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

二甲双胍减少南非艾滋病毒和代谢综合征患者脑血管功能障碍的研究：II 期试点试验。

• 批准号: 10463837
• 负责人: Eric Hermann Decloedt
• 金额: $ 14.58万
• 依托单位: STELLENBOSCH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-11 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10463837
• 关键词: Address; Adipose tissue; Affect; Africa South of the Sahara; Anti-Retroviral Agents; Arginine; Biological Markers; Blood Vessels; Blood flow; Brain Diseases; CCL2 gene; Cardiovascular Diseases; Central obesity; Cerebral small vessel disease; Cerebrovascular Circulation; Cerebrovascular Disorders; Chronic; Clinical; Clinical Trials; Collaborations; Country; Data; Dementia; Development; Diagnosis; Drug usage; Endothelial Cells; Endothelium; Etiology; Fingers; Future; Glucose; Goals; Guidelines; HIV; HIV Seronegativity; HIV Seropositivity; Health; High Density Lipoprotein Cholesterol; High Prevalence; Hypertriglyceridemia; Image; Impairment; Incidence; Income; Individual; Inflammation; Inflammatory; Institution; Intercellular adhesion molecule 1; Interleukin-8; International; Life Expectancy; Longevity; Measures; Mediating; Memory; Meta-Analysis; Metabolic; Metabolic Diseases; Metabolic syndrome; Metformin; NF-kappa B; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Participant; Patients; Performance; Peripheral; Persons; Pharmaceutical Preparations; Pharmacotherapy; Phase; Pilot Projects; Plasma; Polycystic Ovary Syndrome; Population; Prevalence; Regimen; Regulation; Research; Risk; Service setting; South Africa; South African; Testing; Training; Tumor necrosis factor receptor 11b; Universities; Vascular Dementia; Vascular Diseases; antiretroviral therapy; arterial spin labeling; arterial stiffness; arterial tonometry; base; blood glucose regulation; blood pressure elevation; brachial artery; cardiovascular risk factor; cerebrovascular; clinical effect; cost; endothelial dysfunction; fasting glucose; hazard; high risk; improved; indexing; lipoprotein-associated phospholipase A(2); low and middle-income countries; middle cerebral artery; mild cognitive impairment; neuroimaging; neuroimaging marker; novel; open label; p65; pilot trial; reactive hyperemia; standard of care; waist circumference; white matter

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.

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 经常一起发生的疾病。代谢综合征的后果不仅仅是增加了 血管代谢疾病数据表明MetS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痴呆进展至轻度痴呆相关。 认知障碍到痴呆症。MetS引起内皮功能障碍和脂肪组织低水平炎症 组织.代谢综合征相关的内皮功能障碍与肥胖状态无关， MetS异常与更多内皮功能障碍相关。大脑中动脉硬化 血流量与较高的MetS评分相关。 增加获得有效的抗逆转录病毒联合疗法的机会， 艾滋病毒感染者（PLWH）。然而，长寿带来了独特的健康挑战，其中之一是 包括代谢综合征在内的非传染性疾病的发展。来自撒哈拉以南非洲的新数据 表明与艾滋病毒阴性者相比，艾滋病毒感染者中代谢综合征的患病率更高。的 预计PLWH中MetS的发病率会增加。腹部肥胖在PLWH中达到了惊人的比例 在撒哈拉以南非洲，cART的流行率与高收入国家相似。抗病毒 治疗方案与较高的治疗后出现的MetS相关。鉴于艾滋病毒阳性人口不断增加， MetS，MetS和HIV都是慢性炎症性疾病，因此迫切需要确定 有效和负担得起的药物治疗，解决血管疾病的可改变方面。 已显示二甲双胍通过抑制几种炎性分子来影响内皮细胞。试点 临床试验数据支持二甲双胍即使在短期治疗中也能显著改善内皮功能。 二甲双胍是一种低成本和众所周知的药物，用于治疗糖尿病患者的异常葡萄糖稳态。 2型糖尿病患者Metalloy在公共服务环境中广泛使用，并被认为具有 除降糖外的临床效果。基于上述基本原理，我们建议在HIV-1患者中研究二甲双胍。 接受开放标签cART标准治疗的病毒学抑制的MetS阳性受试者 二甲双胍，以评估其对脑血管功能的影响。 这项在PLWH伴MetS患者中进行的初步研究的目的是获得二甲双胍对 使用非侵入性神经成像生物标志物评估脑血管功能。此外，我们将测试假设 二甲双胍部分通过内皮调节介导脑血管变化， 与成像相关的内皮功能和可溶性标志物的综合面板 指标.这项研究的结果将成为未来临床试验的基础，该试验将评估有益效果。 二甲双胍在降低PLWH患者脑小血管疾病负担方面的作用。