Sex differences in GLP-1 signaling across species

Two billion humans are currently overweight or obese1. While glucagon-like peptide 1 receptor (GLP1R) agonists have emerged as the most promising treatment for this epidemic, side effects including nausea and vomiting constitute a significant obstacle to their use. Of the patients currently being treated, women represent nearly 70%. While early studies have noted sex differences in the response to these drugs, the nature of these differences remain poorly characterized. Using real world electronic medical record (EMR) data, we find that women experience more than double the rates of persistent nausea and vomiting when prescribed GLP1R agonists. To investigate this sex difference in greater detail, we developed novel, species-specific in vivo phenomic assays to quantify aversive behaviors. In both mice and rats, aversive responses to either semaglutide or tirzepatide were greater in females than males. To investigate the basis for this difference, we constructed a mouse single cell transcriptomic atlas of body and brain regions most relevant to the action of GLP-1. Using this atlas we find that multiple neuronal cell types involved in the processing of aversive stimuli and nausea had higher GLP1R expression in females than males. Heightened susceptibility of females to the aversive effects of GLP1R agonists could therefore involve increased activation of these brain circuits. Finally, we demonstrate that in mice, both the efficacy and tolerability of GLP1R agonists vary with the phase of the estrous cycle, being highest during proestrus (when estrogen levels peak) and lowest in diestrus (low estrogen levels). Similarly, we report that higher circulating estrogen levels in humans is associated with heightened risk of nausea and vomiting among women taking a GLP1R agonist. Based on these findings, we anticipate that women will continue to be disproportionately impacted by the adverse effects associated with all members of this drug class. Research to better understand and ultimately mitigate this heightened susceptibility is an important priority for new drug development in this area, and novel approaches to model the impact of endogenous hormone signaling will be critical to developing better treatments for more people.