Thyroid Hormone Mimetics: the Past, Current Status and Future Challenges
Curr Atheroscler Rep
Thyroid Hormone Mimetics: the Past, Current Status and Future Challenges
L.P.B. Elbers 0 1 2
J.J.P. Kastelein 0 1 2
B. Sjouke 0 1 2
0 Department of Internal Medicine, Medical Center Slotervaart , Amsterdam , The Netherlands
1 Department of Vascular Medicine, Academic Medical Center , Meibergdreef 9, 1105 AZ Amsterdam , The Netherlands
2 Conflict of Interest L. P. B. Elbers and B. Sjouke declare that they have no conflict of interest. J.J.P. Kastelein declares personal fees for consulting from Cerenis, The Medicines Company, CSL Behring, Regeneron, Eli Lilly , Esperion, AstraZeneca, Pronova, Boehringer Ingelheim, Catabasis, Novartis, Merck, Kowa, Sanofi, Gemphire, Cymabay, Amgen, Dezima Pharmaceuticals, Isis Pharmaceuticals and Genzyme
The association between thyroid hormone status and plasma levels of low-density lipoprotein cholesterol has raised the awareness for the development of thyroid hormone mimetics as lipid-lowering agents. The discovery of the two main types of thyroid hormone receptors (α and β) as well as the development of novel combinatorial chemistry providing organ specificity has drastically improved the selectivity of these compounds. In the past decades, several thyroid hormone mimetics have been investigated with the purpose of lowering low-density lipoprotein cholesterol levels. However, until now, none of the thyromimetics reached the stage of completing a phase III clinical trial without deleterious side effects. Here, we review the currently available literature on thyromimetics investigated for the treatment of dyslipidemia, their rise, their downfall and the challenges for the development of novel agents. This article is part of the Topical Collection on Nonstatin Drugs
Thyroid hormone mimetics; Thyroid hormone receptor; Dyslipidemia; Low-density lipoprotein cholesterol
Published online: 17 February 2016
# The Author(s) 2016. This article is published with open access at Springerlink.com
Since the 1950s, thyroid hormones have been shown to affect
lipid homeostasis [
] and thyroid hormone status has shown to
be inversely related to low-density lipoprotein cholesterol
(LDL-C) levels. In line, physicians and researchers have
appreciated the relationship between hypothyroidism and
atherosclerotic vascular disease for over 100 years [
]. Thyroid hormone
supplementation results in beneficial effects on lipid and
lipoprotein concentrations in patients with hypothyroidism [
the American Thyroid Association has recommended that all
patients with hypercholesterolaemia should be screened for
thyroid dysfunction prior to initiation of lipid-lowering therapy [
The association between thyroid hormone status and
atherogenic lipoprotein particles has raised the attention for thyroid
hormone mimetics as lipid-lowering agents. Although the precise
mechanism of atherogenic lipoprotein particle reduction by
thyroid hormone and thyroid hormone mimetics is not completely
elucidated to date, several mechanisms have been proposed.
First, thyroid hormone increases the activity of the promotor
of the human low-density lipoprotein receptor (LDLR) gene,
resulting in increased LDLR expression and, as a consequence,
decreased plasma LDL-C levels [
]. Moreover, thyroid
hormone mimetics have shown to induce Cyp7a1, the
ratelimiting enzyme of bile acid synthesis, independent of the
LDLR, in LDLR knockout mice [
]. Third, thyroid hormone
has shown to induce reverse cholesterol transport via
upregulation of hepatic scavenger receptor B1 (SR-B1) levels [
discovery of the two main types of thyroid hormone receptors
(TRs TRα and TRβ) [
] as well as the development of
combinational chemistry to provide organ specificity has drastically
improved the selectivity of thyroid hormone mimetics, and
some have shown to significantly reduce atherosclerosis in
apolipoprotein E (ApoE) knockout mice, an established pre-clinical
model for atherosclerosis [
]. However, to date, (potential)
side effects have limited their clinical use in the arena of
cardiometabolic disease. Here, we discuss the different
thyromimetics that have been investigated for the treatment of
dyslipidemia, their discontinuation and the challenges for the
development of novel compounds (Fig. 1). Moreover, we
provide a literature update on the thyromimetics currently in
development for the treatment of dyslipidemia.
Thyroid and Thyroid Hormone
One of the first studies that tested the use of thyroid (hormone)
to reduce plasma cholesterol in human was published in 1957
]. It was observed that administration of dried thyroid
reduced plasma LDL-C levels, suggesting that this could be
considered as an agent for the prevention of coronary heart
disease. A few years later (1960s), the Coronary Drug Project
(CDP) was performed to determine whether dextrothyroxine,
the D-enantiomer of thyroxine, and other lipid-modifying
agents improved survival in men who had suffered from a
heart attack [
]. Again, the positive effects of LDL-C
lowering were observed but the side effects, particularly related to
an excess of adverse cardiovascular outcomes, resulted in the
discontinuation of this specific arm of the CDP. This further
stimulated the justification to develop thyroid hormone
analogues that target the liver without the negative effects on the
heart and other extrahepatic organs (e.g. complaints of
increased metabolism including excessive sweating). Years
later, tiratricol (triiodo-thyroacetic acid) was tested in human but
this compound also had deleterious effects on the heart and led
to increased bone turnover, discontinuing its pursuit for the
treatment of cardiometabolic disease [
First Organ-Selective Thyromimetics
In 1986, the first organ-selective thyromimetic,
3,3-dibromo-3′pyridazinone-1-thyronine (L-94901), was described [
compound had cholesterol-lowering effects in hypothyroid rats
without deleterious effects on the heart. At that time, several
similar compounds were developed such as CGH-509A and
CGS 23425. CGH-509A reduced cholesterol levels in rodents
]. CGS 23425 decreased the levels of ApoB-100 [
23425 also increased apolipoprotein A1 levels and LDL-C
clearance in rats, without cardiotoxicity [
]. T-0681 reduced
the development of atherosclerosis by 80 % in rabbits on a
high-cholesterol chow diet [
] and promoted reverse
cholesterol transport in mice [
]. Due to unclear reasons, the
development of these compounds was not pursued in humans.
Thyroid Hormone Receptor Beta Agonists
After the first efforts on the development of selective thyroid
hormone receptor modulators, cloning of the thyroid receptor
led to the identification of two major thyroid receptor subtypes
with different tissue distributions throughout the body. The TRα
isoform is predominantly present in the brain, heart, and skeletal
muscles, whereas TRβ is predominantly present in the liver and
also in the brain [
]. Efforts were now focused on the design of
several TRβ-selective compounds, characterized by increased
binding to TRβ compared with TRα receptors.
2,5Diiodothyropropionic acid (DITPA) is a thyromimetic
compound that binds weakly to both TRα as well as TRβ receptors,
but with a modestly higher affinity for TRβ. Approximately
6 months of DITPA therapy resulted in a decrease in total
cholesterol (TC) as well as LDL-C levels by ~20 and 30 %,
respectively, in patients with congestive heart failure [
effects were observed when patients used DITPA as an add-on to
statin therapy . Body weight was also reduced [
DITPA decreased thyroid-stimulating hormone (TSH) levels
without inducing signs or symptoms of hypothyroidism or
thyrotoxicosis. However, high rates of side effects, including fatigue
and gastrointestinal complaints, were observed. Moreover,
DITPA therapy resulted in potentially deleterious effects on
serum markers of both bone formation (osteocalcin) as well as
turnover/degradation (N-telopeptide and deoxypyridinoline). As
a consequence, the DITPA program was discontinued [
GC-1 (or sobetirome; Table 1) is one of the first compounds
designed in a series of analogues, with, amongst others, a
3′isopropyl substitution at the distal phenyl ring of the molecule
(instead of iodine in T3). GC-1 has at least a ~3–18-fold
selectivity for TRβ over TRα [
]. This selectivity is (partly)
based on the presence of a single amino acid (Asn-331) within
the TRβ domain . Sobetirome has shown to reduce serum
cholesterol and triglyceride levels by 25 and 75 %, respectively,
in chow-fed euthyroid mice [
]. In a phase I study, GC-1 reduced
LDL-C levels up to 41 %, in normolipidaemic subjects, after
2 weeks [
]. In line, Kannisto and co-workers recently showed
that GC-1 is able to reduce atherosclerosis, defined as cholesterol
content in the arterial wall, in aortas of ApoE-deficient mice [
Moreover, in a recent study, it has been shown that unlike 3,5,3′
5′-tetraiodothyronine (T4), GC-1 did not influence tolerance to
physical exercise in hypothyroid rats [
]. This is of importance
since both hypothyroidism as well as hyperthyroidism itself are
associated with exercise intolerance [
Effect on lipid
↓ LDL-C up to 41 %
NA, generally well
↓ TC by 17–27 %
↓ LDL-C by 22–
↓ TG by 16–33 %
↓ Lp(a) by 27–43 %
↓ ApoB by 21–31 %
↓ TC up to 23 %
↓ LDL-C up to 30 %
↓ TG up to 24 %
↓ ApoB up to 60 %
Significant increases in
in phase III
Deleterious effects on
cartilage in canines
No evidence for any
deleterious effects on
the heart and liver, to
↓ = lowering
TC total cholesterol, LDL-C low-density lipoprotein cholesterol, TG triglycerides, Lp(a) lipoprotein (a), ApoB apolipoprotein B, NA not available
GC-24 is a TRβ receptor agonist with similar affinity for
TRβ to TRα, but with a much higher selectivity. This increased
selectivity (~40-fold for TRβ over TRα) was reached by the
addition of a phenyl group at the 3′ position of the distal aryl
ring of GC-1 [
] and the subsequent creation of a new
hydrophobic cluster [
]. GC-24, in contrast to GC-1, has shown to
have no activity in the brain, which has been suggested to be
caused by a limited entry through the blood-brain barrier [
Another group of TRβ analogues comprised KB141 and
KB2115 (or eprotirome; Table 1). KB141 was designed in a
series of compounds varying in length of a carboxylic acid
chain, which resulted in a profound effect on affinity and
specificity of the agents [
]. Seven days of treatment with 154, 462
or 924 nmol/kg/day of KB-141 resulted in plasma cholesterol
reductions up to ~35 % from baseline. Although a small
increase in heart rate was observed in cholesterol-fed Sprague
Dawley rats treated with KB141, no tachycardia was observed
in monkeys [
]. In addition to the identification of the different
TR subtypes, the insight that TRα and TRβ are differently
distributed throughout the body resulted in the development
of agents with both TRβ as well as liver selectivity.
Eprotirome, a compound with these characteristics, was the first
thyroid hormone mimetic designed for the treatment of
dyslipidemia that reached phase III of clinical development. A
12week treatment with eprotirome as an add-on to statins has
shown to significantly decrease LDL-C, triglyceride and
lipoprotein (a) levels by 22–32, 16–33 and 27–43 %, respectively,
in patients with hypercholesterolaemia [
]. The eprotirome
program has, however, been terminated prematurely due to
deleterious effects on cartilage observed in canines . A
phase III study in patients with familial hypercholesterolaemia,
which was performed in parallel with the study in dogs,
revealed significant increases in aspartate aminotransferase
(AST) and alanine aminotransferase (ALT) levels by 114 and
189 %, respectively, after 6 weeks of treatment with 100 μg of
eprotirome [33•]. To date, it is unknown whether these adverse
hepatic effects of eprotirome were off-target and
compoundspecific, due to an effect mimicking thyrotoxicosis in the liver
or due to a drug-drug interaction at the level of the liver.
Although an extensive review of the literature about the
effects of thyromimetics on hepatic steatosis and insulin
sensitivity is beyond the scope of this review, it is worth noting
that given the weight-reducing potential of TR activation, both
sobetirome as well as eprotirome have been studied as
therapeutic strategies for the treatment of metabolic disorders,
including non-alcoholic fatty liver disease (NAFLD), in rodents.
Although treatment with both GC-1 as well as KB2115
resulted in a decrease of hepatic steatosis, the effects on glycaemia
and insulin sensitivity were variable and time-, dosage- and
In the search for finding thyromimetics with selectivity for
both TRβ as well as the liver, Madrigal Pharmaceuticals
recently developed a series of pyridazinone analogues, which,
amongst others, resulted in the identification of MGL-3196
(Table 1). This compound has a 28-fold TRβ selectivity over
] and is currently being investigated in phase I clinical
trials. MGL-3196 significantly reduced LDL-C, ApoB and
non-HDL levels up to 30, 24 and 28 %, respectively, after a
2-week daily dose of 5–200 mg (compared with increases of
3.1, 4.2 and 8.9 %, respectively, with placebo). In contrast to
eprotirome, which mildly increased transaminase levels in
phases 1 and 2 [
], no increases in liver parameters were
observed in healthy volunteers with mildly elevated LDL-C
levels treated with MGL-3196 for 2 weeks [26••].
Moreover, no evidence for any deleterious effects on the
heart was observed [26••]. The question remains whether
MGL-3196 is safe as an add-on to statins, since these are
considered as the cornerstone for lipid-lowering therapy in
patients with dyslipidemia. A phase I dose interaction study
(NCT02542969) has recently been completed [
results of this study are eagerly awaited.
Thyroid Hormone Receptor Beta and Liver-Selective
The goal of the development of liver-targeted prodrugs was to
deliver the thyromimetics to the site where cholesterol is
produced (i.e. the liver) while reducing the exposure of the
compound to other tissues in order to prevent side effects. The
liverselective, cytochrome P450-activated, prodrug MB07811 (2R,
]dioxaphosphonane undergoes first-pass hepatic extraction.
Subsequent cleavage of this prodrug generates the negatively
charged phosphonate-containing thyromimetic
acid (MB07344), which distributes poorly into most tissues.
MB07344 is rapidly eliminated in the bile to escape the
enterohepatic recirculation [
] and has been shown to reduce
cholesterol and both serum as well as hepatic triglycerides in
]. Other studies showed that MB07811 markedly
reduced hepatic steatosis and plasma free fatty acids and
triglycerides in rodents with hepatic steatosis [
levels remained unchanged, and MB07811 did not increase
heart weight or decrease pituitary expression of
thyroidstimulating hormone β (TSHβ). Beside this, no effects on
muscle and bone were observed at therapeutic dosages [
rabbits, dogs and monkeys, it was observed that the effects of
MB07811 and atorvastatin in lowering plasma TC were
]. This led to the hypothesis that this compound could
have clinical utility as a treatment to further reduce plasma TC
levels in patients that did not yet reach their cholesterol
treatment goals despite statin treatment. In 2006, a phase Ia clinical
trial demonstrated the safety and tolerability of MB07811 in a
single-dose study [
]. The results of a subsequent phase Ib trial
with MB07811 were promising since it was both efficacious
(placebo-corrected decreases in LDL cholesterol of 15–41 %
and in triglyceride levels of >30 % in patients with mild
hypercholesterolaemia compared with placebo) as well as safe in
different dosages up to 40 mg [
]. No differences in heart rate,
heart rhythm or blood pressure, between MB07811- and
placebo-treated patients, were observed. Unexpectedly,
MB07811 caused a mild elevation of liver enzymes. Beside
this, it decreased total and free thyroxine (FT4) levels by day
7 with both doses of MB07811 [
]. A phase II randomized,
placebo-controlled study assessing the efficacy, safety and
tolerability of MB07811 given orally to subjects with primary
hypercholesterolaemia for 12 weeks was planned, but this study
has been stopped prior to initiation as the developing company
Metabasis Therapeutics, Inc. was acquired by Ligand
Pharmaceuticals, Inc. [
]. Further trials were not initiated.
Thyroid Hormone Receptor Beta Agonists
Recently, a series of 1-benzylindole-based TRβ agonists were
prepared and evaluated, in a search for more TRβ-selective
hepato-specific modulators [
]. This work investigated the
potential use of indoles as inner ring isosteres. Two
compounds of interest were found, later named as SKL-12846
and SKL-13784. Liver concentrations of these compounds
were 100-fold greater than the heart or brain concentrations
and at least 10-fold greater than the plasma concentration. The
liver specificity of SKL-12846 and SKL-13784 is achieved by
active uptake by specific transporters [
]. These two
compounds were orally administered to cholesterol-fed rats and
showed to produce a significant reduction in TC levels. Of
note, heart rate and heart weight increased following treatment
with both compounds. The increase in heart rate produced by
the two analogues was, however, less than 15 %, which is
considered to be the upper limit for clinical use [
]. No effect
was seen on TSH levels due to its low brain penetration. A
more recent study, however, showed that SKL-13784
significantly reduced endogenous T4 levels at doses lower than its
lipid-lowering dose, by an unclarified mechanism [
may raise concern over this compound’s ability to alter thyroid
hormone metabolism in the liver and, therefore, the impact on
the potential usefulness of this liver-selective TRβ agonist.
Beside this, the research that has been performed on these
compounds, to date, does not rule out whether these
compounds could have deleterious effects on the liver itself.
In summary, during the past decades, several thyromimetics
have been developed with varying but convincing efficacies
on atherogenic lipids and lipoproteins. Until now, none of the
thyromimetics reached the stage of completing a phase III
clinical trial without deleterious side effects. Several
explanations could underlie these discontinuations. First, the
development of TRβ-selective thyromimetics is complicated by the
fact that endocrine physiology is highly complex and that the
precise distribution of TRα and TRβ throughout the body is
not completely elucidated to date. Even if thyroid hormone
mimetics were shown not to interfere with the
hypothalamicpituitary-thyroid axis, they could still result in unexpected side
effects. Moreover, even if exclusive TRβ and liver selectivity
would be reached, this would not exclude a potential effect on
other organ systems. It was, for example, recently shown that
hyperthyroidism leads to a hypercoagulable state [
] and that
patients with hyperthyroidism are at increased risk of
developing venous thrombosis [
]. One could speculate that
the agonistic effect of thyromimetics on the TRβ could induce
a hypercoagulable state.
To the best of our knowledge, currently, only MGL-3196 is
being actively tested in humans. The effects of MGL-3196,
resulting in LDL-C reductions up to 30 % from baseline
without effects on liver parameters, are promising, and the results
of recently completed clinical trials (e.g. NCT02542969) and
the effects on cardiovascular outcomes need to be awaited.
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Papers of particular interest, published recently, have been
• Of importance
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