Ozempic and Wegovy have become two of the most widely prescribed drugs in the world, but a new study suggests that roughly one in ten people may be genetically wired to get little benefit from them.
Research published in Genome Medicine identified specific genetic variants that appear to cause "GLP-1 resistance," a condition where the body produces higher-than-normal levels of the hormone glucagon-like peptide-1 but responds to it less effectively. GLP-1 drugs are designed to mimic that hormone, so if the body is already partially resistant to it, the medications may produce a weaker effect.
The study focused on variants in an enzyme called peptidyl-glycine alpha-amidating monooxygenase, or PAM, which plays a role in activating multiple hormones including GLP-1. One specific variant, called p.S539W, produced a counterintuitive result: instead of lowering GLP-1 levels, it was associated with elevated levels of the hormone. Despite those higher levels, participants did not clear blood sugar more efficiently. Their bodies needed more GLP-1 to achieve the same biological result.
"These findings support the idea that some patients may have partial biologic resistance to incretin-based therapies," said Robert Glatter, MD, an attending physician at Lenox Hill Hospital in New York City and assistant professor at Zucker School of Medicine at Hofstra/Northwell, who was not involved in the study.
The PAM variants identified in the research are more common among people with diabetes and may also impair insulin release from the pancreas. GLP-1 itself does several things in the body: it regulates blood sugar, stimulates insulin release after meals, slows the emptying of the stomach, and reduces appetite. Drugs in this class, including semaglutide products like Ozempic and Wegovy, are built to replicate those effects.
The current study examined how the genetic variants affect blood sugar regulation specifically, not weight loss directly. GLP-1 drugs are typically prescribed at higher doses for obesity than for diabetes management, and researchers have not yet determined whether the same resistance mechanism affects the drugs' weight loss outcomes. That remains an open question.
Mir Ali, MD, a bariatric surgeon and medical director of MemorialCare Surgical Weight Loss Center at Orange Coast Medical Center in Fountain Valley, California, said the findings match what he sees in practice. "This aligns with my clinical experience, where I frequently see a variable response to GLP-1 medications," he said. Ali was not part of the research team.
For patients who do not respond well to GLP-1 drugs, a separate review cited by Healthline suggests that combination approaches to obesity pharmacotherapy may offer alternatives. The field of pharmacogenomics, which tailors drug choices to individual genetic profiles, is increasingly being applied to obesity medicine, and the new findings give that approach a more concrete biological foundation.
