Mechanistic Phase II Clinical Trial of Metformin in Pulmonary Arterial Hypertension.
Mechanistic Phase II Clinical Trial of Metformin in Pulmonary Arterial Hypertension.
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DOI：
10.1161/jaha.120.018349
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发表时间：
2020-11-17
影响因子：
5.4
通讯作者：
Hemnes AR
中科院分区：
文献类型：
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作者：
Brittain EL;Niswender K;Agrawal V;Chen X;Fan R;Pugh ME;Rice TW;Robbins IM;Song H;Thompson C;Ye F;Yu C;Zhu H;West J;Newman JH;Hemnes AR
代谢功能障碍在肺动脉高压（PAH）中非常普遍，并且可能导致肺血管疾病和右心室（RV）衰竭，部分原因是氧化应激增加。目前，多环芳烃还没有治愈的方法，代谢干预的人体研究在其他疾病中通常耐受良好，但对多环芳烃的研究有限。二甲双胍是一种常用的口服降糖药，可减少糖异生，增加脂肪酸氧化，减少氧化应激，因此可能与多环芳烃有关。我们对特发性或遗传性多环芳烃患者进行了一项为期8周的单中心、开放标签的II期临床试验，每天给予高达2g的二甲双胍，共同主要终点为安全性，包括乳酸酸中毒的发生和研究退出，以及血浆氧化应激标志物。探索性终点包括9例患者超声心动图右心室功能、二甲双胍治疗前后血浆代谢组学分析以及磁共振波谱法右心室甘油三酯含量。我们招募了20名患者；19/20达到了目标剂量，并全部完成了研究方案。没有临床显著的乳酸酸中毒或氧化应激标志物的变化。二甲双胍没有改变6分钟步行距离，但显著改善RV分数面积变化（23±8%至26±6%，P=0.02），尽管其他超声心动图参数不变。8/9患者RV甘油三酯含量下降(3.2±1.8% ~ 1.6±1.4%，P=0.015)。在一项探索性代谢组学分析中，血浆代谢组学与RV脂质降低≥50%相关的包括二羟基丁酸盐、乙酰腐胺、羟基硬脂酸盐和葡萄糖醛酸盐（均P<0.05）。在整个队列中，脂质代谢物是二甲双胍改变最大的。在这项单臂、开放标签的II期研究中，二甲双胍治疗在PAH患者中是安全且耐受性良好的。探索性分析表明，二甲双胍可能与改善右心室面积变化有关，并且在一部分患者中，与脂质和葡萄糖代谢标志物改变相关的右心室甘油三酯含量降低。URL: http://www.clinicaltrials.gov;唯一标识符：NCT01884051。
Metabolic dysfunction is highly prevalent in pulmonary arterial hypertension (PAH) and likely contributes to both pulmonary vascular disease and right ventricular (RV) failure in part because of increased oxidant stress. Currently, there is no cure for PAH and human studies of metabolic interventions, generally well tolerated in other diseases, are limited in PAH. Metformin is a commonly used oral antidiabetic that decreases gluconeogenesis, increases fatty acid oxidation, and reduces oxidant stress and thus may be relevant to PAH. We performed a single‐center, open‐label 8‐week phase II trial of up to 2 g/day of metformin in patients with idiopathic or heritable PAH with the co‐primary end points of safety, including development of lactic acidosis and study withdrawal, and plasma oxidant stress markers. Exploratory end points included RV function via echocardiography, plasma metabolomic analysis performed before and after metformin therapy, and RV triglyceride content by magnetic resonance spectroscopy in a subset of 9 patients. We enrolled 20 patients; 19/20 reached the target dose and all completed the study protocol. There was no clinically significant lactic acidosis or change in oxidant stress markers. Metformin did not change 6‐minute walk distance but did significantly improve RV fractional area change (23±8% to 26±6%, P=0.02), though other echocardiographic parameters were unchanged. RV triglyceride content decreased in 8/9 patients (3.2±1.8% to 1.6±1.4%, P=0.015). In an exploratory metabolomic analysis, plasma metabolomic correlates of ≥50% reduction in RV lipid included dihydroxybutyrate, acetylputrescine, hydroxystearate, and glucuronate (P<0.05 for all). In the entire cohort, lipid metabolites were among the most changed by metformin. Metformin therapy was safe and well tolerated in patients with PAH in this single‐arm, open‐label phase II study. Exploratory analyses suggest that metformin may be associated with improved RV fractional area change and, in a subset of patients, reduced RV triglyceride content that correlated with altered lipid and glucose metabolism markers. URL: http://www.clinicaltrials.gov; Unique identifier: NCT01884051.