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型糖尿病的危险因素的星座 经常一起出现的梅利列。大都会的后果超出了增加的风险 血管代谢疾病。数据正在出现，表明大都会和脑小血管之间的因果关系 疾病。 Mets与血管性痴呆的发生率增加和轻度进展有关 痴呆症的认知障碍。 Mets引起内皮功能障碍和脂肪的低水平炎症 组织。与MetS相关的内皮功能障碍独立于肥胖状态，数量增加 MetS异常与更多的内皮功能障碍相关。脑动脉僵硬 血流与较高的METS评分有关。 增强获得有效组合抗逆转录病毒疗法（CART）的机会提高了预期寿命 患有艾滋病毒（PLWH）的人实质上。但是，长寿提出了独特的健康挑战，其中一个是 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兴数据 与HIV阴性同行相比，PLWH中MetS的患病率更高。这 预计PLWH中MetS的发病率将增加。腹部肥胖正在达到PLWH中令人震惊的比例 在撒哈拉以南非洲的购物车中，患病率与高收入国家类似。抗逆转录病毒 方案与较高的治疗生长群有关。鉴于HIV阳性人群的增长 大都会大都会和艾滋病毒都是慢性炎症状况，迫切需要识别 有效且负担得起的药物疗法解决了可修改的血管疾病方面。 二甲双胍已显示通过抑制几种炎症分子来影响内皮细胞。飞行员 临床试验数据支持即使在短期治疗中，二甲双胍也会显着改善内皮功能。 二甲双胍是一种低成本且著名的药物，用于治疗异常葡萄糖稳态。 患有2型糖尿病的人。二甲双胍可在公共服务环境中广泛使用，被认为具有 降低葡萄糖的临床作用。基于上述基本原理，我们建议研究HIV- 积极的参与者，受到标准护理推车在病毒学上抑制的大都会大都会的参与者接受开放标签 二甲双胍评估其对脑血管功能的影响。 这项在PLWH中使用Mets进行的试验研究的目的是获得有关二甲双胍对的初步数据 使用非侵入性神经成像生物标志物的脑血管功能。此外，我们将检验假设 二甲双胍通过使用A的内皮调节来介导脑血管变化 内皮功能和可溶性标记的综合面板将与成像相关 指标。该研究的结果将构成未来临床试验的基础，该试验将评估有益效果 二甲双胍减轻PLWH脑小血管疾病的负担。