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GLP-1 weight-loss drugs have revolutionized the treatment of obesity, diabetes and many other diseases, but there’s an important caveat: They’re not right for everyone.
Some people experience severe weight loss; others see little to no change in scale. Some people tolerate these medications, but others stop taking them because of nausea and vomiting. In clinical trials, about 10 to 15 percent of people who take the drug are considered “non-responders” because they don’t lose at least 5 percent of their weight.
A new study published Wednesday in the journal Nature finds that part of the reason people respond so differently to drugs may lie in their DNA.
Researchers at the nonprofit 23andMe Institute have identified two versions of a gene that can help predict whether people will lose some extra weight as a result of taking medications, or will be more prone to nausea and vomiting. Genetics is only one factor in how people respond to GLP-1, but when combined with other factors such as age, gender and other medical conditions, the researchers created a model to predict potential weight loss benefits and risk of side effects.
“There are many factors that influence how people experience GLP-1…and we’ve shown that genetics also play a role,” said Adam Auton, vice president of human genetics at 23andMe Research Institute and one of the study’s authors. 23andMe is integrating survey-based reporting into its “Total Health” product, a $499 genetic testing service that includes clinician oversight.
G. Caleb Alexander, an epidemiologist at the Johns Hopkins Bloomberg School of Public Health who was not involved in the study, said the study addresses an important but underappreciated problem.
“Many clinicians and patients do not seem to realize that GLP-1 does not work for everyone,” Alexander said in an email. “It’s unclear why the vast majority of people don’t lose weight after taking GLP-1 – a question of huge scientific and clinical importance.”
His own recent research in JAMA Internal Medicine shows that the drugs work similarly in different patient groups based on factors such as age, race and whether they have diabetes, but he said it’s “entirely possible that genetic determinants of GLP-1 effectiveness have yet to be identified.”
Obesity precision medicine
“Personalized medicine” has been one of the most popular buzzwords in healthcare for years, heralding a new era in which treatments are not one-size-fits-all but are matched to an individual’s biology. The field of pharmacogenomics—the use of genetic information to target drugs—can allow doctors to provide treatments that are more likely to be effective and avoid treatments that may have harmful effects. Despite the successes that have been achieved, most medicine still requires trial and error and a degree of guesswork.
The new study is a step toward creating precision obesity tools to guide the use of powerful and expensive drugs. Giving patients more realistic expectations about their weight loss potential can save time, frustration and money spent learning whether a medication is working.
Robert C. Green, a medical geneticist at Harvard Medical School, praised the study as well done. He said it was a reminder of the enormous promise that genomics has in improving medicine, not just in diagnosing and treating rare diseases but also in improving routine clinical care.
“The promise of pharmacogenomics is waiting to be realized,” Green said. “Now, to realize the promise of pharmacogenomics in our health care system, we must find a way to incorporate some level of genomics into every patient’s treatment.”
Identifying two genes that influence GLP-1 response
In the new study, scientists searched the genomes of 15,000 people who took these drugs. DNA is a string of letters 3 billion long, spelled differently by everyone. The team examined the code, looking for changes common to people who lost weight or experienced side effects such as nausea and vomiting.
This method flags variations in two genes – GLP1R and GIPR – Medications that mimic the effects of our natural gut hormones target these two substances directly. Semaglutide drugs, such as Ozempic and Wegovy, target the GLP-1 pathway, which is involved in insulin secretion, appetite and gastric emptying. Tezepatide drugs such as Mounjaro and Zepbound target the GLP-1 pathway as well as a second pathway (GIP pathway).
Research shows that some people carry a specific version of the GLP1R gene, which produces a protein in which one of the amino acid building blocks is different. People with this variant are more likely to lose weight after taking GLP-1. The overall impact is relatively small. People carry two copies of each gene, one from each parent. Those who carried one copy of the GLP1R gene variant lost just over 1.5 pounds more than those who carried the regular version. With two copies of the variant, they lost an additional three pounds.
The authors propose that an alternative version of the GLP1R gene produces a protein that functions identically but moves more efficiently through the cell to the surface, where it can be targeted with drugs.
The same GLP1R variants associated with weight loss are also associated with an increased risk of nausea and vomiting. The scientists also discovered a variant of a different GIPR gene that was common among people who reported these side effects while taking the drug tezepatide. A very small number of people who carry two copies of either variant are particularly vulnerable to experiencing discomfort when taking the drug tezepatide, and are 15 times more likely to vomit.
Ruth Loos, a genetic epidemiologist at the University of Copenhagen who was not involved in the study, notes that the additional weight loss may not seem like much on average, but for those with two copies of the GLP1R variant, it amounted to more than 10 percent of the total weight loss experienced in the study population.
She said it was nice to see the findings replicated in a separate database within the NIH’s All of Us database, but she would like to see more follow-up because some other studies have not yet found similar effects.
Andres Acosta, an obesity expert at the Mayo Clinic who was not involved in the study, said it is not one but many genetic variants that contribute to differences in how people respond to these drugs. He co-founded a startup called Phenomix Sciences, which has commercialized a different test that also uses genetics to predict response to GLP-1.
“This paper builds on decades of work by us and others to understand the genetics of obesity and predictors of response to obesity interventions,” Acosta said. “It confirms the importance of precision obesity as a tool to improve individual-level outcomes.”
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