The Effect of a Diiodothyronine Mimetic on Insulin Sensitivity in Male Cardiometabolic Patients: A Double-Blind Randomized Controlled Trial

Background and aims
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.
Materials and Methods
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 1H-Magnetic Resonance Spectroscopy (MRS) were performed before and after treatment.
Results
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−1min−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.
Conclusion
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.
Trial Registration
clinicaltrials.gov NCT01408667

研究背景与目的
肥胖及其相关的心血管代谢共病在全球范围内呈上升趋势。由于甲状腺激素模拟物（thyroid hormone mimetics）能够将甲状腺激素的有益代谢效应与对心脏、骨骼和肌肉的不良影响相分离，此类药物被视为减重策略的辅助治疗方案。本研究旨在评估TRC150094——一种甲状腺激素模拟物——的安全性与有效性。

材料与方法
本试验为为期4周的随机、安慰剂对照、双盲研究，在印度与荷兰开展。40名受试者按1:1的比例随机分组，分别接受每日一次50mg剂量的TRC150094或安慰剂，干预时长共4周。分别于治疗前后开展高胰岛素正葡萄糖钳夹技术（Hyperinsulinemic euglycemic clamp）与氢质子磁共振波谱（1H-Magnetic Resonance Spectroscopy, MRS）检测。

研究结果
基线状态下，受试者均存在显著受损的肝脏及外周胰岛素敏感性。每日一次50mg剂量的TRC150094安全性良好，耐受性佳。TRC150094治疗后，肝脏及外周胰岛素敏感性未见显著改善：内源性葡萄糖生成（Endogenous Glucose Production）的抑制率从59.5%升至62.1%（p=0.477），葡萄糖消失速率从28.8 µmol·kg⁻¹·min⁻¹变为26.4 µmol·kg⁻¹·min⁻¹（p=0.185）。TRC150094给药未对空腹血浆游离脂肪酸水平产生显著影响，给药前后均为0.51 mmol/L（p=0.887）；胰岛素介导的脂解抑制率从57%降至54%（p=0.102），差异亦无统计学意义。此外，肝内甘油三酯含量未发生改变。

研究结论
综合来看，本研究数据显示：与实验模型中观察到的强效代谢作用不同，每日50mg剂量的TRC150094并未改善心血管代谢风险升高受试者的代谢稳态。未来仍需开展进一步研究，以评估TRC150094在更严重代谢紊乱患者（如显性糖尿病及高甘油三酯血症患者）中是否存在有益作用。

试验注册
clinicaltrials.gov注册号：NCT01408667