GLP-1 medications like Ozempic don’t work for everyone. Genetic variants offer new clues
The weight you lose and the nausea you feel from GLP-1 drugs may be linked to common genetic variants, but they cannot fully explain why some people lose more weight than others.
By Lori Youmshajekian edited by Lauren J. Young
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Among the millions of people who have tried weight loss drugs such as Wegovy and Zepbound, nearly one in four people do not respond to treatment. They lose little, if any, weight and see few improvements in their health. This has baffled scientists and frustrated patients, but a new study based on genetic data collected by 23andMe suggests that common quirks of our genetic code may explain at least part of why this happens.
In an article published Wednesday in Natureresearchers analyzed self-reported data from nearly 28,000 people who took a Glucagon-like peptide 1 (GLP-1) drug– these include semaglutide, sold under the names Wegovy and Ozempic, or tirzepatide, sold under the names Zepbound and Mounjaro. Researchers have identified a variant in the GLP1R gene – which codes for the receptor on which drugs activate increase satiety levels– which was linked to greater weight loss. The result “makes perfect biological sense,” says Adam Auton, co-author of the study and vice president of human genetics at the 23andMe Research Institute. “The genetic variant we found is located directly in this gene [for] the GLP-1 receptor, which happens to be the target of these drugs.
Humans usually have two copies of a 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 on average about 1.7 pounds more than those who did not have one, while those with two copies of the variant lost more than three pounds more than people without a copy.
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That’s not an insignificant amount of weight: The total average weight loss of study participants 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 weight loss, as little as 5 percent, confers certain health benefitssuch as lower cholesterol levels, which can translate into broad improvements in public health, says Giles Yeo, an obesity geneticist at the University of Cambridge, who was not involved in the study. “Even if the impact is small at the individual level, at the population level, a significant number of people would have a positive effect,” says Yeo.
The rs10305420 variant is present in about 40% of people of European and Middle Eastern ancestry, according to the study. Earlier research found conflicting results on the variant; Some studies suggest this could make medications work worse. But Auton says the discrepancy may reflect the smaller number of participants and comorbidities of previous studies.
The authors of the new study hypothesize that this variant could improve the efficiency of receptor transport to a cell’s surface. This could increase the number of available receptors that GLP-1 drugs can bind to, potentially improving their effectiveness, Auton says.
The variant was also linked to a higher risk of gastrointestinal side effects, which themselves can suppress appetite and contribute to weight loss. “The sicker you feel, the less you’re going to eat,” says Yeo.
The study authors identified a second variant, rs1800437, this time in the GIPR gene, which was also associated with more severe nausea and vomiting, but only in people taking tirzepatide. This medication differs from semaglutide by targeting gastric inhibitory polypeptide (GIP) receptors in addition to GLP-1. Tirzepatide generally causes less nausea than semaglutide, an effect some scientists believe is because the GIP receptor acts as a “buffer” for the nausea caused by activation of GLP-1 receptors. This buffering effect could be reduced in people with the rs1800437 variant, says Auton. People who each had two copies of the rs1800437 and rs10305420 variants were about 15 times more likely to vomit when treated with tirzepatide than those who did not have them.
If a person’s genes could help clinicians identify the best drug from the start, it could change the way these treatments are prescribed. But genetics can only explain part of the variation in weight loss seen in people taking these drugs. According to the new analysis, gender, age, other health conditions such as diabetes, and the specific GLP-1 drug a person is taking are all indicators of how they might respond to the drug. Auton says the study is an “important proof of concept” for the influence of genetics, but adds that personalized GLP-1 treatment must ultimately take into account many factors related to a person’s health and biology. Yeo says there could also be rarer genetic variants not captured in the analysis that could exert more influence on variations in weight loss. The current analysis is also limited to genetic variants in predominantly white populations, he says.
“Your genes matter,” Yeo says, “but it’s not just your genes. »
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