How well weight loss injections work and how many side effects occur varies from person to person. A genome-wide association study has now uncovered two gene variants that influence the effects and side effects of the active ingredients semaglutide and tirzepatide. According to this, a variation in the GLP-1 receptor can help you lose weight effectively, but at the same time it can also increase the risk of nausea and vomiting. If the results are confirmed in further studies, they could help to tailor obesity therapies to the individual.
GLP-1 agonists such as semaglutide and tirzepatide bind to the same receptor as the body’s satiety hormone GLP1. Because they regulate blood sugar, they originally came onto the market as diabetes medications, but are now increasingly being used as weight loss aids. But their effects vary greatly: while some test subjects lost more than a quarter of their body weight in studies, others hardly benefited from the supposed miracle cures. There are also big differences in the side effects: Some people tolerate the injections without any problems, while others suffer from nausea, vomiting, diarrhea or constipation.
“To investigate the genetic basis of this variability, we conducted a genome-wide association study of weight loss and side effects in 27,885 people who used GLP1 receptor agonists to lose weight,” reports a team led by Qiaojuan Su from the 23andMe Research Institute in California. To do this, the researchers evaluated the volunteers’ genetic information and compared it with the test subjects’ information about their weight loss and any side effects they had experienced.
More effect, more side effects
Su and her colleagues discovered two gene variants that were associated with weight loss success and side effects. The first variant affects the GLP-1 receptor. People who have a thymine base instead of a cytosine base due to a mutation in the responsible gene lost slightly more weight on average when treated with semaglutide than people without this mutation. According to the researchers, the variant probably results in more GLP-1 receptors on the cell surface and thus an increased effect of the weight loss injections. If the mutation affected only one copy of the gene, people lost an average of 0.76 kilograms more; if both gene copies were affected, their weight was reduced by an additional 1.52 kilograms on average. However, people with this weight loss gene variant also suffered more often from side effects such as nausea and vomiting.
The second gene variant identified concerns the gene for the gastric inhibitor polypeptide receptor, or GIPR for short. Similar to the GLP-1 receptor, GIPR plays an important role in regulating blood sugar levels and body weight. While semaglutide only binds to the GLP-1 receptor, tirzepatide also activates the GIP receptor. Studies have previously suggested that activation of the receptor can reduce the side effects of GLP-1 agonists. In fact, Su and her team found that a mutation that potentially affects the function of the GIP receptor was associated with an increased risk of nausea with tirzepatide use. This variant had no influence on weight loss.
Individualized medicine
In line with previous studies, further analyzes showed that numerous non-genetic factors also determine weight loss success and the extent of side effects. Women, younger people and people without type 2 diabetes lost more weight on average, but also suffered more from nausea and vomiting. Together with genetic variations, these factors can explain 25 percent of the differences in effects and side effects. “Further research is needed to uncover the factors responsible for the remaining 75 percent,” writes Ruth Loos of the University of Copenhagen, who was not involved in the study, in an accompanying commentary.
It is still unclear whether the gene variants discovered directly or indirectly influence the effects of semaglutide and tirzepatide. It is already known from previous studies that these mutations also shape food preferences and eating habits and could therefore also affect weight. The replicability of the results is also still questionable. But even if there is still a need for further research, according to Loos, the study opens up the prospect that one day genetic information, together with non-genetic information, can be included in the treatment decision regarding GLP-1 agonists. “This would help ensure that patients receive the medications that are most likely to benefit them and that they can best tolerate,” says Loos. “A deeper understanding of why some people lose significant weight while others lose significantly less will be critical to tailoring therapy and advancing precision medicine.”
Source: Qiaojuan Su (23andMe Research Institute, Palo Alto, California, USA) et al., Nature, doi: 10.1038/s41586-026-10330-z