The first triple hormone receptor agonist — simultaneously activating GLP-1, GIP, and glucagon receptors. Currently in Phase 2/3 clinical trials with a ~5-day half-life supporting weekly subcutaneous administration.
Retatrutide (LY3437943) is a triple hormone receptor agonist developed by Eli Lilly — the same company behind tirzepatide. While semaglutide targets one receptor (GLP-1) and tirzepatide targets two (GLP-1 + GIP), retatrutide is the first compound to simultaneously engage all three: GLP-1, GIP, and the glucagon receptor.
The addition of glucagon receptor agonism is pharmacologically significant. Glucagon is traditionally known as insulin's counter-regulatory hormone, but glucagon receptor activation also influences hepatic metabolism and energy expenditure through mechanisms distinct from the incretin pathways. This triple-receptor approach represents an evolution beyond the single and dual agonist compounds currently available.
Retatrutide is currently in Phase 2 and Phase 3 clinical trials. Published Phase 2 data (2023) demonstrated the compound's pharmacological activity across multiple endpoints. As an investigational compound, the pharmacokinetic data available is based on clinical trial publications rather than the extensive post-market data available for semaglutide and tirzepatide.
Retatrutide is not FDA-approved as of early 2026. All pharmacokinetic and dosing data on this page is derived from published clinical trial results. The compound's regulatory status may change as Phase 3 trials are completed and reviewed.
Retatrutide's triple agonism creates a pharmacological profile that engages three distinct but interconnected metabolic pathways simultaneously.
The GLP-1 component mirrors the pharmacology of semaglutide and tirzepatide — potentiating glucose-dependent insulin secretion, slowing gastric emptying, and modulating appetite signaling through central nervous system GLP-1 receptors.
Like tirzepatide, retatrutide activates GIP receptors, which are expressed on pancreatic beta cells, adipose tissue, and bone. The GIP pathway enhances beta-cell sensitivity and has distinct effects on adipose tissue metabolism that complement GLP-1 signaling.
The glucagon receptor component is unique to retatrutide among this compound class. Glucagon receptor activation stimulates hepatic glucose production, lipolysis, and thermogenesis. In the context of concurrent GLP-1/GIP agonism, the glucagon component may contribute to energy expenditure through metabolic pathways that neither incretin receptor activates alone.
The interplay between these three receptor systems creates a pharmacological profile that is not simply additive. The glucagon component's catabolic effects are modulated by the concurrent incretin activity — GLP-1 and GIP maintain glycemic control while glucagon receptor activation drives additional metabolic processes.
Retatrutide's pharmacokinetic profile is characterized from Phase 1 and Phase 2 clinical trial data. The parameters support once-weekly subcutaneous dosing.
| Parameter | Value |
|---|---|
| Half-Life | ~120 hours (~5 days) |
| Bioavailability (SubQ) | ~95% (estimated) |
| Time to Peak (Tmax) | ~48 hours |
| Duration of Activity | ~336 hours (~14 days) |
| Time to Steady State | ~3.5–4 weeks |
| Route | Subcutaneous |
| Evidence Level | Phase 2/3 clinical trials |
Retatrutide's ~120-hour half-life places it in the same pharmacokinetic class as tirzepatide — both reach steady state in approximately 3.5–4 weeks and support once-weekly dosing with similar peak-to-trough profiles. The albumin-binding fatty acid chain mechanism responsible for the extended half-life is analogous to the approach used in both semaglutide and tirzepatide.
| Parameter | Semaglutide | Tirzepatide | Retatrutide |
|---|---|---|---|
| Receptors | GLP-1 | GLP-1, GIP | GLP-1, GIP, Glucagon |
| Half-Life | ~7 days | ~5 days | ~5 days |
| Dose Range | 0.25–2.5 mg | 2.5–15 mg | 0.5–12 mg |
| Time to SS | ~4.5 weeks | ~3.5 weeks | ~3.5 weeks |
| Approval | FDA Approved | FDA Approved | Phase 2/3 Trials |
The following titration schedule is based on published Phase 2 clinical trial protocols. As an investigational compound, dosing patterns may evolve as more clinical data becomes available.
Retatrutide's titration begins at 0.5 mg — lower than tirzepatide's 2.5 mg starting dose. The lower starting point reflects the compound's triple-receptor potency. The glucagon receptor component adds pharmacological activity beyond what the incretin receptors provide alone, warranting a more conservative initial dose.
As retatrutide becomes available through compounding pharmacies, observed community protocols vary. Common patterns include slower titration schedules (2 mg → 4 mg → 6 mg → 8 mg) and maintenance at lower doses (4–8 mg) rather than escalating to 12 mg. Protocol tracking helps maintain consistency regardless of the titration approach chosen.
Compounded lyophilized retatrutide requires reconstitution before use. The process follows standard peptide preparation procedures.
Compounded retatrutide vials commonly come in 5 mg, 10 mg, or 15 mg sizes. Confirm the exact total content on the vial label — this determines your water volume calculation.
Clean the rubber stoppers on both the retatrutide vial and bacteriostatic water vial with fresh alcohol swabs. Allow to fully air dry before piercing.
Use the Milligram calculator for exact volumes. Example: a 10 mg vial + 2 mL bac water = 5 mg/mL. For a 2 mg dose, draw 0.4 mL (40 units on a U-100 syringe).
Draw your calculated bacteriostatic water volume and inject slowly into the retatrutide vial, aiming the stream against the glass wall. Never spray directly onto the lyophilized powder cake.
Swirl the vial with a gentle rolling motion until the powder dissolves completely. The solution should be clear and colorless. If particulates remain after 2–3 minutes of gentle swirling, do not use the vial.
Refrigerate immediately at 2–8°C after reconstitution. Mark the date and concentration on the vial. Reconstituted with bacteriostatic water, stability is generally estimated at up to 28 days refrigerated.