Is polypharmacy the future for pharmacological management of obesity?

Despite the rapidly increasing prevalence and associated costs of obesity, treatment options have remained remarkably limited. Some 650 million people are estimated to be living with obesity, but until recently the lipase inhibitor orlistat was the only mainstay pharmacological option, alongside dietary restriction. However, with FDA approval of the glucagon-like peptide 1 receptor (GLP-1R) agonists, liraglutide and semaglutide, for the management of obesity, it is hoped the tide is beginning to turn. Roux-en-Y gastric bypass (RYGB) surgery remains the most effective intervention for weight loss, being attributable to changes in energy intake/expenditure. This is largely driven by substantial post-surgical modulation of circulating gut hormones, including GLP-1, as well as peptide tyrosine-tyrosine (PYY), oxyntomodulin (OXM), glucose-dependent insulinotropic hormone (GIP), cholecystokinin (CCK) and ghrelin. In order to mimic these effects of RYGB, there has been a recent surge of interest in pursuit of both administration of individual peptide combinations as well as development of unimolecular peptide hormone-based polypharmacy; single peptidic agents that co-activate several different receptor signalling pathways. Dual agonist therapies such as the GLP-1/GIP co-agonist Tirzepatide, are nearing regulatory approval for management of non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM). Given the significant appetite and weight reductions attained with these agents, it is hoped that such unimolecular peptide hormone drugs, along with similar molecules in development, will ultimately yield successful modern polypharmacy to help manage the current obesity epidemic