Retatrutide

Retatrutide (LY3437943) is a synthetic 39-amino-acid peptide developed by Eli Lilly that acts as a triple agonist of the GIP, GLP-1, and glucagon (GCG) receptors. Its sequence is based on a glucagon-derived backbone with targeted amino acid substitutions to enable activity at all three receptors, plus a C-20 fatty diacid side chain for extended half-life and once-weekly dosing.

The triple agonist mechanism produces complementary metabolic effects: GLP-1 receptor activation suppresses appetite and improves insulin secretion; GIP receptor activation enhances fat metabolism and insulin sensitivity; and glucagon receptor activation increases energy expenditure, hepatic fat oxidation, and thermogenesis. The addition of glucagon receptor agonism distinguishes retatrutide from dual agonists and may explain its superior efficacy in reducing liver fat and overall body weight.

Phase 2 clinical trial results published in the New England Journal of Medicine demonstrated remarkable efficacy, with participants achieving up to 24.2% mean body weight reduction after 48 weeks at the 12 mg dose. In the liver fat substudy, retatrutide reduced liver fat by up to 82.4% from baseline, with 86% of participants achieving complete resolution of fatty liver disease. Phase 3 trials are currently underway. If approved, retatrutide would be the first triple-receptor agonist in its class and could set new benchmarks for obesity and metabolic disease treatment.