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Retatrutide (Triple Agonist GLP-1/GIP/Glucagon)
Also known as: LY3437943, Eli Lilly Triple Agonist, GGG Triagonist
Confidence
Updated 2026-03-18
Retatrutide is a novel triple-agonist peptide developed by Eli Lilly that activates GLP-1, GIP, and glucagon receptors simultaneously. In Phase II trials, it produced the largest weight loss ever observed with a drug therapy — up to 24.2% body weight reduction at 48 weeks. The addition of glucagon receptor agonism to the dual GLP-1/GIP mechanism (tirzepatide) is theorized to enhance energy expenditure and hepatic fat reduction.
Class
Triple Incretin Receptor Agonist (GLP-1/GIP/Glucagon)
Routes
Subcutaneous
Half-Life
~6 days (enabling once-weekly dosing)
Retatrutide simultaneously activates three receptors: GLP-1R (appetite suppression, insulin secretion, gastric emptying delay), GIPR (enhanced insulin response, potential fat metabolism effects), and glucagon receptor (increased energy expenditure, hepatic glycogenolysis, lipolysis, thermogenesis). The glucagon component is the key differentiator — it increases basal metabolic rate and hepatic fat oxidation, potentially explaining the superior weight loss. Balanced agonism prevents glucagon-induced hyperglycemia through GLP-1/GIP counterregulation.
Half-Life
~6 days (enabling once-weekly dosing)
Bioavailability
Subcutaneous: expected high (similar to tirzepatide)
No approved indications. Under investigation for: obesity, type 2 diabetes, MASLD/MASH (metabolic-associated steatotic liver disease). Phase III trials active.
Phase II trial (n=338, published NEJM 2023): 24.2% mean body weight loss at highest dose (12mg) at 48 weeks. 26% of participants on 12mg lost ≥30% body weight. Dramatic MASLD improvement — 86% of participants with fatty liver disease showed resolution on MRI. HbA1c reductions similar to tirzepatide. These are the most impressive weight loss results for any drug therapy to date. Phase III TRIUMPH trials ongoing — results expected 2025–2026.
Human Studies
5
Animal Studies
15
Phase II: nausea (22–28%), diarrhea (17–22%), vomiting (8–13%), constipation. Similar GI side effect profile to GLP-1 agonists. Dose-dependent. Heart rate increase observed at higher doses (glucagon effect). No pancreatitis signals in Phase II. Long-term safety unknown — Phase III will be critical. Theoretical concerns: excessive weight loss, sarcopenia, gallbladder events, thyroid signals.
Investigational. Eli Lilly Phase III (TRIUMPH program). Potential for FDA approval 2026–2027 if Phase III succeeds. Likely to be a blockbuster if approved. No compounded versions available.
Drug Interactions: Expected similar to semaglutide/tirzepatide — hypoglycemia risk with insulin/sulfonylureas, delayed gastric emptying affecting oral drug absorption. Monitoring: Body weight, A1C, liver function (MASLD applications), heart rate, renal function, GI tolerability. Research Gaps: Phase III efficacy confirmation. Long-term cardiovascular outcomes. Sarcopenia/lean mass preservation. Head-to-head with tirzepatide.
Subcutaneous (Phase II trial dosing)
Common Range
0.5 mg → 8–12 mg (target dose)
Timing
Once weekly
Frequency
Weekly
Cycling
Dose escalation over 20–24 weeks: starting at 0.5mg weekly with gradual titration to target dose
Important Note
NOT FDA-approved. Phase III dosing may differ from Phase II. Not available outside of clinical trials. Doses based on published Phase II data.
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Dual GIP/GLP-1 Receptor Agonist
Tirzepatide is a dual glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 receptor agonist approved for type 2 diabetes and chronic weight management. It represents a novel dual-incretin approach that has demonstrated superior weight loss and glycemic control compared to selective GLP-1 agonists in multiple Phase III trials.
GLP-1 Receptor Agonist
Semaglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist approved for type 2 diabetes and chronic weight management. It represents the leading edge of the incretin-based therapy revolution and has become one of the most widely prescribed peptide therapeutics globally. Available in both injectable (Ozempic, Wegovy) and oral (Rybelsus) formulations.
GLP-1 Receptor Agonist
Liraglutide is a GLP-1 receptor agonist FDA-approved for type 2 diabetes (Victoza) and chronic weight management (Saxenda). As an acylated GLP-1 analog with 97% homology to native GLP-1, it was one of the first once-daily GLP-1 agonists to gain widespread clinical adoption and paved the way for longer-acting agents like semaglutide.
GLP-1 Receptor Agonist
Exenatide is a synthetic form of exendin-4, a peptide originally isolated from Gila monster venom, and was the first GLP-1 receptor agonist approved by the FDA. Available as twice-daily (Byetta) and once-weekly (Bydureon) formulations, it established the GLP-1 agonist class as a cornerstone of diabetes management.
Disclaimer: This content is for educational and informational purposes only and does not constitute medical advice. Always consult with a licensed healthcare provider before starting, stopping, or modifying any peptide therapy. PeptideSupplierMatch does not prescribe, sell, or distribute peptides.
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