Scientists believe they may be closer to explaining why GLP-1 drugs are less effective for some people.
Medications such as Ozempic, Mounjaro, Wegovy and Zepbound were originally developed to help people with type 2 diabetes manage blood sugar, but they are now also widely used for weight loss. These drugs, known as GLP-1 receptor agonists, mimic a natural gut hormone that helps the body release insulin, slow digestion and regulate appetite.
Researchers have identified genetic variants that may make some patients respond less well to these drugs. In the Stanford-led study, the main focus was on how effectively the medications controlled blood sugar levels in people with type 2 diabetes, not on weight-loss outcomes.
The team found that around 10 percent of people may carry variants associated with GLP-1 resistance. In those individuals, the body appears to produce more of the hormone, but it does not seem to work as efficiently as expected. The finding suggests that biology, not just dose or willpower, may help explain why some people see less benefit from treatment.
According to Cleveland Clinic, GLP-1 helps trigger insulin release from the pancreas. When the body does not produce enough insulin, blood sugar rises, which is a key factor in diabetes. The hormone also helps limit the amount of glucose entering the bloodstream and affects areas of the brain that process hunger and satiety.
‘affects areas of your brain that processes hunger and satiety.’
The study, carried out by Stanford Medicine and published in Genome Medicine, suggests these genetic differences could affect how well certain patients respond over time. Researchers say the variants reduce the activity of an enzyme called PAM, which helps activate several hormones in the body, including GLP-1.
“saw that individuals who had those variants were unable to lower their blood glucose levels as effectively after six months of treatment,”
If doctors were able to identify that reduced response in advance, it could help them adjust a patient’s treatment plan sooner and move them onto a more suitable option faster. That could matter even more as GLP-1 medicines become more common and more expensive, and as doctors try to match the right drug and dose to the right patient.
Lead author Mahesh Umapathysivam, MBBS, DPhil, an endocrinologist and clinical researcher at Adelaide University in Australia added:
“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.”
Scientists still do not fully understand what causes GLP-1 resistance in some patients. In the Stanford work, researchers closely examined two genetic variants that reduce the activity of PAM, an enzyme that is involved in processing peptide hormones. They initially expected people with the PAM variant to have lower GLP-1 levels in their blood, but the results showed the opposite.
“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 to GLP-1″ Goyn said.
It is still unclear whether the same issue affects people taking these drugs primarily for weight loss, because the available research has not yet produced a firm answer. The Stanford study centered on blood sugar control, while newer research into GLP-1 weight-loss response has pointed to other genes, including variants in the GLP1R gene itself, that may influence how much weight people lose and whether they experience side effects such as nausea.
The study made clear that its findings were centered on blood sugar control, so the researchers did not draw definite conclusions about weight-loss outcomes.
That is especially important because these medications are often prescribed at higher doses for weight management, meaning more study is needed to determine whether that changes the impact of the variants. It also means genetics may turn out to be only one piece of the puzzle, alongside dose, treatment length, diet, other medications and underlying metabolic health.
“It’s very common for pharmaceutical companies to collect genetic data on their participants,” Goyn added later on. “For the newer GLP-1 medications, it would be useful to look at whether there are genetic variants, like the variants in PAM, that explain poor responders to their medications.”
Researchers say the next step is to test whether genetic screening could eventually help doctors predict which patients are likely to benefit most from GLP-1 therapy. For now, the finding is best seen as an early step toward precision medicine rather than a clinical test that is ready for routine use.