Stuve Olaf, Weideman Rick A, McMahan Danni M, Jacob David A, Little Bertis B
Department of Neurology and Neurotherapeutics, University of Texas, Southwestern Medical School, Neurology Section (111H), Dallas VA Medical Center, 4500 Lancaster Road, Dallas, TX 75216, USA.
Pharmacy Service, Dallas VA Medical Center, Dallas, TX, USA.
Ther Adv Neurol Disord. 2020 Jun 25;13:1756286420935676. doi: 10.1177/1756286420935676. eCollection 2020.
Our aim was to determine whether specific nonsteroidal anti-inflammatory (NSAID) agents are associated with a decreased frequency of Alzheimer's disease (AD).
Days of drug exposure were determined for diclofenac, etodolac, and naproxen using US Department of Veterans Affairs (VA) pharmacy transaction records, combined from two separate VA sites. AD diagnosis was established by the International Classification of Diseases, ninth revision (ICD-9)/ICD-10 diagnostic codes and the use of AD medications. Cox regression survival analysis was used to evaluate the association between AD frequency and NSAID exposure over time. Age at the end of the study and the medication-based disease burden index (a comorbidity index) were used as covariates.
Frequency of AD was significantly lower in the diclofenac group (4/1431, 0.28%) compared with etodolac (328/14,646, 2.24%), and naproxen (202/12,203, 1.66%). For regression analyses, naproxen was chosen as the comparator drug, since it has been shown to have no effect on the development of AD. Compared with naproxen, etodolac had no effect on the development of AD, hazard ratio (HR) 1.00 [95% confidence interval (CI): 0.84-1.20, = 0.95]. In contrast, diclofenac had a significantly lower HR of AD compared with naproxen, HR 0.25 (95% CI: 0.09-0.68, <0.01). After site effects were controlled for, age at end of the study (HR = 1.08, 95% CI: 1.07-1.09, <0.001) was also found to influence the development of AD, and the medication-based disease burden index was a strong predictor for AD, HR 5.17 (95% CI: 4.60-5.81) indicating that as comorbidities increase, the risk for AD increases very significantly.
Diclofenac, which has been shown to have active transport into the central nervous system, and which has been shown to lower amyloid beta and interleukin 1 beta, is associated with a significantly lower frequency of AD compared with etodolac and naproxen. These results are compelling, and parallel animal studies of the closely related fenamate NSAID drug class.
我们的目的是确定特定的非甾体抗炎药（NSAID）是否与阿尔茨海默病（AD）发病率降低有关。
利用美国退伍军人事务部（VA）两个不同地点的药房交易记录，确定双氯芬酸、依托度酸和萘普生的用药天数。AD诊断依据国际疾病分类第九版（ICD - 9）/ICD - 10诊断代码以及AD药物的使用情况确定。采用Cox回归生存分析评估AD发病率与NSAID长期暴露之间的关联。将研究结束时的年龄和基于药物的疾病负担指数（一种合并症指数）用作协变量。
双氯芬酸组的AD发病率（4/1431，0.28%）显著低于依托度酸组（328/14646，2.24%）和萘普生组（202/12203，1.66%）。在回归分析中，选择萘普生作为对照药物，因为已证明其对AD的发生没有影响。与萘普生相比，依托度酸对AD的发生没有影响，风险比（HR）为1.00 [95%置信区间（CI）：0.84 - 1.20，P = 0.95]。相比之下，与萘普生相比，双氯芬酸的AD风险比显著更低，HR为0.25（95% CI：0.09 - 0.68，P < 0.01）。在控制了地点效应后，还发现研究结束时的年龄（HR = 1.08，95% CI：1.07 - 1.09，P < 0.001）也会影响AD的发生，并且基于药物的疾病负担指数是AD的一个强预测指标，HR为5.17（95% CI：4.60 - 5.81），这表明随着合并症的增加，AD的风险会显著增加。
双氯芬酸已被证明可主动转运至中枢神经系统，并且已证明其可降低β淀粉样蛋白和白细胞介素1β，与依托度酸和萘普生相比，其AD发病率显著更低。这些结果令人信服，并且与密切相关的芬那酸类NSAID药物的动物研究结果一致。
