LY3437943 · GIP / GLP-1 / Glucagon Triple Agonist
A triple receptor agonist targeting GIP, GLP-1 and glucagon receptors simultaneously. Currently the most potent metabolic compound in clinical research, demonstrating unprecedented fat loss results in Phase II trials.
Retatrutide (LY3437943) is an investigational drug developed by Eli Lilly that simultaneously activates three metabolic hormone receptors: glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1) and glucagon receptors. This triple-agonist mechanism distinguishes it from semaglutide (GLP-1 only) and tirzepatide (GIP/GLP-1 dual agonist), and has produced superior weight loss results in head-to-head research contexts.
Each receptor agonism contributes differently to the compound's metabolic effects:
GLP-1 agonism: Slows gastric emptying, reduces appetite, improves insulin sensitivity and glucose-dependent insulin secretion — the same mechanism responsible for Ozempic's effects.
GIP agonism: Amplifies insulin secretion, has direct effects on fat tissue metabolism and appears to complement GLP-1 agonism synergistically rather than additively.
Glucagon agonism: Increases resting energy expenditure (metabolic rate), promotes fat oxidation in the liver and has thermogenic effects — this third mechanism is what separates Retatrutide from dual agonists and drives additional fat loss.
Published results from the Phase II trial in non-diabetic adults with obesity showed mean weight loss of 17.5% at 24 weeks and 24.2% at 48 weeks in the highest dose group — approximately double the weight loss achieved with semaglutide over comparable periods. Subjects lost an average of 24kg over 48 weeks.
In adults with Type 2 diabetes, significant improvements in HbA1c, fasting glucose and lipid profiles were also documented alongside the weight loss effects.
GLP-1 agonists as a class have demonstrated cardiovascular protective effects in outcome trials (LEADER, SUSTAIN-6). The additional glucagon agonism of Retatrutide raises some theoretical questions about heart rate effects (glucagon increases heart rate), which are being monitored in ongoing trials. Current data does not suggest a safety concern but this requires continued evaluation.
As of 2026, Retatrutide is in Phase III clinical trials. It is not FDA approved and is not available as a prescription medication. Research compound sources exist but human dosing, long-term safety and optimal protocols are not established outside of the clinical trial context.