Thyroid hormone analogues for the treatment of metabolic disorders

New potential for unmet clinical needs?

Timothy J. Shoemaker, Tatsuyoshi Kono, Cary N. Mariash, Carmella Evans-Molina

Research output: Contribution to journalArticle

25 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)954-964
Number of pages11
JournalEndocrine Practice
Volume18
Issue number6
DOIs
StatePublished - Nov 1 2012

Fingerprint

Thyroid Hormone Receptors
Thyroid Hormones
Hormones
Type 2 Diabetes Mellitus
Obesity
Lipids
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Cardiovascular Agents
Lipoprotein(a)
Apolipoproteins B
Hyperlipidemias
Pharmaceutical Preparations
Toxicology
Canidae
Atherosclerosis
Homeostasis
Language
Cholesterol
Safety
Weights and Measures

ASJC Scopus subject areas

  • Endocrinology
  • Endocrinology, Diabetes and Metabolism

Cite this

Thyroid hormone analogues for the treatment of metabolic disorders : New potential for unmet clinical needs? / Shoemaker, Timothy J.; Kono, Tatsuyoshi; Mariash, Cary N.; Evans-Molina, Carmella.

In: Endocrine Practice, Vol. 18, No. 6, 01.11.2012, p. 954-964.

Research output: Contribution to journalArticle

@article{18c455d816d6498585afb927f980e67a,
title = "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.",
author = "Shoemaker, {Timothy J.} and Tatsuyoshi Kono and Mariash, {Cary N.} and Carmella Evans-Molina",
year = "2012",
month = "11",
day = "1",
doi = "10.4158/EP12086.RA",
language = "English",
volume = "18",
pages = "954--964",
journal = "Endocrine Practice",
issn = "1530-891X",
publisher = "American Association of Clinical Endocrinology",
number = "6",

}

TY - JOUR

T1 - Thyroid hormone analogues for the treatment of metabolic disorders

T2 - New potential for unmet clinical needs?

AU - Shoemaker, Timothy J.

AU - Kono, Tatsuyoshi

AU - Mariash, Cary N.

AU - Evans-Molina, Carmella

PY - 2012/11/1

Y1 - 2012/11/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84871386807&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84871386807&partnerID=8YFLogxK

U2 - 10.4158/EP12086.RA

DO - 10.4158/EP12086.RA

M3 - Article

VL - 18

SP - 954

EP - 964

JO - Endocrine Practice

JF - Endocrine Practice

SN - 1530-891X

IS - 6

ER -