Retatrutide

Retatrutide (LY3437943) is an investigational once-weekly subcutaneous peptide by Eli Lilly that simultaneously activates the GLP-1 receptor (GLP-1R), the glucose-dependent insulinotropic polypeptide receptor (GIPR), and the glucagon receptor (GCGR). GLP-1R agonism suppresses appetite and slows gastric emptying; GIPR agonism amplifies glucose-dependent insulin secretion and sensitizes adipose tissue to GLP-1; GCGR agonism raises resting energy expenditure through hepatic fat oxidation and, in preclinical models, brown-adipose thermogenesis, a mechanism absent from dual agonists such as tirzepatide. The phase 2 obesity trial (Jastreboff et al., NEJM 2023) found a mean 24.2% body weight reduction at 48 weeks with 12 mg; approximately half of participants exceeded 25% loss, and liver fat declined by a mean of 82.4% at 24 weeks. A concurrent phase 2 trial in type 2 diabetes (Rosenstock et al., Lancet 2023) showed greater HbA1c and weight reductions vs. placebo and dulaglutide 1.5 mg. Phase 3 TRIUMPH-1 topline data (May 2026) reported 28.3% mean weight loss at 80 weeks with 12 mg in 2 339 adults with obesity without diabetes. Retatrutide remains investigational; no regulatory approval had been granted as of mid-2026, and long-term cardiovascular outcomes are not yet established.