Thyroid hormone analogs for treatment of hypercholesterolemia and heart failure: Past, present and future prospects

Thyroid hormone has the unique properties of lowering cholesterol in hypothyroid individuals and improving cardiac performance. Beginning in the 1950s, extensive efforts were made to develop thyroid hormone analogs that could utilize the cholesterol-lowering property in euthyroid individuals without affecting the heart. These efforts culminated in the development of analogs that selectively bind to β1-type nuclear thyroid hormone receptors (TRs), which are responsible for cholesterol-lowering activity, without activating α1-type receptors in the heart. β1-Selective compounds may be useful in lowering cholesterol in euthyroid individuals who are intolerant to treatment with 'statins'. Screening of compounds for those that might be suitable for improving cardiac performance in heart failure led to the identification of 3,5-diiodothyropropionic acid (DITPA). DITPA binds to both α- and β-type TRs with relatively low affinity. In postinfarction models of heart failure and in a pilot clinical study, DITPA increased cardiac performance without affecting heart rate. This compound also lowers cholesterol and may be a useful adjunct to standard heart failure therapy. Although there is both experimental and clinical evidence indicating that thyroid analogs act differently than thyroid hormones, the details of their mechanism of action have not been completely elucidated. A number of potential mechanisms are reviewed, including serum protein binding, tissue disposition, receptor binding, and gene activation. Clinical trials for thyroid hormone analogs are in prospect.