Effects of GLP-l receptor agonists on cardiometabolic alterations in HIV-associated lipohypertrophy

GLP-1受体激动剂对HIV相关脂肪肥大心脏代谢改变的影响

• 批准号: 10598535
• 负责人: Allison Ross Eckard
• 金额: $ 74.87万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-10 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10598535
• 关键词: Adipose tissue; Affect; Agonist; Area; Belief; Beta Cell; Body Weight decreased; Cardiovascular Diseases; Cardiovascular system; Cell physiology; Chronic; Clinical; Clinical Trials; Control Groups; Controlled Clinical Trials; Cytokine Activation; Deposition; Desire for food; Diabetes Mellitus; Disease; Double-Blind Method; Drug Interactions; Energy Metabolism; Enrollment; Event; Fatty acid glycerol esters; Functional disorder; GLP-I receptor; General Population; HIV; HIV therapy; HIV-1; Heart; Hepatic; High Prevalence; Hormone secretion; Hormones; Individual; Inflammation; Inflammatory; Insulin Resistance; Integrase Inhibitors; Intervention; Intervention Studies; Link; Liver; Metabolic; Metabolic Diseases; Mitochondria; Obesity; Participant; Pericardial body location; Peripheral; Personal Satisfaction; Persons; Pharmaceutical Preparations; Physiology; Placebo Control; Population; Protease Inhibitor; Provider; Public Health; Quality of life; Randomized; Reporting; Research Personnel; Rest; Rheumatoid Arthritis; Risk; Role; Running; Site; Specificity; TNF gene; Testing; Toxic effect; Viral Load result; Visceral; Visceral fat; adipokines; antiretroviral therapy; arterial stiffness; cardiometabolism; cardiovascular disorder risk; cardiovascular effects; cardiovascular risk factor; design; diabetic; endothelial dysfunction; experience; fighting; gastrointestinal epithelium; glucagon-like peptide 1; immune activation; improved; inflammatory marker; insulin secretion; non-diabetic; obesity treatment; randomized placebo-controlled clinical trial; receptor; subcutaneous; success; tool; trial design

PROJECT SUMMARY Despite the advent of safer antiretroviral therapy agents with low potential for mitochondrial toxicity, accumulation of central and ectopic fat remains a common and significant challenge facing HIV providers and threatens the well-being of individuals living with HIV. Limited progress has been made in understanding and managing lipohypertrophy. Initially linked to the use of protease inhibitors, we have recently reported similar gains in peripheral and central fat after initiation of successful HIV treatment with both protease inhibitors and integrase inhibitors. These observations have challenged current beliefs and raised the concerns that fat accumulation may indeed be due to HIV itself, directly and/or indirectly, through the heightened inflammatory state that accompanies HIV. The role of alteration in gut hormone secretion and gut epithelial barrier dysfunction in HIV-associated metabolic disorders is largely unknown, but it is plausible since chronic inflammation (such as that seen in HIV) has been shown to affect the secretion of gut hormones. Studies of glucagon-like peptide-1 receptor agonists (GLP-1RAs) in diabetics have shown them to be safe, well-tolerated, with very low to no concerns about drug-drug interactions, and, importantly, have caused weight loss that appear to occur, at least in some studies, preferentially via losses in visceral fat. Some GLP- 1RAs have even shown to decrease clinical CVD events in diabetics. Thus, this promising class of drugs may offer a powerful tool to fight the triple threat facing the success of long-term HIV treatment: namely, 1) excess fat accumulation and ectopic fat deposition, 2) insulin resistance and a high prevalence of diabetes, and 3) endothelial dysfunction and cardiovascular disease (CVD) risk. GLP-1RAs act by partially-delineated mechanisms, several of which will be studied in this proposal. We will conduct a randomized, double-blinded, placebo-controlled clinical trial to assess whether a potent and safe GLP-1RA may positively affect visceral fat and ectopic fat accumulation, insulin resistance, inflammation markers, and the downstream effect on CVD in people living with HIV. A similarly-designed trial will enroll an HIV-uninfected, obese group, matched to the group with HIV by key factors and will run in parallel. Including a parallel study of people without HIV will be helpful in making significant observations about the specificity of the findings to the HIV population. Major strengths of this study include the extensive experience of the primary site’s principle investigator in leading clinical trials involving cardiometabolic complications in HIV, as well as the expertise and successful collaborative record of the investigative team on HIV-related metabolic complications, CVD risk, and immune activation, as well as GLP-1 physiology, pathophysiology and treatment of obesity and diabetes, and statistical expertise.

项目摘要 尽管具有线粒体毒性潜力较低的更安全的抗逆转录病毒治疗剂冒险 中央和生态脂肪的积累仍然是艾滋病毒提供者和 威胁艾滋病毒感染者的福祉。在理解和 管理脂肪性体内植物。最初与蛋白酶抑制剂的使用有关，我们最近报道了类似的 通过蛋白酶抑制剂和 整合酶抑制剂。这些观察结果挑战了当前的信念，并引起了人们的担忧 积累确实可能是由于HIV本身直接和/或间接引起的，通过增强的炎症 涉及艾滋病毒的状态。改变在肠道分泌和肠道上皮屏障中的作用 与HIV相关的代谢性疾病的功能障碍在很大程度上未知，但由于慢性是合理的 炎症（例如艾滋病毒中看到的）已证明会影响肠道激素的分泌。 糖尿病患者中胰高血糖素样肽-1受体激动剂（GLP-1RA）的研究表明它们是 安全，耐受性良好，对药物相互作用非常低至不关心，重要的是， 至少在某些研究中，似乎会通过内脏脂肪损失而发生的体重减轻。一些GLP- 1RA甚至显示可降低糖尿病患者的临床CVD事件。那是有希望的毒品可能 提供有力的工具来应对长期艾滋病毒治疗成功的三重威胁：即1）超过 脂肪积累和生态脂肪沉积，2）胰岛素抵抗和糖尿病患病率高，3） 内皮功能障碍和心血管疾病（CVD）风险。 GLP-1RA通过部分删除的作用 机制，其中一些将在此提案中研究。 我们将进行一项随机，双盲，安慰剂对照的临床试验，以评估是否是 潜在且安全的GLP-1RA可能会对内脏脂肪和生态脂肪的积累，胰岛素抵抗，胰岛素抵抗， 炎症标记以及艾滋病毒患者对CVD的下游影响。类似设计的试验 将注册一个艾滋病毒未感染的肥胖小组，与艾滋病毒的群体相匹配，并将持续 平行线。包括对没有艾滋病毒的人的平行研究将有助于对 调查结果对艾滋病毒人群的特异性。 这项研究的主要优势包括主要网站主要研究者的丰富经验 在涉及艾滋病毒中心脏代谢并发症的领先临床试验中，专业知识和成功 关于HIV相关代谢并发症，CVD风险和免疫的调查团队的协作记录 激活以及GLP-1生理学，肥胖和糖尿病的病理生理学和治疗以及统计 专业知识。