Suicide and Self-Harm Events With GLP-1 Receptor Agonists in Adults With Diabetes or Obesity: A Systematic Review and Meta-Analysis.

Importance: Bariatric surgery, once the criterion standard in obesity treatment, has a small but concerning association with increased suicidality. Glucagon-like peptide 1 receptor agonists (GLP-1 RAs), originally developed to treat diabetes, now provide substantial efficacy in the treatment of obesity. However, concerns of risk of suicidality with these medicines have been raised. Objective: To evaluate the risk of suicidality and self-harm in randomized, placebo-controlled trials of GLP-1 RAs in adults with diabetes or obesity. Data Sources: MEDLINE, Embase, ClinicalTrials.gov, and Cochrane databases were systematically searched from inception to August 29, 2023. Study Selection: Reports of randomized clinical trials (RCTs) lasting 6 or more months comparing GLP-1 RAs with placebo for the treatment of diabetes or obesity published in peer-reviewed journals were identified. Two independent reviewers screened all search-identified studies for inclusion. Records of outcomes were queried from primary papers, ClinicalTrials.gov entries, and corresponding authors. Data Extraction and Synthesis: Two independent researchers abstracted data and assessed data quality and validity using PRISMA guidelines. Data were pooled using random-effects models. Main Outcomes and Measures: Pooled incidence of completed or attempted suicide, occurrences of suicidal ideation, or self-harm. Results: A total of 27 of 144 RCTs meeting inclusion criteria systematically recorded suicide and/or self-harm-related events and included 32 354 individuals receiving GLP-1 RAs and 27 042 treated with placebo, over 69 653 and 63 853  person-years of exposure, respectively. Event incidence was very low in the GLP-1 RA (0.047 per 100 person-years) and placebo (0.042 per 100 person-years) groups, with no statistically significant difference (rate ratio [RR], 0.76; 95% CI, 0.48-1.21; P = .25). Subgroup analyses did not suggest differences in outcomes based on diabetes status or GLP-1 RA used. Five studies were considered at risk of bias due to the loss of more than 5% of participants to follow-up. Otherwise, studies were not found to be heterogeneous nor at high risk of bias. Conclusions and Relevance: There is unlikely to be an increase in the very low incidence of suicide-related adverse events among individuals receiving GLP-1 RAs within the context of RCTs. While these findings may further ease concerns about these adverse effects, continued monitoring is warranted to identify particular patients who may be at risk as extended use of GLP-1 RAs expands.