Retatrutide
LY3437943 · Triple-G agonist · GGG
−24.2% body weight at 48 weeks, 12 mg (Phase 2, NEJM 2023)
Overview
Retatrutide is a single-molecule triple agonist of the GIP, GLP-1, and glucagon receptors — sometimes called a 'triple-G' agonist. Adding glucagon-receptor activity to the dual-incretin mechanism is thought to increase energy expenditure on top of appetite suppression.
In a 48-week Phase 2 trial (338 adults), the 12 mg dose produced a mean body-weight reduction of about 24.2% versus roughly 2.1% on placebo — among the largest reductions reported for a pharmacological agent — with weight still trending downward at the end of the study. The same molecule reached about 17.5% mean reduction at the 24-week interim. Phase 3 confirmation (the TRIUMPH program) is ongoing.
Because efficacy figures derive from a single Phase 2 study and the compound is not approved, the data below should be treated as preliminary; the headline weight-loss and adverse-event numbers are drawn from the published NEJM 2023 report.
Key parameters
- Dose range
- 1–12 mg weekly (trial range)
- Frequency
- Once weekly
- Half-life
- ~6 days (≈144 h)
- Route
- Subcutaneous
- Vial sizes
- 10 mg · 20 mg · 30 mg
- Regulatory status
- Investigational. In Phase 3 development (TRIUMPH program) as of 2026; not approved by any regulator. Research-vial material is for laboratory use only.
Mechanism of action
GLP-1 receptor agonism
Suppresses appetite and improves glucose-dependent insulin secretion.
GIP receptor agonism
Second incretin axis contributing to appetite and metabolic effects.
Glucagon receptor agonism
Increases energy expenditure and hepatic lipid mobilization, the feature distinguishing retatrutide from dual agonists.
Dosing protocol & phases
| Phase | Weeks | Dose | Notes |
|---|---|---|---|
| Initiation | Weeks 1–4 | 2 mg once weekly | Phase 2 used a 2 mg start; the lower starting dose meaningfully blunted early GI effects versus a 4 mg start. |
| Titration | Every 4 weeks | Step up toward assigned target | Phase 2 evaluated targets of 4, 8, and 12 mg. |
| Maintenance | Ongoing | Up to 12 mg once weekly | Highest dose studied in Phase 2. |
Reconstitution guide
For educational and research reference only. Not intended for human consumption, not medical advice. Compounds discussed are sold and used for laboratory research purposes only.
10 mg vial + 2 mL bacteriostatic water
Concentration5,000 mcg/mL · 5 mg/mL
| Target dose | Draw volume | U-100 units |
|---|---|---|
| 2,000 mcg | 0.4 mL | 40 |
| 4,000 mcg | 0.8 mL | 80 |
Suited to the lower titration range (2–4 mg).
30 mg vial + 2 mL bacteriostatic water
Concentration15,000 mcg/mL · 15 mg/mL
| Target dose | Draw volume | U-100 units |
|---|---|---|
| 4,000 mcg | 0.267 mL | 26.7 |
| 8,000 mcg | 0.533 mL | 53.3 |
| 12,000 mcg | 0.8 mL | 80 |
Higher-strength mix that keeps 8–12 mg draws inside a 100-unit syringe.
Reconstitution calculator
Pre-filled with Retatrutide's vial sizes. Adjust the water volume and target dose to see the exact draw, with warnings for doses that are hard to measure or won't fit a syringe.
At 5,000 micrograms per millilitre, a 2,000 microgram dose is 0.4 millilitres, or 40 units on a U-100 syringe, giving 5 doses per vial.
Supplies needed
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Recommended supply
Retatrutide — research vial
From our verified partner Dynotides, with a third-party certificate of analysis per batch.
Injection supplies
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Bacteriostatic water
Diluent for reconstituting lyophilized vials.
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Insulin syringes (U-100)
0.3–0.5 mL, 29–31 G for accurate small draws.
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Alcohol prep pads
Sterile swabs for the vial stopper and site.
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Sharps container
Safe disposal of used needles.
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Storage fridge
Keeps reconstituted vials at 2–8 °C.
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Insulated travel case
Cooled, TSA-friendly case for travel.
Missed-dose guidance
No approved-label guidance exists because retatrutide is investigational. As a long-acting once-weekly agent, the practical convention used for comparable incretins is to take a delayed dose if several days remain before the next one and otherwise to skip it and resume the weekly schedule, never doubling up.
Side effects & safety
| Category | Effect | Trial incidence |
|---|---|---|
| Gastrointestinal | Nausea12 mg group, NEJM 2023 Phase 2; clearly dose-dependent and concentrated during escalation. | 47% |
| Gastrointestinal | DiarrheaCommon and dose-related in Phase 2 (reported roughly in the 20–33% range across higher-dose arms); a single exact 12 mg figure is not uniformly reported across summaries, so left unquantified. | — |
| Gastrointestinal | Vomiting12 mg group, NEJM 2023 Phase 2. | 21% |
| Gastrointestinal | ConstipationReported on the order of ~20% at higher doses; mild–moderate. | — |
| Cardiovascular | Resting heart-rate increaseDose-dependent rise (roughly 5–11 bpm at higher doses) that peaked near week 24 and then declined — a recognized class effect of glucagon-containing agonists. | — |
| Metabolic | Transient rises in glucose/HbA1c at the highest dose early onAttributed to the glucagon component; offset over time by weight loss in the obesity cohort. | — |
Clinical trials & evidence
Phase 2 obesity trial
Phase 248 weeks · 338 adults with obesity
Up to −24.2% body weight at 12 mg; weight not yet plateaued at 48 weeks.
NCT04881760 ↗TRIUMPH-1 (Phase 3)
Phase 3Ongoing · Adults with obesity
Confirmatory efficacy/safety study; results pending.
NCT05929066 ↗
Storage & handling
- Lyophilized
- Refrigerate the lyophilized powder at 2–8 °C, protected from light; brief room-temperature excursions in transit are generally tolerated for peptides of this class.
- Reconstituted
- Refrigerate at 2–8 °C and use within ~28 days; do not freeze.
Comparisons
| Vs. | Target | Half-life | Dosing | Efficacy | Status |
|---|---|---|---|---|---|
| Tirzepatide | GIP + GLP-1 + glucagon vs GIP + GLP-1 | ~6 d vs ~5 d | Weekly (both) | −24.2% vs −20.9% (different trials) | Investigational vs approved |
| Semaglutide | Triple vs GLP-1 | ~6 d vs ~7 d | Weekly (both) | −24.2% vs −14.9% (different trials) | Investigational vs approved |
Featured in these stacks
Cagrilintide + Retatrutide
This is the most aggressive weight-loss combination on paper: it stacks the long-acting amylin analog cagrilintide on top of retatrutide, the triple-G agonist that activates the GIP, GLP-1, and glucagon receptors at once. Retatrutide alone produced the largest weight reductions reported for any pharmacological agent in its Phase 2 trial — about 24% at 48 weeks, with the curve still falling — and the glucagon component adds an energy-expenditure mechanism on top of the appetite suppression shared with other incretins. Adding amylin-mediated satiety layers a fourth, mechanistically distinct hunger signal onto that base.
Retatrutide + MOTS-c
This pairing combines a powerful appetite-and-expenditure agent with a metabolic-conditioning peptide. Retatrutide, the triple-G agonist (GIP/GLP-1/glucagon), drives the weight loss — appetite suppression plus glucagon-mediated energy expenditure. MOTS-c is a mitochondrial-derived peptide encoded within the 12S rRNA gene that activates AMPK and is reported to improve insulin sensitivity, glucose handling, and metabolic flexibility, acting in skeletal muscle as a so-called 'exercise mimetic.'
Sources & references
- [1]Jastreboff AM et al. Triple–Hormone-Receptor Agonist Retatrutide for Obesity — a Phase 2 Trial. N Engl J Med 2023;389:514–526. ↗ source
- [2]Eli Lilly — Phase 2 retatrutide results published in NEJM (up to 24.2% weight reduction at 48 weeks). ↗ source
- [3]ClinicalTrials.gov — Retatrutide Phase 2 obesity trial (NCT04881760). ↗ source
Frequently asked questions
What makes retatrutide a 'triple agonist'?
It activates three receptors — GIP, GLP-1, and glucagon. The glucagon component is thought to add an energy-expenditure effect on top of the appetite suppression shared with dual agonists, which may explain why its Phase 2 weight loss outran approved dual and single agonists.
Is retatrutide approved?
No. As of 2026 it remains investigational and in Phase 3 development (TRIUMPH). The figures here come from a single Phase 2 trial.
Why does the heart rate go up, and does it stay elevated?
A modest, dose-dependent rise in resting heart rate is typical of glucagon-receptor activity. In the Phase 2 trial it peaked around week 24 and then declined, but cardiovascular safety is precisely what the larger Phase 3 program is designed to characterize.
Related protocols
Tirzepatide
Mounjaro
−20.9% body weight at 72 weeks, 15 mg (SURMOUNT-1)
Semaglutide
Ozempic
−14.9% mean body weight at 68 weeks (STEP 1)
Cagrilintide
AM833
−10.8% body weight at 26 weeks (monotherapy, Lancet 2021)
MOTS-c
Mitochondrial-derived peptide
Mitochondrial-derived peptide regulating metabolic homeostasis (preclinical)
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For educational and research reference only. Not intended for human consumption, not medical advice. Compounds discussed are sold and used for laboratory research purposes only.