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

项目摘要 尽管出现了更安全的抗逆转录病毒治疗药物，其线粒体毒性可能性较低， 中央和异位脂肪的积累仍然是HIV提供者面临的常见和重大挑战， 威胁到艾滋病毒感染者的健康。在了解和 管理脂肪肥大。最初与蛋白酶抑制剂的使用有关，我们最近报道了类似的 开始使用蛋白酶抑制剂成功治疗HIV后，外周和中央脂肪增加， 整合酶抑制剂。这些观察结果挑战了目前的信念，并提出了脂肪 积累可能确实是由于艾滋病毒本身，直接和/或间接，通过增加炎症反应， 伴随着艾滋病病毒。肠激素分泌和肠上皮屏障改变的作用 HIV相关代谢紊乱中的功能障碍在很大程度上是未知的，但由于慢性 炎症（如艾滋病病毒中所见）已被证明会影响肠道激素的分泌。 胰高血糖素样肽-1受体激动剂（GLP-1 RA）在糖尿病患者中的研究表明， 安全，耐受性良好，对药物相互作用的担忧非常低或没有，重要的是， 至少在一些研究中，体重减轻似乎优先通过内脏脂肪的减少而发生。一些GLP- 1 RA甚至显示出减少糖尿病患者的临床CVD事件。因此，这类有前途的药物可能 提供了一个强大的工具，以应对长期艾滋病毒治疗成功所面临的三重威胁：1）过度 脂肪堆积和异位脂肪沉积，2）胰岛素抵抗和糖尿病的高患病率，以及3） 内皮功能障碍和心血管疾病（CVD）风险。GLP-1 RA通过部分描述的 机制，其中一些将在本提案中进行研究。 我们将进行一项随机、双盲、安慰剂对照的临床试验，以评估 有效且安全的GLP-1 RA可能对内脏脂肪和异位脂肪蓄积、胰岛素抵抗 炎症标志物，以及对HIV感染者CVD的下游影响。一个类似设计的试验 将招募一个未感染艾滋病毒的肥胖组，通过关键因素与艾滋病毒感染组相匹配， 并联包括对没有艾滋病毒的人进行平行研究将有助于对以下方面进行重要观察： 研究结果对艾滋病病毒感染人群的特异性。 本研究的主要优势包括主要研究中心主要研究者的丰富经验 在涉及艾滋病毒心脏代谢并发症的领先临床试验中， 调查小组关于艾滋病毒相关代谢并发症、心血管疾病风险和免疫功能的合作记录 GLP-1激活，以及GLP-1生理学，病理生理学和肥胖症和糖尿病的治疗，以及统计学 专业知识

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.