More than a quarter of people with type 2 diabetes take GLP-1 receptor agonists, but popular diabetes drugs may not work as well in people who have certain genetic variants, according to a new study by Stanford Medicine scientists and colleagues.
The genetic variants, carried by about 10% of the general population, cause a surprising and still mysterious phenomenon researchers refer to as GLP-1 resistance, in which levels of the hormone GLP-1 (glucagon-like peptide-1), which helps regulate blood sugar, are higher but less biologically effective.
It is unclear whether the variants affect weight loss from these drugs, such as Ozempic and Wegovy, which are increasingly prescribed to treat obesity. They are usually taken in higher doses for weight loss than for diabetes.
The new study, published March 29 in Genomic Medicinefocused on blood sugar regulation. It was a ten-year, international effort that included experiments on humans and mice, as well as analysis of data from diabetes drug trials.
In some of the trials, we saw that people who had these variants were not able to lower their blood glucose levels as effectively after six months of treatment.”
Anna Gloyn, DPhil, professor of pediatrics and genetics, and one of the study’s senior authors
At that point, a doctor would likely change the patient’s regimen. Knowing in advance who is likely to respond would help patients get 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 study’s lead authors are Mahesh Umapathysivam, MBBS, DPhil, an endocrinologist and clinical researcher at the University of Adelaide in Australia and a former intern with Gloyn, and Elisa Araldi, PhD, an associate professor of medicine and surgery at the University of Parma in Italy and a former intern with Stoffel.
“When I treat patients in the diabetes clinic, I see a huge variation in these GLP-1-based drugs, and it’s difficult to predict that response clinically,” Umapathysivam said. “This is the first step to being able to use someone’s genetic makeup to help us improve that decision-making process.”
The study is the first in-depth investigation of GLP-1 resistance, but researchers have yet to identify the mechanism.
“That’s the million dollar question,” Gloyn said. “We’ve written down this huge list of all the ways we thought resistance to GLP-1 might arise. No matter what we’ve done, we haven’t been able to pinpoint exactly why it’s resistant.”
Unexpected resistance
The researchers focused on two genetic variants that impair an enzyme known as PAM (peptidylglycine alpha-amidotic monooxygenase), which is uniquely capable of activating many hormones in the body, including GLP-1.
“PAM is a really exciting enzyme because it’s the only enzyme we have that’s capable of a chemical process called amidation, which increases the half-life or potency of biologically active peptides,” Gloyn said.
“We thought that if you have a problem with this enzyme, there’s going to be a lot of aspects of your biology that aren’t working right.”
In fact, PAM variants were known to be more common in people with diabetes. Gloyn had shown that they reduce the release of insulin from the pancreas. The researchers wondered whether the genetic problem also affects GLP-1, a gut hormone that plays an important role in controlling blood sugar after a meal by stimulating the release of insulin, slowing stomach emptying and reducing appetite. GLP-1 receptor agonist drugs work by mimicking this hormone.
They recruited adult participants with and without a PAM variant known as p.S539W, had them drink a sugary solution, and had their blood measured every five minutes for the next four hours. (They studied participants who did not have diabetes because the disease introduces more confounding variables.)
The researchers suspected that people with the PAM variant would have lower levels of GLP-1 in their blood, perhaps because the unamidated form would be less stable.
“What we actually saw was that they had increased levels of GLP-1,” Gloyn said. “This was the opposite of what we thought we would find.”
“Despite the fact that people with the PAM variant had higher circulating levels of GLP-1, we didn’t see evidence of higher biological activity. They didn’t lower their blood sugar levels faster. They needed more GLP-1 to have the same biological effect, meaning they were resistant to GLP-1.”
Confirmation is requested
The results were so surprising, Gloyn’s team spent the next several years confirming them.
“We couldn’t understand that, so we looked at as many different ways as we could to see if this was a really strong observation,” he said.
They collaborated with researchers in Zurich who were studying mouse models that had the PAM gene knocked out. The mice also showed signs of GLP-1 resistance: increased levels of GLP-1 that didn’t help regulate blood sugar.
A key function of GLP-1 – and drugs that mimic it – is to slow the passage of food through the stomach, known as gastric emptying, which helps both glucose regulation and weight loss. The researchers found that mice lacking the PAM gene had faster gastric emptying. Treating the mice with a GLP-1 receptor agonist did not slow their gastric emptying.
They also observed less response to GLP-1 in the pancreas and intestine of these mice, indicative of GLP-1 resistance, yet there was no change in the expression of GLP-1 receptors in these tissues.
Working with researchers in Copenhagen, they showed that a PAM defect does not change the ability of GLP-1 receptors to bind GLP-1, nor how the hormone signals through the receptor. This suggests that resistance to GLP-1 occurs further down the line.
Results may vary
To see if GLP-1 resistance translates into treatment differences, the researchers looked at data from several clinical trials of GLP-1 receptor agonists in people with diabetes. In a meta-analysis of three trials, with a total of 1,119 participants, those with PAM variants were less responsive to medication and less successful in lowering their HbA1c, a measure of average blood sugar levels. About a quarter of non-carriers achieved the recommended HbA1c target after six months of treatment, compared with 11.5% of participants with the p.S539W variant and 18.5% of participants with the p.D563G variant.
Participants with the variants did not respond differently to other common diabetes treatments, including sulfonylureas, metformin, and DPP-4i.
“What was really striking was that we didn’t see any effect of whether you have a variation in your response to other types of diabetes drugs,” Gloyn said. “We can see very clearly that this is specific to drugs that act through GLP-1 receptor pharmacology.”
In two other clinical trials, sponsored by pharmaceutical companies, which were not included in the meta-analysis due to methodological differences, drug responses were similar between carriers and non-carriers. Those trials used long-acting GLP-1 receptor agonists, Gloyn said, which may help address GLP-1 resistance.
A complex puzzle
Gloyn’s team first noticed resistance to GLP-1 nearly 10 years ago, before the explosion of interest in GLP-1 receptor agonists as weight-loss drugs. Only two of the clinical trials analyzed in the study provided weight data, which showed no difference in weight loss between those with and without PAM variants, but the data are too limited to be conclusive, Gloyn said.
There is likely a wealth of clinical trial data on how genetics influence various responses to GLP-1 receptor agonists, including weight loss, although these data have been difficult to find.
“It’s very common for pharmaceutical companies to collect genetic data on their participants,” he said. “For the newer GLP-1 drugs, it would be useful to look at whether there are genetic variants, such as variants in PAM, that explain the poor response to their drugs.”
At present, the mechanism leading to GLP-1 resistance remains unresolved, but is likely complex and multifactorial, Gloyn said. He likens the phenomenon to insulin resistance, which is still not fully understood decades after its discovery. However, scientists have found ways to deal with insulin resistance.
“There’s a whole class of drugs that are insulin sensitizers, so maybe we can develop drugs that will allow people to be sensitized to GLP-1 or find formulations of GLP-1, like long-acting versions, that avoid 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 work.
The study received funding from Wellcome, the Medical Research Council, the 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 Health Research Foundation Ingelheim and Diabetes Australia.
