FDA: No Signs of Link Between GLP-1s and Suicidal Thoughts, Actions

There is no evidence that glucagon-like peptide-1 (GLP-1) receptor agonists, used to treat type 2 diabetes and overweight/obesity, induce suicidal thoughts or actions, according to preliminary findings of a US Food and Drug Administration review released Thursday.

The agency based that assessment on a review of the FDA Adverse Event Reporting System, but it also did not find a significant link within large outcomes studies or observational analyses.

“However, because of the small number of suicidal thoughts or actions observed in both people using GLP-1 receptor agonists and in the comparative control groups, we cannot definitively rule out that a small risk may exist; therefore, FDA is continuing to look into this issue,” the drug safety communication states. The agency plans to perform a meta-analysis of clinical trials of GLP-1 receptor agonists and to examine postmarketing data within its Sentinel system, which contains health insurance claims and patient health records.

I am unaware of any compelling evidence of an increased risk with GLP-1s. A. Michael Lincoff

There are several GLP-1 receptor agonists on the market, including liraglutide (Saxenda/Victoza; Novo Nordisk), semaglutide (Wegovy/Ozempic; Novo Nordisk), tirzepatide (Zepbound/Mounjaro; Eli Lilly), and others. They have spiked in popularity recently, particularly for weight loss, although the SELECT trial has shown that the drugs—in this case, semaglutide—have cardiovascular benefits as well.

The GLP-1 receptor agonists come with well-known GI side effects but concerns about suicidal thoughts and actions emerged over the past year. In July, the European Medicines Agency announced that it was looking into such reports. And in September, Reuters reported that the FDA also would be assessing the situation.

The new update provides some reassurances, as does a study recently published online in Nature Medicine, which included a look at electronic health records from 240,618 patients with overweight or obesity who were prescribed semaglutide or a non-GLP-1 receptor agonist medication for weight reduction. Compared with the other agents, semaglutide was associated with a lower risk of incident and recurrent suicidal ideation (HRs 0.27 and HR 0.44, respectively). Similar findings were seen in patients with type 2 diabetes.

An author on that paper, Nora Volkow, MD, director of the National Institute on Drug Abuse, said in a statement emailed to TCTMD that “our findings do not support concerns of increased suicidality in patients who are prescribed semaglutide, though more research is needed. Importantly, our study does not indicate that taking semaglutide could reduce risk of suicidal ideations or that it actively protects against suicidal ideations—such a conclusion would require clinical trials and further exploration that goes beyond an observational study.”

The findings do, however, “highlight the importance for screening for suicidal ideations in patients with obesity and diabetes so that proper support can be given to those at risk, and to ensure that studies like ours to evaluate long-term effects of semaglutide or other medications can properly evaluate potential suicidal risk,” Volkow said.

A. Michael Lincoff, MD (Cleveland Clinic, OH), co-chair of the SELECT steering committee, noted that their trial did not demonstrate an increase in psychiatric adverse events with semaglutide, although there was no further breakdown in terms of suicidal ideation or other events. A forthcoming paper focused on safety will provide additional insights into this specific issue, Lincoff told TCTMD.

For now, the Nature Medicine paper provides information that is “concordant with what we believe” regarding the risk of suicidal ideation, Lincoff said. “I am unaware of any compelling evidence of an increased risk with GLP-1s.”

Still, he added, “it’s good to see some more refined data that is supporting this view.”