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

项目总结 尽管出现了更安全、线粒体毒性低的抗逆转录病毒治疗药物， 中心性和异位脂肪堆积仍然是艾滋病毒提供者和 威胁到艾滋病毒携带者的福祉。在理解和理解方面取得了有限的进展 管理脂肪肥大。最初与使用蛋白酶抑制剂有关，我们最近也报道了类似的情况 外周和中央脂肪增加在开始成功的HIV治疗后，用蛋白酶抑制剂和 整合酶抑制剂。这些观察结果挑战了当前的信念，并引发了人们对肥胖的担忧 积聚可能确实是由于艾滋病毒本身，直接和/或间接地通过加剧的炎症 与艾滋病病毒相伴的州。胃肠激素分泌与肠上皮屏障功能改变的关系 HIV相关代谢紊乱的功能障碍在很大程度上是未知的，但这是可能的，因为慢性 炎症(如艾滋病毒中的炎症)已被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-1RAs)的研究表明，它们是 安全，耐受性好，对药物-药物相互作用的担忧很低，甚至没有，更重要的是，已经引起了 至少在一些研究中，体重减轻似乎主要是通过减少内脏脂肪来实现的。一些普洛斯- 1RAS甚至被证明可以减少糖尿病患者的临床心血管事件。因此，这类前景看好的药物可能 提供一个强大的工具来对抗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发病率，以及3) 内皮功能障碍与心血管疾病(CVD)风险。GLP-1RAs通过部分描绘的方式发挥作用 机制，其中几个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 有效和安全的GLP-1RA可能对内脏脂肪和异位脂肪积聚、胰岛素抵抗、 炎症标志物，以及对艾滋病毒携带者心血管疾病的下游影响。类似设计的试验 将招募一个未感染艾滋病毒的肥胖组，在关键因素上与感染艾滋病毒的组相匹配，并将在 平行的。包括对非艾滋病毒携带者的平行研究将有助于对以下问题进行重大观察 这些发现对艾滋病毒人群的特异性。 这项研究的主要优势包括主要场地首席调查员的丰富经验 在涉及艾滋病毒心脏代谢并发症的领先临床试验中，以及专业知识和成功 关于艾滋病毒相关代谢并发症、心血管疾病风险和免疫的调查小组的合作记录 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 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.