Department of Medicine, Indiana University School of Medicine Indianapolis, IN 46202, USA.
Endocr Pract. 2012 Nov-Dec;18(6):954-64. doi: 10.4158/EP12086.RA.
To provide a comprehensive review of the discovery and development of selective thyroid hormone receptor agonists and provide a discussion of their use in hyperlipidemia, obesity, and type 2 diabetes mellitus.
Preclinical and clinical English language literature from 1930 to present was reviewed and thematically summarized.
Human trials have shown that thyroid hormone receptor β (TRβ) agonists effectively lower low-density lipoprotein, triglycerides, apolipoprotein B, and lipoprotein(a) levels. In preclinical studies, TRβ agonists enhance reverse cholesterol transport and decrease atherosclerosis in selected models. While animal data suggest these drugs may have additional utility to modulate weight and improve glucose homeostasis, human studies have not shown similar results.
TRβ agonists are a novel therapeutic class for lipid management. Their mechanism of action for lipid lowering is distinct from statin drugs, suggesting a strong possibility for synergistic effects with combined therapy. The long-term effects of these drugs on cardiovascular outcomes, however, are unknown. Recently, the development of the most promising agent in this class, eprotirome, was halted over toxicology concerns following long-term canine studies. Consequently, the future of contemporary TRβ agonists is unclear. The creation of a next generation of TRβ agonists that provide additional tissue specific effects or bind TRβ with even higher selectivity may lead to improved safety and efficacy and allow for their application to other metabolic disorders like obesity and type 2 diabetes mellitus.
全面回顾选择性甲状腺激素受体激动剂的发现和开发，并讨论其在高脂血症、肥胖症和 2 型糖尿病中的应用。
综述了 1930 年至今的临床前和临床英文文献，并进行了主题总结。
临床试验表明，甲状腺激素受体β（TRβ）激动剂能有效降低低密度脂蛋白、甘油三酯、载脂蛋白 B 和脂蛋白（a）水平。在临床前研究中，TRβ 激动剂增强了胆固醇逆向转运，减少了特定模型中的动脉粥样硬化。虽然动物数据表明这些药物可能具有额外的调节体重和改善葡萄糖稳态的作用，但人体研究并未显示出类似的结果。
TRβ 激动剂是一种新型的治疗血脂异常的药物。它们的降脂作用机制与他汀类药物不同，这表明联合治疗可能具有协同作用的强烈可能性。然而，这些药物对心血管结局的长期影响尚不清楚。最近，由于长期犬类研究发现毒性问题，该类最有前途的药物依替罗肽的开发被停止。因此，当代 TRβ 激动剂的未来尚不明朗。开发具有更高组织特异性或与 TRβ 结合更高选择性的新一代 TRβ 激动剂，可能会提高安全性和疗效，并将其应用于肥胖症和 2 型糖尿病等其他代谢疾病。
