More than one-quarter of people with Type 2 diabetes now use GLP-1 receptor agonists, a class of medications that includes Ozempic. But new research from Stanford Medicine and international collaborators suggests these widely prescribed drugs may be less effective for some patients because of their genetics.
The study found that about 10% of people carry genetic variants linked to a phenomenon known as GLP-1 resistance. Individuals with these variants appear to produce higher levels of the hormone GLP-1 (glucagon-like peptide-1), which helps regulate blood sugar, yet the hormone does not seem to work as effectively in their bodies.
Researchers focused on blood sugar control and did not reach firm conclusions about weight loss effects. Drugs such as Ozempic and Wegovy are typically prescribed at higher doses for obesity treatment than for diabetes management, and more research is needed to determine whether the same genetic factors influence weight loss outcomes.
Published in Genome Medicine, the study brought together scientists from multiple countries over a period of 10 years. The work included experiments in both humans and mice, along with analyses of data from clinical trials involving diabetes medications.
“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, professor of pediatrics and of genetics at Stanford Medicine and one of the study’s senior authors. At that stage, physicians would often consider changing a patient’s treatment plan. Identifying likely responders in advance could help patients reach the most effective therapy sooner and move diabetes care closer to precision medicine, she said.
The study’s other senior author is Markus Stoffel, MD, PhD, professor of metabolic diseases at the Institute of Molecular Health Sciences at ETH Zurich in Switzerland. Lead authors include Mahesh Umapathysivam, MBBS, DPhil, an endocrinologist and clinical researcher at Adelaide University in Australia and a former trainee with Gloyn, and Elisa Araldi, PhD, associate professor of medicine and surgery at the University of Parma in Italy and a former trainee with Stoffel.
“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,” Umapathysivam said. “This is the first step in being able to use someone’s genetic make-up to help us improve that decision-making process.”
Scientists Investigate a Diabetes Drug Mystery
This research represents the first detailed examination of GLP-1 resistance, but scientists still do not know exactly what causes it.
“That is the million-dollar question,” Gloyn said. “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.”
The team concentrated on two genetic variants that reduce the activity of an enzyme called PAM (peptidyl-glycine alpha-amidating monooxygenase). This enzyme plays a unique role in the body because it activates a variety of hormones, including GLP-1.
“PAM is a truly fascinating enzyme because it’s the only enzyme we have that’s capable of a chemical process called amidation, which increases the half-life or the potency of biologically active peptides,” Gloyn said.
“We thought, if you have a problem with this enzyme, there’s going to be multiple aspects of your biology that are not working properly.”
Previous research had already shown that PAM variants occur more often in people with diabetes. Gloyn had also demonstrated that these variants impair the pancreas’s ability to release insulin. Researchers wanted to determine whether the same genetic changes also affected GLP-1, a hormone released from the gut that helps control blood sugar after eating by stimulating insulin production, slowing stomach emptying, and reducing appetite. GLP-1 receptor agonists work by mimicking this hormone.
An Unexpected Discovery About GLP-1 Levels
To investigate, researchers recruited adults with and without a PAM variant known as p.S539W. Participants drank a sugary solution, and blood samples were collected every five minutes over a four-hour period. The study involved people without diabetes to reduce the influence of other factors that could affect the results.
Scientists initially expected participants with the PAM variant to have lower levels of GLP-1 because the hormone might be less stable without proper amidation.
“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 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.”
Mouse Studies Confirm GLP-1 Resistance
The findings were so unexpected that the researchers spent several years testing whether the result was real.
“We couldn’t understand this, which is why we looked as many different ways as we could to see if this was a really robust observation,” Gloyn said.
To verify the findings, the team partnered with scientists in Zurich who had developed mice lacking the PAM gene. These animals displayed similar signs of GLP-1 resistance. They had elevated GLP-1 levels, yet the hormone was less effective at controlling blood sugar.
One of GLP-1’s major functions is slowing gastric emptying, which is the rate at which food leaves the stomach. This effect contributes to both blood sugar regulation and weight loss. Mice without the PAM gene showed faster gastric emptying, and treatment with a GLP-1 receptor agonist failed to slow the process.
Researchers also detected weaker responses to GLP-1 in both the pancreas and digestive tract of these mice. However, levels of GLP-1 receptors themselves remained unchanged.
Working with scientists in Copenhagen, the researchers further demonstrated that PAM defects do not interfere with GLP-1 binding to its receptor or with signaling at the receptor level. These findings suggest the source of GLP-1 resistance likely occurs farther downstream in the biological pathway.
Genetic Variants Affect Diabetes Drug Response
The team next examined whether GLP-1 resistance influenced real-world treatment outcomes.
Using data from three clinical trials that included 1,119 participants with diabetes, researchers found that people carrying PAM variants generally responded less well to GLP-1 receptor agonists. Their HbA1c levels, a measure of long-term blood sugar control, improved less than those of non-carriers.
After six months of treatment, approximately 25% of participants without the variants reached recommended HbA1c targets. Among carriers of the p.S539W variant, only 11.5% achieved those goals. For carriers of the p.D563G variant, the figure was 18.5%.
Importantly, the genetic variants did not appear to affect responses to several other common diabetes medications, including sulfonylureas, metformin, and DPP-4i drugs.
“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.”
Two additional pharmaceutical company-sponsored trials produced different results, with carriers and non-carriers responding similarly. Those studies involved longer-acting GLP-1 receptor agonists, which may be better able to overcome GLP-1 resistance, according to Gloyn.
Questions Remain About Weight Loss and Future Treatments
The research team first detected 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. Those results showed no differences between people with and without PAM variants, but the available evidence was too limited to draw firm conclusions.
Gloyn noted that large amounts of genetic data from clinical trials likely already exist and could help answer important questions about why some people respond poorly to GLP-1 therapies.
“It’s very common for pharmaceutical companies to collect genetic data on their participants,” she said. “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.”
Although the biological mechanism remains unclear, Gloyn believes the answer is likely complex and influenced by multiple factors. She compares the situation to insulin resistance, which researchers still do not completely understand despite decades of study.
Even so, treatments have been developed to help overcome insulin resistance, raising the possibility that similar approaches could eventually be created for GLP-1 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 of GLP-1, like the longer-acting versions, that avoid the GLP-1 resistance.” she said.
Researchers from the University of Oxford, University of Dundee, University of Copenhagen, University of British Columbia, Churchill Hospital, Newcastle University, 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 and UM-1DK126185), 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.