More than a quarter of people with Type 2 diabetes take GLP-1 receptor agonists, but these widely used medications may not be as effective for individuals who carry certain genetic variants, according to an April 12 study by Stanford Medicine scientists and collaborators.
The study found that about 10% of the general population has genetic variants that cause what researchers call GLP-1 resistance. In this condition, levels of the hormone GLP-1 are higher but less biologically effective in regulating blood sugar. The research focused on blood sugar control and did not determine whether the variants affect weight loss from drugs like Ozempic and Wegovy, which are also prescribed for obesity at higher doses.
The decade-long international study involved experiments in humans and mice, as well as analysis of clinical trial data. Anna Gloyn, DPhil, professor at Stanford University School of Medicine and senior author of the study, said: "That is the million-dollar question. We have ticked off this enormous list of all the ways in which we thought GLP-1 resistance might come about. No matter what we've done, we've not been able to nail precisely why they are resistant." Lead author Mahesh Umapathysivam said: "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. This is the first step in being able to use someone's genetic make-up to help us improve that decision-making process."
Researchers examined two genetic variants affecting an enzyme called PAM (peptidyl-glycine alpha-amidating monooxygenase), which activates many hormones including GLP-1. Contrary to their expectations, people with a PAM variant had increased levels of GLP-1 but showed no evidence of greater biological activity or faster reduction in blood sugar levels after consuming a sugary solution.
Mouse models lacking the PAM gene also displayed elevated GLP-1 without improved glucose regulation or slowed gastric emptying—a key function linked with both glucose control and weight loss from these drugs. Additional experiments indicated that while PAM defects do not alter how well receptors bind or signal with GLP-1 hormone itself, resistance likely emerges further downstream.
Analysis from three clinical trials involving over 1,100 participants revealed those carrying PAM variants were less responsive to treatment with GLP-1 receptor agonists; fewer reached recommended HbA1c targets compared with non-carriers after six months on therapy. However, responses did not differ for other common diabetes treatments such as sulfonylureas or metformin.
While some industry-funded trials using longer-lasting versions showed similar responses among carriers and non-carriers—possibly indicating such formulations could overcome resistance—the underlying mechanism remains unclear. Gloyn likened it to insulin resistance: "There are a whole class of medications that are insulin sensitizers, so perhaps we can develop medications that will allow people to be sensitized to GLP-1s or find formulations...that avoid the GLP-1 resistance." She also noted pharmaceutical companies often collect relevant genetic data during trials but accessing this information can be challenging for independent researchers.
The findings suggest potential benefits for personalized medicine approaches in treating Type 2 diabetes by identifying patients unlikely to respond optimally before starting therapy.
