Telmisartan to reduce insulin resistance in HIV-positive individuals on combination antiretroviral therapy: the TAILoR dose-ranging Phase II RCT
Telmisartan to reduce insulin resistance in HIV-positive individuals on combination antiretroviral therapy: the TAILoR dose-ranging Phase II RCT
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替米沙坦降低 HIV 阳性个体联合抗逆转录病毒治疗的胰岛素抵抗：TAILoR 剂量范围 II 期随机对照试验
DOI：
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发表时间：
2019
影响因子：
--
通讯作者：
M. Pirmohamed
中科院分区：
文献类型：
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作者：
S. Pushpakom;R. Kolamunnage;Claire Taylor;T. Foster;C. Spowart;M. García;G. Kemp;T. Jaki;S. Khoo;P. Williamson;M. Pirmohamed
联合抗逆转录病毒疗法（cART）是人类免疫缺陷病毒（HIV）感染治疗的标准，但可能导致代谢异常，例如胰岛素抵抗、血脂异常和脂肪营养不良，从而增加心血管疾病的风险。
该试验的目的是评估替米沙坦（一种血管紧张素 II 受体拮抗剂和过氧化物酶体增殖物激活受体 γ 部分激动剂）是否可以降低接受 cART 的 HIV 阳性个体的胰岛素抵抗，并影响心脏代谢疾病的血液和影像生物标志物。
替米沙坦的 II 期、多中心、随机、开放标签、剂量范围试验为期 48 周，采用包括两个阶段的适应性设计，用于确定替米沙坦的最佳剂量。参与者被随机分配接受三种剂量的替米沙坦（20、40 和 80mg）中的一种或不接受干预（对照）。
招募对象来自英国 19 个艾滋病毒专科中心。
共有 377 名符合预先规定的纳入/排除标准的 HIV 感染患者。
20、40 和 80 毫克替米沙坦片剂。
主要结局指标是第 24 周时胰岛素抵抗稳态模型评估 (HOMA-IR) 的降低，这是胰岛素抵抗的标志。次要结果指标是血浆脂质谱的变化；定量胰岛素敏感性检查指数 (QUICKI) 和修订版 QUICKI、胰岛素抵抗替代标记物、血浆脂肪因子（脂联素、瘦素、白细胞介素 8、肿瘤坏死因子 α、抵抗素）；高敏C反应蛋白（hs-CRP）；通过磁共振成像/质子磁共振波谱测量，身体脂肪重新分布；肾脏标志物的变化（白蛋白与肌酐比、中性粒细胞明胶酶相关脂质运载蛋白）；以及对替米沙坦的耐受性。
在中期分析中，80毫克替米沙坦被带入研究的第二阶段。各治疗组的基线特征是平衡的。 24周时，替米沙坦（80mg；n = 106）和不干预组之间的 HOMA-IR [0.007，标准误差 (SE) 0.106]、QUICKI (0.001，SE 0.001) 和修订版 QUICKI (0.002，SE 0.002) 没有差异(n = 105) 条手臂。 48 周的纵向分析表明 HOMA-IR、脂质或脂肪因子水平没有变化；然而，在 48 周内，修正后的 QUICKI [0.004，95% 置信区间 (CI) 0.000 至 0.008] 和血浆 hs-CRP（–0.222，95% CI –0.433 至 –0.011）有显着但有限的改善。亚组研究还显示，24 周时肝脏脂肪含量显着降低（1.714，95% CI –2.787 至 –0.642；p = 0.005），48 周时尿白蛋白排泄量显着降低（–0.665，95% CI –1.31 至 –0.019；p = 0.04）。替米沙坦组和对照组之间的严重不良事件没有差异。
患者的 HOMA-IR 在基线时有适度升高，我们的试验可能不足以检测胰岛素抵抗随时间的较小改善。
使用新颖的适应性设计，我们证明替米沙坦（80mg）对 HOMA-IR 的主要结果测量和一些次要结果（血浆脂质和脂肪因子）没有显着影响。替米沙坦确实导致了次要纵向结果指标的有利且生物学上合理的变化：修订后的 QUICKI、hs-CRP、肝脂肪积累和尿白蛋白排泄。总的来说，我们的研究结果表明，替米沙坦并不能降低服用抗逆转录病毒药物的艾滋病毒感染患者的胰岛素抵抗。
将研究脂肪细胞调节的机制基础，以开发生物标志物和干预措施。
当前对照试验 ISRCTN51069819。
该项目由功效和机制评估 (EME) 计划、医学研究委员会和国家健康研究所合作伙伴资助。
Combination antiretroviral therapy (cART) is the standard for human immunodeficiency virus (HIV) infection treatment but can result in metabolic abnormalities, such as insulin resistance, dyslipidaemia and lipodystrophy, which can increase the risk of cardiovascular disease.
The objective of the trial was to evaluate whether or not telmisartan, an angiotensin II receptor antagonist and a peroxisome proliferator-activated receptor-γ partial agonist, could reduce insulin resistance in HIV-positive individuals on cART, and affect blood and imaging biomarkers of cardiometabolic disease.
A Phase II, multicentre, randomised, open-labelled, dose-ranging trial of telmisartan over a period of 48 weeks with an adaptive design comprising two stages was used to identify the optimal dose of telmisartan. Participants were randomised to receive one of the three doses of telmisartan (20, 40 and 80 mg) or no intervention (control).
Recruitment was from 19 HIV specialist centres in the UK.
A total of 377 patients infected with HIV who met the prespecified inclusion/exclusion criteria.
20-, 40- and 80-mg tablets of telmisartan.
The primary outcome measure was reduction in the homeostatic model assessment of insulin resistance (HOMA-IR), a marker of insulin resistance, at 24 weeks. Secondary outcome measures were changes in plasma lipid profile; Quantitative Insulin Sensitivity Check Index (QUICKI) and revised QUICKI, alternative markers of insulin resistance, plasma adipokines (adiponectin, leptin, interleukin 8, tumour necrosis factor alpha, resistin); high-sensitivity C-reactive protein (hs-CRP); body fat redistribution, as measured by magnetic resonance imaging/proton magnetic resonance spectroscopy; changes in renal markers (albumin-to-creatinine ratio, neutrophil gelatinase-associated lipocalin); and tolerability to telmisartan.
At the interim analysis, 80 mg of telmisartan was taken forward into the second stage of the study. Baseline characteristics were balanced across treatment arms. There were no differences in HOMA-IR [0.007, standard error (SE) 0.106], QUICKI (0.001, SE 0.001) and revised QUICKI (0.002, SE 0.002) at 24 weeks between the telmisartan (80 mg; n = 106) and non-intervention (n = 105) arms. Longitudinal analysis over 48 weeks showed that there was no change in HOMA-IR, lipid or adipokine levels; however, but there were significant, but marginal, improvements in revised QUICKI [0.004, 95% confidence interval (CI) 0.000 to 0.008] and plasma hs-CRP (–0.222, 95% CI –0.433 to –0.011) over 48 weeks. Substudies also showed a significant reduction in the liver fat content at 24 weeks (1.714, 95% CI –2.787 to –0.642; p = 0.005) and urinary albumin excretion at 48 weeks (–0.665, 95% CI –1.31 to –0.019; p = 0.04). There were no differences in serious adverse events between the telmisartan and control arms.
The patients had modest elevations of HOMA-IR at baseline, and our trial could have been under-powered to detect smaller improvements in insulin resistance over time.
Using a novel adaptive design, we demonstrated that there was no significant effect of telmisartan (80 mg) on the primary outcome measure of HOMA-IR and some secondary outcomes (plasma lipids and adipokines). Telmisartan did lead to favourable, and biologically plausible, changes of the secondary longitudinal outcome measures: revised QUICKI, hs-CRP, hepatic fat accumulation and urinary albumin excretion. Taken collectively, our findings showed that telmisartan did not reduce insulin resistance in patients infected with HIV on antiretrovirals.
The mechanistic basis of adipocyte regulation will be studied to allow for development of biomarkers and interventions.
Current Controlled Trials ISRCTN51069819.
This project was funded by the Efficacy and Mechanism Evaluation (EME) programme, a Medical Research Council and National Institute for Health Research partnership.
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影响因子：
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作者：
Brown, TT;Cole, SR;Dobs, AS
通讯作者：
Dobs, AS
人类免疫缺陷病毒 (HIV)-1 病毒蛋白 R 抑制过氧化物酶体增殖物激活受体 {gamma} 的转录活性并抑制脂肪细胞分化：对 HIV 相关脂肪营养不良的影响。
DOI：
10.1210/me.2007-0124
发表时间：
2008
期刊：
Molecular endocrinology (Baltimore, Md.)
影响因子：
--
作者：
Shrivastav,Shashi;Kino,Tomoshige;Cunningham,Tshaka;Ichijo,Takamasa;Schubert,Ulrich;Heinklein,Peter;Chrousos,GeorgeP;Kopp,JeffreyB
通讯作者：
Kopp,JeffreyB
影响因子：
158.5
作者：
Friis-Moller, Nina;Reiss, Peter;Lundgren, Jens D.
通讯作者：
Lundgren, Jens D.
影响因子：
7.7
作者：
Koster, JC;Remedi, MS;Hruz, PW
通讯作者：
Hruz, PW