About 10% of the population carries certain genetic variants linked to a newly identified phenomenon called GLP-1 resistance. In these individuals, levels of the hormone GLP-1 (glucagon-like peptide-1), which helps regulate blood sugar, are actually higher than normal but appear to be less effective at doing their job.

It is still unclear whether these genetic variants influence weight loss outcomes from GLP-1 drugs such as Ozempic and Wegovy, which are increasingly used to treat obesity. These medications are typically prescribed at higher doses for weight loss than for diabetes.

The study, published March 29 in Genome Medicine, focused on how these drugs affect blood sugar. It represents a decade of work involving experiments in both humans and mice, along with analysis of clinical trial data.

“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, and one of the study’s senior authors. At that point, a doctor would likely change the patient’s drug regimen. Knowing ahead of time who is likely to respond would help patients get on the right drugs faster — a step toward precision medicine, Gloyn said.

The other senior author is Markus Stoffel, MD, PhD, professor of metabolic diseases at the Institute of Molecular Health Sciences, ETH Zurich in Switzerland. The lead authors of the study are 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.”

Although this is the most detailed investigation so far into GLP-1 resistance, the underlying biological mechanism remains unknown.

“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.”

PAM Gene Variants and GLP-1 Resistance

The research focused on two specific genetic variants that affect an enzyme called PAM (peptidyl-glycine alpha-amidating monooxygenase). This enzyme plays a unique role in activating many hormones in the body, 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 are more common in people with diabetes and can impair insulin release from the pancreas. The team wanted to determine whether these variants also disrupt GLP-1, a hormone produced in the gut that helps control blood sugar after meals by stimulating insulin release, slowing stomach emptying, and reducing appetite. GLP-1 receptor agonist drugs are designed to mimic this hormone.

To investigate, researchers studied adults with and without a PAM variant known as p.S539W. Participants drank a sugary solution, and their blood was tested every five minutes over a four-hour period. (They studied participants who did not have diabetes because the disease introduces more confounding variables.)

The team initially expected that individuals with the PAM variant would have lower GLP-1 levels, possibly because the hormone would be less stable without proper processing.

“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.”

Confirming the Findings in Humans and Mice

Because the results were unexpected, the researchers spent several years verifying them through multiple approaches.

“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.

They partnered with scientists in Zurich who were studying mice lacking the PAM gene. These animals showed similar signs of GLP-1 resistance, with elevated hormone levels that failed to improve blood sugar control.

One of GLP-1’s key roles is slowing gastric emptying, which helps regulate blood sugar and contributes to weight loss. In mice without the PAM gene, food moved through the stomach more quickly, and treatment with GLP-1 drugs did not slow this process.

The researchers also found reduced responsiveness to GLP-1 in both the pancreas and the gut of these mice. However, the number of GLP-1 receptors in these tissues remained unchanged.

Further experiments with collaborators in Copenhagen showed that the PAM defect does not affect how GLP-1 binds to its receptor or how signals are transmitted. This suggests the resistance occurs further along in the biological pathway.

Clinical Trial Data Show Reduced Drug Response

To understand how GLP-1 resistance affects treatment outcomes, the team analyzed data from several clinical trials involving people with diabetes.

In a combined analysis of three trials with 1,119 participants, individuals with PAM variants responded less effectively to GLP-1 drugs and were less likely to reach target HbA1c levels, a measure of long-term blood sugar control. After six months of treatment, about 25% of participants without the variants met the recommended HbA1c target, compared with 11.5% of those with the p.S539W variant and 18.5% of those with the p.D563G variant.

Importantly, these genetic variants did not affect how patients responded to other common diabetes medications, including sulfonylureas, metformin and DPP-4i.

“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 clinical trials funded by pharmaceutical companies showed no difference between carriers and non-carriers, although these studies used longer-acting GLP-1 drugs. According to Gloyn, these longer-lasting formulations may help overcome GLP-1 resistance.

A Complex and Unresolved 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 of the trials included weight data, and they showed no clear difference between individuals with and without PAM variants. However, the data is limited and not definitive.

There may be more genetic data from clinical trials that could shed light on how people respond to these drugs, but accessing that information has been challenging.

“It’s very common for pharmaceutical companies to collect genetic data on their participants,” Gloyn 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.”

For now, the biological cause of GLP-1 resistance remains unclear and is likely influenced by multiple factors. Gloyn compared it to insulin resistance, which scientists still do not fully understand despite decades of research. Even so, effective treatments for insulin resistance have been developed.

“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 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 work.

The study received funding from Wellcome, Medical Research Council, European Union Horizon 2020 Programme, 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.