucose output that are still being characterized.
Retatrutide was developed at Eli Lilly as the natural extension of their work on Tirzepatide (dual GLP-1/GIP agonist), with the addition of glucagon-receptor agonism aimed at incorporating the energy-expenditure-increasing arm of the metabolic axis. The compound entered clinical trials in 2019. Initial Phase 1 and Phase 2 data in type 2 diabetes (2022) and obesity (2023) generated significant scientific and investor interest as the magnitude of weight loss exceeded all prior incretin-based therapies. Lilly's Phase 3 TRIUMPH program is underway, with TRIUMPH-1 in obesity and TRIUMPH-4 in obesity with cardiovascular disease being the lead obesity studies; SYNERGY-NASH addresses the MASH indication.
Phase 2 Retatrutide trial tolerability has been broadly comparable to Tirzepatide and Semaglutide — gastrointestinal effects (nausea, vomiting, diarrhea) dominate and are dose-dependent, occurring most frequently during dose escalation and waning over time. The glucagon-receptor activation adds modest tachycardia (1-3 bpm increase at higher doses) and slightly more pronounced effects on hepatic glucose output that require careful dose titration in subjects with diabetes. Dropout rates due to adverse events in Phase 2 were broadly in line with other incretins. As with all GLP-1-class compounds, pancreatitis monitoring is appropriate and the FDA black-box warning for thyroid C-cell tumors (based on rat data) carries over to this class.
Dose Range
1-12 mg
Frequency
Once weekly (SubQ), dose-titrated
Duration
Long-term per clinical protocol
Dose Range
0.5 mg start, titrate to tolerance
Frequency
Once weekly
Duration
Long-term with careful titration
Dosing information is for educational purposes only. Consult a healthcare professional before using any peptide.
Typical Vial Size
10 mg
Water Type
Bacteriostatic water (BAC water)
Mixing Volume
2 mL
Half-Life
~6 days (~144 hours)
Molecular Weight
~4,731 Da
Store reconstituted vial refrigerated at 2-8°C. Use within 30 days. Once-weekly subcutaneous injection in abdomen, thigh, or upper arm. Start at the lowest practical dose (typically 0.5-1 mg weekly) and titrate up over 4-8 week intervals to minimize gastrointestinal adverse events.
FDA Status
Not FDA approved. In Phase 3 clinical trials (TRIUMPH program for obesity, SYNERGY-NASH for MASH). FDA submission anticipated 2026-2027 pending Phase 3 readouts.
Legal Status
Unregulated research chemical. Prohibited by WADA (incretin-class).
USA
Not approvedPhase 3 trials in progress (TRIUMPH program); FDA filing expected 2026-2027
EU
Not approvedPhase 3 trials in progress; EMA filing expected after Phase 3 readout
UK
Not approvedResearch-only; classified as research chemical
Australia
Not approvedTGA has not authorized
Canada
Not approvedNot authorized for human use
Jastreboff AM, Kaplan LM, Frías JP, Wu Q, Du Y, Gurbuz S, Coskun T, Haupt A, Milicevic Z, Hartman ML
New England Journal of Medicine (2023)
Pivotal Phase 2 obesity trial showing 24.2% mean weight loss at 12 mg weekly over 48 weeks in adults with obesity — the strongest weight-loss effect reported for any pharmacological agent and the data set that drove Retatrutide into Phase 3.
View Study →Rosenstock J, Frías JP, Jastreboff AM, Du Y, Lou J, Gurbuz S, Thomas MK, Hartman ML, Haupt A, Milicevic Z, Coskun T
The Lancet (2023)
Phase 2 type 2 diabetes trial demonstrating substantial HbA1c reductions and weight loss with Retatrutide in T2D patients, supporting parallel development for the diabetes indication alongside obesity.
View Study →Müller TD, Blüher M, Tschöp MH, DiMarchi RD
Nature Reviews Drug Discovery (2022)
Authoritative review of the rationale for incretin-based combination therapies including triple agonists like Retatrutide, with a focus on how glucagon-receptor activation complements GLP-1 and GIP signaling to amplify weight loss.
View Study →GLP-1 receptor agonist revolutionizing the treatment of obesity and type 2 diabetes.
Dual GIP/GLP-1 receptor agonist delivering unprecedented weight loss and metabolic benefits.
Fat-metabolizing fragment of human growth hormone without growth-promoting effects.
The unmodified C-terminal fragment of growth hormone — the original lipolytic peptide.
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