Stanford Medicine and an international team have identified genetic variants in the PAM enzyme that leave roughly 10% of people with a hidden form of "GLP-1 resistance": their bodies actually produce higher levels of the blood-sugar hormone GLP-1, yet it works poorly. The finding, published June 5 in Genome Medicine, helps explain why blockbuster GLP-1 drugs such as Ozempic and Wegovy underperform in some patients.
Across 1,119 participants in three clinical trials, 25% of non-carriers reached healthy blood-sugar targets after six months. Among carriers, only 11.5% of those with the p.S539W variant and 18.5% of those with p.D563G hit the same goal. Senior authors Anna Gloyn (Stanford) and Markus Stoffel (ETH Zurich) led the work with collaborators at Oxford, Dundee and Copenhagen.
Screening for these variants up front could steer resistant patients toward other therapies sooner, a step toward precision medicine in diabetes care. The team focused on blood-sugar control rather than weight loss, which they say needs further study.