Why GLP-1 Weight Loss Drugs Don’t Work for Everyone: The Role of Genetics

Genetic variations may help explain why some people respond better to weight-loss medications like Ozempic and Wegovy than others, according to recent research analyzing data from thousands of individuals who have used glucagon-like peptide-1 (GLP-1) receptor agonists.

A study published in Nature examined self-reported data from nearly 28,000 people who had taken GLP-1 drugs such as semaglutide (sold as Wegovy and Ozempic) or tirzepatide (sold as Zepbound and Mounjaro). Researchers identified a specific variant in the GLP1R gene—known as rs10305420—that is associated with greater weight loss. Individuals with one copy of this variant lost an average of about 1.7 pounds more than those without it, while those with two copies lost more than three pounds more on average.

The genetic variant we found lands right in this gene [for] the GLP-1 receptor, which happens to be the target for these medications.

Adam Auton, study co-author and vice president of human genetics at the 23andMe Research Institute

The findings suggest that differences in how well the drugs work may be partly rooted in a person’s genetic makeup. However, researchers emphasized that these genetic factors do not fully account for the wide variation in weight loss outcomes observed among users.

The weight you lose and the nausea you experience from GLP-1 drugs may be linked to common gene variants, but they can’t fully explain why some people lose more weight than others.

Scientific American, reporting on the Nature study

In addition to variants influencing effectiveness, the research also points to genetic factors that may increase the likelihood of gastrointestinal side effects such as nausea, vomiting, diarrhea, or constipation. These adverse events are commonly reported by users of GLP-1 medications and can impact treatment adherence.

Another study highlighted in Genome Medicine found that approximately 10% of people carry genetic variations linked to what researchers describe as “GLP-1 resistance.” These individuals tend to have higher-than-normal levels of the GLP-1 hormone, yet experience diminished biological response to the medication, suggesting a form of reduced sensitivity despite elevated hormone levels.

Experts note that these genetic insights align with clinical observations of variable patient responses. While GLP-1 receptor agonists have demonstrated significant efficacy in clinical trials—often resulting in more than 10% body weight loss—about one in ten users achieve less than 5% weight loss and are considered non-responders. Tolerability also varies widely, with at least one in three users reporting adverse gastrointestinal effects.

The research underscores the complexity of individual responses to obesity pharmacotherapy and highlights the potential for genetic information to inform personalized treatment approaches in the future. However, scientists caution that genetics is only one piece of a larger puzzle involving metabolic, lifestyle, and environmental factors.

As the use of GLP-1-based medications continues to grow globally, understanding the biological reasons behind differential responses may help improve patient outcomes and guide the development of alternative or complementary therapies for those who do not benefit adequately from current options.