What is Retatrutide?
Retatrutide (LY3437943) is a novel once-weekly subcutaneous investigational peptide developed by Eli Lilly. It is the first clinical candidate to simultaneously activate all three of the GLP-1, GIP, and glucagon receptors — a mechanism researchers call 'triple G' agonism. Phase II data published in the New England Journal of Medicine in 2023 showed unprecedented weight reductions averaging up to 24.2% at the highest dose after 48 weeks, surpassing any previously reported pharmacological weight-loss signal. Phase III trials are ongoing as of mid-2025.
Mechanism of action
GLP-1 receptor agonism reduces appetite and slows gastric emptying. GIP receptor agonism enhances insulin secretion and may support adipose tissue remodeling. Glucagon receptor agonism stimulates hepatic fat oxidation and energy expenditure, potentially counteracting the metabolic adaptation to caloric restriction. The combination of all three signals is hypothesized to produce additive or synergistic weight loss while preserving more metabolic rate than single-agonist approaches.
Researched benefits
- Phase II trial: up to 24.2% mean body weight reduction at 48 weeks (highest dose group)
- Significant reductions in waist circumference, blood pressure, and lipid markers
- Improvements in glucose and insulin resistance markers across all dose groups
- Reductions in liver fat fraction suggesting benefit in metabolic-associated steatohepatitis (MASH)
- Greater fat mass loss relative to lean mass loss compared to GLP-1 agonists in exploratory analyses
Researched dosage
Most research protocols use 1000–12000 mcg administered 1× per day via subcutaneous injection. Phase II studied doses of 1, 2, 4, 8, and 12 mg weekly with a titration scheme similar to other GLP-1 class agents. As retatrutide is still investigational, doses outside of clinical trials are not established. Dose values are in mcg for consistency with the database schema (1000–12000 mcg = 1–12 mg).
A typical cycle runs 48 weeks on, then 0 weeks off before reassessment.
Use the calculator below to convert your target Retatrutide dose into exact insulin-syringe units.
Reconstitution & storage
A standard 5 mg vial reconstituted with 2 mL of bacteriostatic water yields 2500 mcg/mL. As an investigational compound, retatrutide is not commercially available. Research samples should be stored per manufacturer specification, typically at 2–8°C.
Side effects & considerations
- Nausea, vomiting, diarrhea, and constipation (class effects, common during titration)
- Decreased appetite (intended pharmacological effect)
- Injection-site reactions
- Possible thyroid C-cell and pancreatitis signal consistent with GLP-1 class
Retatrutide stacks
- Lean-Mass Preservation During Aggressive Weight Loss — paired with Ipamorelin, Sermorelin. Preserve skeletal muscle during rapid weight reduction. Given the scale of weight loss seen with retatrutide, researchers have modeled pairing with GH secretagogues (Ipamorelin, Sermorelin) to study lean-mass preservation during aggressive caloric deficit. This is a research hypothesis, not a clinical recommendation.
Selected research
- Retatrutide, a GIP, GLP-1, and glucagon receptor agonist, for people with type 2 diabetes — The Lancet, 2023
- Triple hormone receptor agonist retatrutide for obesity: a phase 2 trial — New England Journal of Medicine, 2023
- GIP, GLP-1, and glucagon receptor triple agonism as a therapeutic approach for metabolic disease — Nature Reviews Endocrinology, 2022