Use of the Thyroid Hormone Analogue Eprotirome in Statin-Treated Dyslipidemia

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 g 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.

Stimulation of murine biliary cholesterol secretion by thyroid hormone is dependent on a functional ABCG5/G8 complex

“…***P < 0.001; **P < 0.01; *P < 0.05. lipid-lowering effects in humans by selectively stimulating TRb in the liver has revitalized the interest for understanding the molecular effects of TH. [4][5][6] We here explored by which mechanisms TH exerts its powerful effects on biliary cholesterol secretion by specifically analyzing the role of the ABCG5/G8 half-transporter complex in mice. This complex has been shown to be of major importance for sterol excretion into bile, but there are also data indicating that ABCG5/G8-independent mechanisms may promote cholesterol secretion.…”

“…[1][2][3] TH is known to exert a number of beneficial effects on cholesterol and lipoprotein metabolism, 4 and promising results have recently been reported from the clinical development of liver-selective TH analogs, such as eprotirome. 5,6 One of the mechanisms by which TH may lower plasma cholesterol is by an increased secretion of biliary cholesterol, 7 a main route for elimination of cholesterol from the body. 8 An important and presumably rate-limiting step in the process of biliary secretion of cholesterol is mediated by the half-transporters ATP-binding cassette, subfamily G (WHITE), member 5 (ABCG5) and ATP-binding cassette, subfamily G (WHITE), member 8 (ABCG8).…”

Lipoprotein(a): resurrected by genetics

“…These analogues mainly affect lipoprotein metabolism without any thyroid hormone-related effects as they have no influence on the hypothalamicpituitary-thyroid axis [155]. These thyromimetics indeed have a consistent effect not only on lowering LDL-C but also on Lp(a) level [156]. Reduced atherosclerosis has already been demonstrated in animal studies [157,158] but needs to be confirmed in the clinical setting.…”

TRC150094, a novel functional analog of iodothyronines, reduces adiposity by increasing energy expenditure and fatty acid oxidation in rats receiving a high‐fat diet

“…However, the results reported here showing the capacity of TRC to increase the oxidative muscle fibers (particularly in muscle having relatively low oxidative capacity) may have clinical importance especially when coupled with the other biochemical changes induced by TRC. The evidence of translation of effects seen in animals to humans in clinical trials of thyromimetics such as DIPTA and KB2115 is encouraging (31).…”