Reductions in serum levels of <scp>LDL</scp> cholesterol, apolipoprotein B, triglycerides and lipoprotein(a) in hypercholesterolaemic patients treated with the liver‐selective thyroid hormone receptor agonist eprotirome

Angelin, Bo; Kristensen, Jens D.; Eriksson, Mats; Carlsson, Bo; Klein, Irwin; Olsson, Anders; Ridgway, E. Chester; Ladenson, Paul W.

doi:10.1111/joim.12261

Cited by 45 publications

(25 citation statements)

References 37 publications

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“…In the last few years, many thyromimetics have been designed to be used to reduce hypercholesterolaemia and/or hypertriglyceridemia in the absence of T3‐induced adverse thyrotoxic effects on the heart, skeletal muscle, bone or pituitary gland 13,19,20,32,36,37 . After initial encouraging results, the development of some of these drugs (ie KB2115, GC‐1) was hampered due to unwanted side effects 21 …”

Section: Discussionmentioning

confidence: 99%

Potential role of two novel agonists of thyroid hormone receptor‐β on liver regeneration

et al. 2020

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Objectives Although the hepatomitogenic activity of triiodothyronine (T3) is well established, the wide range of harmful effects exerted by this hormone precludes its use in liver regenerative therapy. Selective agonists of the beta isoform of thyroid hormone receptor (TRβ) do not exhibit T3‐induced cardiotoxicity and show a good safety profile in patients with NASH. The aim of this study was to investigate whether two novel TRβ agonists, the prodrug TG68 and the active compound IS25 could stimulate hepatocyte proliferation without T3/TRα‐dependent side effects. Methods Rats were treated with three different doses (12.5, 25 and 50 μg/100 g body weight) for one week. Hepatocyte proliferation, liver injury and serum biochemical parameters were measured by immunohistochemistry, qRT‐PCR and Western blot. Results Both drugs increased hepatocyte proliferation as assessed by bromodeoxyuridine incorporation (from 14% to 28% vs 5% of controls) and mitotic activity. Enhanced proliferation occurred in the absence of significant signs of liver injury as shown by lack of increased serum transaminase levels or of apoptosis. No cardiac or renal hypertrophy typically associated with treatment with T3 was observed. Importantly, no proliferation of pancreatic acinar cells, such as that seen after administration of T3 or the TRβ agonist GC1 was detected following either TG68 or IS25, demonstrating the hepato‐specificity of these novel TRβ agonists. Conclusions The present study shows that TG68 and IS25 induce massive hepatocyte proliferation without overt toxicity. Hence, these agents may have a significant clinical application for regenerative therapies in liver transplantation or other surgical settings.

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Section: Discussionmentioning

confidence: 99%

Potential role of two novel agonists of thyroid hormone receptor‐β on liver regeneration

et al. 2020

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“…The specificity towards hepatic TRb comes from its tissue distribution pattern; it accumulates preferentially in the liver. KB2115 (eprotirome) displays a higher TRb selectivity (15-fold higher compared to TRa) and similar liver accumulation as GC-1; both of these compounds have been shown to reduce serum cholesterol in mice and humans [31,32]. Tissue distribution patterns for KB3495 have not been published, but KB3495 displays approximately half the IC50 concentration with recombinant TRb compared to TRa.…”

Section: Discussionmentioning

confidence: 98%

The thyroid receptor β modulator GC-1 reduces atherosclerosis in ApoE deficient mice

et al. 2014

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“…Increasing doses of the liver-selective TRb agonist eprotirome were associated with LDL cholesterol reduction in a graded manner, with similar effects on apolipoprotein B, triglycerides, and lipoprotein(a) (84). The broad effects of eprotirome on lipids could derive from its specific pharmacodynamics or higher TRb engagement in the liver compared with thyroxine.…”

Section: Current State Of the Fieldmentioning

confidence: 98%

Thyroid and Cardiovascular Disease: Research Agenda for Enhancing Knowledge, Prevention, and Treatment

Cappola

Desai

Medici

et al. 2019

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Thyroid hormones have long been known to have a range of effects on the cardiovascular system. However, significant knowledge gaps exist concerning the precise molecular and biochemical mechanisms governing these effects and the optimal strategies for management of abnormalities in thyroid function in patients with and without preexisting cardiovascular disease. In September 2017, The National Heart, Lung, and Blood Institute convened a Working Group with the goal of developing priorities for future scientific research relating thyroid dysfunction to the progression of cardiovascular disease. The Working Group reviewed and discussed the roles of normal thyroid physiology, the consequences of thyroid dysfunction, and the effects of therapy in three cardiovascular areas: cardiac electrophysiology and arrhythmias, the vasculature and atherosclerosis, and the myocardium and heart failure. This report describes the current state of the field, outlines barriers and challenges to progress, and proposes research opportunities to advance the field, including strategies for leveraging novel approaches using omics and big data. The Working Group recommended research in three broad areas: 1) investigation into the fundamental biology relating thyroid dysfunction to the development of cardiovascular disease and into the identification of novel biomarkers of thyroid hormone action in cardiovascular tissues; 2) studies that define subgroups of patients with thyroid dysfunction amenable to specific preventive strategies and interventional therapies related to cardiovascular disease; and 3) clinical trials focused on improvement in cardiovascular performance and cardiovascular outcomes through treatment with thyroid hormone or thyromimetic drugs.

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Reductions in serum levels of LDL cholesterol, apolipoprotein B, triglycerides and lipoprotein(a) in hypercholesterolaemic patients treated with the liver‐selective thyroid hormone receptor agonist eprotirome

Cited by 45 publications

References 37 publications

Potential role of two novel agonists of thyroid hormone receptor‐β on liver regeneration

Potential role of two novel agonists of thyroid hormone receptor‐β on liver regeneration

The thyroid receptor β modulator GC-1 reduces atherosclerosis in ApoE deficient mice

Thyroid and Cardiovascular Disease: Research Agenda for Enhancing Knowledge, Prevention, and Treatment

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