A large cohort study found no increased risk of suicidality—including suicidal ideation, self-harm, or completed suicide—among patients with type 2 diabetes receiving glucagon-like peptide-1 receptor agonists compared with those receiving dipeptidyl peptidase-4 inhibitors or sodium-glucose cotransporter-2 inhibitors.

In the study, published in The BMJ, investigators used data from the UK Clinical Practice Research Datalink to analyze the outcomes of 36,082 glucagon-like peptide (GLP)-1 receptor agonist users and 234,028 dipeptidyl peptidase (DPP)-4 inhibitor users in the first cohort as well as 32,336 GLP-1 receptor agonist users and 96,212 sodium-glucose cotransporter (SGLT)-2 inhibitor users. Initial crude analyses suggested an increased incidence of suicidality with GLP-1 receptor agonists compared with DPP-4 inhibitors (3.9 vs 1.8 per 1,000 person-years, hazard ratio [HR] = 2.08, 95% confidence interval [CI] = 1.83–2.36). However, after adjusting for confounders using propensity score fine stratification weighting—including age, sex, diabetes severity, psychiatric history, socioeconomic status, and medication history—the association was null (HR = 1.02, 95% CI = 0.85–1.23).

"In crude analyses, GLP-1 receptor agonist use was associated with an increased incidence of suicidality compared with DPP-4 inhibitors. This estimate decreased to a null value after confounding factors were accounted for," reported Samantha B. Shapiro and colleagues.

A similar pattern was observed when comparing GLP-1 receptor agonists with SGLT-2 inhibitors, where crude incidence rates were 4.3 vs 2.7 per 1,000 person-years (HR = 1.60, 95% CI = 1.37–1.87), but the adjusted HR was 0.91 (95% CI = 0.73–1.12).

The investigators followed patients until March 2021, with median follow-up periods of 1.3 years for GLP-1 receptor agonist users and 1.7 years for DPP-4 inhibitor users in the first cohort, and 1.2 years for both groups in the second cohort. A weighted Cox proportional hazards model confirmed no statistically significant difference in suicidality risk between GLP-1 receptor agonists and either comparator drug class. Similar findings were observed when suicidal ideation, self-harm, and suicide were analyzed separately in both cohorts.

GLP-1 receptor agonists are widely prescribed for type 2 diabetes management and have shown beneficial cardiorenal effects and reduced all-cause mortality in large cardiovascular outcome trials. Concerns regarding a potential link between GLP-1 receptor agonists and suicidality emerged in 2023 following a safety signal from the Icelandic Medicines Agency, prompting investigations by the European Medicines Agency and the FDA. However, clinical trials have not shown imbalances in suicidal ideation or self-harm between treatment groups.

The investigators concluded that "GLP-1 receptor agonists do not seem to increase the risk of suicidality among patients with type 2 diabetes."

Full disclosures are detailed in the study.