GLP-1 medications have transformed the treatment of type 2 diabetes and are increasingly used for weight loss. But a new study suggests they don’t work equally well for everyone, and part of the reason may come down to genetics.
Researchers found that certain genetic variants, carried by roughly 10% of the population, are linked to a reduced response to GLP-1 receptor agonists when it comes to blood sugar control. The findings, published in Genome Medicine, offer one of the clearest explanations so far for why responses to these drugs can vary widely from person to person.
The study combined several approaches, including experiments in people and mice as well as analyses of clinical trial data. Together, the results point to a phenomenon researchers call “GLP-1 resistance,” where the hormone is present but less effective in the body.
“In some of the trials, we saw that individuals who had those variants were unable to lower their blood glucose levels as effectively after six months of treatment,” said Anna Gloyn, DPhil, a professor of pediatrics and genetics and one of the study’s senior authors.
GLP-1 is a hormone that helps regulate blood sugar after eating by stimulating insulin release, slowing digestion and reducing appetite. Medications like semaglutide and tirzepatide mimic this hormone to improve blood sugar control and, in many cases, support weight loss.
In this study, researchers focused on genetic variants that affect an enzyme called PAM, which plays a role in activating several hormones in the body, including GLP-1. People with these variants were expected to have lower levels of active GLP-1. Instead, researchers found the opposite.
“What we actually saw was they had increased levels of GLP-1,” Gloyn said. “This was the opposite of what we imagined we would find.”
Despite having higher levels of the hormone, participants with the variants did not show stronger biological effects. Their blood sugar levels did not improve more quickly, suggesting that their bodies were less responsive to GLP-1 overall.
“Despite people with the PAM variant having higher circulating levels of GLP-1, we saw no evidence of higher biological activity,” Gloyn said. “More GLP-1 was needed to have the same biological effect, meaning they were resistant to GLP-1.”
The researchers confirmed these findings in mouse models and then looked at data from clinical trials involving more than 1,000 people with diabetes. In those trials, participants with the genetic variants were less likely to reach target blood sugar levels after six months of treatment.
The differences were specific to GLP-1–based medications. Participants with the same variants responded similarly to other common diabetes treatments, including metformin and sulfonylureas.
“What was really striking was that we saw no effect from whether you have a variant on your response to other types of diabetes medications,” Gloyn said. “We can see very clearly that this is specific to medications that are working through GLP-1 receptor pharmacology.”
At the same time, not all data pointed in the same direction. In some trials using longer-acting GLP-1 medications, responses were similar regardless of genetic status, suggesting that certain formulations or doses may help overcome reduced sensitivity.
The study focused primarily on blood sugar control, and it remains unclear how these genetic differences affect weight loss outcomes. Limited data from two trials showed no clear difference, but researchers say more evidence is needed.
“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,” said lead author Dr. Mahesh Umapathysivam. “This is the first step in being able to use someone’s genetic make-up to help us improve that decision-making process.”
For now, the findings are best understood as an early step toward more personalized treatment. Researchers say genetic testing is not yet part of routine care for guiding GLP-1 therapy, and many factors beyond genetics, including diet, lifestyle and medication adherence, also influence outcomes.
Still, the results offer a clearer picture of why these medications can feel unpredictable in real life. Rather than a single, uniform effect, GLP-1 drugs appear to interact with individual biology in more complex ways than previously understood.
The study was supported by Wellcome, the Medical Research Council, the European Union Horizon 2020 Programme, the National Institutes of Health, the National Institute for Health Research Oxford Biomedical Research Centre, the Canadian Institutes of Health Research, the Novo Nordisk Foundation, Boehringer Ingelheim and Diabetes Australia.