Glitazone Treatment and Incidence of Parkinson's Disease among People with Diabetes: A Retrospective Cohort Study.
Glitazone Treatment and Incidence of Parkinson's Disease among People with Diabetes: A Retrospective Cohort Study.
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DOI：
10.1371/journal.pmed.1001854
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发表时间：
2015-07
期刊：
影响因子：
15.8
通讯作者：
Douglas I
中科院分区：
文献类型：
--
作者：
Brauer R;Bhaskaran K;Chaturvedi N;Dexter DT;Smeeth L;Douglas I
最近的体外和动物实验表明，过氧化物酶体增殖激活受体γ (PPAR α)激动剂药物，如抗糖尿病格列酮（GTZ）药物，对帕金森病（PD）模型具有神经保护作用。这些发现尚未在人类身上进行过测试。我们假设，处方GTZ药物的个体与处方其他治疗糖尿病的个体相比，PD的发病率较低。使用来自英国临床实践研究数据链（CPRD）的初级保健数据，我们进行了一项回顾性队列研究，其中新开GTZ的糖尿病患者（GTZ暴露组）按年龄、性别、实践和糖尿病治疗阶段与最多5名开其他糖尿病治疗的患者（其他抗糖尿病药物暴露组）进行匹配。从1999年开始对患者进行随访，直到首次记录PD诊断，数据库观察结束或研究结束（2013年8月1日）。使用条件泊松回归计算发病率比（IRR），并根据可能的混杂因素进行调整。44,597名GTZ暴露者与120,373名其他抗糖尿病使用者相匹配。175名gtz暴露者被诊断为PD，而其他抗糖尿病药物暴露组为517人。gtz暴露组PD发病率（IR）为6.4 / 10,000患者年，而其他抗糖尿病治疗组为8.8 / 10,000患者年（IRR 0.72, 95%可信区间[CI] 0.60-0.87）。调整潜在的混杂变量，包括吸烟、其他药物、头部损伤和疾病严重程度，没有实质性影响（完全调整的IRR为0.75,0.59-0.94）。目前使用GTZ处方的患者的风险降低（当前GTZ暴露的IRR为0.59,0.46-0.77），但过去使用GTZ处方的患者的风险没有降低（过去使用GTZ暴露的IRR为0.85,0.65-1.10）。我们的研究仅包括首次服用GTZ时未被诊断为PD的糖尿病患者，因此无法确定使用GTZ是否可以预防或减缓PD的进展。在糖尿病患者中，目前的GTZ处方与PD发病率的降低有关。这表明PPAR γ通路可能是PD中一个富有成效的药物靶点。在一项回顾性队列研究中，Ruth Brauer及其同事研究了格列酮治疗与帕金森病发病率之间的关系。帕金森病（PD）是一种常见的进行性神经系统疾病。这种情况是由通常产生多巴胺的神经细胞逐渐丧失引起的，多巴胺是一种调节身体运动的神经递质。PD通常直到人们60岁左右才开始发展，尽管它有时会影响年轻人。其症状发展缓慢，包括震颤（手、腿、手臂、下巴和面部颤抖）、动作缓慢和僵硬（肌肉僵硬）。随着这些症状的恶化，受影响的个体可能会出现行走、说话、吞咽和睡眠困难，并可能变得抑郁。目前还没有人找到一种方法来阻止产生多巴胺的神经细胞的丧失，但是替代或模仿失去的多巴胺的药物可以减轻这些症状的严重程度。PD不会直接致人死亡，但它会对身体造成很大的压力，使患者容易受到危及生命的感染。然而，现在许多PD患者的预期寿命正常或接近正常。最近的实验表明，与过氧化物酶体增殖激活受体结合的药物（PPARγ激动剂药物）可能对PD动物模型具有神经保护作用（防止神经细胞丢失）。PPARγ调节身体如何使用脂肪和糖，PPARγ激动剂药物，如罗格列酮和吡格列酮（格列酮[GTZ]药物）用于治疗糖尿病患者，这种疾病的特点是血液中糖含量高。然而，目前尚不清楚GTZ药物是否对人的PD提供保护。在这项回顾性队列研究中，研究人员调查了暴露于GTZ药物的糖尿病患者是否比使用其他降糖药的患者PD发病率更低。一项回顾性队列研究使用已经收集的一组（队列）人的数据来寻找特定特征（如药物使用和结果）之间的关联。研究人员在英国临床实践研究数据链（一个包含超过1300万人的初级保健数据的数据库）中确定了44597名新近接触GTZ药物的糖尿病患者。他们将每名患者与多达5名其他抗糖尿病药物使用者（120,373名对照）进行匹配，这些使用者在年龄，性别，相同的初级保健实践和糖尿病治疗阶段方面相似；糖尿病患者最初通常服用一种药物，但随着病情的发展，通常会转而服用不同的药物或联合用药。最后，研究人员对整个队列进行了随访，从1999年1月开始（当格列酮被引入治疗糖尿病时），直到诊断为PD，数据库结束，或研究结束（2013年8月）。随访期间，175名格列酮使用者和517名非格列酮使用者被诊断为PD。在使用格列酮的个体和使用其他降糖治疗的个体中，PD的发病率分别为6.4 / 10000患者年和8.8 / 10000患者年（发病率比[IRR]为0.72；IRR比较两组人群中疾病新发病例的发生率）。调整潜在的混杂变量（可能影响个体患PD可能性的特征），如吸烟和头部损伤，并没有改变IRR。值得注意的是，目前使用GTZ药物的人患PD的风险降低，而过去使用GTZ药物的人则没有。这些发现表明，在糖尿病患者中，与使用其他抗糖尿病药物相比，目前（但不是过去）使用GTZ与PD临床表现降低28%相关。由于该研究仅包括在开始GTZ治疗时未诊断为PD的糖尿病患者，因此这些研究结果无法确定GTZ的使用是否与PD的预防或疾病进展的减缓有关。此外，这些结果的准确性可能受到PD的误诊和数据库中各种降糖药物暴露期的错误分类以及残留混淆的影响。最后，这些发现可能不适用于没有糖尿病的人。重要的是，研究人员不建议使用GTZ药物（与一些严重的副作用有关）作为PD的治疗方法。相反，他们认为PPARγ参与的途径可能包含潜在的PD药物靶点，应该在未来的研究中进行研究。这个资源列表包含可以在设备上查看PDF时访问的链接，也可以通过http://dx.doi.org/10.1371/journal.pmed.1001854上文章的在线版本访问这些链接。美国国家神经疾病和中风研究所提供PD的详细信息（英语和西班牙语），包括链接到帮助帕金森患者的美国组织英国国家健康服务选择网站提供了帕金森病的各个方面的信息（包括个人故事）英国非营利组织帕金森suk和美国非营利组织国家帕金森基金会也提供了关于帕金森病和个人故事的详细信息英国非营利组织Healthtalk。Org提供PD患者生活的各个方面的故事。MedlinePlus有更多PD资源的链接以及罗格列酮和吡格列酮的信息（英语和西班牙语）。
Recent in vitro and animal experiments suggest that peroxisome proliferation-activated receptor gamma (PPARɣ) agonist medications, such as antidiabetic glitazone (GTZ) drugs, are neuroprotective in models of Parkinson’s disease (PD). These findings have not been tested in humans. We hypothesized that individuals prescribed GTZ drugs would have a lower incidence of PD compared to individuals prescribed other treatments for diabetes. Using primary care data from the United Kingdom Clinical Practice Research Datalink (CPRD), we conducted a retrospective cohort study in which individuals with diabetes who were newly prescribed GTZ (GTZ-exposed group) were matched by age, sex, practice, and diabetes treatment stage with up to five individuals prescribed other diabetes treatments (other antidiabetic drug-exposed group). Patients were followed up from 1999 until the first recording of a PD diagnosis, end of observation in the database, or end of the study (1 August 2013). An incidence rate ratio (IRR) was calculated using conditional Poisson regression, adjusted for possible confounders. 44,597 GTZ exposed individuals were matched to 120,373 other antidiabetic users. 175 GTZ-exposed individuals were diagnosed with PD compared to 517 individuals in the other antidiabetic drug-exposed group. The incidence rate (IR) of PD in the GTZ-exposed group was 6.4 per 10,000 patient years compared with 8.8 per 10,000 patient years in those prescribed other antidiabetic treatments (IRR 0.72, 95% confidence interval [CI] 0.60–0.87). Adjustments for potential confounding variables, including smoking, other medications, head injury, and disease severity, had no material impact (fully adjusted IRR 0.75, 0.59–0.94). The risk was reduced in those with current GTZ prescriptions (current GTZ-exposed IRR 0.59, 0.46–0.77) but not reduced among those with past prescriptions (past GTZ-exposed IRR 0.85, 0.65–1.10). Our study only included patients with diabetes who did not have a PD diagnosis when they were first prescribed GTZ, and thus, it cannot establish whether GTZ use prevents or slows the progression of PD. In patients with diabetes, a current prescription for GTZ is associated with a reduction in incidence of PD. This suggests PPAR gamma pathways may be a fruitful drug target in PD. In a retrospective cohort study, Ruth Brauer and colleagues examine the association between treatment with glitazone and incidence of Parkinson's disease. Parkinson’s disease (PD) is a common, progressive neurological disease. The condition is caused by the gradual loss of nerve cells that normally produce dopamine, a neurotransmitter that regulates the body’s movements. PD does not usually begin to develop until people are around 60 years old, although it can sometimes affect younger people. Its symptoms, which develop slowly, include tremor (trembling of the hands, legs, arm, jaw, and face), slow movement, and rigidity (muscle stiffness). As these symptoms worsen, affected individuals may have trouble walking, speaking, swallowing, and sleeping, and they may become depressed. No one has found a way to halt the loss of dopamine-producing nerve cells yet, but medications that replace or mimic the lost dopamine can reduce the severity of these symptoms. PD does not directly kill people, but it puts a great strain on the body that can make affected individuals vulnerable to life-threatening infections. Nevertheless, these days, many people with PD have a normal or near-normal life expectancy. Recent experiments suggest that drugs that bind to the peroxisome proliferation-activated receptor gamma (PPARγ agonist medications) may be neuroprotective (prevent nerve cell loss) in animal models of PD. PPARγ regulates how the body uses fats and sugars, and PPARγ agonist medications such as rosiglitazone and pioglitazone (glitazone [GTZ] drugs) are used to treat people with diabetes, a condition characterized by high levels of sugar in the blood. It is not known, however, whether GTZ drugs provide protection against PD in people. In this retrospective cohort study, the researchers investigate whether individuals with diabetes exposed to GTZ drugs have a lower incidence of PD than individuals using other antidiabetic drugs. A retrospective cohort study uses data already collected on a group (cohort) of people to look for associations between specific characteristics such as use of a drug and outcomes. The researchers identified 44,597 patients with diabetes who were newly exposed to GTZ drugs in the UK Clinical Practice Research Datalink, a database that contains primary care data on more than 13 million individuals. They matched each patient with up to five users of other antidiabetic drugs (120,373 controls) who were similar in terms of age, sex, attendance at the same primary care practice, and diabetes treatment stage; people with diabetes usually initially take a single drug but often switch to a different drug or to a combination of drugs as their disease progresses. Finally, the researchers followed up the entire cohort from January 1999 (when glitazones were introduced to treat diabetes) until diagnosis of PD, the end of inclusion in the database, or the end of the study (August 2013). During follow up, 175 glitazone users and 517 non-glitazone users were diagnosed with PD. The incidence rates of PD among glitazone-using individuals and among users of other antidiabetic treatments were 6.4 per 10,000 patient years and 8.8 per 10,000 patient years, respectively (an incidence rate ratio [IRR] of 0.72; an IRR compares the rate of occurrence of new cases of a disease in two groups of people). Adjustment for potential confounding variables (characteristics that might affect an individual’s likelihood of developing PD) such as smoking and head injury did not alter the IRR. Notably, the risk of PD was reduced among current users of GTZ drugs but not among past users. These findings indicate that, among people with diabetes, current (but not past) GTZ use is associated with a 28% lower rate of clinical presentation of PD compared to the use of other antidiabetic drugs. Because the study only included patients with diabetes who did not have a PD diagnosis when they started GTZ treatment, these findings cannot establish whether GTZ use is associated with prevention of PD or with slower progression of the disease. Moreover, the accuracy of these findings may be affected by misdiagnosis of PD and misclassification of exposure periods to various antidiabetic drugs in the database and by residual confounding. Finally, these findings may not be applicable to people without diabetes. Importantly, the researchers do not recommend that GTZ drugs (which have been associated with some serious side effects) be used as a treatment for PD. Rather, they suggest that the pathways in which PPARγ is involved might contain potential drug targets for PD and should be investigated in future research. This list of resources contains links that can be accessed when viewing the PDF on a device or via the online version of the article at http://dx.doi.org/10.1371/journal.pmed.1001854. The United States National Institute of Neurological Disorders and Stroke provides detailed information about PD (in English and Spanish), including links to US organizations that help people with PD The UK National Health Service Choices website provides information on all aspects of PD (including personal stories) The UK not-for-profit organization Parkinson'sUK and the US not-for-profit organization National Parkinson Foundation also provide detailed information about PD and personal stories The UK not-for-profit organization Healthtalk.Org provides stories about all aspects of living with PD MedlinePlus has links to further resources about PD and information about rosiglitazone and pioglitazone (in English and Spanish)