Department of Vascular Medicine, Academic Medical Center, Amsterdam, the Netherlands.
Clinical Research Department, Torrent Pharmaceuticals Limited, Village-Bhat, Dist. Gandhinagar, India.
PLoS One. 2014 Feb 21;9(2):e86890. doi: 10.1371/journal.pone.0086890. eCollection 2014.
Obesity and its associated cardiometabolic co-morbidities are increasing worldwide. Since thyroid hormone mimetics are capable of uncoupling the beneficial metabolic effects of thyroid hormones from their deleterious effects on heart, bone and muscle, this class of drug is considered as adjacent therapeutics to weight-lowering strategies. This study investigated the safety and efficacy of TRC150094, a thyroid hormone mimetic.
This 4-week, randomized, placebo-controlled, double-blind trial was conducted in India and The Netherlands. Forty subjects were randomized at a 1:1 ratio to receive either TRC150094 dosed at 50 mg or placebo once daily for 4 weeks. Hyperinsulinemic euglycemic clamp and (1)H-Magnetic Resonance Spectroscopy (MRS) were performed before and after treatment.
At baseline, subjects were characterized by markedly impaired hepatic and peripheral insulin sensitivity. TRC150094 dosed 50 mg once daily was safe and well tolerated. Hepatic nor peripheral insulin sensitivity improved after TRC150094 treatment, expressed as the suppression of Endogenous Glucose Production from 59.5 to 62.1%; p = 0.477, and the rate of glucose disappearance from 28.8 to 26.4 µmol kg(-1)min(-1), p = 0.185. TRC150094 administration did not result in differences in fasting plasma free fatty acids from 0.51 to 0.51 mmol/L, p = 0.887 or in insulin-mediated suppression of lipolysis from 57 to 54%, p = 0.102. Also, intrahepatic triglyceride content was unaltered.
Collectively, these data show that, in contrast to the potent metabolic effects in experimental models, TRC150094 at a dose of 50 mg daily does not improve the metabolic homeostasis in subjects at an increased cardiometabolic risk. Further studies are needed to evaluate whether TRC150094 has beneficial effects in patients with more severe metabolic derangement, such as overt diabetes mellitus and hypertriglyceridemia.
clinicaltrials.gov NCT01408667.
肥胖及其相关的心血管合并症在全球范围内呈上升趋势。由于甲状腺激素激动剂能够将甲状腺激素的有益代谢作用与其对心脏、骨骼和肌肉的有害作用分离，因此这类药物被认为是减肥策略的相邻治疗方法。本研究旨在探讨甲状腺激素激动剂 TRC150094 的安全性和疗效。
这是一项为期 4 周的、随机、安慰剂对照、双盲试验，在印度和荷兰进行。40 名受试者按 1:1 的比例随机分为两组，分别接受每日一次 50mg 的 TRC150094 或安慰剂治疗 4 周。治疗前后进行高胰岛素正葡萄糖钳夹和（1）H 磁共振波谱（MRS）检查。
在基线时，受试者的肝胰岛素敏感性和外周胰岛素敏感性明显受损。每日一次 50mg 的 TRC150094 剂量安全且耐受性良好。TRC150094 治疗后，肝胰岛素敏感性和外周胰岛素敏感性均无改善，表现为内源性葡萄糖生成的抑制率从 59.5%增加到 62.1%（p=0.477），葡萄糖清除率从 28.8 增加到 26.4 µmol·kg-1·min-1（p=0.185）。TRC150094 给药后，空腹血浆游离脂肪酸从 0.51mmol/L 增加到 0.51mmol/L（p=0.887），胰岛素介导的脂解抑制率从 57%增加到 54%（p=0.102）。此外，肝内甘油三酯含量无变化。
总之，与实验模型中强效的代谢作用相比，50mg 每日剂量的 TRC150094 并不能改善代谢风险增加的受试者的代谢稳态。需要进一步研究以评估 TRC150094 是否对代谢紊乱更严重的患者（如显性糖尿病和高三酰甘油血症）有益。
clinicaltrials.gov NCT01408667。
