Cristóbal Morales
Head of the Metabolic Health, Diabetes and Obesity Unit at Vithas Hospital in Seville and member of the Spanish Society for the Study of Obesity (SEEDO)
This is a remarkably elegant study that reinforces what we have long been saying. Obesity is a highly complex disease in which genetics plays a major role—although it does not explain everything, it accounts for a substantial part. It is also worth noting that this work has been published in a high-impact journal, Nature, and is based on a robust methodology, analysing around 27,000 individuals through a genetic study.
One limitation is that weight loss was self-reported by participants, meaning the data are subject to reporting bias. Nevertheless, the study provides valuable insight into a common clinical challenge: individuals respond differently to treatment. We often refer to hyper-responders and hypo-responders, and each patient may also experience different side effects. Genetics could help explain both phenomena, at least in part.
The study is both relevant and timely, as it sheds light on a current issue in clinical practice. It fits within the broader framework of what we call precision medicine—essentially, the ambition that genetic information will one day allow us to select the most appropriate drug or tailor the optimal treatment for each individual.
That said, genetics is not the whole story. As noted, obesity is a complex condition. Current evidence shows that biological factors such as sex (with women tending to lose more weight), the presence of type 2 diabetes (associated with less weight loss), age (with older individuals typically losing less weight), and fatty liver disease (also linked to reduced weight loss) all play a significant role.
Looking ahead, we are likely to integrate clinical predictors of both treatment efficacy and side effects with biological variables. We are at the beginning—indeed, the dawn—of a new era in medicine: precision medicine.
In this particular study, variants in the GLP-1R gene, located on chromosome 6, are analysed and may help explain why some individuals respond better to treatment, given the mechanism of action of these drugs on the GLP-1 receptor. Similarly, variants in the GIPR receptor gene, located on chromosome 19, may account for differences in side-effect profiles. For instance, certain variants may impair the GIPR pathway, potentially reducing the protective effect against nausea and increasing the likelihood of adverse events.
From my perspective, this points towards a highly promising future. The ability to anticipate treatment response through pharmacogenomics represents a major milestone, enabling a more precise approach not only in selecting therapies but also in optimising their use—distinguishing responders from non-responders and identifying those at higher risk of side effects.
At present, we have two highly effective drugs on the market with strong safety profiles—tirzepatide (Mounjaro) and semaglutide (Wegovy)—which are considered essential therapies. In the future, additional molecules with different mechanisms of action are expected to emerge, making genetic support even more important in guiding treatment selection, always in combination with the patient’s phenotype and clinical characteristics.
This study marks the beginning of a new era in medicine, based on the integration of genetic and clinical variables that we are already accustomed to managing in everyday practice.