More than a quarter of people with Type 2 diabetes take GLP-1 receptor agonists, but the popular diabetes drugs might not work as well for people who have certain genetic variants, according to a new study by Stanford Medicine scientists and their collaborators.
The genetic variants, carried by roughly 10% of the general population, cause a surprising and still mysterious phenomenon that 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's not clear whether the variants affect weight loss from these drugs, such as Ozempic and Wegovy, which are increasingly prescribed to treat obesity. They are typically taken at higher doses for weight loss than for diabetes.
The new study , published March 29 in Genome Medicine, focused on blood sugar regulation. It was a decadelong, international effort involving experiments in humans and mice as well as analysis of diabetes drug 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."
The study is the first in-depth investigation of GLP-1 resistance, but the researchers have yet to pin down the mechanism.
"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."
Unexpected resistance
The researchers focused on two genetic variants that handicap an enzyme known as PAM (peptidyl-glycine alpha-amidating monooxygenase), which is uniquely capable of 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."
In fact, PAM variants were known to be more common in people with diabetes; Gloyn had shown that they impair insulin release by the pancreas. The researchers wondered whether the genetic glitch also affects GLP-1, a gut hormone that plays an important role in blood sugar control after a meal by stimulating insulin release, slowing stomach emptying and reducing appetite. GLP-1 receptor agonist medications 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 measured their blood 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 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."
Seeking confirmation
The results were so surprising, Gloyn's team spent the next several years confirming them.
"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," she 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: elevated levels of GLP-1 that did not 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 with 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 in the gut of these mice, indicative of GLP-1 resistance, yet there was no change in the expression of GLP-1 receptors in these tissues.
Teaming up with researchers in Copenhagen, they showed that a PAM defect does not alter the GLP-1 receptors' ability to bind GLP-1, nor how the hormone signals through the receptor. This suggests GLP-1 resistance emerges further downstream.
Results may vary
To see if GLP-1 resistance translated into therapeutic differences, researchers examined 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 the drugs and less successful in lowering their HbA1c, a measure of average blood sugar levels. About a quarter of non-carriers reached 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 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."
In two other clinical trials, funded by pharmaceutical companies, which were not included in the meta-analysis due to methodological differences, the drug responses were similar between carriers and non-carriers. These trials used longer-acting GLP-1 receptor agonists, Gloyn said, which may help counter GLP-1 resistance.
A complex puzzle
Gloyn's team first observed GLP-1 resistance 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 is too limited to be conclusive, Gloyn said.
A trove of clinical trial data on how genetics influence various responses to GLP-1 receptor agonists, including weight loss, likely exists, though that data has been difficult to come by.
"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."
For now, the mechanism driving GLP-1 resistance remains unresolved, but it is likely complex and multifactorial, Gloyn said. She likens the phenomenon to insulin resistance, which is still not fully understood decades after its discovery. Nevertheless, scientists have found ways to treat insulin 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 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.
