Study of Metformin to reduce Cerebrovascular Dysfunction in South African patients with HIV and Metabolic Syndrome: A Phase II Pilot Trial. SMART

项目摘要 代谢综合征(METS)是心血管疾病和2型糖尿病的一系列危险因素 经常同时发生的糖尿病。METS的后果超出了增加的风险 血管代谢性疾病。越来越多的数据显示，甲硫氨酸和脑小血管之间存在因果关系 疾病。METS与血管性痴呆的发病率增加以及从轻度进展相关 认知障碍导致痴呆症。蛋氨酸引起内皮功能障碍和低水平的脂肪炎症 组织。蛋氨酸相关的内皮功能障碍与肥胖状态无关，随着肥胖人数的增加 甲硫氨酸转运蛋白异常与更多的内皮功能障碍相关。大脑中动脉硬化伴受损 血流与更高的Mets评分有关。 更容易获得有效的联合抗逆转录病毒治疗(CART)，提高了患者的预期寿命 艾滋病毒携带者(PLWH)人数大幅增加。然而，长寿带来了独特的健康挑战，其中之一是 包括甲型肝炎在内的非传染性疾病的发展。来自撒哈拉以南非洲的新兴数据 这表明，与艾滋病毒阴性的同龄人相比，PLWH中METs的患病率更高。这个 预计甲胎蛋白在PLWH中的发病率将会增加。腹型肥胖在PLWH中达到了令人担忧的比例 在撒哈拉以南非洲，使用购物车，其流行率与高收入国家相似。抗逆转录病毒 方案与更高的紧急治疗METs相关。鉴于艾滋病毒阳性人口不断增长， 鉴于甲型肝炎和艾滋病毒都是慢性炎症性疾病，迫切需要确定 有效和负担得起的药物疗法，解决血管疾病的可修改方面。 二甲双胍已被证明通过抑制几种炎症分子来影响内皮细胞。引航员 临床试验数据支持二甲双胍显著改善内皮功能，即使在短期治疗中也是如此。 二甲双胍是一种低成本、广为人知的药物，用于治疗糖尿病患者的血糖稳态异常。 患有2型糖尿病的人。二甲双胍在公共服务机构中广泛使用，被认为具有 降糖以外的临床效果。基于以上的理论基础，我们建议研究二甲双胍在HIV- 被标准护理车病毒抑制的METS阳性参与者接受开放标签 以评价其对脑血管功能的影响。 这项在PLWH和METS中进行的初步研究的目的是获得关于二甲双胍对糖尿病患者的影响的初步数据 使用非侵入性神经成像生物标志物的脑血管功能。此外，我们将检验这一假设 二甲双胍在一定程度上通过内皮调节调节脑血管改变。 将与成像相关的内皮功能和可溶性标记物的综合小组 指标。这项研究的结果将成为未来临床试验的基础，该临床试验将评估有益的效果 二甲双胍在减轻PLWH患者脑部小血管疾病负担中的作用

Project Summary Metabolic syndrome (MetS) is a constellation of risk factors for cardiovascular disease and type 2 diabetes mellitus which frequently occur together. The consequences of MetS extend beyond the increased risk of vascular-metabolic disease. Data is emerging suggesting causality between MetS and cerebral small vessel disease. MetS is associated with an increased incidence of vascular dementia and progression from mild cognitive impairment to dementia. MetS cause endothelial dysfunction and low-level inflammation of adipose tissue. MetS-associated endothelial dysfunction is independent of obesity status with an increased number of MetS abnormalities correlating with more endothelial dysfunction. Middle cerebral artery stiffening with impaired blood flow is associated with a higher MetS score. Enhanced access to effective combination antiretroviral therapy (cART) improved the life expectancy of people living with HIV (PLWH) substantially. Longevity, however, presents unique health challenges, one being the development of non-communicable diseases including MetS. Emerging data from sub-Saharan Africa indicate a higher prevalence of MetS among PLWH compared with their HIV-negative counterparts. The incidence of MetS in PLWH is predicted to increase. Abdominal obesity is reaching alarming proportions in PLWH in sub-Saharan Africa on cART with the prevalence similar to that of high-income countries. Antiretroviral regimens were associated with higher treatment-emergent MetS. Given the growing HIV-positive population with MetS, and that both MetS and HIV are chronic inflammatory conditions, there is an urgent need to identify effective and affordable pharmacotherapy that addresses modifiable aspects of vascular disease. Metformin has been shown to affect endothelial cells by inhibiting several inflammatory molecules. Pilot clinical trial data support that metformin significantly improves endothelial function, even in short-term treatment. Metformin is a low-cost and well-known drug used for the management of abnormal glucose homeostasis in people with type 2 diabetes. Metformin is widely available in public service settings and is considered to have a clinical effect beyond glucose lowering. Based on the rationale above, we propose to study metformin in HIV- positive participants with MetS who are virologically suppressed by standard of care cART to receive open-label metformin to assess its effect on cerebrovascular function. The purpose of this pilot study in PLWH with MetS is to obtain preliminary data on the effect of metformin on cerebrovascular function using non-invasive neuroimaging biomarkers. Furthermore, we will test the hypothesis that metformin mediates the cerebrovascular changes in part via endothelial regulation by using a comprehensive panel of endothelial functional and soluble markers which will be correlated with the imaging metrics. The results of the study will form the basis for a future clinical trial that will assess the beneficial effect of metformin in reducing the burden of cerebral small vessel disease in PLWH.