Overview
Retatrutide (LY3437943, GLP-3 R) is a novel triple agonist developed by Eli Lilly that simultaneously activates three incretin and metabolic hormone receptors: the glucose-dependent insulinotropic polypeptide receptor (GIPR), the glucagon-like peptide-1 receptor (GLP-1R), and the glucagon receptor (GCGR). This triple agonism represents the next generation of metabolic peptide therapeutics, building on the success of GLP-1 agonists (semaglutide) and dual GIP/GLP-1 agonists (tirzepatide). Phase II clinical trial data published in the New England Journal of Medicine (2023) demonstrated that retatrutide produced up to 24.2% mean body weight reduction at 48 weeks — the largest weight loss observed for any pharmacological agent in a clinical trial to date, surpassing even tirzepatide's results.
Mechanism of Action
Retatrutide's mechanism of action involves simultaneous activation of three receptors with complementary metabolic effects. GLP-1R activation provides glucose-dependent insulin secretion, glucagon suppression, gastric emptying delay, and central appetite suppression. GIPR activation enhances insulin secretion and may contribute to the superior weight loss observed with dual/triple agonists compared to GLP-1R agonists alone. GCGR activation is the distinguishing feature of retatrutide: glucagon receptor stimulation increases hepatic glucose production (which is counterbalanced by the GLP-1R-mediated insulin secretion), but more importantly, it increases energy expenditure through thermogenic
Research Evidence
- Up to 24.2% mean body weight reduction at 48 weeks in Phase II trial (Jastreboff et al., NEJM 2023)
- Triple agonism: GIPR + GLP-1R + GCGR — broadest incretin receptor coverage of any approved/investigational agent
- GCGR activation increases energy expenditure via brown adipose thermogenesis and hepatic FAO
- Significant reductions in HbA1c and fasting glucose in subjects with type 2 diabetes
- Once-weekly dosing enabled by C18 fatty diacid modification for albumin binding
Bottom line: Retatrutide is arguably the most scientifically exciting compound in this entire catalog right now. Its Phase 2 NEJM data showing 24% weight loss is unprecedented, and its triple-receptor mechanism is at the cutting edge of metabolic research. It is an investigational compound with no current regulatory approval, supplied for laboratory research use only.
Research Protocols & Dosage
Evidence-based research protocols, administration routes, and dosage considerations for GLP-3 R are detailed in the full compound profile. See also: Dosage guide for GLP-3 R.
Sourcing & Quality
GLP-3 R is available from Purgo Labs with third-party COA verification and research-grade purity standards. View GLP-3 R at Purgo Labs.