Retatrutide (LY3437943) is a 36-amino acid acylated peptide developed by Eli Lilly that acts as a balanced agonist at three receptors simultaneously: GLP-1R, GIPR, and GCGR. This triple agonist profile — "triagonist" — represents a pharmacological step beyond tirzepatide's dual GLP-1/GIP activity.
The Three Receptor Targets
GLP-1R agonism drives glucose-dependent insulin secretion, suppresses glucagon, slows gastric emptying, and activates hypothalamic satiety circuits.
GIPR agonism potentiates insulin secretion synergistically, promotes adipocyte lipid handling, and engages distinct hypothalamic satiety circuits.
GCGR agonism is the key addition. Glucagon receptor agonism markedly increases energy expenditure by stimulating hepatic fatty acid oxidation and thermogenesis; promotes lipolysis in adipose tissue; and may reduce hepatic steatosis. When combined with GLP-1R agonism, the glucose-raising effect of glucagon is blunted by GLP-1's insulin-stimulating activity — neutralizing the hyperglycemic liability while preserving glucagon's thermogenic and lipolytic actions.
Phase 2 TRIUMPH Trial Results
The Phase 2 TRIUMPH trial (Jastreboff et al., 2023, N Engl J Med) enrolled 338 adults with obesity. Key findings at 48 weeks:
- 12mg arm: 24.2% mean weight reduction — exceeding tirzepatide 15mg benchmarks in fewer weeks.
- 8mg arm: ~22.8% mean weight loss.
- Weight loss had not plateaued at 48 weeks in higher dose groups.
- Adverse events consistent with the incretin class; no unexpected safety signals.
Hepatic Effects and MASLD Research
GCGR agonism directly stimulates hepatic fatty acid oxidation and reduces de novo lipogenesis, acting on liver fat independently of weight loss. This positions retatrutide as a compound of particular interest for research into metabolic dysfunction-associated steatotic liver disease (MASLD), where current approved therapies have significant limitations.
Related research compounds:
References
- Jastreboff AM, et al. (2023). Triple–Hormone-Receptor Agonist Retatrutide for Obesity. N Engl J Med, 389, 514–526.
- Coskun T, et al. (2022). Retatrutide, a novel GIP, GLP-1, and glucagon receptor agonist. Mol Metab, 66, 101633.
- Day JW, et al. (2009). A new glucagon and GLP-1 co-agonist eliminates obesity in rodents. Nat Chem Biol, 5(10), 749–757.