GLP-1 drugs like Ozempic don’t work for everyone. Genetic variants offer new clues

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

By Lori Youmshajekian edited by Lauren J. Young

Of all the millions of people who have tried weight-loss drugs such as Wegovy and Zepbound, nearly one in four people don’t respond to treatment. They lose little weight, or none at all, and see few health improvements. This has baffled scientists and frustrated patients, but a new studybased on genetic data collected by 23andMe suggests that common quirks in our genetic code can at least partly explain why it happens.

In a paper published on Wednesday in Nature, researchers analyzed self-reported data from almost 28,000 people who had taken a glucagon-like peptide 1 (GLP-1) drug—these include semaglutide, which is sold as Wegovy and Ozempic, or tirzepatide, which is sold as Zepbound and Mounjaro. The researchers identified a variant in the GLP1R gene—which encodes the receptor that the drugs activate to increase satiety levels—that was linked to greater weight loss. The result “makes perfect biological sense,” says Adam Auton, study co-author and vice president of human genetics at the 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.”

Humans typically have two copies of any given gene, but these copies can vary from each other. The researchers found that people with one copy of the higher-weight-loss variant, rs10305420, lost an average of about 1.7 pounds more than those without it, while those with two copies of the variant lost more than three pounds more than people without any copies.

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That’s not a negligible amount of weight: the study participants’ total average weight lost was about 25 pounds, says Ruth Loos, an obesity geneticist at the University of Copenhagen, who peer-reviewed the study and wrote an accompanying commentary in Nature. Even a small amount of weight loss, as little as 5 percent, confers some health benefits, such as lower cholesterol—and these can add up to broad improvements in public health, says Giles Yeo, an obesity geneticist at the University of Cambridge, who was not involved in the study. “Even though it’s small to the individual, at the population level, a substantial number of people would have a positive effect,” Yeo says.

The rs10305420 variant is present in about 40 percent of people with European and Middle Eastern ancestry, according to the study. Earlier research has found conflicting results about the variant; some studies have suggested that it may worsen the drugs’ efficacy. But Auton says the discrepancy may reflect past studies’ smaller participant numbers and comorbidities.

The authors of the new study hypothesize that the variant may improve the efficiency of transporting receptors to a cell’s surface. That might increase the number of receptors available for GLP-1 drugs to bind to, potentially improving their efficacy, Auton explains.

The variant was also linked to a higher risk of gastrointestinal side effects, which can themselves suppress appetite and contribute to weight loss. “The more sick you feel, the less you’re going to eat,” Yeo says.

The study authors identified a second variant, rs1800437, this time in the GIPR gene, that was also associated with worse nausea and vomiting but only in people taking tirzepatide. This drug differs from semaglutide by targeting receptors for the hormone gastric inhibitory polypeptide (GIP) in addition to GLP-1. Tirzepatide typically causes less nausea than semaglutide—an effect some scientists believe is because the GIP receptor acts like a “buffer” to the nausea caused by activating GLP-1 receptors. That buffering effect might be reduced in people with the rs1800437 variant, Auton explains. People who had two copies each of both the rs1800437 and rs10305420 variants were an estimated 15 times more likely to have vomiting when treated with tirzepatide than those without.

If a person’s genes could help clinicians identify the best drug from the outset, it could change how these treatments are prescribed. But genetics can only explain some of the weight-loss variation seen in people taking these drugs. Sex, age, other health conditions such as diabetes, and the specific GLP-1 drug a person takes are all predictors of how well they might respond to the medication, according to the new analysis. Auton says the study is an “important proof of concept” for the influence of genetics but adds that personalized GLP-1 treatment ultimately needs to consider many factors of a person’s health and biology. Yeo says there could also be rarer genetic variants not captured in the analysis that might exert more influence on weight-loss variations. The current analysis is also limited to genetic variants in largely white populations, he says.

“Your genes do matter,” Yeo says, “but it’s not only your genes.”