Thyroid hormone analogues for the treatment of metabolic disorders: new potential for unmet clinical needs?
OBJECTIVE
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.


METHODS
Preclinical and clinical English language literature from 1930 to present was reviewed and thematically summarized.


RESULTS
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.


CONCLUSIONS
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.
Department of Medicine, Indiana University School of Medicine Indianapolis, IN 46202, USA.
Timothy J
TJ
Shoemaker
Tatsuyoshi
T
Kono
Cary N
CN
Mariash
Carmella
C
Evans-Molina
D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D004195:Disease Models, Animal; D006801:Humans; D006949:Hyperlipidemias / Q000188:drug therapy; D008659:Metabolic Diseases / Q000188:drug therapy*; D051379:Mice; D009765:Obesity / Q000188:drug therapy; D037042:Thyroid Hormone Receptors beta / Q000819:agonists*
D037042:Thyroid Hormone Receptors beta