Reacción a "Two genetic variants linked to the effects of GLP-1 drugs for obesity"

This appears to be a scientifically robust and relevant study, as it identifies genetic associations in GLP-1R and GIPR—that is, in genes encoding the biological targets of semaglutide and tirzepatide—thereby providing clear mechanistic plausibility for the findings. Moreover, the main signal associated with greater weight loss was observed in a large sample and externally replicated in a cohort based on electronic health records, which strengthens the robustness of the result. Overall, the work aligns well with existing evidence showing substantial inter-individual variability in response to these drugs (as with most interventions) and represents a step towards more refined precision medicine approaches in obesity.

However, the clinical implications should be interpreted with caution. Although the genetic signal reaches clear statistical significance—the main association in GLP1R showed a P value of 2.9 × 10⁻¹⁰ and was externally replicated in All of Us (P = 0.001)—the effect size remains modest, at around 0.76 kg of additional weight loss per allele for the lead variant. The authors demonstrate that a combined model including both clinical and genetic variables can stratify patients, but this does not imply that genetics alone is sufficient to define clinical subgroups or to justify routine genetic testing at this stage. Indeed, the study itself indicates that most of the predictive capacity still derives from non-genetic factors such as sex, age, type 2 diabetes, type of drug, dose, and treatment duration.

In this respect, the findings resemble those observed in many cardiometabolic traits—such as type 2 diabetes, glucose levels, HbA1c, BMI, or blood pressure—where genetic associations are robust and biologically informative, yet of limited individual predictive value when considered in isolation. Furthermore, a substantial proportion of the data is self-reported, the cohort is enriched for women and individuals of European ancestry, and the authors are current or former employees of 23andMe (a company specialising in direct-to-consumer genetic testing). It will therefore be important to validate these findings prospectively, independently, and in more diverse populations.