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.