Some GLP-1 drugs are more effective for those with specific gene variants

Some people’s genes influence how much weight they will lose and what side effects they will experience while taking GLP-1 drugs, such as Ozempic and Zepbound.

The genetic testing company 23andMe conducted a study of more than 27,000 customers who were taking GLP-1 drugs. Such drugs work by mimicking the action of GLP-1, a hormone that helps regulate blood sugar and appetite. People who carry a particular genetic variant of the GLP-1 receptor gene GLP1R lost more weight than those who don’t carry that variant, researchers report April 8 in Nature.

“The results that we got made perfect biological sense,” says statistical geneticist Adam Auton, vice president of human genetics at the 23andMe Research Institute in Palo Alto, Calif. That’s because the receptor is the target of GLP-1 mimicking drugs. The variant the researchers found may increase the amount of the receptor protein on the cell surface, giving the drug more targets, Auton says.

People who have one copy of the variant lost an additional 0.76 kilograms (1.7 pounds) over about eight months, while those with two copies of the variant lost about 1.5 kgs (3.3 pounds) more than those without the variant. That variant accounts for about 10 percent of the difference in weight loss people experience on the drugs.

“It’s a small contribution to the weight difference among the patients, but it’s important because of the significance of this gene,” says Andres Acosta, a physician scientist at the Mayo Clinic in Rochester, Minn. Acosta was not involved in the new study but is a cofounder of Phenomix Sciences, a company headquartered in Menlo Park, Calif., that offers AI-powered genetic tests to predict which weight loss medications will work best for a patient.

The same genetic variant found to impact weight loss also increases the likelihood that someone taking a GLP-1 drug will develop nausea and vomiting, the researchers discovered. That’s not always a bad thing, Auton says. “If you’re experiencing side effects of nausea and vomiting, that may actually be a signature that the medication is having an effect.”

People taking tirzepatide, sold under the brand-name Zepbound, were more likely to have nausea and vomiting if they had a specific variant of a different gene called GIPR. The protein it makes is the target of GIP, another hormone involved in blood sugar and appetite control. The GIPR variant didn’t have a discernable effect on weight.

Unlike semaglutide drugs Wegovy and Ozempic, tirzepatide targets both the GLP-1 and GIP receptors. And people who have variants in both the GLP1R and GIPR genes have nearly 15 times increased odds of vomiting when taking tirzepatide, the team found.

Genetics alone doesn’t determine how well the drugs will work, Auton says. But knowing which variants a person carries, he says, “can be quite informative for individuals who are considering these medications. It may help them prepare themselves for the type of experience that they may have.”