Weight loss drugs can cause stomach paralysis, study says

Injectable medications that treat diabetes and obesity increase the risk of a rare but serious side effect: stomach paralysis according to new data on the real-world use of these drugs.

At least three new studies based on large collections of patient records show that the risk of being diagnosed with stomach paralysis or gastroparesis is greater for people who take GLP-1 agonists than for those who do not.

The studies have not been vetted by outside experts or published in medical journals, so the data is considered preliminary. Two were presented on Saturday at the medical conference Digestive Disease Week 2024 in Washington, United States; the third was scheduled to be presented on Monday (20).

Injectable medications called GLP-1 agonists are in high demand because they have been shown to be very effective for weight loss. In clinical trials, some of the strongest medications, such as Wegovy and Zepbound, helped people lose at least 10% of their initial weight. Studies have also concluded that they have benefits for the heart, in addition to helping to reduce abdominal circumference. Drugmaker Novo Nordisk said 25,000 people are starting to use Wegovy every week in the US alone.

Medicines reduce hunger by slowing the passage of food through the stomach. They also help the body release more insulin and send signals to the brain that decrease cravings.

In some people, however, these medications can also cause episodes of vomiting, which can range from unpleasant to severe and may require medical attention. They can also slow down the stomach so much that medical tests show a condition called gastroparesis.

Most of the time, doctors say, gastroparesis improves after stopping the medication. But some people report that their condition has not improved even months after stopping the medication, with life-altering consequences.

Measuring the risk of gastroparesis

In new studies, the risk of gastroparesis appears to be rare , but consistent. Compared to similar people who did not take GLP-1 medications, those who did had about a 50% increased risk of being diagnosed with the condition.

A study led by researchers from University Hospitals in Cleveland, United States, used records collected by the TriNetX database, which includes millions of patient records from 80 contributing healthcare organizations. The analysis focused on adults who were obese, had a body mass index greater than 30, but who were not diagnosed with diabetes and had not been diagnosed with gastroparesis or pancreatitis at least six months before starting to take a GLP-1 medication. Records of more than 286,000 patients were included in the study.

Diabetes itself can also increase the risk of gastroparesis, especially if a person's blood sugar level has not been well controlled for a long period of time.

Among people who were prescribed a GLP-1 weight-loss drug — such as semaglutide (marketed as Ozempic and Wegovy), exenatide (Byetta), and liraglutide (Victoza) — 10 in 10,000, or 0.1%, were diagnosed with gastroparesis at least six months later. By comparison, 4 out of every 10,000 people, or 0.04%, who were matched in the database based on age, sex, ethnicity and other factors, but who were not taking a GLP-1 medication, developed the condition.

The difference, which was statistically significant, resulted in a 52% increase in the risk of being diagnosed with stomach paralysis while taking a GLP-1 medication.

A second study, led by researchers at the University of Kansas, also used records from the TriNetX research network database. It included patients who were prescribed GLP-1 medications for diabetes or obesity between December 2021 and November 2022, and compared them with people who had diabetes or obesity and were seen by a doctor during the same period but who were not prescribed a GLP-1 medicine. Records of nearly 300,000 patients were included in the study.

Compared to those who were not taking a GLP-1 medication, those who were were about 66% more likely to be diagnosed with gastroparesis. This study found that 0.53% of patients on GLP-1 medications were diagnosed with stomach paralysis, or about 1 case of gastroparesis for every 200 people taking the medications.

People taking GLP-1 medications were also more likely to have nausea and vomiting or gastroesophageal reflux disease (GERD) and to be prescribed a proton pump inhibitor. They were also more likely to have their gallbladder removed and to experience drug-induced pancreatitis.

“While these medications work and should be used for appropriate reasons, we want to warn everyone that if you decide to start using them, be prepared for the possibility that you may have a 30% chance of having gastrointestinal side effects, and then the medication may have to be discontinued,” said study author Prateek Sharma, professor of medicine at the University of Kansas School of Medicine.

Some side effects of medications may lessen over time as people get used to the doses. This is one reason why doctors start with a low dose of the medication and gradually increase it over time.

Sharma noted that the study included people with diabetes in both the group taking the GLP-1 drugs and the comparison group, and yet they found a higher incidence of stomach paralysis in those taking the drugs, suggesting that diabetes alone does not was causing the increased risk.

“The medicine was the only thing that was different between these two groups,” he says.

“And we showed that all gastrointestinal side effects or symptoms, such as nausea, vomiting and gastroparesis, were significantly greater in GLP-1 users compared to controls,” says Sharma, who is also president-elect of American Society of Gastrointestinal Endoscopy.

Was an adverse event missed in clinical trials?

Although these drugs have been widely studied, Sharma believes it's possible that gastroparesis is rare enough that it didn't appear in the drugs' clinical trials because they didn't include enough patients.

“You need hundreds of thousands of patients to reach these conclusions, which is why I think these database studies are much more important,” says Sharma.

Another reason it may have been overlooked in clinical trials was the way researchers typically test it, according to Michael Camilleri, a gastroenterologist and researcher at the Mayo Clinic who has studied gastroparesis with the GLP-1 drug liraglutide.

“It's very important, if you're going to study the problem of gastric emptying, you need to look at gastric emptying of solids, not liquids,” says Camilleri. Liquids pass through the stomach more quickly than solids.

“When pharmaceutical companies evaluated the effects of this class of drugs on gastric emptying, they generally used a method that evaluates the emptying of liquids from the stomach,” he says.

This method is called the acetaminophen absorption test and is often used because it is faster and less expensive than a gastric emptying scintigraphy study, which uses a radioactive tracer to see how much solid food is left in the stomach hours after a meal.

Paracetamol is absorbed by the stomach and taken into the bloodstream through liquids. Measuring how quickly paracetamol appears in the blood can give an idea of ​​how quickly liquids are passing through the stomach, but not solids. Camilleri and other experts say that acetaminophen absorption is not an adequate test for gastroparesis in GLP-1 medications.

Camilleri co-authored a third study presented Monday at Digestive Disease Week which looked at gastroparesis with GLP-1 medications.

That study examined records of nearly 80,000 patients prescribed a GLP-1 drug by doctors in the Mayo Clinic health system. The researchers focused on a subset of 839 people who had symptoms of gastroparesis and who had a gold standard test for the condition: a procedure called a gastric emptying scan.

About a third of this group, 241 people, had food in their stomach four hours after eating a test meal, meaning they were diagnosed with gastroparesis.

However, the study did not calculate the difference in the risk of gastroparesis between people who used the medications and those who did not.

Camilleri says it's likely that the risk of gastroparesis is underestimated in these studies because not everyone who showed symptoms would have had the test needed to diagnose it.

In the Mayo Clinic study, women and people who also reported constipation while using GLP-1 medications were more likely to receive a diagnosis of gastroparesis.

Camilleri said constipation could be a clue that people will have problems with gastroparesis when using a GLP-1 medication, but there are still many questions to be answered.

“For people who have this complication, it is extremely serious,” he says.