Thyroxine mimetics

Abstract

Thyroid hormones influence heart rate, serum lipids, metabolic rate, body weight, and multiple aspects of lipid, carbohydrate, protein, and mineral metabolism. Although increased thyroid hormone levels can improve serum lipid profiles and reduce fat, these positive effects are counterbalanced by the harmful effects on the heart, muscle, and bone. Thus, attempts to use thyroid hormones for cholesterol-lowering and weight loss purposes have so far been limited. However, over the past decade, thyroid hormone analogs that are capable of uncoupling the beneficial effects from the deleterious effects have been developed. Such drugs could serve as powerful new tools to address two of the largest medical problems, namely atherosclerosis and obesity. Aggressive reduction in LDL-cholesterol by the use of statins is a cornerstone of preventive cardiovascular risk, but additional therapies to prevent atherosclerosis and its clinical sequelae are still needed. Thyromimetics selective for the liver or the thyroid hormone receptor isoform β1 constitute a novel approach to treat dyslipidemia. In preclinical studies, selective thyromimetics were clearly shown to reduce plasma cholesterol and protect from atherosclerosis through the upregulation of hepatic LDL receptor and promotion of the so-called reverse cholesterol transport. Notably, there is the first evidence from on-going clinical trials that selective thyromimetics may reduce plasma cholesterol in humans also. Most importantly, thyromimetics has a synergistic action when used in combination with 3-hydroxy-3-methylglutaryl CoA reductase inhibitors. Animal data have further suggested that thyromimetics might be useful in the treatment of obesity, hepatic steatosis, and atherosclerosis.

Keywords

• Dyslipidemia, nuclear receptors, obesity, selective thyromimetics