Sodium–Glucose Cotransporter 2 Inhibitors and Lower Risk of Depression in Population with Type 2 Diabetes Mellitus: A Population-Based Active Comparator, New-User Design

Ming-Jyun Kao,1,2,* Ying-Chih Huang,3,4,* Yu-Chieh Huang,5,* Hui-Wen Yang,1,6,7 Sheng-Yin To,1,6,7 Chun-Cheng Liao,8– 10 Yuan-Liang Wen,1,6,7 Li-Ting Kao1,6,11 1School of Pharmacy, College of Pharmacy, National Defense Medical University, Taipei, Taiwan; 2Department of Pharmacy, Taoyuan Armed Forces General Hospital, Taoyuan, Taiwan; 3Department of Pharmacy, Shuang Ho Hospital, Taipei Medical University, New Taipei, Taiwan; 4School of Pharmacy, Taipei Medical University, Taipei, Taiwan; 5Department of Psychiatry, Tri-Service General Hospital, Taipei, Taiwan; 6Graduate Institute of Life Sciences, College of Biomedical Sciences, National Defense Medical University, Taipei, Taiwan; 7School of Public Health, College of Public Health, National Defense Medical University, Taipei, Taiwan; 8Department of Family Medicine, Taichung Armed Forces General Hospital, Taichung, Taiwan; 9Department of Medical Education and Research, Taichung Armed Forces General Hospital, Taichung, Taiwan; 10School of Medicine, National Defense Medical University, Taipei, Taiwan; 11Department of Pharmacy Practice, Tri-Service General Hospital, Taipei, Taiwan*These authors contributed equally to this workCorrespondence: Li-Ting Kao, School of Pharmacy, College of Pharmacy, National Defense Medical University, No. 161, Sec. 6, Minquan E. Road, Neihu District, Taipei, 114201, Taiwan, Tel +886-2-8792-3100 ext. 18893, Email [email protected]: This study aimed to investigate the association between the use of sodium–glucose cotransporter 2 inhibitors (SGLT2i) and the risk of developing depression in patients with type 2 diabetes mellitus.Patients and Methods: This study used Taiwan’s National Health Insurance Database and an active comparator new-user design to evaluate depression risk among 551,917 patients initiating SGLT2i or DPP4i between 2016 and 2018. The primary outcome was depression incidence, assessed over a three-year follow-up. Stratified Cox regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) between groups.Results: Among new SGLT2i users, 3255 cases of depression occurred (7.18 per 1000 person-years) versus 7190 cases among DPP4i users (10.12 per 1000 person-years). After adjustment for demographic and clinical covariates, SGLT2i use was consistently associated with a lower risk of depression in both the full cohort (adjusted HR = 0.77; 95% CI: 0.73– 0.80) and the propensity score–matched cohort (adjusted HR = 0.77; 95% CI: 0.74– 0.81). The association remained robust in multiple sensitivity analyses and across clinical subgroups.Conclusion: SGLT2i use was associated with a reduced risk of depression among individuals with type 2 diabetes mellitus. These findings suggest potential neuropsychiatric benefits of SGLT2i and support further investigation into their broader therapeutic implications.Keywords: sodium–glucose cotransporter 2 inhibitor, type 2 diabetes mellitus, depression