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

Abstract

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.

Conclusion: 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.

Fig. 1

Thyroid hormone receptor (TR)β expression in a rat pancreatic β cell line is 4-fold higher than TRα expression. Ribonucleic acid (RNA) was isolated from induced insulin secretion-1 (INS-1) 832/13 rat insulinoma cells. A, Quantitative real-time polymerase chain reaction (PCR) (qRT-PCR) threshold cycles demonstrating linearity of amplification for TRα, TRβ, and β-actin primer sets using serial 2-fold dilutions of INS-1 reversed-transcribed RNA. The x-axis is displayed in logarithmic scale. B, Reverse-transcribed RNA was subjected to qRT-PCR of TRα and TRβ transcripts using equally efficient primers from Panel A. *Significantly different (P<0.05) in comparison with TRα transcript levels. Results are displayed as the means ± standard error of the mean (SEM).