Health Services Research & Pharmacoepidemiology Unit, Foundation for the Promotion of Health and Biomedical Research of Valencia Region, Fisabio, Valencia, Spain.
Spanish Network for Research on Chronicity, Primary Care, and Health Promotion (RICAPPS), Valencia, Spain.
Diabetologia. 2024 Nov;67(11):2471-2480. doi: 10.1007/s00125-024-06243-z. Epub 2024 Aug 6.
AIMS/HYPOTHESIS: Regulators worldwide are reviewing safety data on glucagon-like peptide-1 receptor agonists (GLP-1RA), following reports by the Icelandic Medicines Agency in July 2023 of suicidal ideation and self-injury (SIS) in individuals taking liraglutide and semaglutide. We aimed to assess the risk of SIS in new users of GLP-1RA when compared with sodium-glucose cotransporter 2 inhibitors (SGLT-2i) users, prescribed to treat type 2 diabetes in individuals with obesity.
This is a cohort study combining several population-wide databases and covering a Spanish population of five million inhabitants, including all adults with obesity who initiated treatment with either GLP-1RA or SGLT-2i for type 2 diabetes from 2015 to 2021. To estimate the comparative effect of GLP-1RA on the risk of SIS, we employed a new user, active comparator design and we carried out multivariable Cox regression modelling with inverse probability of treatment weighting (IPTW) based on propensity scores. We performed several stratified and sensitivity analyses.
We included 3040 patients initiating treatment with GLP-1RA and 11,627 with SGLT-2i. When compared with patients treated with SGLT-2i, those in the GLP-1RA group were younger (55 vs 60 years old, p<0.001), had more anxiety (49.4% vs 41.5%, p<0.001), sleep disorders (43.2% vs 34.1%, p<0.001) and depression (24.4% vs 19.0%, p<0.001), and were more obese (35.1% of individuals with BMI ≥40 vs 15.1%, p<0.001). After propensity score weighting, standardised mean differences between groups were <0.1 for all covariates, showing adequate balance between groups at baseline after adjustment. In the main per-protocol analyses we found no evidence that GLP-1RA increased the incidence of SIS (HR 1.04; 95% CI 0.35, 3.14). Intention-to-treat analyses resulted in an HR of 1.36 (95% CI 0.51, 3.61). In analyses excluding individuals with no BMI information and using imputation for BMI missing values, respective HRs were 0.89 (95% CI 0.26, 3.14) and 1.29 (95% CI 0.42, 3.92). Stratified analyses showed no differences between subgroups.
CONCLUSIONS/INTERPRETATION: Our findings do not support an increased risk of SIS when taking GLP-1RA in individuals with type 2 diabetes and obesity; however, the rarity of SIS events and the wide uncertainty of effect size (although null, effect may be compatible with a risk as high as threefold) calls for a cautious interpretation of our results. Further studies, including final evaluations from regulatory bodies, are called for to discard a causal link between GLP-1RA and suicidality.
目的/假设：继 2023 年 7 月冰岛药品管理局报告利拉鲁肽和司美格鲁肽使用者出现自杀意念和自伤（SIS）后，全球监管机构正在审查胰高血糖素样肽-1 受体激动剂（GLP-1RA）的安全性数据。我们旨在评估新使用 GLP-1RA 的患者与钠-葡萄糖共转运蛋白 2 抑制剂（SGLT-2i）使用者相比，治疗肥胖 2 型糖尿病患者的 SIS 风险。
这是一项队列研究，结合了多个人群数据库，涵盖了西班牙 500 万居民的人群，包括所有在 2015 年至 2021 年间因 2 型糖尿病开始接受 GLP-1RA 或 SGLT-2i 治疗的肥胖成年人。为了估计 GLP-1RA 对 SIS 风险的影响，我们采用了新使用者、活性对照设计，并根据倾向评分进行了多变量 Cox 回归建模。我们进行了几次分层和敏感性分析。
我们纳入了 3040 名开始接受 GLP-1RA 治疗的患者和 11627 名开始接受 SGLT-2i 治疗的患者。与接受 SGLT-2i 治疗的患者相比，GLP-1RA 组的患者年龄更小（55 岁 vs 60 岁，p<0.001），焦虑症（49.4% vs 41.5%，p<0.001）、睡眠障碍（43.2% vs 34.1%，p<0.001）和抑郁症（24.4% vs 19.0%，p<0.001）更为常见，且肥胖程度更高（35.1%的 BMI≥40 的个体 vs 15.1%，p<0.001）。在进行倾向评分加权后，两组之间的标准化平均差异<0.1，表明在调整后基线时两组之间具有足够的平衡。在主要的按方案分析中，我们没有发现 GLP-1RA 增加 SIS 发生率的证据（HR 1.04；95%CI 0.35，3.14）。意向治疗分析得出的 HR 为 1.36（95%CI 0.51，3.61）。在排除无 BMI 信息的个体和使用 BMI 缺失值的插补分析中，相应的 HR 分别为 0.89（95%CI 0.26，3.14）和 1.29（95%CI 0.42，3.92）。分层分析显示各亚组之间无差异。
结论/解释：我们的研究结果不支持 2 型糖尿病和肥胖患者使用 GLP-1RA 会增加 SIS 的风险；然而，SIS 事件的罕见性和效应大小的广泛不确定性（尽管为零，但效应可能与三倍的风险相兼容）要求我们谨慎解释我们的结果。需要进一步的研究，包括监管机构的最终评估，以排除 GLP-1RA 与自杀之间的因果关系。
