Groundbreaking research from Stanford University has identified a genetic reason why blockbuster GLP-1 medications like Ozempic and Wegovy are significantly less effective for a portion of patients.
The international study, involving teams from England, Scotland, and Australia, found that genetic variants can limit the activity of an enzyme called PAM. This enzyme is responsible for activating hormones, including GLP-1. When PAM function is reduced, gastric emptying does not slow as intended, and biological activity remains low despite high circulating levels of the hormone.
Anna Gloyn, a senior author and genetics professor at Stanford, explained the paradox. “Despite people with the PAM variant having higher circulating levels of GLP-1, we saw no evidence of higher biological activity. They were not reducing their blood sugar levels more quickly. More GLP-1 was needed to have the same biological effect, meaning they were resistant,” Gloyn stated.
With over a quarter of type 2 diabetes patients now using GLP-1 therapies, this discovery is critical. Mahesh Umapathysivam, an endocrinologist at Adelaide University and lead author, noted the clinical difficulty in predicting patient response, adding, “This is the first step in being able to use someone’s genetic make-up to help us improve that decision-making process.”
While the direct impact on weight loss is still under investigation, the findings open the door for new treatments. Researchers suggest developing insulin sensitizers to overcome this resistance or formulating longer-acting GLP-1 versions that bypass the genetic limitation entirely.