FDA review finds no sign GLP-1 medicines such as Wegovy cause suicidal thoughts

The FDA said in a drug safety communication dated January 11, 2024 that a preliminary look at reports of suicidal thoughts or actions in people using GLP-1 receptor agonists found no evidence the medicines are the cause ^[1]. The agency said its evaluation is not finished and that it will publish final conclusions once the work wraps up ^[1].

The class includes Ozempic, Rybelsus and Wegovy (semaglutide); Mounjaro and Zepbound (tirzepatide, which also acts on the GIP receptor); Victoza and Saxenda (liraglutide); Trulicity (dulaglutide); Byetta and Bydureon BCise (exenatide); Adlyxin (lixisenatide); and the combination products Xultophy and Soliqua ^[1]. Byetta, cleared in 2005, came first ^[1].

Reviewers went through filings in the FDA Adverse Event Reporting System, known as FAERS. The agency said the details supplied were often incomplete and that suicidal thinking can be driven by many factors, so those filings did not point to a clear link with the drugs. Data from clinical trials — including large outcome studies — and from observational research likewise showed no association ^[1].

The agency left room for doubt. It noted that the number of such events was low in both the groups taking the drugs and the comparison groups, meaning a small risk could not be entirely excluded ^[1].

Two further analyses are planned or in progress: a meta-analysis pooling trial results across every product in the class, and a look at postmarketing data in the Sentinel System, a very large network of insurance claims and patient health records ^[1].

Labels for the versions approved for obesity or overweight already mention the possibility of suicidal thoughts and actions. The FDA said that language traces back to reports seen with older weight-loss medicines rather than to findings specific to GLP-1s ^[1].

The question drew attention well before this update. The European Medicines Agency began examining the issue in July 2023 ^[2], and Reuters reported that September that the FDA would assess it too, after 265 reports of suicidal ideation reached the agency ^[2].

A study published in Nature Medicine looked at electronic health records for 240,618 patients with overweight or obesity who were prescribed either semaglutide or a non-GLP-1 medicine for weight loss. Semaglutide was tied to a lower risk of first-time suicidal ideation (hazard ratio 0.27) and of recurring ideation (hazard ratio 0.44). Results in patients with type 2 diabetes were similar ^[2].

Nora Volkow, director of the National Institute on Drug Abuse and a coauthor, said the results "do not support concerns of increased suicidality in patients who are prescribed semaglutide, though more research is needed" ^[2]. She added that the study does not show the drug protects against suicidal thoughts ^[2]. A. Michael Lincoff of the Cleveland Clinic, who helped lead the SELECT trial of semaglutide, said that trial found no rise in psychiatric side effects, though it did not separate out suicidal ideation. "I am unaware of any compelling evidence of an increased risk with GLP-1s," he said, adding that a forthcoming safety paper should add detail ^[2].

Why it matters for patients

People taking these medicines are being told the same thing as before: do not quit on your own, because stopping can make the condition being treated worse, and check with a clinician first ^[1]. Doctors are advised to watch for and ask about new or worsening depression, thoughts of suicide, or mood and behavior changes, and patients are asked to report them ^[1]. The 988 Suicide and Crisis Lifeline takes calls and texts around the clock at no cost ^[1]. The central open question — whether a very small risk exists — remains unanswered, and no final FDA conclusion has been issued ^[1].

What happens next

The FDA has not said when it will finish. It promised to communicate conclusions and recommendations when the review is complete or when it has more to share ^[1]. Lincoff said a separate SELECT analysis focused on safety will offer more insight into psychiatric events ^[2].