A new study led by researchers at Stanford Medicine suggests that about 1 in 10 people may have a genetic resistance to GLP-1 diabetes drugs, such as Ozempic and Wegovy, when these medications are used to control blood sugar in people with Type 2 Diabetes.
The study found that certain variants in the PAM gene, carried by roughly 10% of the population, are linked to a phenomenon researchers call GLP-1 resistance. People with these variants have higher levels of the GLP-1 hormone, but the hormone is less biologically effective, meaning it does not lower blood sugar as well as expected. This was unexpected, since researchers initially thought these individuals would have lower hormone levels.
After experiments in both humans and mice, the researchers confirmed that this resistance is real. In mouse models, GLP-1 activity was reduced despite normal receptor function, suggesting that the problem likely occurs further downstream in the signaling pathway, though the exact mechanism remains unknown.
Analysis of clinical trial data involving more than 1,100 participants showed that people with PAM variants were less likely to reach target HbA1c blood sugar levels after six months of treatment with GLP-1 receptor agonists. Importantly, this reduced response appeared to be specific to GLP-1 drugs, as responses to other diabetes medications like metformin were unaffected.
The findings could be an important step toward precision medicine, allowing doctors to use genetic testing to predict which patients are less likely to benefit from GLP-1 therapies and choose better treatments earlier. Researchers also note that longer-acting GLP-1 drugs may help overcome this resistance, though more research is needed, especially regarding effects on weight loss