Abstract
OBJECTIVE: This study aimed to assess the latent threat of depression and suicide/self-injury associated with the combination of glucagon-like peptide-1 agonists (GLP-1RAs) and metformin versus GLP-1RAs monotherapy, through analyzing the data from the Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS). METHODS: We systematically searched the FAERS database for reports on the concomitant use of GLP-1RAs and metformin compared with the GLP-1RAs monotherapy in diabetic or obese patients. Reports were categorized on the basis of the Medical Dictionary for Regulatory Activities (MedDRA) terminology. The signal was considered to be significant when the reporting odds ratio (ROR) and lower limit of 95% CI > 1, and information component (IC)025 > 0, in no less than three patients. RESULTS: The addition of metformin increased the risk of death (38.5 vs 12.4%, P < 0.001) and hospitalization - initial or prolonged (13.5 vs 7.2%, P = 0.035) attributed to suicide/self-injury in patients who received GLP-1RAs. Furthermore, the combination of GLP-1RAs with metformin was disproportionately linked to a higher incidence of suicide/self-injury (ROR = 50.89, 95% CI: 40.79-63.48, IC025 = 5) and depression (except suicide and self-injury) (ROR = 17.28, 95% CI: 13.65-21.87, IC025 = 3.64) when compared with the GLP-1RAs monotherapy. The addition of metformin was confirmed to have shorter intervals to time-to-onset (TTO) than the GLP-1RAs monotherapy. CONCLUSIONS: The combination of GLP-1RAs and metformin is linked to a higher risk of depression and suicide/self-injury compared with the GLP-1RAs monotherapy.