Two genetic variants could help explain differences in side effects and weight loss in patients taking GLP-1 drugs, a new study suggested.

To investigate a potential genetic basis for inter-person variability in weight-loss efficacy and the incidence of side effects in people taking the drugs, researchers conducted genome-wide association studies using self-reported 23andMe data from 27,885 individuals (median age, 52 years; 82.4% female).

They found that the GLP-1 receptor variant rs10305420 was associated with a slightly greater decrease in BMI (0.641% loss), corresponding to about 0.76 kg of extra weight lost per allele in individuals who carried this variant compared with those who did not.

Another variant, rs1800437, in the gastric inhibitory polypeptide receptor gene was associated with drug-related nausea and vomiting in people taking tirzepatide, although it was not associated with how much weight they lost.

The authors acknowledged that the effects of the genes were “modest” and that nongenetic factors — such as sex, age, and the type of drug taken — were also “strongly” associated with treatment outcomes and thus remain important predictors of weight loss.

Nevertheless, they concluded in their online report in Nature, “These findings provide direct genetic evidence that variation in the drug target genes contributes to inter-person variability in response and lay the foundation for precision medicine approaches in the treatment of obesity.”

‘An Important Step’

Commenting in an accompanying editorial, Ruth J.F. Loos, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark, wrote, “The current study confirms previous observations that several factors — female sex, younger age, absence of type 2 diabetes, and medication type, dose, and duration — are all associated with greater weight loss but also with a higher likelihood of experiencing nausea and vomiting.”

The study also showed that the relative contribution of the identified GLP-1 and glucose-dependent insulinotropic polypeptide variants is of similar magnitude to the demographic, clinical, and treatment-related factors.

Taken together, that means “genetic and nongenetic factors explained around 25% of the variation in weight-loss responses to GLP-1-based medications,” she noted. “Further work will be needed to uncover the factors that account for the remaining 75%.”

Marie Spreckley, research program manager, University of Cambridge, Cambridge, England, pointed to “important limitations” of the study. “The primary dataset relies on self-reported weight, treatment duration, and side effects, which introduces measurement error and potential reporting bias,” she wrote.

She also noted that the self-reported weight loss was substantially greater than that recorded in linked electronic health records (approximately -11.8% vs -5.8%), highlighting “systematic differences between data sources.”

“The cohort is also not fully representative, being predominantly female and largely of European ancestry, which limits generalizability,” she wrote. “In addition, the median treatment duration was relatively short (around 8 months), so longer-term outcomes are not captured.

“Overall,” she concluded, “this is an important step toward understanding variability and the potential for future precision approaches, but the effects are modest and the evidence is not yet sufficient to support using genetic information to guide treatment decisions in routine clinical practice.”

No specific funding was declared. All authors are current or former employees of 23andMe. Loos reported being partially funded by an unrestricted donation from the Novo Nordisk Foundation. Spreckley declared having no conflicts of interest.

Marilynn Larkin, MA, is an award-winning medical writer and editor whose work has appeared in numerous publications, including Medscape Medical News and its sister publication MDedge, The Lancet (where she was a contributing editor), and Reuters Health.