The Experts below are selected from a list of 141 Experts worldwide ranked by ideXlab platform
Anders G. Olsson - One of the best experts on this subject based on the ideXlab platform.
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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.
Journal of internal medicine, 2014Co-Authors: Bo Angelin, Bo Carlsson, Anders G. Olsson, Jens D. Kristensen, E. Chester Ridgway, Irwin Klein, Mats Eriksson, Paul W. LadensonAbstract:BackgroundLiver-selective thyromimetic agents could provide a new approach for treating dyslipidaemia. MethodsWe performed a multicentre, randomized, placebo-controlled, double-blind study to evalu ...
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Eprotirome in patients with familial hypercholesterolaemia (the AKKA trial): a randomised, double-blind, placebo-controlled phase 3 study.
The lancet. Diabetes & endocrinology, 2014Co-Authors: Barbara Sjouke, Gisle Langslet, Richard Ceska, Stephen J. Nicholls, Steven E. Nissen, Maria Öhlander, Paul W. Ladenson, Anders G. Olsson, G. Kees Hovingh, John J.p. KasteleinAbstract:Summary Background Eprotirome is a liver-selective thyroid hormone receptor agonist that has been shown to lower plasma LDL cholesterol concentrations in previous phase 1 and 2 studies of patients with dyslipidaemia. We aimed to assess the long-term safety and efficacy of 50 μg and 100 μg Eprotirome in patients with familial hypercholesterolaemia. Methods For this randomised, double-blind, placebo-controlled, parallel-group, phase 3 clinical trial, we enrolled patients between Oct 3, 2011, and Feb 14, 2012, at 53 sites in 11 countries in Europe, Africa, and south Asia. Patients were eligible for enrolment if they were aged 18 years or older, diagnosed with heterozygous familial hypercholesterolaemia, and had not reached target LDL cholesterol concentrations after at least 8 weeks of statin therapy with or without ezetimibe. We used a computer-generated randomisation sequence to allocate patients to one of three groups: 50 μg Eprotirome, 100 μg Eprotirome, or placebo. This trial was planned for 52–76 weeks, with primary efficacy analysis at 12 weeks, but it was prematurely terminated when another study found that Eprotirome causes cartilage damage in dogs. Although it was impossible to meet the predefined study outcomes, we analysed changes in the concentrations of LDL cholesterol and other lipids, liver parameters, thyroid hormone concentrations, and adverse effects of treatment with Eprotirome versus placebo at 6 weeks of treatment. Analysis was done in all patients who received 6 weeks of treatment. This study is registered with ClinicalTrials.gov, number NCT01410383. Findings We enrolled 236 patients, randomly allocating 80 to receive placebo, 79 to receive 50 μg Eprotirome, and 77 to receive 100 μg Eprotirome. 69 patients reached the 6 week timepoint (23 given placebo, 24 given 50 μg Eprotirome, and 22 given 100 μg Eprotirome). Mean LDL cholesterol concentrations increased by 9% (95% CI −2 to 20) in the placebo group, decreased by 12% (−28 to 4%; p=0·0677 vs placebo) in the 50 μg Eprotirome group, and decreased by 22% (−32 to −13%; p=0·0045 vs placebo) in the 100 μg Eprotirome group. We noted statistically significant increases between both Eprotirome groups and placebo in aspartate aminotransferase (AST; p vs placebo for both groups). Interpretation Our findings show that Eprotirome can lower LDL cholesterol concentrations in patients with familial hypercholesterolaemia when added to conventional statin treatment with or without ezetimibe, but that it has the potential to induce liver injury. These findings, along with findings of cartilage damage in dogs, raise serious doubts about selective thyroid hormone mimetics as a therapeutic approach to lower LDL cholesterol concentrations. Funding Karo Bio AB.
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Recent advances in preventing cardiovascular disorders by managing lipid levels.
F1000 medicine reports, 2010Co-Authors: Anders G. OlssonAbstract:Advances in clinical lipidology during the last 18 months include the establishment of high-sensitivity C-reactive protein (hsCRP) as an important risk marker for cardiovascular disease. Determining hsCRP levels should help the clinician single out patients at particularly high risk. However, more research needs to be done in this area. Furthermore, statins do not seem to be of benefit in patients with severe congestive heart failure, on chronic hemodialysis, or with aortic stenosis. Next, plasma triglyceride levels are now considered an important risk marker for cardiovascular disease, but the therapeutic benefits related to lowering triglyceride levels remain difficult to achieve. Also, nicotinic acid has gained more interest partly because recent studies have demonstrated positive effects on atherosclerosis development and partly because the side effect of flushing seems to be partially avoidable with the concomitant administration of laropiprant. Both the raising of high-density lipoprotein cholesterol by nicotinic acid and the additional lowering of low-density lipoprotein cholesterol by ezetimibe and Eprotirome will need to demonstrate hard endpoint reductions in large-scale intervention trials. Trials of niacin/laropiprant (the AIM-HIGH and HPS2-THRIVE studies) and ezetimibe (the IMPROVE-IT study) are already under way.
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Use of the thyroid hormone analogue Eprotirome in statin-treated dyslipidemia
The New England journal of medicine, 2010Co-Authors: Paul W. Ladenson, Bo Carlsson, Anders G. Olsson, Jens D. Kristensen, E. Chester Ridgway, Irwin Klein, John D. Baxter, Bo AngelinAbstract:Background Dyslipidemia increases the risk of atherosclerotic cardiovascular disease and is incompletely reversed by statin therapy alone in many patients. Thyroid hormone lowers levels of serum low-density lipoprotein (LDL) cholesterol and has other potentially favorable actions on lipoprotein metabolism. Consequently, thyromimetic drugs hold promise as lipid-lowering agents if adverse effects can be avoided. Methods We performed a randomized, placebo-controlled, double-blind, multicenter trial to assess the safety and efficacy of the thyromimetic compound Eprotirome (KB2115) in lowering the level of serum LDL cholesterol in patients with hypercholesterolemia who were already receiving simvastatin or atorvastatin. In addition to statin treatment, patients received either Eprotirome (at a dose of 25, 50, or 100 μg per day) or placebo. Secondary outcomes were changes in levels of serum apolipoprotein B, triglycerides, and Lp(a) lipoprotein. Patients were monitored for potential adverse thyromimetic effects...
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Use of the Thyroid Hormone Analogue Eprotirome in Statin-Treated Dyslipidemia
Obstetrical & Gynecological Survey, 2010Co-Authors: Paul W. Ladenson, Bo Carlsson, Anders G. Olsson, Jens D. Kristensen, E. Chester Ridgway, Irwin Klein, John D. Baxter, Bo AngelinAbstract:ABSTRACT Statins effectively reduce levels of serum cholesterol and lower the risk of cardiovascular disease, but have limited effectiveness if stringent goals for serum low-density lipoprotein (LDL) cholesterol levels are not met or adverse effects develop, requiring a dose reduction or drug discontinuation. Previous studies have shown that thyroid hormone and some of its metabolites reduce levels of serum LDL cholesterol and have potentially favorable actions on other lipoproteins. The studies were discontinued because of reports of adverse effects on heart and bone, and possible deaths. In a recent report, Eprotirome, a thyromimetic compound with minimal uptake in nonhepatic-tissues, was shown to reduce levels of serum total and LDL cholesterol and apolipoprotein B without apparent side effects in patients not receiving statin therapy. This randomized, placebo-controlled, double-blind, multicenter trial investigated the safety and efficacy of Eprotirome in lowering the level of serum LDL cholesterol in patients with hypercholesterolemia who already were receiving simvastatin or atorvastatin. The aim of the study was to determine whether adding Eprotirome to statin therapy would provide additional lipid-lowering actions without producing adverse extrahepatic thyromimetic effects. Patients were randomly assigned to receive daily oral doses of 25, 50, or 100 mcg of Eprotirome or a placebo for 12 weeks. The primary study outcome was changes in serum LDL cholesterol. The potential adverse thyromimetic effects on the heart, bone, and pituitary were examined. Treatment of patients for 12 weeks already receiving statins with either placebo or Eprotirome at a dose of 25, 50, or 100 μg reduced the mean level of serum LDL cholesterol from 141 mg per deciliter (3.6 mmol per liter) at baseline to 127, 113, 99, and 94 mg per deciliter (3.3, 2.9, 2.6, and 2.4 mmol per liter), respectively; this represented a mean reduction from baseline of 7%, 22%, 28%, and 32%, respectively. Similar reductions were found in the secondary study outcomes, which included serum levels of apolipoprotein B, triglycerides, and Lp(a) lipoprotein. No evidence of adverse effects of Eprotirome on the heart, bone, or pituitary was noted. Although reductions in serum levels of thyroxine occurred in some patients who received Eprotirome, there were no changes in levels of thyrotropin or triiodothyronine. These findings demonstrate that the addition of Eprotirome to statin therapy produces substantial further reductions in serum LDL cholesterol, non–high-density lipoprotein cholesterol, and apolipoprotein B. The drug appears to have an excellent safety profile.
Bo Angelin - One of the best experts on this subject based on the ideXlab platform.
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thyroid hormone reduces pcsk9 and stimulates bile acid synthesis in humans
Journal of Lipid Research, 2014Co-Authors: Ylva Bonde, Olof Breuer, Stefan Sjoberg, Dieter Lutjohann, Bo Angelin, Mats RudlingAbstract:Reduced plasma LDL-cholesterol is a hallmark of hyperthyroidism and is caused by transcriptional stimulation of LDL receptors in the liver. Here, we investigated whether thyroid hormone (TH) actions involve other mechanisms that may also account for the reduction in LDL-cholesterol, including effects on proprotein convertase subtilisin/kexin type 9 (PCSK9) and bile acid synthesis. Twenty hyperthyroid patients were studied before and after clinical normalization, and the responses to hyperthyroidism were compared with those in 14 healthy individuals after 14 days of treatment with the liver-selective TH analog Eprotirome. Both hyperthyroidism and Eprotirome treatment reduced circulating PCSK9, lipoprotein cholesterol, apoB and AI, and lipoprotein(a), while cholesterol synthesis was stable. Hyperthyroidism, but not Eprotirome treatment, markedly increased bile acid synthesis and reduced fibroblast growth factor (FGF) 19 and dietary cholesterol absorption. Eprotirome treatment, but not hyperthyroidism, reduced plasma triglycerides. Neither hyperthyroidism nor Eprotirome treatment altered insulin, glucose, or FGF21 levels. TH reduces circulating PSCK9, thereby likely contributing to lower plasma LDL-cholesterol in hyperthyroidism. TH also stimulates bile acid synthesis, although this response is not critical for its LDL-lowering effect.
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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.
Journal of internal medicine, 2014Co-Authors: Bo Angelin, Bo Carlsson, Anders G. Olsson, Jens D. Kristensen, E. Chester Ridgway, Irwin Klein, Mats Eriksson, Paul W. LadensonAbstract:BackgroundLiver-selective thyromimetic agents could provide a new approach for treating dyslipidaemia. MethodsWe performed a multicentre, randomized, placebo-controlled, double-blind study to evalu ...
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Use of the thyroid hormone analogue Eprotirome in statin-treated dyslipidemia
The New England journal of medicine, 2010Co-Authors: Paul W. Ladenson, Bo Carlsson, Anders G. Olsson, Jens D. Kristensen, E. Chester Ridgway, Irwin Klein, John D. Baxter, Bo AngelinAbstract:Background Dyslipidemia increases the risk of atherosclerotic cardiovascular disease and is incompletely reversed by statin therapy alone in many patients. Thyroid hormone lowers levels of serum low-density lipoprotein (LDL) cholesterol and has other potentially favorable actions on lipoprotein metabolism. Consequently, thyromimetic drugs hold promise as lipid-lowering agents if adverse effects can be avoided. Methods We performed a randomized, placebo-controlled, double-blind, multicenter trial to assess the safety and efficacy of the thyromimetic compound Eprotirome (KB2115) in lowering the level of serum LDL cholesterol in patients with hypercholesterolemia who were already receiving simvastatin or atorvastatin. In addition to statin treatment, patients received either Eprotirome (at a dose of 25, 50, or 100 μg per day) or placebo. Secondary outcomes were changes in levels of serum apolipoprotein B, triglycerides, and Lp(a) lipoprotein. Patients were monitored for potential adverse thyromimetic effects...
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Use of the Thyroid Hormone Analogue Eprotirome in Statin-Treated Dyslipidemia
Obstetrical & Gynecological Survey, 2010Co-Authors: Paul W. Ladenson, Bo Carlsson, Anders G. Olsson, Jens D. Kristensen, E. Chester Ridgway, Irwin Klein, John D. Baxter, Bo AngelinAbstract:ABSTRACT Statins effectively reduce levels of serum cholesterol and lower the risk of cardiovascular disease, but have limited effectiveness if stringent goals for serum low-density lipoprotein (LDL) cholesterol levels are not met or adverse effects develop, requiring a dose reduction or drug discontinuation. Previous studies have shown that thyroid hormone and some of its metabolites reduce levels of serum LDL cholesterol and have potentially favorable actions on other lipoproteins. The studies were discontinued because of reports of adverse effects on heart and bone, and possible deaths. In a recent report, Eprotirome, a thyromimetic compound with minimal uptake in nonhepatic-tissues, was shown to reduce levels of serum total and LDL cholesterol and apolipoprotein B without apparent side effects in patients not receiving statin therapy. This randomized, placebo-controlled, double-blind, multicenter trial investigated the safety and efficacy of Eprotirome in lowering the level of serum LDL cholesterol in patients with hypercholesterolemia who already were receiving simvastatin or atorvastatin. The aim of the study was to determine whether adding Eprotirome to statin therapy would provide additional lipid-lowering actions without producing adverse extrahepatic thyromimetic effects. Patients were randomly assigned to receive daily oral doses of 25, 50, or 100 mcg of Eprotirome or a placebo for 12 weeks. The primary study outcome was changes in serum LDL cholesterol. The potential adverse thyromimetic effects on the heart, bone, and pituitary were examined. Treatment of patients for 12 weeks already receiving statins with either placebo or Eprotirome at a dose of 25, 50, or 100 μg reduced the mean level of serum LDL cholesterol from 141 mg per deciliter (3.6 mmol per liter) at baseline to 127, 113, 99, and 94 mg per deciliter (3.3, 2.9, 2.6, and 2.4 mmol per liter), respectively; this represented a mean reduction from baseline of 7%, 22%, 28%, and 32%, respectively. Similar reductions were found in the secondary study outcomes, which included serum levels of apolipoprotein B, triglycerides, and Lp(a) lipoprotein. No evidence of adverse effects of Eprotirome on the heart, bone, or pituitary was noted. Although reductions in serum levels of thyroxine occurred in some patients who received Eprotirome, there were no changes in levels of thyrotropin or triiodothyronine. These findings demonstrate that the addition of Eprotirome to statin therapy produces substantial further reductions in serum LDL cholesterol, non–high-density lipoprotein cholesterol, and apolipoprotein B. The drug appears to have an excellent safety profile.
Paul W. Ladenson - One of the best experts on this subject based on the ideXlab platform.
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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.
Journal of internal medicine, 2014Co-Authors: Bo Angelin, Bo Carlsson, Anders G. Olsson, Jens D. Kristensen, E. Chester Ridgway, Irwin Klein, Mats Eriksson, Paul W. LadensonAbstract:BackgroundLiver-selective thyromimetic agents could provide a new approach for treating dyslipidaemia. MethodsWe performed a multicentre, randomized, placebo-controlled, double-blind study to evalu ...
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Eprotirome in patients with familial hypercholesterolaemia (the AKKA trial): a randomised, double-blind, placebo-controlled phase 3 study.
The lancet. Diabetes & endocrinology, 2014Co-Authors: Barbara Sjouke, Gisle Langslet, Richard Ceska, Stephen J. Nicholls, Steven E. Nissen, Maria Öhlander, Paul W. Ladenson, Anders G. Olsson, G. Kees Hovingh, John J.p. KasteleinAbstract:Summary Background Eprotirome is a liver-selective thyroid hormone receptor agonist that has been shown to lower plasma LDL cholesterol concentrations in previous phase 1 and 2 studies of patients with dyslipidaemia. We aimed to assess the long-term safety and efficacy of 50 μg and 100 μg Eprotirome in patients with familial hypercholesterolaemia. Methods For this randomised, double-blind, placebo-controlled, parallel-group, phase 3 clinical trial, we enrolled patients between Oct 3, 2011, and Feb 14, 2012, at 53 sites in 11 countries in Europe, Africa, and south Asia. Patients were eligible for enrolment if they were aged 18 years or older, diagnosed with heterozygous familial hypercholesterolaemia, and had not reached target LDL cholesterol concentrations after at least 8 weeks of statin therapy with or without ezetimibe. We used a computer-generated randomisation sequence to allocate patients to one of three groups: 50 μg Eprotirome, 100 μg Eprotirome, or placebo. This trial was planned for 52–76 weeks, with primary efficacy analysis at 12 weeks, but it was prematurely terminated when another study found that Eprotirome causes cartilage damage in dogs. Although it was impossible to meet the predefined study outcomes, we analysed changes in the concentrations of LDL cholesterol and other lipids, liver parameters, thyroid hormone concentrations, and adverse effects of treatment with Eprotirome versus placebo at 6 weeks of treatment. Analysis was done in all patients who received 6 weeks of treatment. This study is registered with ClinicalTrials.gov, number NCT01410383. Findings We enrolled 236 patients, randomly allocating 80 to receive placebo, 79 to receive 50 μg Eprotirome, and 77 to receive 100 μg Eprotirome. 69 patients reached the 6 week timepoint (23 given placebo, 24 given 50 μg Eprotirome, and 22 given 100 μg Eprotirome). Mean LDL cholesterol concentrations increased by 9% (95% CI −2 to 20) in the placebo group, decreased by 12% (−28 to 4%; p=0·0677 vs placebo) in the 50 μg Eprotirome group, and decreased by 22% (−32 to −13%; p=0·0045 vs placebo) in the 100 μg Eprotirome group. We noted statistically significant increases between both Eprotirome groups and placebo in aspartate aminotransferase (AST; p vs placebo for both groups). Interpretation Our findings show that Eprotirome can lower LDL cholesterol concentrations in patients with familial hypercholesterolaemia when added to conventional statin treatment with or without ezetimibe, but that it has the potential to induce liver injury. These findings, along with findings of cartilage damage in dogs, raise serious doubts about selective thyroid hormone mimetics as a therapeutic approach to lower LDL cholesterol concentrations. Funding Karo Bio AB.
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Use of the thyroid hormone analogue Eprotirome in statin-treated dyslipidemia
The New England journal of medicine, 2010Co-Authors: Paul W. Ladenson, Bo Carlsson, Anders G. Olsson, Jens D. Kristensen, E. Chester Ridgway, Irwin Klein, John D. Baxter, Bo AngelinAbstract:Background Dyslipidemia increases the risk of atherosclerotic cardiovascular disease and is incompletely reversed by statin therapy alone in many patients. Thyroid hormone lowers levels of serum low-density lipoprotein (LDL) cholesterol and has other potentially favorable actions on lipoprotein metabolism. Consequently, thyromimetic drugs hold promise as lipid-lowering agents if adverse effects can be avoided. Methods We performed a randomized, placebo-controlled, double-blind, multicenter trial to assess the safety and efficacy of the thyromimetic compound Eprotirome (KB2115) in lowering the level of serum LDL cholesterol in patients with hypercholesterolemia who were already receiving simvastatin or atorvastatin. In addition to statin treatment, patients received either Eprotirome (at a dose of 25, 50, or 100 μg per day) or placebo. Secondary outcomes were changes in levels of serum apolipoprotein B, triglycerides, and Lp(a) lipoprotein. Patients were monitored for potential adverse thyromimetic effects...
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Use of the Thyroid Hormone Analogue Eprotirome in Statin-Treated Dyslipidemia
Obstetrical & Gynecological Survey, 2010Co-Authors: Paul W. Ladenson, Bo Carlsson, Anders G. Olsson, Jens D. Kristensen, E. Chester Ridgway, Irwin Klein, John D. Baxter, Bo AngelinAbstract:ABSTRACT Statins effectively reduce levels of serum cholesterol and lower the risk of cardiovascular disease, but have limited effectiveness if stringent goals for serum low-density lipoprotein (LDL) cholesterol levels are not met or adverse effects develop, requiring a dose reduction or drug discontinuation. Previous studies have shown that thyroid hormone and some of its metabolites reduce levels of serum LDL cholesterol and have potentially favorable actions on other lipoproteins. The studies were discontinued because of reports of adverse effects on heart and bone, and possible deaths. In a recent report, Eprotirome, a thyromimetic compound with minimal uptake in nonhepatic-tissues, was shown to reduce levels of serum total and LDL cholesterol and apolipoprotein B without apparent side effects in patients not receiving statin therapy. This randomized, placebo-controlled, double-blind, multicenter trial investigated the safety and efficacy of Eprotirome in lowering the level of serum LDL cholesterol in patients with hypercholesterolemia who already were receiving simvastatin or atorvastatin. The aim of the study was to determine whether adding Eprotirome to statin therapy would provide additional lipid-lowering actions without producing adverse extrahepatic thyromimetic effects. Patients were randomly assigned to receive daily oral doses of 25, 50, or 100 mcg of Eprotirome or a placebo for 12 weeks. The primary study outcome was changes in serum LDL cholesterol. The potential adverse thyromimetic effects on the heart, bone, and pituitary were examined. Treatment of patients for 12 weeks already receiving statins with either placebo or Eprotirome at a dose of 25, 50, or 100 μg reduced the mean level of serum LDL cholesterol from 141 mg per deciliter (3.6 mmol per liter) at baseline to 127, 113, 99, and 94 mg per deciliter (3.3, 2.9, 2.6, and 2.4 mmol per liter), respectively; this represented a mean reduction from baseline of 7%, 22%, 28%, and 32%, respectively. Similar reductions were found in the secondary study outcomes, which included serum levels of apolipoprotein B, triglycerides, and Lp(a) lipoprotein. No evidence of adverse effects of Eprotirome on the heart, bone, or pituitary was noted. Although reductions in serum levels of thyroxine occurred in some patients who received Eprotirome, there were no changes in levels of thyrotropin or triiodothyronine. These findings demonstrate that the addition of Eprotirome to statin therapy produces substantial further reductions in serum LDL cholesterol, non–high-density lipoprotein cholesterol, and apolipoprotein B. The drug appears to have an excellent safety profile.
Bo Carlsson - One of the best experts on this subject based on the ideXlab platform.
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Role of the Bile Acid Transporter SLC10A1 in Liver Targeting of the Lipid-Lowering Thyroid Hormone Analog Eprotirome
Endocrinology, 2017Co-Authors: Simone Kersseboom, Anja L M Van Gucht, Alies Van Mullem, Giulia Brigante, Stefania Farina, Bo Carlsson, Joanne M. Donkers, Stan F.j. Van De Graaf, Robin P. Peeters, Theo J. VisserAbstract:The thyroid hormone (TH) analog Eprotirome (KB2115) was developed to lower cholesterol through selective activation of the TH receptor (TR) β1 in the liver. Interestingly, Eprotirome shows low uptake in nonhepatic tissues, explaining its lipid-lowering action without adverse extrahepatic thyromimetic effects. Clinical trials have shown marked decreases in serum cholesterol levels. We explored the transport of Eprotirome across the plasma membrane by members of three TH transporter families: monocarboxylate transporters MCT8 and MCT10; Na-independent organic anion transporters 1A2, 1B1, 1B3, 1C1, 2A1, and 2B1; and Na-dependent organic anion transporters SLC10A1 to SLC10A7. Cellular transport was studied in transfected COS1 cells using [14C]Eprotirome and [125I]TH analogs. Of the 15 transporters tested initially, the liver-specific bile acid transporter SLC10A1 showed the highest Eprotirome uptake (greater than a sevenfold induction after 60 minutes) as well as TRβ1-mediated transcriptional activity. Uptake of Eprotirome by SLC10A1 was Na+ dependent and saturable with a Michaelis constant of 8 μM. Eprotirome transport was inhibited by known substrates for SLC10A1 (e.g., cholate and taurocholate), and by TH analogs such as triiodothyropropionic acid and triiodothyroacetic acid. However, no significant SLC10A1-mediated transport was observed of these [125I]TH analogs. We also studied the plasma disappearance and biliary excretion of [14C]Eprotirome injected in control and Slc10a1 knockout mice. Although Eprotirome is also transported by mouse Slc10a1, the pharmacokinetics of Eprotirome were not affected by Slc10a1 deficiency. In conclusion, we have demonstrated that the liver-specific bile acid transporter SLC10A1 effectively transports Eprotirome. However, Slc10a1 does not appear to be critical for the liver targeting of this TH analog in mice. Therefore, the importance of SLC10A1 for liver uptake of Eprotirome in humans remains to be elucidated.
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Role of the bile acid transporter SLC10A1 in liver targeting of the lipid-lowering thyroid hormone analog Eprotirome
'The Endocrine Society', 2017Co-Authors: Kersseboom Simone, Bo Carlsson, Van Gucht, Anja L. M., Van Mullem Alies, Brigante Giulia, Farina Stefania, Donkers, Joanne M., Van De Graaf, Stan F. J., Peeters, Robin P., Visser, Theo J.Abstract:The thyroid hormone (TH) analog Eprotirome (KB2115) was developed to lower cholesterol through selective activation of the TH receptor (TR) b1 in the liver. Interestingly, Eprotirome shows low uptake in nonhepatic tissues, explaining its lipid-lowering action without adverse extrahepatic thyromimetic effects. Clinical trials have shown marked decreases in serum cholesterol levels. We explored the transport of Eprotirome across the plasma membrane by members of three TH transporter families: monocarboxylate transporters MCT8 and MCT10; Na-independent organic anion transporters 1A2, 1B1, 1B3, 1C1, 2A1, and 2B1; and Na-dependent organic anion transporters SLC10A1 to SLC10A7. Cellular transport was studied in transfected COS1 cells using [14C]Eprotirome and [125I]TH analogs. Of the 15 transporters tested initially, the liver-specific bile acid transporter SLC10A1 showed the highest Eprotirome uptake (greater than a sevenfold induction after 60 minutes) as well as TRb1-mediated transcriptional activity. Uptake of Eprotirome by SLC10A1 was Na+ dependent and saturable with a Michaelis constant of 8 mM. Eprotirome transport was inhibited by known substrates for SLC10A1 (e.g., cholate and taurocholate), and by TH analogs such as triiodothyropropionic acid and triiodothyroacetic acid. However, no significant SLC10A1-mediated transport was observed of these [125I]TH analogs. We also studied the plasma disappearance and biliary excretion of [14C]Eprotirome injected in control and Slc10a1 knockout mice. Although Eprotirome is also transported by mouse Slc10a1, the pharmacokinetics of Eprotirome were not affected by Slc10a1 deficiency. In conclusion, we have demonstrated that the liver-specific bile acid transporter SLC10A1 effectively transports Eprotirome. However, Slc10a1 does not appear to be critical for the liver targeting of this TH analog inmice. Therefore, the importance of SLC10A1 for liver uptake of Eprotirome in humans remains to be elucidated. (Endocrinology 158: 3307-3318, 2017)
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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.
Journal of internal medicine, 2014Co-Authors: Bo Angelin, Bo Carlsson, Anders G. Olsson, Jens D. Kristensen, E. Chester Ridgway, Irwin Klein, Mats Eriksson, Paul W. LadensonAbstract:BackgroundLiver-selective thyromimetic agents could provide a new approach for treating dyslipidaemia. MethodsWe performed a multicentre, randomized, placebo-controlled, double-blind study to evalu ...
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Use of the thyroid hormone analogue Eprotirome in statin-treated dyslipidemia
The New England journal of medicine, 2010Co-Authors: Paul W. Ladenson, Bo Carlsson, Anders G. Olsson, Jens D. Kristensen, E. Chester Ridgway, Irwin Klein, John D. Baxter, Bo AngelinAbstract:Background Dyslipidemia increases the risk of atherosclerotic cardiovascular disease and is incompletely reversed by statin therapy alone in many patients. Thyroid hormone lowers levels of serum low-density lipoprotein (LDL) cholesterol and has other potentially favorable actions on lipoprotein metabolism. Consequently, thyromimetic drugs hold promise as lipid-lowering agents if adverse effects can be avoided. Methods We performed a randomized, placebo-controlled, double-blind, multicenter trial to assess the safety and efficacy of the thyromimetic compound Eprotirome (KB2115) in lowering the level of serum LDL cholesterol in patients with hypercholesterolemia who were already receiving simvastatin or atorvastatin. In addition to statin treatment, patients received either Eprotirome (at a dose of 25, 50, or 100 μg per day) or placebo. Secondary outcomes were changes in levels of serum apolipoprotein B, triglycerides, and Lp(a) lipoprotein. Patients were monitored for potential adverse thyromimetic effects...
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Use of the Thyroid Hormone Analogue Eprotirome in Statin-Treated Dyslipidemia
Obstetrical & Gynecological Survey, 2010Co-Authors: Paul W. Ladenson, Bo Carlsson, Anders G. Olsson, Jens D. Kristensen, E. Chester Ridgway, Irwin Klein, John D. Baxter, Bo AngelinAbstract:ABSTRACT Statins effectively reduce levels of serum cholesterol and lower the risk of cardiovascular disease, but have limited effectiveness if stringent goals for serum low-density lipoprotein (LDL) cholesterol levels are not met or adverse effects develop, requiring a dose reduction or drug discontinuation. Previous studies have shown that thyroid hormone and some of its metabolites reduce levels of serum LDL cholesterol and have potentially favorable actions on other lipoproteins. The studies were discontinued because of reports of adverse effects on heart and bone, and possible deaths. In a recent report, Eprotirome, a thyromimetic compound with minimal uptake in nonhepatic-tissues, was shown to reduce levels of serum total and LDL cholesterol and apolipoprotein B without apparent side effects in patients not receiving statin therapy. This randomized, placebo-controlled, double-blind, multicenter trial investigated the safety and efficacy of Eprotirome in lowering the level of serum LDL cholesterol in patients with hypercholesterolemia who already were receiving simvastatin or atorvastatin. The aim of the study was to determine whether adding Eprotirome to statin therapy would provide additional lipid-lowering actions without producing adverse extrahepatic thyromimetic effects. Patients were randomly assigned to receive daily oral doses of 25, 50, or 100 mcg of Eprotirome or a placebo for 12 weeks. The primary study outcome was changes in serum LDL cholesterol. The potential adverse thyromimetic effects on the heart, bone, and pituitary were examined. Treatment of patients for 12 weeks already receiving statins with either placebo or Eprotirome at a dose of 25, 50, or 100 μg reduced the mean level of serum LDL cholesterol from 141 mg per deciliter (3.6 mmol per liter) at baseline to 127, 113, 99, and 94 mg per deciliter (3.3, 2.9, 2.6, and 2.4 mmol per liter), respectively; this represented a mean reduction from baseline of 7%, 22%, 28%, and 32%, respectively. Similar reductions were found in the secondary study outcomes, which included serum levels of apolipoprotein B, triglycerides, and Lp(a) lipoprotein. No evidence of adverse effects of Eprotirome on the heart, bone, or pituitary was noted. Although reductions in serum levels of thyroxine occurred in some patients who received Eprotirome, there were no changes in levels of thyrotropin or triiodothyronine. These findings demonstrate that the addition of Eprotirome to statin therapy produces substantial further reductions in serum LDL cholesterol, non–high-density lipoprotein cholesterol, and apolipoprotein B. The drug appears to have an excellent safety profile.
John J.p. Kastelein - One of the best experts on this subject based on the ideXlab platform.
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Effects of Supra-Physiological Levothyroxine Dosages on Liver Parameters, Lipids and Lipoproteins in Healthy Volunteers: A Randomized Controlled Crossover Study
Scientific Reports, 2017Co-Authors: Barbara Sjouke, G. Kees Hovingh, John J.p. Kastelein, Laura P. B. Elbers, Bregje Van Zaane, Victor E. A. GerdesAbstract:Eprotirome, a liver specific thyroid hormone agonist, was shown to induce significant increases in markers of liver injury along with a modest decrease in atherogenic lipids and lipoproteins. To get more insight into whether these effects on liver parameters were compound specific or the effect of mimicking thyrotoxicosis, we studied the effects of supra-physiological levothyroxine dosages on liver parameters, lipids and lipoproteins. We used data of a single-blinded, randomized controlled crossover trial. Herein, healthy volunteers received levothyroxine or no medication for 14 days. Thyroid hormone excess did not induce clinically relevant changes in liver parameters, while significant reductions in total cholesterol, low-density lipoprotein-cholesterol as well as apolipoprotein-B levels were observed in the intervention periods compared with the control periods. Supra-physiological thyroid hormone levels did not induce clinically relevant increases in markers of liver injury after 2 weeks of exposure, while it reduced total cholesterol, low-density lipoprotein cholesterol and apolipoprotein B levels. This suggests that the effects of Eprotirome on liver parameters in previous studies were either off-target and compound specific or due to drug-drug interaction at the level of the liver. The results of our study are relevant for the development of novel thyroid hormone agonists to reduce atherogenic lipoproteins.
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Eprotirome in patients with familial hypercholesterolaemia (the AKKA trial): a randomised, double-blind, placebo-controlled phase 3 study.
The lancet. Diabetes & endocrinology, 2014Co-Authors: Barbara Sjouke, Gisle Langslet, Richard Ceska, Stephen J. Nicholls, Steven E. Nissen, Maria Öhlander, Paul W. Ladenson, Anders G. Olsson, G. Kees Hovingh, John J.p. KasteleinAbstract:Summary Background Eprotirome is a liver-selective thyroid hormone receptor agonist that has been shown to lower plasma LDL cholesterol concentrations in previous phase 1 and 2 studies of patients with dyslipidaemia. We aimed to assess the long-term safety and efficacy of 50 μg and 100 μg Eprotirome in patients with familial hypercholesterolaemia. Methods For this randomised, double-blind, placebo-controlled, parallel-group, phase 3 clinical trial, we enrolled patients between Oct 3, 2011, and Feb 14, 2012, at 53 sites in 11 countries in Europe, Africa, and south Asia. Patients were eligible for enrolment if they were aged 18 years or older, diagnosed with heterozygous familial hypercholesterolaemia, and had not reached target LDL cholesterol concentrations after at least 8 weeks of statin therapy with or without ezetimibe. We used a computer-generated randomisation sequence to allocate patients to one of three groups: 50 μg Eprotirome, 100 μg Eprotirome, or placebo. This trial was planned for 52–76 weeks, with primary efficacy analysis at 12 weeks, but it was prematurely terminated when another study found that Eprotirome causes cartilage damage in dogs. Although it was impossible to meet the predefined study outcomes, we analysed changes in the concentrations of LDL cholesterol and other lipids, liver parameters, thyroid hormone concentrations, and adverse effects of treatment with Eprotirome versus placebo at 6 weeks of treatment. Analysis was done in all patients who received 6 weeks of treatment. This study is registered with ClinicalTrials.gov, number NCT01410383. Findings We enrolled 236 patients, randomly allocating 80 to receive placebo, 79 to receive 50 μg Eprotirome, and 77 to receive 100 μg Eprotirome. 69 patients reached the 6 week timepoint (23 given placebo, 24 given 50 μg Eprotirome, and 22 given 100 μg Eprotirome). Mean LDL cholesterol concentrations increased by 9% (95% CI −2 to 20) in the placebo group, decreased by 12% (−28 to 4%; p=0·0677 vs placebo) in the 50 μg Eprotirome group, and decreased by 22% (−32 to −13%; p=0·0045 vs placebo) in the 100 μg Eprotirome group. We noted statistically significant increases between both Eprotirome groups and placebo in aspartate aminotransferase (AST; p vs placebo for both groups). Interpretation Our findings show that Eprotirome can lower LDL cholesterol concentrations in patients with familial hypercholesterolaemia when added to conventional statin treatment with or without ezetimibe, but that it has the potential to induce liver injury. These findings, along with findings of cartilage damage in dogs, raise serious doubts about selective thyroid hormone mimetics as a therapeutic approach to lower LDL cholesterol concentrations. Funding Karo Bio AB.