This Nature-published study from the 23andMe Research Institute identifies genetic variants that may help explain why patients experience widely different outcomes when taking GLP-1 weight loss medications, including variability in both efficacy and side effects.

Analysing data from 27,885 individuals, researchers found evidence that differences in genes targeted by GLP-1 therapies, including GLP1R and GIPR, are associated with variation in weight loss response and tolerability, offering new insight into the biological drivers behind patient-to-patient differences.

The research analysed genetic and self-reported data from the individuals who have used GLP-1 receptor agonists such as semaglutide and tirzepatide. The findings suggest that variation in genes targeted by these therapies may contribute to differences in weight loss outcomes and tolerability across patients.

GLP-1 drugs have rapidly transformed obesity treatment, but real-world response varies widely, with some patients losing less than 5% of body weight while others lose more than 20%. The study highlights how genetic differences may help explain this variability, particularly in relation to the GLP1R and GIPR genes.

Researchers identified a missense variant in the GLP1R gene associated with improved weight loss response to GLP-1 medications. The study also found genetic associations between both GLP1R and GIPR and side effects such as nausea and vomiting. Notably, the association between GIPR variation and gastrointestinal side effects appeared to be specific to tirzepatide rather than semaglutide.

“These findings demonstrate the power of large-scale human genetic data to improve understanding of how individuals respond to widely used therapies,” said Adam Auton, vice president of human genetics at the 23andMe Research Institute.

The research team also developed a model combining genetic, demographic, and clinical factors to stratify patients by likely weight loss response and side effect risk. According to the findings, estimated weight loss outcomes ranged from 6% to 20% of starting body weight, while predicted risk of nausea or vomiting ranged from 5% to 78%, depending on genetic and clinical profile.

Alongside the publication, 23andMe has launched a new GLP-1 report within its Total Health service. The tool provides personalised insights into potential weight loss response and side effect risk, integrating genetic data with clinical context and clinician oversight.

“The study highlights significant variability in how people respond to GLP-1 medications,” said Dr Noura Abul-Husn, chief medical officer at the 23andMe Research Institute. “Our goal is to help move weight management away from trial and error toward a more informed and personalised approach.”

The report is available through 23andMe’s Total Health service and includes clinician-reviewed guidance for users considering or currently taking GLP-1 therapies.