Thyroid hormone mimetics: potential applications in atherosclerosis, obesity and type 2 diabetes

Abstract

Atherosclerosis is a major cause of mortality throughout the western world, despite the existence of drugs that lower cholesterol. The incidences of obesity and type 2 diabetes are increasing at alarming rates, and have become major health problems; treatments that involve lifestyle changes have had limited success. New therapies for atherosclerosis, obesity and type 2 diabetes are needed. Thyroid hormone excess has potentially useful effects, including lowering of serum cholesterol and reduction of body fat, but these are counterbalanced by deleterious effects on heart, muscle and bone which preclude the use of natural thyroid hormones to treat patients with dyslipidaemias, obesity and diabetes. For years, scientists have sought thyroid hormone analogues that would elicit the beneficial but not the unwanted effects of thyroid hormones. Advances in molecular and structural biology have facilitated the design of new selective thyroid hormone mimetics that exhibit thyroid hormone receptor isoform-selective binding, and/or liver- and tissue-selective uptake. These compounds reduce serum levels of low-density lipoprotein–cholesterol and triglycerides, enhance several important steps in reverse cholesterol transport and reduce body fat in several animal models, and have not been found to have effects in preclinical animal models. Selective thyroid hormone receptor modulators also reduce blood glucose levels in mouse models of type 2 diabetes, raising the possibility that there could be unexpected beneficial effects on this disease. Clinical trials, which have now involved several hundred patients, reveal that selective thyroid hormone mimetics can reduce serum levels of low-density lipoprotein–cholesterol, triglycerides and lipoprotein(a), which are all risk factors for atherosclerosis, without detectable adverse effects. These actions can also be observed in patients taking other currently used cholesterol-lowering drugs, such as statins. Selective thyroid hormone receptor modulation is a promising new strategy for the prevention and treatment of atherosclerosis and obesity in humans.