Why obesity drugs work better for some people: these genes hold clues

Scientists have identified a set of genetic variants that could help to explain why responses to obesity drugs vary markedly from person to person¹.

One variant is associated with greater weight loss from the powerful GLP-1 medications. Others are linked to an increased risk of side effects such as nausea. The findings, published today in Nature, come from a study of almost 28,000 users of the DNA-testing service 23AndMe who reported taking weight-loss drugs.

The large sample size makes the findings compelling, says Andrea Ganna, a health data scientist at the University of Helsinki. But the genetic effect on weight loss is relatively small. “I don’t see this as something that clinicians are going to use” to inform their practice, he says.

Co-author Adam Auton, vice-president of human genetics at 23andMe Research Institute, a non-profit organization in Palo Alto, California, that offers a DNA-testing service of the same name, acknowledges that the association was modest. “There’s a number of factors that can influence weight loss, of which genetics is a subcomponent.” But he notes that the genetic association with side effects was more substantial.

Wide variation

Next-generation weight-loss drugs mimic natural hormones that influence appetite and metabolism. The obesity drug semaglutide, for example, mimics a hormone called glucagon-like peptide-1 (GLP-1), and the drug tirzepatide includes mimics of both GLP-1 and the hormone glucose-dependent insulinotropic polypeptide (GIP). In one study², participants taking semaglutide lost an average of 10% of their body weight — but some lost more than 25%, and others lost almost none.

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To identify a possible genetic component of this response, the authors examined data from 23andMe participants who had answered questions about their use of obesity treatments, including which drug they had used, how long they used it for, how much weight they had lost and which side effects they had experienced. Researchers then analysed hundreds of thousands of genetic variants in the participants’ genomes to search for correlations with the drugs’ efficacy and side effects.

The authors found that people carrying one copy of a specific variant in the gene encoding the receptor for GLP-1 lost, on average, 0.76 kilograms more over a median of 8 months of treatment than did people who had no copies. People carrying two copies of the variant lost around 1.5 kilograms more.