Cagrilintide and retatrutide combination therapy enhances weight loss and metabolic outcomes in obese male rats.

Peptide multi-receptor agonists have advanced obesity treatment, yet challenges remain in achieving maximal weight loss and metabolic control, especially in patients with obesity and type 2 diabetes. Here we demonstrate enhanced metabolic benefits of a combination therapy with retatrutide, a unimolecular GLP-1R/GIPR/GCGR tri-agonist, and cagrilintide, an AMLNR/CALCR co-agonist, in diet-induced obese male rats. Daily co-administration produces dose-dependent reductions in body weight and food intake that exceed both equimolar monotherapies and matched-dose comparator combinations incorporating semaglutide or tirzepatide. The combination therapy also improves circulating markers of metabolic health, including cholesterol, triglycerides and insulin levels. Pair-feeding and weight-matching studies reveal that the enhanced weight loss cannot be explained by reduced food intake alone and enable discrimination between weight-loss-dependent and drug-specific molecular responses. Plasma proteomic profiling highlights enrichment of bioenergetic processes with the combination therapy, whereas brain transcriptomic profiling identifies convergent central neuronal programmes linked to energy balance regulation. Collectively, our preclinical findings support five-receptor polypharmacology as a strategy for efficaciously lowering body weight and provide guidance for the design of next-generation unimolecular multi-receptor agonists.