GLP-1 receptor agonists: Are they friends or foes in colorectal cancer?

• Glucagon-like peptide-1 (GLP-1) agonist medications have become increasingly popular over the last year.
• Previous research has revealed both potential positive and negative health effects when using GLP-1 agonist medications to bind and activate the GLP-1 receptor.
• Researchers from Boston Children’s Hospital have found that blocking, rather than activating, the GLP-1 receptor triggers the body’s innate defensive immune response to the development of colorectal cancer via a mouse model.

Over the last year, a lot of attention has been placed on glucagon-like peptide-1 (GLP-1) agonist medications.

These medications target a protein called the GLP-1 receptor located on pancreatic cells, binding to and activating them to help stimulate insulin production and slow food from exiting the stomach.

GLP-1 agonists were originally approved for use to treat type 2 diabetes . Currently, some GLP-1 agonists are being used off-label for treating obesity . Some GLP-1 medications, such as Wegovy and Zepbound , have also received Food and Drug Administration (FDA) approval for weight management in adults with obesity.

Some recent studies have reported other potential positive effects of GLP-1 medications, including improved cardiovascular health and protection against kidney disease .

On the flip side, other research found GLP-1 medications may be linked to negative effects including an increased risk for pancreatitis , depression , and thyroid cancer .

Now researchers from Boston Children’s Hospital have found that blocking, rather than activating, the GLP-1 receptor triggers the body’s innate defensive immune response to the development of colorectal cancer via a mouse model.

This study was recently published in the journal Cell Metabolism .

GLP-1 receptor can dampen anti-cancer immune response

Previous research has shown GLP-1 may play a role in regulating the body’s immune system.

Additionally, GLP-1 mRNA expression has been noted in certain types of immune cells, such as T lymphocytes — a type of white blood cell that helps the body fight off germs and diseases.

A process called costimulation — a secondary signal that immune cells need to activate an immune response — is vital for T lymphocytes to work correctly.

In the first portion of this study, the researchers discovered that the GLP-1 receptor acts as a negative costimulatory molecule in T lymphocytes. When T cells receive negative costimulatory signals, their activity is suppressed.

If T cells do not receive positive costimulatory signals, they may become anergic. This means they are inactive and do not initiate an immune response to an antigen, such as those on viruses or bacteria.

Blocking GLP-1 receptor triggers anti-tumor activity

From there, the scientists used a mouse model to discover that the GLP-1 receptor acts as a checkpoint molecule, curbing the immune system’s response to cancer.

Blocking the GLP-1 receptor — or GLP-1 receptor antagonism — triggered anti-tumor immune activity in mice with colorectal cancer, researchers found.

“While agonism has a significant immunoregulatory and immunosuppressive function, the antagonism of [the] GLP-1 receptor is immunostimulatory,” Paolo Fiorina, MD, PhD , research associate in the Department of Pediatrics Research in the Division of Nephrology Research at Boston Children’s Hospital and senior author of this study explained to Medical News Today .

“[The] GLP-1 receptor is not acting as an enabler of cancer […] actually it is the opposite. GLP-1 receptor agonism reduces inflammation in a variety of ways because of its anti-inflammatory and immunoregulatory functions,” he added.

“But we also demonstrated that by blocking the receptor we stimulate the immune system to destroy cancer,” said Fiorina.

“We believe that antagonizing [the] GLP-1 receptor may play a therapeutic role in other oncological areas because we are not targeting one specific cancer, but we are stimulating the immune system. We plan to develop a clinical-grade way to antagonize [the] GLP-1 receptor to bring it to the clinic in oncology.”

– Paolo Fiorina, MD, PhD

What does this mean for GLP-1 receptor agonist drugs like Wegovy?

As the popular GLP-1 receptor agonist medications like Ozempic and Wegovy activate — rather than block — the GLP-1 receptor, what might this mean for those taking these drugs?

After reviewing this study, Anton Bilchik, MD, PhD , surgical oncologist, chief of medicine, and director of the Gastrointestinal and Hepatobiliary Program at Providence Saint John’s Cancer Institute in Santa Monica, CA, not involved in the research, told MNT this was one of the most provocative, interesting studies he has seen in a long time simply because there has been an explosion of interest and use of GLP-1 agonist drugs such as Ozempic and Mounjaro .

“There’s been evidence to support the use of these drugs in not only reducing weight loss but also in reducing the chance of developing cardiovascular disease,” Bilchik told us. “So to suggest that these drugs that work through this pathway may have an immune effect that increases the risk of developing colorectal cancer is, quite frankly, astonishing.”

“What this study is showing is that blocking the GLP-1 — so GLP-1 antagonist — reduces the chances of colorectal cancer in a mice model,” he added. “So what the study is suggesting is that GLP-1 agonists may have an adverse effect.”

Bilchik said it is “hugely important” for researchers to continue looking for potential adverse effects of GLP-1 medications.

“There is no other type of medication that is being increased more and being utilized more than these GLP-1 agonist drugs, and so far, the recommendations have been expanding in terms of not only treating diabetes and obesity but also reducing the risk of cardiovascular disease,” he continued. “So the fact there may be adverse effects to the use of these drugs, particularly relating to cancer, is enormously important and warrants further investigation.”

Mixed evidence about the role of semaglutide drugs in cancer

MNT also spoke with Glenn S. Parker, MD, FACS, FASCRS , vice chairman of surgery and chief of the Division of Colon and Rectal Surgery at Hackensack Meridian Jersey Shore University Medical Center in New Jersey about this study.

Parker, who was not involved in the research, commented that previous studies have found people who have overweight or obesity have an increased risk of developing colon and rectal cancer.

He also cited a study that found people with type 2 diabetes taking GLP-1 receptor agonists may have a reduced risk of developing colorectal cancer.

“While prevention of the disease is paramount, a recent international collaboration entitled ‘Glucagon-like peptide 1 receptor is a T cell negative costimulatory molecule’ triggered anti-tumor immunity in a murine model of colon and rectal cancer,” he continued.

“Using [the] GLP-1 receptor as an antagonist demonstrated anti-tumor effects with a significant reduction in tumor size,” Parker pointed out.

“Although this research may show the potential future of [the] GLP-1 receptor to be used as immunotherapy, additional studies will be necessary first in murine cancer cell lines to replicate the data,” he added.

“Additional research to be considered is if the patient population is obese or not, who develop colon and rectal cancer while taking GLP-1 receptor [medications]. These individuals may have a different molecular genetic profile affecting the anti-tumor immunity,” the expert cautioned.