A Big Data Research Study on the Relationship Between Metformin Use and Dementia

痴呆症是一种与衰老相关的常见且令人非常恐惧的疾病。在美国， 到2050年，痴呆症患病率预计将增加近两倍，达到1300万人。2型糖尿病 糖尿病(T2 DM)是痴呆症的危险因素，也在迅速增加。新出现的数据表明，一线治疗 对于T2 DM，二甲双胍可能会降低痴呆的风险。在动物模型中，二甲双胍改善记忆和 似乎可以预防痴呆症。如果这一发现在人类身上得到证实，它可能会为临床决策提供依据。 包括在糖尿病病程的早期多久开始使用二甲双胍，以及在什么时候是否继续使用二甲双胍 患者过渡到使用胰岛素。然而，缺乏确凿的数据。随机对照试验(RCT)有 没有进行二甲双胍是否能预防人类痴呆症的研究。现在这样做还为时过早 考虑到文献的现状以及所需的高成本和长时间的后续工作，进行一次随机对照试验。 现有观察性研究的不一致结果可能是由于对混淆的控制不足所致。 目前的提案使用了来自退伍军人健康中心的丰富的电子健康数据资源 管理(VA)和团体健康(GH)，这是美国西北部的一个综合医疗系统， 对二甲双胍的使用和事件之间的关联进行严格的回溯性队列研究 痴呆症。我们将使用电子健康记录(EHR)来识别大约100,000名退伍军人患者和 20,000名患有T2 DM且无痴呆且未服用糖尿病药物的GH患者。 我们将使用新的用户设计和最先进的分析方法，包括倾向性评分和反转 控制包括糖尿病严重程度在内的潜在混杂因素的治疗权重的概率。这个 较长的观察期(退伍军人事务部17年，乔治亚州20年)将确保充足的电力。丰富的电子病历数据 包括诊断、程序、实验室和生命体征措施将使我们能够控制许多 潜在的混杂因素，如血红蛋白A1c水平，内科和精神科合并症，以及 伴随药物的使用。初步分析将使用VA数据，并将使用 GH数据；在两个独特的大型医疗保健系统中独立复制将提高我们的 调查结果。我们将解决以下具体目标：1.比较服用二甲双胍的人患痴呆症的风险 对于T2 DM和那些启动磺脲类药物。2.比较服用二甲双胍与服用二甲双胍的患者患痴呆症的风险。 那些推迟最初药物治疗的人，3.确定二甲双胍-痴呆症的关联性是否因 按性别划分的年龄组(50-65岁与65岁)。探索性分析将调查二甲双胍的剂量 以及痴呆症的持续时间和风险。通过使用相同的措施和方法在非常 不同的患者群体，我们将产生迄今为止关于二甲双胍潜在的最有力的证据 降低患痴呆症的风险。结果将为提供者和患者之间关于二甲双胍使用的讨论提供信息，并可能指导 设计一种后续的、有效的随机对照试验，目标是最有可能受益于二甲双胍的人。

Dementia is a common and greatly feared condition associated with aging. In the United States, the prevalence of dementia is expected to nearly triple to 13 million persons by 2050. Type 2 diabetes mellitus (T2DM), a risk factor for dementia, is also rapidly increasing. Emerging data suggests the first line treatment for T2DM, metformin, may decrease dementia risk. In animal models, metformin improves memory and appears to protect against dementia. If this finding is established in humans, it could inform clinical decisions including how early in the course of diabetes to initiate metformin and whether to continue metformin when patients transition to insulin. However, definitive data are lacking. Randomized controlled trials (RCTs) have not been conducted to study whether metformin prevents dementia in humans. It would be premature to conduct an RCT given the current state of the literature and the high cost and long follow-up time required. Inconsistent results from extant observational studies may be due to inadequate control for confounding. The current proposal uses rich electronic health data resources from the Veterans Health Administration (VA) and Group Health (GH), an integrated healthcare system in the Northwest United States, to conduct a rigorous retrospective cohort study of the association between metformin use and incident dementia. We will use electronic health records (EHR) to identify a cohort of about 100,000 VA patients and 20,000 GH patients who have T2DM and are free of dementia and not taking diabetes medications at baseline. We will use a new user design and state of the art analytic methods including propensity scores and inverse probability of treatment weighting to control for potential confounding factors including diabetes severity. The long observation periods (17 years in VA and 20 years in GH) will ensure adequate power. The rich EHR data including diagnoses, procedures, laboratory and vital signs measures will enable us to control for many potential confounding factors such as hemoglobin A1c levels, medical and psychiatric comorbidities, and the use of concomitant medications. The primary analysis will use VA data, and findings will be replicated using GH data; independent replication in two unique large healthcare systems will improve the validity of our findings. We will address the following specific aims: 1. Compare risk of dementia in people initiating metformin for T2DM versus those initiating a sulfonylurea. 2. Compare risk of dementia in people initiating metformin vs. those delaying initial pharmacologic therapy, 3. Determine if the metformin – dementia association varies by age groups (50-65 vs. >65 years of age) and by gender. Exploratory analysis will investigate metformin dose and duration and risk of dementia. By using the same measures and methods to replicate results in very different patient populations, we will generate the strongest evidence to date regarding metformin’s potential to reduce risk of dementia. Results will inform provider-patient discussions about metformin use and could guide design of a subsequent, efficient RCT that targets people most likely to benefit from metformin.