Retatrutide (LY3437943): Triple Agonist Research Profile
LY3437943Triple G agonist
Retatrutide is a 39-amino-acid peptide that represents the first triple incretin receptor agonist to reach Phase 2 clinical trials. Developed by Eli Lilly under the designation LY3437943, it simultaneously activates GLP-1, GIP, and glucagon receptors. The addition of glucagon receptor agonism is the key differentiator from existing dual-agonists like tirzepatide (GLP-1/GIP only). Glucagon receptor activation drives hepatic glycogenolysis, lipolysis, and thermogenesis — energy-expenditure mechanisms that are absent from GLP-1-only or GLP-1/GIP compounds. Phase 2 trial data published in the New England Journal of Medicine showed unprecedented weight reduction of 24.2% at 48 weeks, surpassing all previously reported pharmacological weight management outcomes.
Technical Specifications
CAS Number
2381089-83-2
Molecular Formula
C225H348N48O68
Molecular Weight
4803.56 g/mol
Amino Acids
39
Sequence
39-amino-acid triple agonist with GLP-1, GIP, and glucagon receptor activity
Purity
≥99% (HPLC)
Appearance
White lyophilized powder
Salt Form
Acetate
Solubility
Soluble in water
Storage
-20°C lyophilized, 2-8°C reconstituted
Origin & Discovery
Retatrutide (LY3437943) was developed by Eli Lilly as a novel triple incretin receptor agonist. It is engineered to activate three receptors simultaneously: GLP-1, GIP (glucose-dependent insulinotropic polypeptide), and glucagon receptors. This triple-agonist design represents the next generation beyond single-agonist (semaglutide) and dual-agonist (tirzepatide) compounds.
Mechanism of Action
Retatrutide's triple-agonist design engages three complementary metabolic receptor systems.
GLP-1 Receptor Agonism: Like semaglutide, retatrutide activates the GLP-1 receptor to enhance glucose-dependent insulin secretion, reduce appetite through hypothalamic signaling, and delay gastric emptying. This pathway is well-validated for both glycemic control and weight management.
GIP Receptor Agonism: Glucose-dependent Insulinotropic Polypeptide (GIP) receptor activation complements GLP-1 effects on insulin secretion and may enhance fat metabolism. GIP receptor signaling in adipose tissue modulates lipid storage and energy balance. The GIP component follows the approach validated by tirzepatide.
Glucagon Receptor Agonism: The novel third component. Glucagon receptor activation increases hepatic glucose output, promotes hepatic and adipose tissue lipolysis, and enhances thermogenesis (energy expenditure as heat). This drives a net increase in energy expenditure that compounds the appetite-reducing effects of GLP-1/GIP agonism. The glucagon component may also promote hepatic fat oxidation, which is of interest for NASH research.
The combination of reduced energy intake (GLP-1 appetite suppression) with increased energy expenditure (glucagon thermogenesis) creates a dual mechanism for energy balance modification that is not achievable with single or dual agonists alone.
Phase 2 Clinical Trial Data
Jastreboff et al. (2023) published Phase 2 results in the New England Journal of Medicine. The trial enrolled 338 participants with obesity (BMI ≥30) or overweight (BMI ≥27) with weight-related comorbidities. At the highest dose (12 mg), retatrutide produced a mean body weight reduction of 24.2% at 48 weeks, compared to 2.1% with placebo. This 24.2% figure exceeded all previously published pharmacological weight reduction outcomes, including semaglutide 2.4 mg (14.9% in STEP 1) and tirzepatide 15 mg (22.5% in SURMOUNT-1). Notably, 100% of participants in the 12 mg group achieved ≥5% weight loss, and 93% achieved ≥10%. The trial also demonstrated significant improvements in glycemic parameters, with HbA1c reductions observed across all dose groups.
Citations
Jastreboff AM, et al. (2023) "Retatrutide Phase 2 trial results." N Engl J Med, 389(6), 514-526.
Frequently Asked Questions
What is Retatrutide?▼
Retatrutide (LY3437943) is a 39-amino-acid triple incretin receptor agonist developed by Eli Lilly. It simultaneously activates GLP-1, GIP, and glucagon receptors. Phase 2 data showed 24.2% mean weight reduction at 48 weeks, the highest ever reported for a pharmacological agent.
How does Retatrutide differ from Tirzepatide?▼
Tirzepatide is a dual agonist (GLP-1/GIP) while Retatrutide is a triple agonist (GLP-1/GIP/glucagon). The added glucagon receptor activation drives thermogenesis and lipolysis, contributing to greater weight reduction in clinical trials (24.2% vs 22.5%).
How does Retatrutide compare to Semaglutide?▼
Semaglutide is a single GLP-1R agonist (14.9% weight reduction in STEP 1). Retatrutide adds GIP and glucagon receptor agonism, achieving 24.2% weight reduction in Phase 2. The triple mechanism combines appetite suppression with increased energy expenditure.