Objective To compare the risk of dementia associated with sodium-glucose cotransporter-2 (SGLT-2) inhibitors versus dipeptidyl peptidase-4 (DPP-4) inhibitors in adults aged 40-69 years with type 2 diabetes. Design Population based cohort study. Setting Korean National Health Insurance Service data, 2013-21. Participants 110 885 propensity score matched pairs of adults with type 2 diabetes aged 40-69 years who were initiators of either an SGLT-2 inhibitor or a DPP-4 inhibitor. Main outcome measures The primary outcome was new onset dementia. Secondary outcomes were dementia requiring drug treatment and individual types of dementia, including Alzheimer’s disease and vascular dementia. Control outcomes were genital infections (positive), and osteoarthritis related clinical encounters and cataract surgery (negative). Hazard ratios and 95% confidence intervals (CIs) were estimated using Cox models. Follow-up time stratified analyses (>2 years and ≤2 years) and subgroup analyses by age, sex, concomitant use of metformin, and baseline cardiovascular risk were performed. Results 110 885 propensity score matched pairs of initiators of an SGLT-2 inhibitor or a DPP-4 inhibitor were followed-up for a mean 670 (standard deviation 650) days, generating 1172 people with newly diagnosed dementia: incidence rate 0.22 per 100 person years in initiators of SGLT-2 inhibitors and 0.35 per 100 person years in initiators of DPP-4 inhibitors, with hazard ratios of 0.65 (95% CI 0.58 to 0.73) for dementia, 0.54 (0.46 to 0.63) for dementia requiring drugs, 0.61 (0.53 to 0.69) for Alzheimer’s disease, and 0.48 (0.33 to 0.70) for vascular dementia. The hazard ratios for the control outcomes were 2.67 (2.57 to 2.77) for genital infections, 0.97 (0.95 to 0.98) for osteoarthritis related encounters, and 0.92 (0.89 to 0.96) for cataract surgery. When calibrated for residual confounding measured by cataract surgery, the hazard ratio for dementia was 0.70 (0.62 to 0.80). The association was greater for more than two years of treatment (hazard ratio of dementia 0.57, 95% CI 0.46 to 0.70) than for two years or less (0.52, 0.41 to 0.66) and persisted across subgroups. Conclusion SGLT-2 inhibitors might prevent dementia, providing greater benefits with longer treatment. As this study was observational and therefore prone to residual confounding and informative censoring, the effect size could have been overestimated. Randomised controlled trials are needed to confirm these findings. Patient level data are not publicly allowed according to data use agreement. Aggregate level data can be requested from the corresponding author.

中文翻译：

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40-69 岁 2 型糖尿病成人开始使用钠-葡萄糖协同转运蛋白 2 抑制剂与二肽基肽酶 4 抑制剂后发生痴呆的风险：基于人群的队列研究


目的 比较 40-69 岁 2 型糖尿病成人中钠-葡萄糖协同转运蛋白 2 (SGLT-2) 抑制剂与二肽基肽酶 4 (DPP-4) 抑制剂相关的痴呆风险。设计基于人群的队列研究。设置韩国国民健康保险服务数据，2013-21。参与者 110 885 倾向评分匹配了一对年龄为 40-69 岁的 2 型糖尿病成人，他们是 SGLT-2 抑制剂或 DPP-4 抑制剂的起始者。主要结局指标 主要结局是新发痴呆。次要结局是需要药物治疗的痴呆症和个别类型的痴呆症，包括阿尔茨海默病和血管性痴呆。对照结果是生殖器感染（阳性）、骨关节炎相关的临床经历和白内障手术（阴性）。使用 Cox 模型估计风险比和 95% 置信区间 (CI)。按年龄、性别、二甲双胍的同时使用和基线心血管风险进行随访时间分层分析（>2 年和≤2 年）和亚组分析。结果 对 110 885 组配对的 SGLT-2 抑制剂或 DPP-4 抑制剂起始剂进行了平均 670 天（标准差 650）天的随访，产生了 1172 名新诊断的痴呆症患者：发病率为每 100 人 0.22 人SGLT-2 抑制剂起始者每 100 人年为 0.35 年，DPP-4 抑制剂起始者每 100 人年为 0.35 年，痴呆症风险比为 0.65（95% CI 0.58 至 0.73），需要药物治疗的痴呆症为 0.54（95% CI 0.46 至 0.63），0.61阿尔茨海默病为 0.53 至 0.69，血管性痴呆为 0.48（0.33 至 0.70）。生殖器感染的对照结果的风险比为 2.67（2.57 至 2.77），0.97（0.95 至 0.97）。98）对于骨关节炎相关的遭遇，以及0.92（0.89至0.96）对于白内障手术。当针对白内障手术测量的残留混杂因素进行校准时，痴呆症的风险比为 0.70（0.62 至 0.80）。治疗两年以上的相关性（痴呆风险比为 0.57，95% CI 0.46 至 0.70）比治疗两年或更短的时间（0.52，0.41 至 0.66）更大，并且在各个亚组中持续存在。结论 SGLT-2 抑制剂可以预防痴呆，并通过长期治疗提供更大的益处。由于这项研究是观察性的，因此容易出现残留混杂和信息审查，因此效应大小可能被高估。需要随机对照试验来证实这些发现。根据数据使用协议，患者级别的数据不允许公开。可以向相应作者索取聚合级别数据。