What Is the Dark Side of GLP-1 Receptor Agonists?

The approval of the GLP-1 receptor agonist semaglutide for weight regulation in January 2023 ushered in a new era of obesity therapy. In recent months, however, drug regulatory authorities have also documented rare, occasionally severe side effects associated with the use of these agents in diabetes therapy that doctors may not necessarily have been aware of.

"When millions of people are treated with medications like semaglutide, even relatively rare side effects occur in a large number of individuals," said Susan Yanovski, MD, codirector of the Office of Obesity Research at the National Institute of Diabetes and Digestive and Kidney Diseases in Bethesda, Maryland, in a JAMA news report.

Despite the low incidence of these adverse events and the likelihood that the benefits outweigh these risks in individuals with severe obesity, doctors and patients should be aware of these serious side effects, she added.

GLP-1 receptor agonists like semaglutide or liraglutide mimic certain intestinal hormones. Almost all their characteristic side effects involve the gastrointestinal tract: nausea, vomiting, constipation, and diarrhea. However, these are not the rare, severe side effects that are gaining increasing attention.

Severe Gastric Problems

A recent analysis published in JAMA shows that GLP-1 receptor agonists are associated with a ninefold higher risk of pancreatitis, compared with bupropion, an older weight-loss medication. Patients receiving GLP-1 receptor agonists also had four times more frequent intestinal obstruction and more than three times more frequent gastroparesis. The absolute risks for these complications, however, were less than 1% per year of use.

There were no indications of an increased risk for gallbladder diseases. Acute pancreatitis and acute gallbladder diseases are known complications of GLP-1 receptor agonists.

These results "reinforce that these are effective medications, and all medications have side effects," said Yanovski. She emphasized that despite a significant increase in relative risk, however, the absolute risk remains very low.

Anesthetic Complications

In the spring of 2023, reports of patients taking GLP-1 receptor agonists and vomiting or aspirating food during anesthesia surfaced in some scientific journals. It was particularly noticeable that some of these patients vomited unusually large amounts of stomach contents, even though they had not eaten anything, as directed by the doctor before the operation.

Experts believe that the slowed gastric emptying intentionally caused by GLP-1 receptor agonists could be responsible for these problems.

The American Society of Anesthesiologists now recommends that patients do not take GLP-1 receptor agonists on the day of surgery and discontinue weekly administered agents like Wegovy 7 days before the procedure.

Increased Suicidality Risk?

In July, case reports of depression and suicidal ideation led the European Medicines Agency to investigate about 150 cases of potential self-harm and suicidal thoughts in patients who had received liraglutide or semaglutide. The review now also includes other GLP-1 receptor agonists. Results of the review process are expected this month.

Yanovski noted that it is unclear whether these incidents are caused by the drugs, but suicidal thoughts and suicidal behavior have also been observed with other medications for obesity treatment (eg, rimonabant). "It is certainly a good idea to use these medications cautiously in patients with a history of suicidality and monitor the patients accordingly," she said.

Long-Term Safety

GLP-1 receptor agonists likely need to be used long term, potentially for life, for the effects on body weight to persist. Whether there are side effects and complications that only become apparent over time is currently unknown — especially when these medications are used for weight reduction.

Studies in rodents have suggested an increased risk of medullary thyroid carcinomas. Whether a similar signal exists in humans may only become apparent in many years. In patients who have had medullary thyroid carcinoma themselves or in the family, dulaglutide, liraglutide, semaglutide, and tirzepatide, a dual GLP-1/GIP receptor agonist, are contraindicated.

With dual agonists like tirzepatide or even triple agonists like retatrutide (GLP-1/GIP/glucagon), patients can lose significantly more weight than with the monoagonist semaglutide. Gastrointestinal events were also frequent in studies of dual agonists.

Awaiting Guideline Updates

Guidelines for using these new medications are still scarce. "There are clinical guidelines for obesity therapy, but they were all written before the GLP-1 receptor agonists came on the market," said Yanovski. "Medical societies are currently working intensively to develop new guidelines to help doctors use these medications safely and effectively in clinical practice."

This article was translated from the Medscape German edition.

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