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Thyroid hormone mimetics: potential applications in atherosclerosis, obesity and type 2 diabetes

Nature Reviews Drug Discovery volume 8, pages 308–320 (2009)Cite this article

Key Points

  • Atherosclerosis is a major cause of mortality throughout the western world, despite the existence of drugs that lower cholesterol.

  • The incidences of obesity and type 2 diabetes are increasing at alarming rates, and have become major health problems; treatments that involve lifestyle changes have had limited success.

  • New therapies for atherosclerosis, obesity and type 2 diabetes are needed.

  • Thyroid hormone excess has potentially useful effects, including lowering of serum cholesterol and reduction of body fat, but these are counterbalanced by deleterious effects on heart, muscle and bone which preclude the use of natural thyroid hormones to treat patients with dyslipidaemias, obesity and diabetes. For years, scientists have sought thyroid hormone analogues that would elicit the beneficial but not the unwanted effects of thyroid hormones.

  • Advances in molecular and structural biology have facilitated the design of new selective thyroid hormone mimetics that exhibit thyroid hormone receptor isoform-selective binding, and/or liver- and tissue-selective uptake. These compounds reduce serum levels of low-density lipoprotein–cholesterol and triglycerides, enhance several important steps in reverse cholesterol transport and reduce body fat in several animal models, and have not been found to have effects in preclinical animal models.

  • Selective thyroid hormone receptor modulators also reduce blood glucose levels in mouse models of type 2 diabetes, raising the possibility that there could be unexpected beneficial effects on this disease.

  • Clinical trials, which have now involved several hundred patients, reveal that selective thyroid hormone mimetics can reduce serum levels of low-density lipoprotein–cholesterol, triglycerides and lipoprotein(a), which are all risk factors for atherosclerosis, without detectable adverse effects. These actions can also be observed in patients taking other currently used cholesterol-lowering drugs, such as statins.

  • Selective thyroid hormone receptor modulation is a promising new strategy for the prevention and treatment of atherosclerosis and obesity in humans.

Abstract

Thyroid hormones influence heart rate, serum lipids, metabolic rate, body weight and multiple aspects of lipid, carbohydrate, protein and mineral metabolism. Although increased thyroid hormone levels can improve serum lipid profiles and reduce fat, these positive effects are counterbalanced by harmful effects on the heart, muscle and bone. Thus, attempts to use thyroid hormones for cholesterol-lowering and weight loss purposes have so far been limited. However, over the past decade, thyroid hormone analogues that are capable of uncoupling beneficial effects from deleterious effects have been developed. Such drugs could serve as powerful new tools to address two of the largest medical problems in developed countries — atherosclerosis and obesity.

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Figure 1: Beneficial and deleterious effects of thyroid hormone and mechanisms of thyroid hormone mimetic selectivity.
Figure 2: Effects of thyroid hormone mimetics and statins on cholesterol metabolism.
Figure 3: Predicted dynamics of the hypothalamic–pituitary–thyroid (HPT) axis in the presence of thyroid hormone mimetics.

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Acknowledgements

The authors thank J. Kristensen for critical reading and J. Hing Lin for help with figure preparation.

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  1. Methodist Hospital Research Institute, F8-044 6565 Fannin, Houston, 77030, Texas, USA

    John D. Baxter & Paul Webb

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Competing interests

John D. Baxter is a consultant to and shareholder of Karo Bio A.B., which has commercial interests in thyroid hormone mimetics. He is also an inventor of a patent issued with regard to GC-1 that is owned by the University of California.

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Glossary

Obesity

A condition characterized by accumulation of excess body fat and defined in humans by body mass index values of 30 kg per m2 or greater.

Atherosclerosis

A chronic inflammatory syndrome that affects blood vessel walls. There is hardening of arteries caused by macrophage infiltration and accumulation of cholesterol.

Type 2 diabetes

A condition that is characterized by high blood glucose levels associated with resistance to the hormone insulin.

Hypercholesterolaemia

A metabolic abnormality characterized by high serum cholesterol that can lead to increased atherosclerotic plaque formation and increased cardiovascular disease when there is increased low-density lipoprotein–cholesterol.

Hormone

A small molecule that is released by an organ and subsequently affects other tissues. Endocrine hormones, such as thyroid hormone, are directly secreted into the blood.

Nuclear hormone receptor

A soluble protein that acts by modulating expression of target genes in response to lipophilic hormones and other small molecules.

Transcription factor

A protein that binds to specific DNA sequences and controls the rate of transcription of genetic information into RNA.

Corepressor

A protein that decreases gene transcription by interacting with a transcription factor.

Co-activator

A protein that increases gene transcription by interacting with a transcription factor.

Enantiomer

A compound that is a non-superimposable mirror image of another.

Hormone resistance

A condition in which hormone (for example, insulin or thyroid hormone ) is produced at normal or increased levels, but the response is reduced by alterations in the signal transduction machinery.

Atherosclerotic plaque

An area of macrophage accumulation in the vessel wall that is associated with deposition of cholesterol crystals and calcification in more advanced lesions.

Lipoprotein particle

An assembly of lipids and proteins that serves to transport hydrophobic lipids in the aqueous environment of blood.

Polymorphism

When multiple alleles of the same gene exist in a given population.

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Baxter, J., Webb, P. Thyroid hormone mimetics: potential applications in atherosclerosis, obesity and type 2 diabetes. Nat Rev Drug Discov 8, 308–320 (2009). https://doi.org/10.1038/nrd2830

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