There are fundamental sex-based differences in how weight loss medications interact with human biology, according to a study by Olio Labs, which also reveals why women experience more severe side effects from GLP-1 drugs such as Ozempic and Zepbound.
"This isn't just about improving GLP-1 drugs, it's about rethinking how we design future therapies for real-world patients from the start," said Dr David Tingley, co-founder and CEO of Olio Labs. "By discovering these fundamental sex-based differences in drug response, our research opens the door to more personalised treatment approaches that could significantly improve outcomes for millions of patients."
The study’s authors noted that women experience more than double the rates of persistent nausea and vomiting when prescribed GLP-1r agonists. To investigate this sex difference in greater detail, they developed novel, species-specific in vivo phenomic assays to quantify aversive behaviours. They reported that 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, they constructed a mouse single cell transcriptomic atlas of body and brain regions most relevant to the action of GLP-1. Using this atlas, they identified multiple neuronal cell types involved in the processing of aversive stimuli and nausea that 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, they hypothesised.
They also demonstrated that in mice, both the efficacy and tolerability of GLP-1ra vary with the phase of the oestrous cycle, being highest during proestrus (when oestrogen levels peak) and lowest in dioestrus (low oestrogen levels). Similarly, higher circulating oestrogen levels in humans is associated with heightened risk of nausea and vomiting among women taking a GLP-1ra. Based on these findings, they concluded that women will continue to be disproportionately impacted by the adverse effects associated with all members of this drug class.
“Our results underscore the value of including female subjects in pre-clinical studies, such that sex differences in efficacy or tolerability can be assessed at early stages of the development pipeline...” they concluded. “We anticipate that by lowering GLP1R agonist dosing during phases associated with the highest oestrogen level, the most severe side-effects could be mitigated. In the short-term this could help to mitigate the increase of nausea and vomiting we observed at peak oestrogen levels, and thereby reduce discontinuation rates in women, which are higher than in men.”
The study reveals that female mice have nearly double the GLP-1 receptor expression in brain regions linked to nausea, explaining their heightened side effects. If this receptor expression pattern is consistent across species it could explain why women experience higher rates of nausea and vomiting.
"Olio is revolutionising drug discovery. Their platform combines a novel computational approach with validated preclinical models and real patient data to develop better treatments for specific populations,” said Patricia Martin, Olio Labs Advisor and former COO – Lilly Diabetes. “Their patient-first approach has the potential to advance personalised medicine.”
Olio Labs has developed a revolutionary therapeutic design platform that moves beyond traditional drug discovery methods. The core of the platform is its AI-powered Combination Design Engine (CoDE) platform, which leverages:
Human medical record and biological data
In-vivo phenomic screening
In-depth neural and endocrine circuit maps
AI-powered integration of biological expertise
The company's platform harnesses a vast 120 million patient electronic medical record dataset alongside a proprietary in vivo screening platform that accurately translates to humans and predicts clinical trial failures. Together, these integrated technologies create a powerful system for advancing medical research and improving treatment outcomes.
"Olio is redefining the future of medicine by using technology to reinvent the drug discover process with physiology at the center - effectively addressing the needs of patient populations that have long been overlooked and bridging the gender divide in pharma," said Kristina Simmons, founder and managing partner of Overwater Ventures. "Obesity is one of the largest problems in America right now, and Olio's research will help millions of women have a better solution without the side effects."
To access the study, 'Sex differences in GLP-1 signaling across species', please click here