Retatrutide, also known by the research identifier LY3437943, is an investigational peptide designed to activate three receptors involved in metabolic regulation: GIP, GLP-1, and glucagon receptors. The addition of glucagon-receptor activity differentiates retatrutide from dual-receptor compounds such as tirzepatide.
In a phase 2 trial involving 338 adults with obesity, researchers evaluated several retatrutide dose groups over 48 weeks. Average body-weight changes at week 48 were approximately −8.7% in the 1-mg group, −17.1% in the combined 4-mg groups, −22.8% in the combined 8-mg groups, and −24.2% in the 12-mg group, compared with −2.1% with placebo. Gastrointestinal events were the most frequently reported adverse events and were dose-related. Dose-dependent increases in heart rate were also observed, peaking around week 24 before declining.
These phase 2 findings are promising but do not establish final safety or effectiveness. Multiple phase 3 studies are examining retatrutide in obesity, type 2 diabetes, cardiovascular disease, and comparisons with tirzepatide. For example, TRIUMPH-5 is a phase 3 study comparing retatrutide directly with tirzepatide, with primary completion expected in December 2026.
Research significance
Retatrutide provides a model for studying whether coordinated activity at GIP, GLP-1, and glucagon receptors can influence appetite, glucose regulation, energy expenditure, and body composition. Until larger phase 3 results are published and reviewed, conclusions should remain limited to its investigational status.
References
- Jastreboff AM, Kaplan LM, Frías JP, et al. Triple-hormone-receptor agonist retatrutide for obesity — a phase 2 trial. New England Journal of Medicine. 2023;389:514–526. DOI: 10.1056/NEJMoa2301972.
- ClinicalTrials.gov. A study of retatrutide compared with tirzepatide in adults who have obesity (TRIUMPH-5). Identifier: NCT06662383.
