Ozempic, Wegovy without nausea may be possible, mouse study finds

• Over the last few years, the number of people taking glucagon-like peptide-1 (GLP-1) receptor agonists for weight loss has increased significantly.
• While only certain GLP-1 medications are FDA-approved to treat obesity, others are being used off-label for their weight loss benefits.
• A common side effect of taking GLP-1 medications is nausea.
• Researchers from Monell Chemical Senses Center have identified a specific population of neurons in the brain that could be key for appetite suppression with GLP-1 drugs without nausea.

Over the last few years, the number of people taking glucagon-like peptide-1 (GLP-1) receptor agonists — medications traditionally used to treat type 2 diabetes — for weight loss has greatly increased.

A recent poll found that 12% of Americans — about 1 in 8 adults — have taken a GLP-1 medication.

While only certain GLP-1 medications are FDA-approved to treat obesity, others are being used off-label for their weight loss benefits.

A common side effect of taking GLP-1 medications is nausea. Now, Monell Chemical Senses Center researchers have identified a specific population of neurons in the brain they believe may hold the key for GLP-1 drugs to suppress appetite without nausea.

The study was recently published in the journal Nature .

Focusing on hindbrain GLP-1R neurons

For this study, researchers used a mouse model to look for a neurological connection between GLP-1 medications and the side effect of nausea.

“The majority of people who take these drugs experience nausea at some point — some have it more severe than others,” Amber L. Alhadeff, PhD , assistant member at Monell Chemical Senses Center, Philadelphia, PA, adjunct assistant professor in the Department of Neuroscience at the University of Pennsylvania and senior author of this study explained to Medical News Today.

“But because it is the most prevalent side effect of GLP-1 medications, we were really interested in understanding whether the appetite suppression and weight loss stem from the same or different neural circuits as those that mediate the nausea,” Alhadeff said.

Scientists focused on hindbrain GLP-1R neurons, which Alhadeff said are a population of neurons at the back of the brain that express the receptor that binds GLP-1 drugs like Ozempic and Wegovy .

“In our recent publication, we discovered that this population of hindbrain GLP-1R neurons is the main drug target that mediates the appetite suppression and weight loss effects of GLP-1 drugs,” she added.

Targeting neurons that reduce appetite without nausea

During the study, Alhadeff and her team found that in mice the individual GLP-1R neurons are calibrated to react to stimuli that are either nutritive or nourishing, or aversive or unpleasant.

Additionally, researchers found that GLP-1R neurons in the area of the hindbrain known as the area postrema respond mostly to unpleasant stimuli, while those in a different area called the nucleus tractus solitarius are most likely to acknowledge nourishing stimuli.

“Interestingly, activation of the area postrema GLP-1R neurons causes nausea, but activation of nucleus tractus solitarius GLP-1R neurons causes satiety without nausea,” Alhadeff explained.

“The implication is that there is a neuron population — nucleus tractus solitarius GLP-1R neurons that can decrease appetite and cause weight loss without making individuals feel sick and so we hope that this finding will lead to the development of more selective weight loss drugs.”

“We all know that nausea is almost always accompanied by appetite loss, and so we thought that the GLP-1 drugs may suppress appetite simply by making individuals feel nauseated. However, our new findings suggest that you can still have appetite suppression without nausea. This implies that future drugs could be developed to suppress appetite without the side effects. Next steps will involve figuring out how to make drugs that are more selective with fewer side effects.”

— Amber L. Alhadeff, PhD, senior study author

Findings may improve GLP-1 drug tolerability

After reviewing this study, Shruti Pandiri, MD , assistant professor of medicine in the Division of Endocrinology with the Center for Weight Loss & Metabolic Health at Hackensack University Medical Center in New Jersey, told MNT the findings of this study have the potential to lead to the development of GLP-1-based obesity drugs with improved tolerability. This could be a major advance in the treatment of this chronic disease.

“Nausea is a common side effect of GLP-1 medications, affecting approximately 30-40% of patients,” Pandiri said. “It is usually mild and transient, but it can be severe enough to lead some patients to discontinue treatment.”

MNT also spoke with Mir Ali, MD, a board certified bariatric surgeon and medical director of MemorialCare Surgical Weight Loss Center at Orange Coast Medical Center in Fountain Valley, CA about this study.

“Anything that can reduce side effects for medications is a good idea,” Ali said.

“One thing that they’re not really considering is some of the nausea is because the medications (slow down) emptying of the GI tract. And that’s one of the benefits of the medication — when the stomach is emptying slower, the patient stays full for longer and that also contributes to the weight loss. So if you eliminate that effect of the medication, then the medication may not be as effective,” Ali continued.

“The next thing would be to see if this is something that can be applied to humans,” he added. “And then there would have to be a comparison to see if there’s a medication that just affects the satiety effect of the medication but not the GI effect if they’re equally effective in weight loss.”

— Mir Ali, MD, board certified bariatric surgeon

How to alleviate nausea caused by GLP-1 drugs

For those taking GLP-1 medications and dealing with nausea, Pandiri and Ali offered the following suggestions:

• Take the medication with food, which can help slow down the absorption of the medication and reduce the risk of nausea.
• Start with a low dose and gradually increase the dose — this can help the body adjust to the medication and reduce the risk of side effects.
• Stay hydrated — drinking plenty of fluids can help to prevent dehydration , which can worsen nausea.
• Eat bland foods , which can help to settle the stomach.
• Eat smaller portions.
• Ask your doctor to prescribe anti-nausea medication.