Anna Gloyn had a puzzle on her hands: why did some of her patients respond beautifully to Ozempic while others barely budged? After ten years of international collaboration involving human trials and mouse models, Stanford Medicine researchers have finally cracked open one crucial piece of the answer—a genetic variant that makes GLP-1 medications work less effectively for about one in ten people.
The discovery matters because GLP-1 receptor agonists have become a cornerstone of diabetes treatment. More than one-quarter of people with Type 2 diabetes now use these drugs, and they've transformed obesity care as well. Yet doctors have long struggled with an uncomfortable truth: the same medication produces wildly different results in different patients. For some, blood sugar control improves dramatically within weeks. For others, even after six months of treatment, the drug barely moves the needle. Understanding why opens a door to precision medicine—matching the right therapy to the right patient from the start.
The research, published in Genome Medicine, focused on two genetic variants that reduce activity of an enzyme called PAM, which activates several hormones including GLP-1. Researchers recruited adults both with and without the PAM variant p.S539W and had them drink a sugary solution while blood samples were collected every five minutes over four hours. What they found was genuinely surprising. Participants carrying the variant didn't produce lower levels of GLP-1, as scientists had predicted. Instead, they had higher levels—yet those elevated levels weren't actually working. Their blood sugar wasn't dropping as effectively as it should have been.
"This was the opposite of what we imagined we would find," Gloyn reflected on the discovery. The implication is profound: individuals with these variants produce abundant GLP-1, but their bodies don't respond to it properly. It's like having the gas pedal pressed but the engine not engaging.
Mahesh Umapathysivam, the study's lead author and an endocrinologist in Adelaide, Australia, knows firsthand how frustrating treatment variability can be. "When I treat patients in the diabetes clinic, I see a huge variation in response to these GLP-1-based medications and it is difficult to predict this response clinically," he said. "This is the first step in being able to use someone's genetic make-up to help us improve that decision-making process."
The work involved researchers from Stanford, ETH Zurich in Switzerland, Adelaide University in Australia, and the University of Parma in Italy. Co-senior author Markus Stoffel and Gloyn's team have spent years investigating why this particular enzyme matters so much. PAM is the only enzyme in the human body capable of a chemical process called amidation, which increases the potency and half-life of biologically active peptides. When it doesn't work properly, the ripple effects can touch multiple systems.
Yet crucial mysteries remain. Scientists still don't know precisely why these genetic variants cause GLP-1 resistance—only that they do. Gloyn's team has methodically eliminated hypothesis after hypothesis without finding the exact mechanism. The research also focused on blood sugar control rather than weight loss; because Ozempic and Wegovy are prescribed at different doses depending on whether they're treating diabetes or obesity, more work will be needed to determine whether the same genetic variants affect weight loss outcomes. Still, the ability to identify who won't respond well before starting treatment—potentially saving months of ineffective therapy—represents a genuine step forward in helping patients find their optimal path to health.