Genetic Variants Linked to Weight Loss Outcomes and Side Effects from GLP-1 Drugs

Researchers have identified genetic variants in two genes related to appetite and digestion that influence weight loss and side effects from GLP-1 receptor agonist drugs. These drugs, including semaglutide (Wegovy and Ozempic) and tirzepatide (Mounjaro), mimic gut hormones to reduce hunger.

The study, published in the journal Nature, analyzed genetic and self-reported data from 23andMe participants who used these medications.

7% over approximately eight months of treatment. Some participants lost up to 30% of their body weight, while others experienced minimal change. Drug trials indicate average losses of 14% on semaglutide and 20% on tirzepatide.

6 lbs). Individuals with two copies of this variant lose roughly double that amount. This variant is more prevalent in people of European ancestry, with 64% carrying one copy and 16% carrying two, compared to 7% of African Americans carrying one copy.

A second variant, rs1800437 in the gastric inhibitory polypeptide receptor gene, links to higher rates of nausea and vomiting in users of tirzepatide.

This could affect up to 1% of users with severe vomiting, 15 times the normal rate. The variant does not influence weight loss outcomes. Professor Ruth Loos from the University of Copenhagen, who commented on the research, noted the variant's dual association with weight loss and nausea.

“The study found a genetic variant associated with weight loss, which was also associated with nausea. People lose more weight if they have this variant.”

The genetic effects are described as modest, comparable to influences from sex, age, ethnicity, drug type, dose, and treatment duration. Women are more than twice as likely as men to lose 15% of body weight on Mounjaro. Younger individuals, those of white or Asian descent, and longer treatment durations also correlate with greater losses.

Behavioral factors, such as exercise and diet, along with clinical support and underlying health conditions, drive most variability in outcomes. At least 1.6 million people in the UK have used weight-loss drugs in the past year, primarily through private online pharmacies.

The UK's National Health Service provides Wegovy and Mounjaro only to a small group with obesity and related health issues. The findings suggest potential for precision medicine, where genetic profiles guide drug selection to maximize benefits and minimize side effects.

However, experts emphasize that genetics explain only a small portion of differences, and the results need replication in other studies. Dr. Marie Spreckley from the University of Cambridge highlighted the complexity of factors involved.

“Genetics is only one part of a much more complex picture. The main drivers of outcomes are behavioural, clinical, and treatment-related factors.”

Professor Naveed Sattar from the University of Glasgow stated that the research is scientifically interesting but distant from altering clinical practice. More robust trial data is required to assess benefits and harms of these therapies.