Currently, more than a quarter of people with type 2 diabetes use GLP-1 receptor agonists, a class of medications that includes Ozempic. But a new study by Stanford Medicine and international collaborators suggests that these widely prescribed drugs may be less effective for some patients because of genetics.
The study found that about 10% of people carry a genetic variation associated with a phenomenon known as GLP-1 resistance. People with these mutations appear to produce higher levels of the hormone GLP-1 (glucagon-like peptide 1), which helps regulate blood sugar levels, but this hormone does not seem to work as effectively in the body.
Researchers focused on blood sugar control and could not reach firm conclusions about weight loss benefits. Drugs such as Ozempic and Wigovy are typically prescribed at higher doses for obesity treatment than for diabetes management, and further research is needed to determine whether the same genetic factors influence weight loss results.
Published in genomic medicineThe study brought together scientists from multiple countries over a 10-year period. The study included experiments in both humans and mice, as well as data analysis from clinical trials of diabetes drugs.
“In some trials, we found that people with these mutations were unable to effectively lower their blood sugar levels even after six months of treatment,” said Anna Grohn, DPhil, professor of pediatrics and genetics at Stanford University and one of the study’s senior authors. At that stage, doctors often consider changing the patient’s treatment plan. Identifying patients who would benefit in advance could help patients reach the most effective treatments sooner, moving diabetes care closer to precision medicine, he said.
The study’s other senior author is Markus Stoffel, MD, professor of metabolic diseases at the Institute of Molecular Health Sciences at the Swiss Federal Institute of Technology Zurich. Lead authors include Mahesh Umapathysivam, MBBS, DPhil, endocrinologist and clinical researcher at the University of Adelaide in Australia and a former Gloyn trainee, and Elisa Araldi, PhD, associate professor of medicine and surgery at the University of Parma in Italy and a former Stoffel trainee.
“When we treat patients in diabetes clinics, we see wide variation in response to these GLP-1-based drugs, but this response is difficult to predict clinically,” Umapathysivam said. “This is the first step toward being able to use someone’s genetic makeup to improve their decision-making process.”
Scientists investigate the mysteries of diabetes drugs
This study represents the first detailed investigation into GLP-1 resistance, but scientists still don’t know exactly what causes it.
“That’s the million-dollar question,” Guinn said. “We ticked off this huge list of all the ways we thought GLP-1 resistance could occur. No matter what we did, we couldn’t figure out exactly why GLP-1 resistance occurred.”
The research team focused on two genetic mutations that reduce the activity of an enzyme called PAM (peptidyl glycine alpha amidation monooxygenase). This enzyme plays a unique role in the body because it activates various hormones, including GLP-1.
“PAM is a really attractive enzyme because it is the only enzyme that can perform a chemical process called amidation, which increases the half-life and potency of biologically active peptides,” Groin said.
“We thought that if there was a problem with this enzyme, there might be different aspects of biology that weren’t working properly.”
Previous studies had already shown that PAM mutations occur more frequently in diabetic patients. Groin also demonstrated that these mutants impair the pancreas’ ability to release insulin. The researchers wanted to see if the same genetic changes also affected GLP-1. GLP-1 is a hormone released by the intestines that helps control blood sugar levels after meals by stimulating insulin production, slowing stomach emptying, and suppressing appetite. GLP-1 receptor agonists work by mimicking this hormone.
Unexpected discovery regarding GLP-1 levels
For the study, researchers recruited adults with and without the PAM variant known as p.S539W. Participants drank a sugary solution and had blood samples taken every five minutes over four hours. This study included people without diabetes to reduce the influence of other factors that could influence the results.
Scientists initially expected participants with the PAM mutation to have lower GLP-1 levels because the hormone may be less stable without proper amidation.
“What we actually observed was that their GLP-1 levels were increasing,” Groin said. “This was the exact opposite of what we imagined we would find.”
“Even though people with the PAM mutation had higher circulating levels of GLP-1, we saw no evidence of higher biological activity. They did not lower blood sugar levels faster; they needed more GLP-1 to achieve the same biological effect, meaning they were resistant to GLP-1.”
GLP-1 resistance confirmed in mouse study
The discovery was so unexpected that researchers spent several years testing whether the results were real.
“We couldn’t figure this out. That’s why we looked at as many different methods as we could to see if this was really a solid observation,” Guinn said.
To test this finding, the research team partnered with scientists in Zurich who had developed mice lacking the PAM gene. These animals showed similar signs of GLP-1 resistance. They had elevated levels of GLP-1, but the hormone was less effective at controlling blood sugar levels.
One of GLP-1’s main functions is to slow gastric emptying, the rate at which food is emptied from the stomach. This effect contributes to both blood sugar regulation and weight loss. Mice lacking the PAM gene had faster gastric emptying, but treatment with a GLP-1 receptor agonist failed to slow the process.
The researchers also detected a weaker response to GLP-1 in both the pancreas and gastrointestinal tract of these mice. However, GLP-1 receptor levels themselves did not change.
The researchers, in collaboration with scientists in Copenhagen, further demonstrated that loss of PAM does not prevent GLP-1 from binding to its receptor or from signaling at the receptor level. These findings suggest that the cause of GLP-1 resistance may occur further downstream in biological pathways.
Genetic mutations influence drug response in diabetes
The research team next investigated whether GLP-1 resistance affected actual treatment outcomes.
Using data from three clinical trials involving 1,119 participants with diabetes, researchers found that people carrying PAM variants generally had a lower response to GLP-1 receptor agonists. Their HbA1c levels, a measure of long-term glycemic control, improved less than in non-carriers.
After 6 months of treatment, approximately 25% of non-mutated participants reached the recommended HbA1c target. Only 11.5% of p.S539W variant carriers achieved these goals. For carriers of the p.D563G variant, this number was 18.5%.
Importantly, this genetic variation does not appear to affect response to several other common diabetes medications, including sulfonylurea drugs, metformin, and DPP-4i drugs.
“What was really impressive was that having the mutation had no effect on response to other types of diabetes drugs,” Groin said. “We can see very clearly that this is unique to drugs that work through the pharmacology of the GLP-1 receptor.”
Additionally, two drug company-sponsored trials yielded different results, with carriers and non-carriers responding similarly. These studies include long-acting GLP-1 receptor agonists, which may better overcome GLP-1 resistance, Gloyn said.
Questions remain about weight loss and future treatments
The research team first discovered signs of GLP-1 resistance nearly a decade ago, long before GLP-1 drugs became widely known for weight loss.
Only two of the clinical trials included weight loss data. Although these results showed no difference between those with and without the PAM variant, the available evidence was too limited to draw firm conclusions.
Gloyn noted that large amounts of genetic data from clinical trials probably already exist and could help answer important questions about why some people respond poorly to GLP-1 therapy.
“It’s very common for pharmaceutical companies to collect genetic data on participants,” she says. “For new GLP-1 therapeutics, testing whether genetic mutations, such as PAM variants, exist may help explain poor response to the drug.”
The biological mechanism remains unclear, but Grohn believes the answer is likely complex and influenced by multiple factors. She compares this condition to insulin resistance, which despite decades of study, researchers still don’t fully understand.
Still, treatments are being developed to help overcome insulin resistance, raising the possibility that similar approaches will eventually be created for GLP-1 resistance.
“There are many drugs that improve insulin resistance, so we may be able to develop drugs that sensitize people to GLP-1, or find formulations of GLP-1, such as long-acting forms, that circumvent GLP-1 resistance,” she said.
Researchers from the University of Oxford, University of Dundee, University of Copenhagen, University of British Columbia, Churchill Hospital, University of Newcastle, University of Bath and University of Exeter also contributed to the study.
Funding was provided by Wellcome, the Medical Research Council, the European Union Horizon 2020 Program, the National Institutes of Health (grants U01-DK105535, U01-DK085545, UM-1DK126185), the National Institutes of Health Oxford Biomedical Research Centre, the Canadian Institutes of Health Research, the Novo Nordisk Foundation, Boehringer Ingelheim, and Diabetes Australia.
