Abstract
OBJECTIVE: The current study is to examine the association between GLP-1 receptor agonist (GLP-1 RA) use and suicide attempt risk in individuals with type 2 diabetes mellitus (T2DM), including those with comorbid cannabis use disorder (CUD). METHODS: We conducted a retrospective study using the TriNetX Research Network. Adults aged 30-85 years with a diagnosis of T2DM were categorized by GLP-1 RA exposure and CUD sourced from over 20 countries across the Americas, Europe-Middle East-Africa, and Asia-Pacific from 2003 to 2023. Individuals with a prior diagnosis of suicidal ideation were excluded. The primary outcome was a new diagnosis of suicide attempt within one year. Cox proportional hazards models were used to estimate adjusted hazard ratios (aHRs), controlling for age, sex, depression, body mass index, and glycated hemoglobin A1c (HbA1c) levels. Kaplan-Meier curves were used to visualize cumulative risk. RESULTS: Among 6,424,228 individuals with T2DM, GLP-1 RA use was associated with significantly lower risk of suicide attempt compared to unexposed individuals (aHR: 0.63; 95 % CI: 0.47,0.85). In contrast, patients with CUD exhibited markedly elevated risk (aHR: 5.50; 95 % CI: 4.39,6.89). This elevated risk persisted among those concurrently using GLP-1 RAs and diagnosed with CUD (aHR: 5.75; 95 % CI: 3.42,9.69). No significant risk reduction was observed among CUD patients using GLP-1 RAs compared to those not using them (aHR: 1.00; 95 % CI 0.37-2.69). CONCLUSIONS: The inverse association between GLP-1 RAs and suicide attempt was attenuated among cannabis users. These findings underscore the importance of addressing substance use when assessing psychiatric risk in diabetes care.