A pooled US Food and Drug Administration analysis spanning 91 placebo-controlled trials and more than 107,000 patients found no signal for suicidal ideation, self-harm, or related psychiatric adverse events with glucagon-like peptide-1 receptor agonist use.
Following an extensive review of clinical trial, observational, and postmarketing data, the US Food and Drug Administration concluded that glucagon-like peptide-1 receptor agonist (GLP-1 RA) medications are not associated with suicidal ideation or behavior and is requesting corresponding updates to product labeling.
The request applies to Saxenda (liraglutide), Wegovy (semaglutide), and Zepbound (tirzepatide), which are approved for weight reduction in patients with obesity or overweight. These products initially included warnings in the Warnings and Precautions section related to suicidal ideation and behavior based on reports observed with older weight loss medications. In contrast, labeling for GLP-1 RAs approved for glycemic control in patients with type 2 diabetes mellitus has not included such language. The FDA stated that the labeling update will align safety messaging across all approved medications in this drug class.
GLP-1 RAs mimic the action of a naturally occurring intestinal hormone that lowers blood glucose levels after meals and acts on central nervous system pathways involved in appetite regulation and food intake. The first GLP-1 RA was approved in 2005 as adjunctive therapy to improve glycemic control in patients with type 2 diabetes, and several agents are now in clinical use for metabolic indications.
The FDA initiated further evaluation in July 2023 after receiving postmarketing reports of suicidal ideation and behavior in patients treated with GLP-1 RAs. An initial review of clinical trial data, communicated publicly in January 2024, did not identify an association but was limited by a small number of reported events. To improve the precision of risk estimates, the agency conducted a comprehensive meta-analysis of 91 placebo-controlled GLP-1 RA trials that included 107,910 patients. The analysis did not show an increased risk of suicidal ideation or behavior or other psychiatric adverse events, including anxiety, depression, irritability, or psychosis, compared with placebo.
The FDA also conducted a large retrospective cohort study using administrative claims data from the Sentinel System, comparing more than 2.2 million new users of GLP-1 RAs with users of sodium-glucose cotransporter 2 inhibitors. After adjustment for baseline confounders, the study did not find an increased risk of intentional self-harm, including among patients with both type 2 diabetes and obesity.
The agency advised patients to continue taking GLP-1 RA medications as prescribed and encouraged physicians to discuss the updated safety findings with patients. Patients reporting suicidal ideation or behavior should be referred for appropriate mental health evaluation.
Source: FDA
