Brauer Ruth, Bhaskaran Krishnan, Chaturvedi Nishi, Dexter David T, Smeeth Liam, Douglas Ian
Non-communicable Disease Epidemiology, London School of Hygiene & Tropical Medicine, London, United Kingdom.
Institute of Cardiovascular Sciences, University College London, London, United Kingdom.
PLoS Med. 2015 Jul 21;12(7):e1001854. doi: 10.1371/journal.pmed.1001854. eCollection 2015 Jul.
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.
近期的体外和动物实验表明，过氧化物酶体增殖物激活受体γ（PPARɣ）激动剂药物，如抗糖尿病的格列酮（GTZ）类药物，在帕金森病（PD）模型中具有神经保护作用。这些发现尚未在人体中得到验证。我们推测，与使用其他糖尿病治疗药物的个体相比，使用GTZ药物的个体患PD的发病率更低。
利用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，将新使用GTZ的糖尿病患者（GTZ暴露组）与年龄、性别、医疗机构及糖尿病治疗阶段相匹配的最多5名使用其他糖尿病治疗药物的个体（其他抗糖尿病药物暴露组）进行配对。对患者从1999年开始随访，直至首次记录到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），并对可能的混杂因素进行调整。44597名GTZ暴露个体与120373名其他抗糖尿病药物使用者进行了匹配。175名GTZ暴露个体被诊断为PD，而其他抗糖尿病药物暴露组有517名个体被诊断为PD。GTZ暴露组的PD发病率为每10000患者年6.4例，而使用其他抗糖尿病治疗药物的个体为每10000患者年8.8例（IRR 0.72，95%置信区间[CI] 0.60 - 0.87）。对包括吸烟、其他药物、头部损伤和疾病严重程度等潜在混杂变量进行调整后，没有实质性影响（完全调整后的IRR 0.75，0.59 - 0.94）。当前使用GTZ处方的个体风险降低（当前GTZ暴露组IRR 0.59，0.46 - 0.77），但既往使用过GTZ处方的个体风险未降低（既往GTZ暴露组IRR 0.85，0.65 - 1.10）。我们的研究仅纳入了首次使用GTZ时未诊断为PD的糖尿病患者，因此，无法确定使用GTZ是否能预防或减缓PD的进展。
在糖尿病患者中，当前使用GTZ处方与PD发病率降低相关。这表明PPARγ通路可能是PD中一个有效的药物靶点。
