Blockbuster Weight-Loss Drugs Not Tied to Suicidality, Studies Show

There is no evidence that a blockbuster class of weight-loss and diabetes drugs known as glucagon-like peptide 1 (GLP-1) receptor agonists causes suicidality, according to a review by the Food and Drug Administration.

Meanwhile, an independent large clinical trial found that patients who took the GLP-1 drug semaglutide were significantly less likely to experience suicidal ideation than those taking other drugs for obesity or type 2 diabetes.

The question remains, What is psychiatrists’ role in prescribing these medications or helping patients manage their weight? GLP-1 drugs mimic a hormone in the intestines that stimulates the release of insulin and reduces blood glucose after eating a meal. It also slows the passage of food through the digestive tract, which can help people feel full longer. GLP-1 receptors are also present in neuronal circuits in the hypothalamus involved in appetite control.

Kenn Lee, M.B.B.Ch., a consultation- liaison psychiatrist at Fairfield General Hospital in the United Kingdom, wrote an opinion piece with colleagues on psychiatrists’ role in managing antipsychotic-induced obesity for the British Journal of Psychiatry Bulletin in 2023. “Many of the medications we prescribe to manage people’s mental illness increase the risk of QTc prolongation, weight gain or obesity, and metabolic diseases,” he said.

“Just as we psychiatrists monitor our patients for extrapyramidal side effects, we should actively monitor for other side effects, such as weight gain, as part of holistic care,” he told Psychiatric News.

Among patients with serious mental illness, more than one-quarter are overweight (26%) and nearly two-thirds (60%) are obese, roughly twice the rate of overweight in the global general population, according to a global meta-analysis published in 2021 by Afzal and colleagues in Frontiers in Endocrinology.

“Patients with serious mental illness often experience marginalization and stigmatization in the health care system, and we know that they are less likely to regularly access primary care services or to have a stable support network,” Lee said. Psychiatrists should work with patients to identify and reduce barriers to ensure they receive the best available medical care, he added. They can also partner with appropriate specialists, such as endocrinologists or bariatric physicians when needed, Lee added.

Ultimately, management of obesity requires a structured, holistic weight management plan. It must include nonpharmacological treatment, such as lifestyle modification, and a review of medications that can contribute to weight gain, Lee added.

In the clinical trial results that led to the FDA’s approval of Wegovy for weight management in 2021, participants with obesity who took 2.4 mg weekly injections of semaglutide lost 12.4% of their body weight over those taking a placebo, according to the FDA. However, participants with diabetes and obesity lost about only half as much. Gastrointestinal distress, usually mild to moderate, is the most common side effect.

At the end of April, the U.S. Senate launched an investigation into Danish maker Novo Nordisk’s prices for its semaglutide formulations (Ozempic, Wegovy, Rybelsus). Patients in the U.S. pay $1,349 a month for Wegovy, versus $140 in Germany and $59 in the United Kingdom, according to a letter written to the drugmaker by Sen. Bernard Sanders, chair of the Senate Committee on Health, Education, Labor, and Pensions. Meanwhile, researchers estimated that generic formulations of GLP-1 medications could be profitably manufactured for less than $1 for a one-month dose, according to a report issued in JAMA Network Open in March.

“As important as these drugs are, they will not do any good for the millions of patients who cannot afford them. Further, if the prices for these products are not substantially reduced, they also have the potential to bankrupt Medicare, Medicaid, and our entire health care system,” Sanders wrote.

Large Study of Suicidal Ideation

Wang and colleagues published the results of a large study in Nature Medicine in January comparing the electronic health records of more than 105,000 overweight or obese patients, half of whom took semaglutide and half of whom took non-GLP-1 obesity medications (bupropion, naltrexone, orlistat, topiramate, phentermine, or setmelanotide).

Researchers found that patients taking semaglutide were 27% less likely to experience initial suicidal ideation than those taking non-GLP-1 anti-obesity medication over the six-month study. Researchers also studied health records for 1,730 overweight or obese patients with a prior history of suicidal ideation: Those taking semaglutide were 44% less likely to experience recurrent suicidal ideation than those taking non-GLP-1 anti-obesity medication.

The results were replicated in a separate group of matched participants who had type 2 diabetes and took either semaglutide or other non-GLP-1 diabetes medications.

Adverse Event Review Continues

The FDA said it has spent several months conducting detailed reviews of reports of suicidal thoughts or actions involving GLP-1 medications received through its FDA Adverse Event Reporting System (FAERS). “Because the information provided was often limited, and because these events can be influenced by other potential factors, we determined that the information ... did not demonstrate a clear relationship ... ,” the FDA wrote. “Similarly, our reviews of the clinical trials, including large outcome studies and observational studies, did not find an association between use of GLP-1 drugs and the occurrence of suicidal thoughts or actions.”

Ultimately, the FDA said that it could not definitively rule out that a small risk of suicidal ideation may exist, so it is continuing to look into the issue. A similar review is underway by the European Medicines Agency’s safety committee that began last July after it received about 150 reports of self-injury and/or suicidal thoughts among Icelandic patients taking liraglutide or semaglutide.

The FDA is also investigating adverse event reports of aspiration (when saliva, food, or drink is inhaled into the lungs) and alopecia (hair loss) among patients taking these medications. ■