Study finds genetic basis for GLP-1 weight loss efficacy and side effects

23andMe Research Institute, a nonprofit medical research organization, announced the publication of a study that identifies genetic predictors for GLP-1 weight loss efficacy and side effects. 

GLP-1 receptor agonists, including semaglutide and tirzepatide, have transformed the clinical management of weight and obesity. However, patients experience substantial variability in both weight loss efficacy and the incidence of side effects. Some individuals lose less than 5% of their body weight, whereas others lose more than 20%. Some individuals experience side effects such as nausea and vomiting, whereas others do not. 

Published today in Nature, the study investigates the genetic basis of this variability. Researchers at 23andMe conducted a large-scale genome-wide association study (GWAS) utilizing data from 27,885 individuals who have used GLP-1 medications. The findings provide direct evidence that variation in the genes targeted by GLP-1 medications contribute to why people respond differently to GLP-1 therapies. 

The study demonstrates the incredible power of our crowdsourced research community to advance scientific understanding of human genetic variation."

Adam Auton, Vice President of Human Genetics at 23andMe Research Institute and author of the study

By analyzing both genetic markers and self-reported patient experiences, the research team uncovered several key insights into how human genetics influence the effects of these widely prescribed medications:

• Weight Loss: Researchers identified a missense variant, a small change in a gene sequence that alters the protein it makes, in the GLP1R gene that is significantly associated with increased efficacy of GLP-1 medications. 

• Nausea and Vomiting: The study identified associations linking variation in both the GLP1R and GIPR genes to GLP-1 medication-related nausea or vomiting.

• Drug-Specific Effects: The association between the GIPR genetic variation and nausea and vomiting side effects is restricted specifically to individuals using tirzepatide (Mounjaro© and Zepbound©), and not semaglutide (Ozempic© and Wegovy©).

These discoveries lay the foundation for more personalized approaches in the treatment of obesity, suggesting a future where genetic testing could help guide treatment strategies.

The 23andMe research team successfully incorporated these findings into a broader model of GLP-1 medication response that includes demographic and clinical factors, demonstrating the ability to stratify patients by both weight loss efficacy and risk for certain side effects. 

The organization has released a new report, called GLP-1 Medications Weight Loss and Nausea, to members of its Total Health service. The new report provides insight into weight loss and nausea risk when taking a GLP-1 medication based on these new findings from 23andMe research. This new report includes an interactive tool that allows individuals to explore how genetics and other factors like age and certain medical conditions may impact weight loss and nausea on GLP-1 medications. Together, these factors can predict significant variability in an individual's likelihood of weight loss or side effects. Among 23andMe research participants, weight loss estimates vary between 6% and 20% of starting weight, and the chances of nausea or vomiting range from 5% to 78%, depending on genetics and other factors.

The new GLP-1 Medications: Weight Loss and Nausea report is exclusively available through 23andMe's Total Health service, which includes clinician guidance. Total Health Reports are reviewed by clinicians and intended for use in a supervised clinical context. 

"While there is high interest in GLP-1 medications, there is significant variation in how well they work for different people. The market is crowded with weight loss support and medications, but the approach to weight management is typically one of trial and error. This can lead people to leap into treatment with a high degree of uncertainty and unrealistic expectations about efficacy and possible side effects, said Dr. Noura Abul-Husn, MD, PhD, Chief Medical Officer at the 23andMe Research Institute. "We believe these reports are a step forward in meeting an unmet need for a more informed and personalized approach to weight management."

"The new GLP-1 report is a part of our Total Health service, where a clinician is part of the conversation," continued Abul-Husn. "GLP-1 treatment decisions are complex and having access to clinical expertise to help contextualize your genetic results alongside your full health picture is exactly the kind of guidance this report is designed to support."