Retatrutide
Triple Incretin Receptor AgonistinvestigationalAlso known as: LY3437943, GGG Triple Agonist
An investigational triple-agonist peptide targeting GLP-1, GIP, and glucagon receptors, producing unprecedented weight loss of up to 24% in clinical trials.
Overview
Retatrutide is a novel investigational peptide developed by Eli Lilly that simultaneously activates three incretin-related receptors: GLP-1, GIP (glucose-dependent insulinotropic polypeptide), and glucagon receptors. This triple-agonist approach represents the next frontier beyond dual agonists like tirzepatide. In Phase 2 trials, retatrutide produced remarkable weight loss of up to 24.2% at 48 weeks — the highest reported for any anti-obesity medication to date. The glucagon receptor component adds direct hepatic fat reduction and increased energy expenditure beyond what GLP-1/GIP dual agonism achieves. Retatrutide is currently in Phase 3 clinical trials for obesity and type 2 diabetes, with potential approval expected around 2026-2027.
Mechanism of Action
Retatrutide is a single molecule that activates three distinct receptors: (1) GLP-1 receptor — promotes insulin secretion, suppresses appetite, and slows gastric emptying; (2) GIP receptor — enhances insulin secretion, improves fat metabolism, and may have central weight-regulatory effects; (3) Glucagon receptor — increases hepatic glucose output (counterbalanced by GLP-1/GIP insulin effects), stimulates energy expenditure, promotes lipolysis, and reduces hepatic fat. The glucagon component uniquely drives thermogenesis and liver fat reduction, explaining the superior weight loss compared to dual agonists.
Molecular Formula
Investigational (not fully disclosed)
Molecular Weight
~4500 g/mol (estimated)
Sequence
Modified peptide with GLP-1, GIP, and glucagon receptor binding domains (proprietary)
Dosage Protocols
Dose Range
1mg – 12mg
Frequency
Once weekly
Route
subcutaneous
Cycle Length
48 weeks (trial duration)
Phase 2 trial used dose escalation to 1mg, 4mg, 8mg, or 12mg weekly. The 12mg group achieved 24.2% weight loss. Gradual titration required to manage GI side effects.
Source: Phase 2 clinical trial (Jastreboff et al., NEJM 2023)
Side Effects
| Effect | Severity |
|---|---|
| Nausea | moderate |
| Diarrhea | mild |
| Vomiting | moderate |
| Constipation | mild |
| Decreased appetite | mild |
| Increased heart rate | mild |
Pros & Cons
Produces the highest weight loss of any anti-obesity drug tested to date (up to 24.2% at 48 weeks)
Triple receptor agonism provides unique benefits including direct liver fat reduction via glucagon signaling
Convenient once-weekly injection
Strong HbA1c reductions for diabetes management alongside weight loss
Still investigational — not yet approved, Phase 3 trials ongoing
High rates of GI side effects typical of the incretin class
Long-term safety data not yet available
Glucagon receptor activation theoretically risks hyperglycemia, though balanced by GLP-1/GIP effects in trials
Research Studies
Legal Status
Investigational — not yet approved by any regulatory agency. Currently in Phase 3 clinical trials (Eli Lilly). Not available for prescription or research purchase.
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