Abstract

The global prevalence of type 2 diabetes and obesity, affecting over 507 million 1 and 890 million 2 individuals, respectively, underscores the urgent need for more effective treatments. The most successful treatments currently available include glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs), exemplified by semaglutide (approved in 2017, $19.9 billion sales in 2023) 3 and tirzepatide (approved in 2022, $5.3 billion sales in 2023) 4 . Unlike semaglutide which solely activates GLP-1R (one of the three pivotal receptors regulating glucose homeostasis), tirzepatide also activates glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) to enhance metabolic benefits with reduced side-effects 5 . However, both medications do not target glucagon (GCG) receptor (GCGR). Recently, retatrutide (also known as LY3437943) 6 , 7 , 8 , 9 has shown impressive efficacy in obesity treatment through triple agonism at GLP-1R, GIPR and GCGR. Compared to the corresponding endogenous hormones, retatrutide is more potent at GIPR by a factor of 8.9, and less potent at GCGR and GLP-1R by factors of 0.3 and 0.4, respectively 7 (Fig. 1a ). Retatrutide induces greater body weight losses in obese mice than tirzepatide, due to an increased energy expenditure through GCGR activation 6 . In a phase 2 obesity trial, retatrutide demonstrated an average weight loss of 17.5% at 24 weeks and 24.2% at 48 weeks in the 12 mg dose group 7 . Additionally, in a phase 2 trial targeting type 2 diabetes, retatrutide demonstrated significant improvements in glycemic control and substantial weight reduction, maintaining a safety profile comparable to certain approved GLP-1RAs 8 (Supplementary Table S1 ). These results support the rationale of developing retatrutide as an alternative to semaglutide and/or tirzepatide 5 . Indeed, phase 3 clinical trials of retatrutide for type 2 diabetes, non-alcoholic fatty liver disease, and obesity are presently underway (Supplementary Table S2 ) 10 . To un...