Pioglitazone, a thiazolidinedione used to reduce insulin resistance in patients with type 2 diabetes, was well tolerated in a pilot study of nondiabetic patients with probable Alzheimer’s disease, providing support for continuing studies of this class of drugs in early stages of Alzheimer’s, according to a report published online on Sept. 13 in the Archives of Neurology.
Safety was the primary objective of the study, and while no effects of treatment on clinical efficacy, a secondary outcome, were observed, the authors concluded that “disappointing results of treatment trials based on the amyloid hypothesis, and the reasonable degree of safety identified in this trial, suggest that exploratory studies of thiazolidinediones remain warranted.” The lead author was Dr. David Geldmacher, of the University of Virginia, Charlottesville, one of the two study sites.
In the double-blind, placebo-controlled study, 29 patients who met the criteria for probable Alzheimer’s disease (AD) were randomized to receive pioglitazone, titrated to 45 mg/day, or placebo, plus 100 IU vitamin E daily, for 18 months, between 2001 and 2004. They continued treatment with cholinesterase inhibitors; 20%-27% of the patients also received memantine, once it became available.
Pioglitazone, marketed as Actos as a treatment for type 2 diabetes, is a potent inhibitor of peroxisome proliferator–activated receptor gamma (PPARg), a nuclear receptor that that regulates glucose and lipid metabolism, which are abnormal in AD. This is a “potential therapeutic target for the treatment of AD,” because PPARg activation “robustly suppresses inflammation as well as expression of cytokines and other inflammatory mediators associated with activated microglia,” they said, noting that that, “a local microglia-mediated inflammatory response centers on the amyloid plaques in the AD brain.”
They referred to some evidence that rosiglitazone, another thiazolidinedione, had “limited efficacy,” in patients with early AD, but the results were mixed. This was the first study of pioglitazone in patients with AD, they said.
In the study, almost 29% of those on pioglitazone developed peripheral edema, a known adverse effect associated with pioglitazone, compared with none of the patients on placebo. But otherwise, there were no serious adverse events, and the drug was well tolerated, with “no pattern of effect on blood glucose levels, hemoglobin A1c levels, or other blood chemistry or hematologic measures,” they said (Arch. Neurol. 2010 Sept. 13 [doi:10.1001/archneurol.2010.229]).
As expected, because of the small size of the study, “no significant effect of treatment was observed on any clinical outcome measures,” which included measures of cognition and activities of daily living, the authors said.
The authors recommended that future studies of these agents should focus on earlier stages of disease and “be augmented by biomarkers, such as nuclear imaging techniques, to measure changes in microglial activation associated with treatment.” They noted that these studies will need to closely monitor patients for peripheral edema and other cardiovascular morbidities.
The study was supported by the National Institute of Aging. Pioglitazone manufacturer Takeda Pharmaceuticals North America provided the pioglitazone and placebo tablets free of charge but had no other role in the conduct or analysis of the study. Two of the four authors have received consulting fees from Takeda and consulting fees and research support from GlaxoSmithKline. One of the study sites, Case Western Reserve University, Cleveland, has a patent for the use of pioglitazone in the treatment of AD and other CNS disorders.
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根据9月13日在线发表于《神经病学纪要》(Archives of Neurology)的一篇报告，在一项对非糖尿病、疑似阿尔茨海默病(AD）患者的初步研究中，用于减少II型糖尿病患者胰岛素抵抗的噻唑烷二酮类药物匹格列酮耐受性良好，该结果为该类药物用于AD早期治疗的继续研究提供了依据。
本项研究的首要目的是安全性，而作为次要指标的临床疗效并未观察到。主要作者David Geldmacher博士来自研究基地之一的弗吉尼亚大学。
在2001年至2004年间进行的该项双盲、安慰剂对照研究中，29位符合疑似AD标准的患者随机接受匹格列酮(调整剂量至45mg/天)或安慰剂，每天加服100 IU维生素E，持续时间为18个月。他们仍继续服用胆碱酯酶抑制剂，20%~27%的患者还在美金刚上市后服用该药物。
以商品名Actos销售的匹格列酮为II型糖尿病治疗药物，是过氧化物酶体增殖物激活受体γ(PPARg)强效抑制剂。PPARg属于一种调节葡萄糖和脂质代谢的核受体，在AD患者体内表达异常。作者指出，PPARg为“AD可能的治疗靶位”，并称该研究是匹格列酮针对AD患者的首次研究。
在该项研究中，接近29%的接受匹格列酮的患者出现了已知与该药物有关的外周水肿不良反应，而安慰剂组未见该不良反应。但除此之外，未见其他严重不良事件，药物耐受性良好，并且“未见对所检测的血糖水平、糖化血红蛋白A1c水平或其他血液生化或血液学参数的影响。” (Arch. Neurol. 2010 Sept. 13 [doi:10.1001/archneurol.2010.229])。
作者称，正如所料，由于研究规模较小，“所有检测的临床指标均未见显著疗效差异”，指标包括认知功能和日常生活活动能力。
作者建议，该类药物的进一步研究应侧重于疾病早期阶段，并且“应增加生物标记物检测，例如应用核磁技术检测与治疗有关的小胶质细胞活化的变化。”他们指出，这些研究将需要密切监测患者外周水肿和其他心血管疾病的发病率。
该研究为美国老年研究所资助项目。匹格列酮制造商北美武田制药免费提供匹格列酮和安慰剂，但未参与研究实施和分析。四位作者中的两位接受了武田制药的咨询费和葛兰素史克制药的咨询费和研究经费。该研究的基地之一、克里夫兰的凯斯西储大学拥有一项有关匹格列酮用于治疗AD和其他中枢神经系统疾病的专利。
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