More than one in four people with type 2 diabetes uses GLP-1 receptor agonists, a type of widely prescribed medication. But a new study by Stanford Medicine and international collaborators suggests that these drugs may be less effective in some people due to genetic differences.
Approximately 10% of the population carries a specific genetic variation associated with a newly identified phenomenon called GLP-1 resistance. In these people, levels of the hormone GLP-1 (glucagon-like peptide-1), which helps regulate blood sugar, are actually higher than normal, but they appear to be less effective at work.
It remains unclear whether these genetic variations influence weight loss results with GLP-1 drugs such as Ozempic and Wigovy, which are increasingly used to treat obesity. These drugs are usually prescribed in higher doses for weight loss than for diabetes.
The study was published on March 29th. genomic medicinefocused on how these drugs affect blood sugar. This represents 10 years of research, including experiments on both humans and mice, along with analysis of clinical trial data.
“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 Gwin, DPhil, professor of pediatrics and genetics, one of the study’s senior authors. At that point, the doctor will likely change the patient’s medication regimen. Knowing in advance who is likely to react would allow patients to get the right medication sooner, a step toward precision medicine, Grohn said.
The 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. The study’s lead authors are Dr. Mahesh Umapathishivam, MBBS, DPhil, an endocrinologist and clinical researcher at the University of Adelaide in Australia and a former resident of Grown, and Dr. Elisa Araldi, MBBS, DPhil, an associate professor of medicine and surgery at the University of Parma in Italy and a former trainee of Stoffel.
“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.”
Although this is the most detailed study of GLP-1 resistance to date, the underlying biological mechanisms remain unclear.
“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.”
PAM gene mutations and GLP-1 resistance
The study focused on two specific genetic variations that affect an enzyme called PAM (peptidyl-glycine alpha-amidation monooxygenase). This enzyme plays a unique role in activating many hormones in the body, 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 variants are more common in diabetic patients and can impair insulin release from the pancreas. The researchers wanted to see whether these variants interfere with GLP-1, a hormone produced in the intestine that helps control blood sugar levels after meals by stimulating insulin release, slowing stomach emptying, and reducing appetite. GLP-1 receptor agonists are designed to mimic this hormone.
To find out, researchers looked at adults with and without the PAM variant known as p.S539W. Participants drank a sugar-laced solution and blood tests were taken every five minutes for four hours. (They studied participants without diabetes, as diabetes introduces an additional confounding variable.)
The researchers initially expected that people with the PAM mutation would have lower GLP-1 levels, perhaps because the hormone is less stable without proper processing.
“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.”
Confirmation of research results in humans and mice
The results were so unexpected that the researchers spent several years testing multiple approaches.
“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.
They partnered with scientists in Zurich who were studying mice lacking the PAM gene. These animals showed similar signs of GLP-1 resistance and elevated hormone levels that failed to improve glycemic control.
One of the important roles of GLP-1 is to slow gastric emptying, which helps regulate blood sugar levels and contributes to weight loss. In mice without the PAM gene, food passed through the stomach faster, and treatment with the GLP-1 drug did not slow this process.
The researchers also found that both the pancreas and intestines of these mice had reduced reactivity to GLP-1. However, the number of GLP-1 receptors in these tissues did not change.
Further experiments with collaborators in Copenhagen showed that defects in PAM do not affect how GLP-1 binds to its receptor or transmits signals. This suggests that resistance occurs further down the biological pathway.
Clinical trial data shows reduced drug response
To understand how GLP-1 resistance affects treatment outcomes, the research team analyzed data from several clinical trials in diabetic patients.
A combined analysis of three trials involving 1,119 participants found that people with PAM mutations had a lower response to GLP-1 drugs and were less likely to reach target HbA1c levels, an indicator of long-term glycemic control. After 6 months of treatment, approximately 25% of participants without the mutation achieved the recommended HbA1c goal, compared with 11.5% of participants with the p.S539W mutation and 18.5% of those with the p.D563G mutation.
Importantly, these genetic variations did not affect the patients’ response to other common diabetes medications, such as sulfonylureas, metformin, and DPP-4i.
“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.”
Two additional drug company-funded clinical trials found no differences between carriers and non-carriers, despite using long-acting GLP-1 drugs. According to Gloyn, these longer-lasting formulations may help overcome GLP-1 resistance.
A complex and unsolved biological puzzle
Researchers first noticed signs of GLP-1 resistance nearly a decade ago, before GLP-1 drugs became widely used for weight loss. Only two trials included weight data and showed no clear differences between people with and without PAM mutations. However, data are limited and inconclusive.
There may be more genetic data from clinical trials that could shed light on how people respond to these drugs, but that information has been difficult to access.
“It’s very common for pharmaceutical companies to collect genetic data on participants,” Grohn said. “For new GLP-1 therapeutics, testing whether genetic mutations, such as PAM variants, exist may help explain poor response to the drug.”
So far, the biological causes of GLP-1 resistance remain unknown and are likely influenced by multiple factors. Groin compared it to insulin resistance, which scientists still don’t fully understand despite decades of research. Still, effective treatments for insulin resistance are being developed.
“There are many drugs that improve insulin resistance, so we may be able to develop drugs that sensitize people to GLP-1 or find long-acting GLP-1 preparations 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.
This research received funding from 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 Institutes of Health Oxford Biomedical Research Centre, the Canadian Institutes of Health Research, the Novo Nordisk Foundation, Boehringer Ingelheim and Diabetes. Australia.
