Genetic differences may influence how individuals respond to GLP-1 drugs used for obesity treatment, as well as their risk of experiencing side effects, a study involving nearly 28,000 users of these medications has revealed. The research focused on mutations in the GLP1R gene, which encodes the protein targeted by GLP-1 drugs, finding a modest but statistically significant association with improved weight loss outcomes.
Participants carrying one copy of the GLP1R variant lost an average of 1.7 pounds (0.76 kilograms) more over a median treatment duration of eight months compared to those without the mutation. Those with two copies of the variant experienced an even greater weight reduction, averaging 3.3 pounds more. Additionally, mutations in both GLP1R and GIPR genes were linked to side effects such as nausea and vomiting. Notably, the association between GIPR mutations and vomiting was observed only in users of Eli Lilly’s tirzepatide, marketed as Mounjaro for diabetes and Zepbound for obesity. Carriers of this variant were 83% more likely to experience vomiting after taking tirzepatide than non-carriers.
While the genetic impact on weight loss was relatively small, researchers emphasized that these findings provide direct genetic evidence supporting the role of drug-target gene variation in individual responses. This insight could pave the way for precision medicine approaches in obesity treatment.
In a significant development, another study examined the cardiovascular benefits of GLP-1 drugs, suggesting these effects may be more closely related to dosage rather than the extent of weight loss. This raises the possibility that the heart-related advantages of GLP-1 medications might operate independently from their obesity-related effects.
The study analyzed data from 47,199 patients with cardiovascular disease who were treated with Novo Nordisk’s semaglutide, sold as Ozempic for diabetes and Wegovy for obesity, over a period of up to two years. As expected, higher doses correlated with greater weight loss. Two years after discontinuing treatment, those who had received higher doses exhibited lower risks of death from any cause, as well as reduced risks of heart attack, stroke, cardiovascular death, cerebrovascular disease, heart failure, and heart valve disorders. Interestingly, these cardiovascular risk reductions were not influenced by the amount of weight lost.
Further tissue analysis revealed that the cell-surface proteins targeted by GLP-1 drugs were most abundant in the pancreas, consistent with their role in diabetes management, but the heart exhibited the second-highest concentration. The study’s lead researcher, Venky Soundararajan from the data analytics firm nference in Cambridge, Massachusetts, proposed the hypothesis that GLP-1 drugs might exert direct effects on the heart. He noted that although this remains speculative, the lack of correlation between heart benefits and weight loss, combined with molecular data, justifies further experimental investigation into the drugs’ cardiac actions.
Separately, researchers achieved sex reversal in mice by introducing a single DNA mutation outside a gene, demonstrating the profound impact of non-coding DNA on development. In experiments with XX mouse embryos, which normally develop as females, a mutation was inserted into Enh13, a DNA region regulating the Sox9 gene essential for testis formation. Normally, Sox9 must be suppressed for ovary development. The mutation disrupted this repression, activating Sox9 and resulting in complete male development both internally and externally.
This finding is particularly remarkable because the mutation occurred in the non-coding genome—the 98% of DNA that does not encode proteins but regulates gene activity. The study leader, Nitzan Gonen of Bar-Ilan University in Israel, highlighted that even a single DNA letter change out of approximately 2.8 billion can cause significant developmental consequences. The research holds important implications for individuals with Differences of Sex Development (DSD), a condition affecting about 1 in 4,000 births worldwide, where over half of cases lack a genetic diagnosis despite sequencing of protein-coding regions.
Co-author Elisheva Abberbock, also from Bar-Ilan University, emphasized that focusing solely on genes is insufficient, as critical disease-causing mutations may reside in non-coding regions that regulate gene expression.
