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: 10295849
• 负责人: Eric Hermann Decloedt
• 金额: $ 15.65万
• 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 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10295849
• 关键词: Address; Adipose tissue; Affect; Africa South of the Sahara; Anti-Retroviral Agents; Arginine; Biological Markers; Blood Pressure; 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; Pharmaceutical Preparations; Pharmacotherapy; Phase; Pilot Projects; Plasma; Polycystic Ovary Syndrome; Population; Prevalence; Regimen; Regulation; Research; Risk; Service setting; South Africa; South African; Spin Labels; Testing; Training; Tumor necrosis factor receptor 11b; Universities; Vascular Dementia; Vascular Diseases; antiretroviral therapy; arterial stiffness; arterial tonometry; base; blood glucose regulation; 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; virology; 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.

项目概要 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 常同时发生。 MetS 的后果不仅仅是增加风险 血管代谢疾病。不断出现的数据表明 MetS 与脑小血管之间存在因果关系 疾病。 MetS 与血管性痴呆发病率增加以及轻度进展相关 认知障碍导致痴呆。 MetS 导致内皮功能障碍和脂肪低水平炎症 组织。 MetS 相关的内皮功能障碍与肥胖状态无关，随着肥胖数量的增加 MetS 异常与更多的内皮功能障碍相关。大脑中动脉硬化并受损 血流量与较高的 MetS 评分相关。 增加获得有效联合抗逆转录病毒疗法（cART）的机会，提高了患者的预期寿命 艾滋病毒感染者（PLWH）的数量很大。然而，长寿带来了独特的健康挑战，其中之一是 包括 MetS 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 HIV 阴性人群相比，PLWH 中 MetS 的患病率更高。这 预计 PLWH 中 MetS 的发生率将会增加。感染者腹部肥胖的比例已达到惊人的程度 撒哈拉以南非洲地区 cART 的流行率与高收入国家相似。抗逆转录病毒 治疗方案与较高的治疗出现的 MetS 相关。鉴于艾滋病病毒感染者人数不断增加 MetS，并且 MetS 和 HIV 都是慢性炎症性疾病，迫切需要确定 有效且负担得起的药物疗法，可解决血管疾病的可改变方面。 二甲双胍已被证明可以通过抑制多种炎症分子来影响内皮细胞。飞行员 临床试验数据支持二甲双胍显着改善内皮功能，即使在短期治疗中也是如此。 二甲双胍是一种低成本且众所周知的药物，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，并被认为具有 临床效果超出降糖范围。基于上述理由，我们建议研究二甲双胍治疗 HIV- 通过标准护理 cART 进行病毒学抑制的 MetS 阳性参与者将接受开放标签治疗 二甲双胍评估其对脑血管功能的影响。 这项针对患有 MetS 的 PLWH 的试点研究的目的是获得有关二甲双胍对 MetS 的影响的初步数据。 使用非侵入性神经影像生物标志物评估脑血管功能。此外，我们将检验假设 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记物的综合面板 指标。研究结果将为未来评估有益效果的临床试验奠定基础 二甲双胍减轻PLWH脑小血管疾病负担的作用。