5E-03 - GLP-1 Receptor Agonists and the Risk of Suicidality Among Patients With Type 2 Diabetes

Background: Increased reports of thoughts of suicide and self-harm among users of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have prompted multiple regulatory agencies to conduct reviews on the drug class. Observational evidence on this potential association remains inconclusive.

Objectives: To determine whether GLP-1 RA use is associated with an increased risk of suicide and self-harm when compared with dipeptidyl peptidase-4 (DPP-4) or sodium-glucose cotransporter-2 (SGLT-2) inhibitor use among patients with type 2 diabetes.

Methods: Using primary care, hospitalization, and mortality data from the United Kingdom, we assembled two active-comparator new-user cohorts of patients with type 2 diabetes: one of patients newly prescribed GLP-1 RAs or DPP-4 inhibitors between January 2007 and December 2020, and one of patients newly prescribed GLP-1 RAs or SGLT-2 inhibitors between January 2013 and December 2020. Both cohorts were followed until March 2021. We used propensity score fine stratification weighting to balance the exposure groups on 57 potential confounders, including age, sex, smoking, BMI, history of mental health disorders and behaviours associated with self-harm and suicide attempt, socioeconomic status, proxies for diabetes severity, common comorbidities, other medication use, and markers of health-seeking behaviour. Patients were followed using an on-treatment exposure definition. We fit weighted Cox proportional hazards models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for a composite of suicidal ideation, self-harm, or completed suicide.

Results: The first cohort included 36,082 GLP-1 RA users (median follow-up: 1.3 years) and 234,028 DPP-4 inhibitor users (median follow-up: 1.7 years). In crude analyses, GLP-1 RA use was associated with an increased incidence of suicidality compared with DPP-4 inhibitors (crude incidence rates (IRs) of 3.9 vs. 1.8 per 1,000 person-years, respectively; HR 2.08, 95% CI 1.83–2.36). This estimate decreased to a null value after weighting (HR 1.02, 95% CI 0.85–1.23). The second cohort included 32,336 GLP-1 RA users (median follow-up: 1.2 years) and 96,212 SGLT-2 inhibitor users (median follow-up: 1.2 years). Similarly, GLP-1 RA use was associated with an increased risk of suicidality when compared with SGLT-2 inhibitors in crude analyses (crude IRs 4.3 vs. 2.7 per 1,000 person-years, HR 1.60, 95% CI 1.37–1.87) but not after weighting (HR 0.91, 95% CI 0.73–1.12). Similar findings were observed when analyzing suicidal ideation, self-harm, and suicide separately in both cohorts.

Conclusions: The use of GLP-1 RAs was not associated with an increased risk of suicidality in this large, population-based study from the United Kingdom.