Chang En-Wei, Huang Jing-Yang, Lo Shih-Chang, Huang Chien-Ning, Yang Yi-Sun, Kornelius Edy
School of Medicine, Chung Shan Medical University, Taichung, Taiwan.
Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan.
Front Pharmacol. 2025 Jun 11;16:1601118. doi: 10.3389/fphar.2025.1601118. eCollection 2025.
Individuals with bipolar disorder face a significantly elevated suicide risk, and comorbid type 2 diabetes mellitus (T2DM) further complicates their psychiatric and medical outcomes. Sodium-glucose co-transporter-2 inhibitors (SGLT-2i) have demonstrated cardiometabolic benefits in T2DM, but their impact on psychiatric outcomes remains unclear. This study investigates whether SGLT-2i use is associated with a lower risk of suicide-related events compared to dipeptidyl peptidase-4 inhibitors (DPP-4i) in individuals with bipolar disorder and T2DM.
We conducted a retrospective cohort study using the TriNetX US Collaborative Network, a large electronic health record database. Patients were included if they had bipolar disorder, were receiving active psychiatric treatment, and initiated either SGLT-2i or DPP-4i between 1 January 2015, and 30 June 2024. The primary outcome was the occurrence of suicide-related events, including suicidal ideation, suicide attempt, or intentional self-harm. Secondary outcomes included all-cause mortality, end-stage renal disease (ESRD), diabetic ketoacidosis (DKA), acute kidney injury (AKI), sepsis, genital infections, urinary tract infections (UTIs), and lower-limb amputation. Propensity score matching (1:1) was used to balance baseline characteristics. Cox proportional hazards models estimated hazard ratios (HRs) with 95% confidence intervals (CIs).
The matched cohort included 1,711 patients per group (SGLT-2i vs. DPP-4i). Over a median follow-up of 887 vs. 797 days, suicide-related events occurred in 5.1% of SGLT-2i users vs. 7.3% of DPP-4i users (HR: 0.660, 95% CI: 0.473-0.921, p = 0.0145). All-cause mortality was also lower in the SGLT-2i group (HR: 0.594, 95% CI: 0.451-0.783, p < 0.001). No significant increase in adverse events such as DKA or infections was observed.
In this real-world cohort study, SGLT-2i use was associated with a significantly lower risk of suicide-related events and all-cause mortality compared to DPP-4i in individuals with bipolar disorder and T2DM. Subgroup analyses stratified by age, sex, race, glycemic control (HbA1c), kidney function (eGFR), and baseline lithium use revealed no evidence of increased suicide risk in any subgroup. These findings suggest that SGLT-2 inhibitors may have a neutral to potentially protective effect on suicide-related outcomes. Further prospective studies are warranted to confirm these observations and explore the underlying mechanisms.
双相情感障碍患者面临的自杀风险显著升高，而2型糖尿病（T2DM）合并症会使他们的精神和医疗结局更加复杂。钠-葡萄糖协同转运蛋白2抑制剂（SGLT-2i）已在T2DM中显示出心脏代谢益处，但其对精神结局的影响仍不清楚。本研究调查了在患有双相情感障碍和T2DM的个体中，与二肽基肽酶-4抑制剂（DPP-4i）相比，使用SGLT-2i是否与较低的自杀相关事件风险相关。
我们使用大型电子健康记录数据库TriNetX美国协作网络进行了一项回顾性队列研究。纳入的患者需患有双相情感障碍，正在接受积极的精神治疗，并在2015年1月1日至2024年6月30日期间开始使用SGLT-2i或DPP-4i。主要结局是自杀相关事件的发生，包括自杀意念、自杀未遂或故意自伤。次要结局包括全因死亡率、终末期肾病（ESRD）、糖尿病酮症酸中毒（DKA）、急性肾损伤（AKI）、败血症、生殖器感染、尿路感染（UTI）和下肢截肢。倾向评分匹配（1:1）用于平衡基线特征。Cox比例风险模型估计风险比（HR）及95%置信区间（CI）。
每组匹配队列包括1711名患者（SGLT-2i组与DPP-4i组）。在中位随访887天（SGLT-2i组）和797天（DPP-4i组）期间，SGLT-2i使用者中有5.1%发生了自杀相关事件，而DPP-4i使用者中有7.3%发生了自杀相关事件（HR：0.660，95%CI：0.473-0.921，p = 0.0145）。SGLT-2i组的全因死亡率也较低（HR：0.594，95%CI：0.451-0.783，p < 0.001）。未观察到DKA或感染等不良事件有显著增加。
在这项真实世界队列研究中，与DPP-4i相比，在患有双相情感障碍和T2DM的个体中，使用SGLT-2i与显著更低的自杀相关事件风险和全因死亡率相关。按年龄、性别、种族、血糖控制（糖化血红蛋白）、肾功能（估算肾小球滤过率）和基线锂使用情况进行分层的亚组分析显示，没有证据表明任何亚组的自杀风险增加。这些发现表明，SGLT-2抑制剂可能对自杀相关结局具有中性至潜在的保护作用。需要进一步的前瞻性研究来证实这些观察结果并探索潜在机制。
