Genetic Variants Linked to Weight Loss Outcomes on GLP-1 Drugs in New Study

A new study reveals that specific genetic variants influence the effectiveness of weight-loss drugs such as semaglutide (Wegovy, Ozempic) and tirzepatide (Mounjaro). Researchers analyzed genetic data from individuals who self-reported their experiences with these GLP-1 receptor agonist medications.

The findings indicate that variations in genes related to appetite and digestion can lead to differences in weight loss and side effects.

The study, published in the journal Nature, examined data from 15,000 people who had undergone genetic testing through 23andMe and reported using weight-loss drugs. 7% of their body weight over approximately eight months of treatment. Weight loss ranged from little or nothing to as much as 30% in some cases.

One genetic variant, rs10305420 in the GLP1 receptor gene, was associated with increased weight loss among users of GLP-1 drugs. 76 kg on average, with those having two copies experiencing double the effect. This variant is more prevalent in people of European ancestry, where 64% carry one copy and 16% carry two copies, compared to 7% of African Americans carrying one copy.

Another variant, rs1800437 in the gastric inhibitory polypeptide receptor gene, was linked to higher rates of nausea and vomiting in users of tirzepatide.

This side effect could be up to 15 times more severe in affected individuals, potentially impacting 1% of users. The study suggests these genetic associations partially explain why responses to the drugs vary widely. > "The study found a genetic variant associated with weight loss, which was also associated with nausea.

“— Professor Ruth Loos, University of Copenhagen, as reported in Nature (2023)”

“The research team, including experts from 23andMe and the University of Copenhagen, noted that the genetic effects are modest. They called for additional studies to confirm the findings. Drug trials report average weight losses of 14% for semaglutide and 20% for tirzepatide.”

Non-genetic factors play a larger role in outcomes. Women are more than twice as likely as men to lose 15% of their body weight on Mounjaro. Younger age, Asian or white ethnicity, higher doses, and longer treatment duration also correlate with greater weight loss.

6 million people have used weight-loss drugs in the past year, primarily through private online pharmacies. The National Health Service provides Wegovy and Mounjaro only to a small group with obesity and related health conditions. Experts emphasize that behavioral factors, such as exercise and diet, along with clinical support, drive most variability in results.

The study highlights potential for precision medicine, where genetic profiles could guide drug selection. However, Professor Naveed Sattar from the University of Glasgow stated that the findings are scientifically interesting but not yet ready to alter clinical practice. More robust trial data is needed to assess benefits and harms.

Dr. Marie Spreckley from the University of Cambridge noted that genetics form only part of a complex picture. Treatment-related factors and underlying health issues remain dominant. The research provides evidence for genetic contributions but underscores the need for comprehensive approaches to obesity treatment.