One In 10 People May Have Resistance To GLP-1 Diabetes Drugs

Genetic variants could impact how well GLP-1 receptor agonists work for some patients, new study finds.

Apr. 11, 2026 at 4:32am

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A ghostly, translucent X-ray image showing the internal structures of the human digestive system, including the pancreas, in glowing lines against a dark background, conceptually representing the complex biological factors behind GLP-1 resistance.An X-ray view of the human digestive system reveals the complex biological mechanisms behind GLP-1 resistance, a genetic phenomenon that can impact the effectiveness of popular diabetes medications.Stanford Today

A new study by Stanford Medicine scientists and their collaborators has found that 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. The variants, carried by roughly 10% of the general population, cause a phenomenon researchers refer to as GLP-1 resistance, in which levels of the hormone GLP-1 are higher but less biologically effective.

Why it matters

Knowing ahead of time who is likely to respond to GLP-1 receptor agonists would help patients get on the right drugs faster, a step toward precision medicine. The study is the first in-depth investigation of GLP-1 resistance, but the researchers have yet to pin down the exact mechanism behind it.

The details

The genetic variants 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. Despite people with the PAM variant having higher circulating levels of GLP-1, the researchers saw no evidence of higher biological activity - more GLP-1 was needed to have the same effect, meaning they were resistant to GLP-1. The researchers collaborated with researchers in Zurich who were studying mouse models that had the PAM gene knocked out, and they also examined data from several clinical trials of GLP-1 receptor agonists in people with diabetes.

  • The new study was published on March 29, 2026.
  • The researchers first observed GLP-1 resistance nearly 10 years ago, before the explosion of interest in GLP-1 receptor agonists as weight-loss drugs.

The players

Anna Gloyn

Professor of pediatrics and of genetics at Stanford Medicine and one of the study's senior authors.

Markus Stoffel

Professor of metabolic diseases at the Institute of Molecular Health Sciences, ETH Zurich in Switzerland and the other senior author of the study.

Mahesh Umapathysivam

An endocrinologist and clinical researcher at Adelaide University in Australia and a former trainee with Gloyn, who is the lead author of the study.

Elisa Araldi

Associate professor of medicine and surgery at the University of Parma in Italy and a former trainee with Stoffel, who is also a lead author of the study.

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What they’re saying

“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. This is the first step in being able to use someone's genetic make-up to help us improve that decision-making process.”

— Mahesh Umapathysivam, Endocrinologist and clinical researcher

“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.”

— Anna Gloyn, Professor of pediatrics and of genetics

What’s next

Researchers are still working to determine the exact mechanism behind GLP-1 resistance, which they liken to the still not fully understood phenomenon of insulin resistance. They hope to develop medications that can sensitize people to GLP-1 or find formulations of GLP-1 receptor agonists that avoid the resistance.

The takeaway

This study is an important first step in understanding genetic factors that can impact how well GLP-1 receptor agonist medications work for patients with Type 2 diabetes. Identifying those who are likely to be resistant to these drugs could help clinicians get patients on the most effective treatments faster, moving toward a more personalized approach to diabetes management.