Researchers have developed a novel GLP-1 receptor agonist that preserves blood sugar control while reducing nausea and vomiting, offering a potential safer approach to treating diabetes and obesity.
Around one in eight US adults currently take a GLP-1 drug such as Ozempic, Wegovy or Zepbound to manage diabetes, obesity or other conditions, according to a KFF Health Tracking poll. While these therapies are effective at controlling blood sugar and promoting weight loss, many patients experience side effects including nausea and vomiting. For individuals with diabetes who also have conditions such as cancer or HIV, maintaining glycaemic control while avoiding weight loss or appetite suppression is particularly important.
Researchers are now exploring ways to make these therapies safer and more precise.
A new study from the labs of Penn School of Nursing Professor Bart de Jonghe and Perelman School of Medicine Professor Matthew Hayes demonstrates that a novel type of agonist preserves glycaemic control while reducing malaise and vomiting behaviours in preclinical models. The compound uses a mechanism called ‘biased agonism,’ which selectively activates certain signalling pathways to achieve therapeutic effects without triggering unwanted side effects.
“Biased agonism gives us an opportunity here to create precision medicine,” says Hayes. “The outcome is not going to be one-size-fits-all for GLP-1 pharmacotherapies.”
When a GLP-1 agonist binds to its receptor, it can activate two main signalling pathways within the cell. One pathway produces cyclic adenosine monophosphate (cAMP), a key regulator of blood sugar. The other recruits β-arrestin, a protein that promotes receptor internalisation – pulling the receptor into the cell, where it can be recycled or reused – and can trigger alternative signalling pathways.
When a GLP-1 agonist binds to its receptor, it can activate two main signalling pathways within the cell.
The team studied a GLP-1 receptor agonist called Exendin-4-Phe (Ex-Phe-1), a molecule created by researchers in the United Kingdom by substituting an amino acid in the standard GLP-1 agonist Exendin-4. They found that Ex-Phe-1 increased cAMP production but recruited less β-arrestin than conventional GLP-1 drugs, resulting in fewer side effects.
Researchers tested Ex-Phe-1 across three preclinical models. In all cases, the agonist maintained glycaemic control. Its effects on food intake and weight, however, varied between species, as did the degree to which blood sugar was controlled compared with Exendin-4.
“These differences may reflect species-specific factors, including drug administration routes, dosing and diets as well as differences in tolerance or drug clearance rates,” said de Jonghe. “Studying the effects in multiple models is important as it prevents overgeneralising findings.”
Hayes says the team is now investigating why reduced β-arrestin recruitment may lessen nausea and vomiting more broadly, not just within the GLP-1 pathway which could lead to new opportunities for drug development.
By refining how GLP-1 receptor agonists work at the molecular level, the hope is that these findings will inform new personalised treatments that balance efficacy with tolerability.
