If you aren’t losing weight with GLP-1 drugs, this may be one reason why
GLP-1 weight loss drugs, which have revolutionized the treatment of obesity, diabetes and many other diseases, come with an important warning: They do not work for everyone.
Some people experience profound weight loss; others barely see the scale shifting. Some tolerate the medications, but others find the nausea and vomiting so bothersome that they stop taking them. In clinical trials, about 10 to 15 percent of people taking the drugs are considered “non-responders” because they do not lose at least 5 percent of their body weight.
A new study published Wednesday in the journal Nature finds that part of the reason why people’s responses to drugs vary so widely may lie in their DNA.
Researchers at the nonprofit 23andMe Research Institute have identified two gene versions that help predict whether people will lose a few extra pounds with drugs or be more prone to nausea and vomiting. Genetics is only part of how people respond to GLP-1s, but when combined with other factors such as age, gender, and other medical conditions, researchers created a model to predict the potential benefit of weight loss and the risk of side effects.
“There are many factors that influence people’s experiences with GLP-1s. … We were able to show that genetics also play a role,” said Adam Auton, vice president of human genetics at the 23andMe Research Institute and one of the study’s authors. 23andMe is integrating a report based on the findings into its “Total Health” product, a $499 genetic testing service that includes supervision from a clinician.
Epidemiologist G. Caleb Alexander from Johns Hopkins Bloomberg School of Public Health, who was not involved in the research, said that the study targets an important and poorly known question.
“Many clinicians and patients do not realize that GLP-1s do not work for everyone,” Alexander said in an email. “It is unclear why a significant minority of individuals do not lose weight while taking GLP-1; this is a question of enormous scientific and clinical importance.”
His latest research in JAMA Internal Medicine suggests that the drugs work similarly across groups of patients based on factors such as age, race and whether people have diabetes, but he said: “It is entirely plausible that there are genetic determinants of GLP-1 activity that have not yet been identified.”
Precision medicine against obesity
“Personalized medicine,” one of the buzzwords in healthcare for years, has heralded a new era in which treatments are tailored to a person’s biology rather than a one-size-fits-all. The field of pharmacogenomics, which uses genetic information to target drugs, may allow doctors to offer treatments that are more likely to work and avoid treatments that may have harmful effects. Successes have been made, but much of medicine continues to operate by trial and error and some guesswork.
The new study is a step toward creating precise obesity tools to guide the use of a powerful and expensive class of drugs. Giving patients more realistic expectations about their weight-loss potential can save time, frustration, and money spent trying to find out whether a drug works.
Medical geneticist Robert C. Green of Harvard Medical School praised the study as a success. He said it was a reminder of the tremendous promise of genomics to improve medicine, not only in the diagnosis and treatment of rare diseases, but also by improving routine clinical care.
“The promise of pharmacogenomics is there waiting to be fulfilled,” Green said. “To fulfill the promise of pharmacogenomics in our healthcare system now, we must find a way to incorporate some degree of genomics into every patient encounter.”
Identification of two genes affecting GLP-1 response
In the new study, scientists investigated the genomes of 15,000 people who took the drug. DNA is a string of letters that is 3 billion long, and each person has different variations in its spelling. The team examined the code, looking for changes shared among people who reported losing more weight or experiencing side effects such as nausea and vomiting.
This approach flagged variants of two genes – GLP1R and GIPR – Both are directly targeted by drugs that mimic the effects of our natural gut hormones. Semaglutide drugs such as Ozempic and Wegovy target the GLP-1 pathway, which plays a role in insulin secretion, appetite and gastric emptying. Tirzepatide drugs such as Mounjaro and Zepbound target the GLP-1 pathway as well as a second pathway, the GIP pathway.
The study showed that some people carry a specific version of the GLP1R gene, which creates a protein in which one of the amino acid building blocks is different. People with this variant were more likely to lose weight with GLP-1s. The overall effect was relatively modest. People carry two copies of each gene, one from each parent. Those with one copy of the GLP1R gene variant lost slightly more than 1.5 pounds than those with the normal version. They lost more than three extra pounds with two copies of the variant.
The authors suggest that the alternative version of the GLP1R gene creates a protein that is functionally identical but more efficiently transported throughout the cell to the surface where it can be targeted by the drug.
The same GLP1R variant linked to weight loss was also associated with an increased risk of nausea and vomiting. Scientists also found a variant of a different GIPR gene that was common in people who reported these side effects while taking tirzepatide medications. Rare people who carry two copies of both variants were likely to have a particularly difficult time on the medication tirzepatide; The likelihood of vomiting increased 15 times.
On average, the extra weight loss might not seem like much, but for those with two copies of the GLP1R variant, it was more than 10 percent of the total weight loss experienced by people in the study population, said Ruth Loos, a genetic epidemiologist at the University of Copenhagen who was not involved in the study.
He said it was good to see the findings replicated in a separate database from the National Institutes of Health’s All of Us database, but he would like to see more follow-up because some other studies have failed to find a similar effect.
Not one but many genetic variants contribute to differences in how people respond to these drugs, said Andres Acosta, an obesity expert at the Mayo Clinic who was not involved in the research. He co-founded a startup called Phenomix Sciences, which commercialized a different test that also used genetics to predict response to GLP-1s.
“This paper lays the foundation for decades of work by us and others on the genetics of obesity and predictors of response to obesity intervention,” Acosta said. “It confirms the importance of precision obesity as a tool to improve outcomes at the individual level.”
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