Your Genetics May Determine How Well GLP-1 Weight Loss Drugs Work

Nearly one in four people who try weight-loss drugs such as Wegovy and Zepbound lose little to no weight at all, seeing few health improvements despite sustained use. A landmark study published April 8 in Nature offers the most detailed genetic explanation yet for why that gap exists, tracing it to specific variants in the human genome.

Researchers at 23andMe Research Institute conducted a genome-wide association study involving 27,885 people who had taken a GLP-1 receptor agonist, either semaglutide, sold as Wegovy and Ozempic, or tirzepatide, sold as Zepbound and Mounjaro. The scale of the response gap is striking: some participants lost less than 5% of their body weight, while others shed more than 20%.

The central finding centers on a missense variant designated rs10305420, within the GLP1R gene, which encodes the receptor that these drugs activate to increase satiety levels. People who carry one copy of this variant lost roughly 1.7 pounds more on average than those without it, corresponding to approximately 0.76 kilograms of additional weight loss per allele. The study's participants lost an average of about 25 pounds total.

"The result makes perfect biological sense," said Adam Auton, study co-author and vice president of human genetics at 23andMe Research Institute. "The genetic variant we found lands right in this gene for the GLP-1 receptor, which happens to be the target for these medications," he added.

The finding was validated in a separate dataset: the All of Us research cohort, using electronic health records from 4,855 individuals, confirmed the association with statistical significance (P = 0.001).

The study also identified a second genetic variant, rs1800437, this time in the GIPR gene, linked to increased nausea and vomiting, but only in people taking tirzepatide, not those taking semaglutide. Tirzepatide, unlike semaglutide, targets both the GLP-1 and GIP receptors simultaneously, which explains why variation in the GIPR gene would carry drug-specific consequences.

Ruth Loos, an obesity geneticist at the University of Copenhagen who peer-reviewed the study and wrote an accompanying commentary in Nature, noted that even a small amount of weight loss, as little as 5%, confers health benefits such as lower cholesterol. Giles Yeo, an obesity geneticist at the University of Cambridge who was not involved in the research, reinforced the public health calculus: "Even though it's small to the individual, at the population level, a substantial number of people would have a positive effect," Yeo said.

The researchers incorporated the genetic findings into a broader predictive model alongside demographic and clinical factors, demonstrating the capacity to stratify patients by likely weight loss and risk for specific side effects. 23andMe released a report called "GLP-1 Medications Weight Loss and Nausea" to members of its Total Health service.

The identification of these genetic variants could underpin the development of precision medicine approaches in the treatment of obesity, pointing toward a future in which a patient's genome helps determine not just whether to prescribe a GLP-1 drug, but which one.