Antidiabetes agents and risk of incident depression in 686,522 people with type 2 diabetes mellitus: A 20-year population-based cohort study

BACKGROUND: People with diabetes have increased risk of depression that further worsens clinical outcome. However, occurrence of depression among patients with diabetes exposed to antidiabetes agents is under-studied. We investigated whether antidiabetes agents would decrease the risk of depression in people with diabetes. METHODS: This population-based cohort study identified 686,522 patients with incident type-2 diabetes between 2002-2021 in Hong-Kong who were exposed to any antidiabetes agents, using territory-wide medical-record database of public-healthcare services. Associations of exposure to antidiabetes agents and risk of first-diagnosed depression were examined by Cox proportional-hazards models for each individual agent. An array of covariates, including age, sex, calendar-year period, catchment-area, pre-existing physical/psychiatric-comorbidities, average HbA1c-level, diabetic-complications, cardiovascular/lipid-lowering medications, and presence of other antidiabetes agents under investigation was adjusted. Three sets of sensitivity-analyses were conducted by (a) restricting to patients with cumulative drug-exposure ≥90 days and ≥180 days, (b) monotherapy, and (c) incorporating commonly-used non-antidiabetic medications as exposure variables. RESULTS: Lower risk of new-onset depression was associated with exposure to any antidiabetes agents (HR 0.42, 95%CI 0.39-0.45) compared with no exposure in patients with incident type-2 diabetes. Lower depression risk was associated with exposure to metformin (0.61[0.57-0.66]) compared with no antidiabetes agents, and to pioglitazone (0.25[0.10-0.63]), linagliptin (0.26[0.13-0.52]), and insulin (0.63[0.55-0.72]). Sensitivity-analyses affirmed that lower depression risk was associated with metformin and insulin. CONCLUSION: Patients with type-2 diabetes with exposure to several antidiabetes agents is at decreased risk of new-onset depression. Further research is warranted to clarify the depression-reducing mechanisms of antidiabetes agents in this vulnerable population.