Growth Hormone and Rosiglitazone for Visceral Adoposity

描述（由申请人提供）：HIV感染患者的内脏肥胖是一种普遍存在的临床显著问题。内脏肥胖患者具有代谢特征，包括胰岛素抵抗，这可能使动脉粥样硬化加速。针对改善胰岛素敏感性和减少内脏脂肪的干预措施有可能有利地改变该人群的心血管疾病风险。重组人生长激素（rhGH）是一种潜在有效的治疗内脏肥胖症，但其对胰岛素敏感性的不良反应和潜在的长期毒性可能会限制其在胰岛素抵抗患病率高的患者人群中的有用性。噻唑烷二酮类药物，如罗格列酮，可能对这些患者的胰岛素敏感性和身体成分的变化有良好的影响。本提案的总体目的是确定rhGH和罗格列酮联合给药后接受罗格列酮维持治疗是否安全，是否是一种比单独使用任何一种药物更有效的内脏性肥胖治疗方法。该研究是一项随机、双盲、多中心临床试验，在该试验中，符合内脏肥胖人体测量学标准的胰岛素抵抗HIV感染受试者最初将以2 × 2析因设计随机接受12周rhGH、罗格列酮、rhGH +罗格列酮或双安慰剂治疗。在第12周，所有受试者将被重新随机分配至额外的24周罗格列酮或安慰剂维持治疗（最初接受双安慰剂的受试者将在第二次随机分配前接受开放标签rhGH +罗格列酮12周）。本临床试验的具体目的是：（1）确定罗格列酮和rhGH对血糖稳态的个体效应和相互作用;（2）确定罗格列酮和rhGH对身体成分的个体效应和相互作用;（3）确定罗格列酮和rhGH对心血管风险标志物的个体效应和相互作用;和（4）确定罗格列酮长期给药是否减少停止rhGH治疗后内脏脂肪组织（VAT）的再积聚。本研究将在纽约市3个合作研究中心的GCRC中进行。合格的受试者将符合内脏肥胖的人体测量标准，并且通过定量胰岛素敏感性检查指数（QUICKI）具有葡萄糖耐量受损和/或胰岛素抵抗。主要评价将是针对特定目标1的频繁采样静脉耐量试验、口服葡萄糖耐量试验和通过13 C-棕榈酸盐稀释的游离脂肪酸通量;针对特定目标2和4的MRI、双能X射线吸收测定法、间接量热法、食物日记、体力活动记录和氘化水和溴化钠稀释;以及针对特定目标3的脂蛋白检测和其他心血管风险标志物。如果结果如预测的那样，那么重组人生长激素和罗格列酮联合治疗可能被证明是一种非常有效的治疗HIV感染患者内脏肥胖的方法。

DESCRIPTION (provided by applicant): Visceral adiposity in HIV-infected patients is a prevalent and clinically significant clinical problem. Patients with visceral adiposity have a metabolic profile, including insulin resistance, which may predispose to accelerated atherosclerosis. Interventions targeted at improving insulin sensitivity and reducing visceral fat have the potential to favorably modify the risk of cardiovascular disease in this population. Recombinant human growth hormone (rhGH) is a potentially effective treatment for visceral adiposity, but its adverse effects on insulin sensitivity and potential long-term toxicities may limit its usefulness in a patient population with a high underlying prevalence of insulin resistance. Thiazolidinedione drugs, such as rosiglitazone, may have favorable effects on insulin sensitivity and the body composition changes in these patients. The overall objective of this proposal is to determine if co-administration of rhGH and rosiglitazone followed by maintenance therapy with rosiglitazone is safe and a more effective therapy for visceral adiposity than either drug alone. The proposed study is a randomized, double-blind, multicenter clinical trial in which HIV-infected subjects with insulin resistance who meet validated anthropometric criteria for visceral adiposity will be randomized initially in a 2 x 2 factorial design to a 12-week course of rhGH, rosiglitazone, rhGH + rosiglitazone, or double-placebo. At week 12, all subjects will be re-randomized to an additional 24-week course of maintenance therapy with rosiglitazone or placebo (those initially on double-placebo will receive open-label rhGH + rosiglitazone for 12 weeks prior to the second randomization). This clinical trial will address the following specific aims: (1) To determine the individual and interacting effects of rosiglitazone and rhGH on glucose homeostasis; (2) To determine the individual and interacting effects of rosiglitazone and rhGH on body composition; (3) To determine the individual and interacting effects of rosiglitazone and rhGH on markers of cardiovascular risk; and, (4) To determine if longer-term administration of rosiglitazone reduces the re-accumulation of visceral adipose tissue (VAT) after cessation of rhGH therapy. The study will be conducted in the GCRCs of 3 collaborating sites in New York City. Eligible subjects will meet anthropometric criteria for visceral adiposity and have impaired glucose tolerance and/or insulin resistance by the quantitative insulin sensitivity check index (QUICKI). The primary evaluations will be frequently sampled intravenous tolerance tests, oral glucose tolerance tests, and free fatty acid flux by 13C-palmitate dilution for specific aim 1; MRI, dual Xray absorptiometry, indirect calorimetry, food diaries, physical activity records, and deuterated water and sodium bromide dilution for specific aims 2 and 4; and, lipoprotein panels and other markers of cardiovascular risk for specific aim 3. If the results are as predicted, then combination therapy with rhGH and rosiglitazone may prove to be a highly effective treatment for visceral adiposity in HIV-infected patients.