How Cholesterol Metabolism and Transport Present Novel Targets for Lipid Treatment*

The National Cholesterol Education Program treatment guidelines cite reduction of low-density lipoprotein (LDL) cholesterol as the primary therapeutic focus of lipid-modifying treatment. Statin drugs are the most effective agents for reducing LDL. However, the limited efficacy of currently available agents at low doses suggests a need for alternative therapeutic strategies. Serum cholesterol levels reflect a complicated process of synthesis and transport that affords opportunities for intervention at multiple steps in the process. Combination therapy might improve upon lipid-modifying results that can currently be achieved with statin-based therapy, but tolerability issues related to some of the currently available drugs limit their use. Evolving, new classes of lipid-modifying therapies might improve current capabilities to reduce coronary risk. An ideal therapeutic strategy would target cholesterol absorption, excretion, and synthesis. The development of selective cholesterol absorption inhibitors represents a particularly promising approach to enhancement of LDL reduction by means of combination therapy. (Adv Stud Med. 2003;3(4C):S319-S323) T reatment of hypercholesterolemia and other lipid disorders with statin drugs has made a major contribution toward reducing cardiovascular morbidity and mortality in the United States. However, heart disease remains the major cause of death in the United States, emphasizing the need for additional progress in the management of lipids. A lower low-density lipoprotein (LDL) targets offer 1 potential means to achieve more progress in the battle against heart disease. Although statins are the most potent agents currently available for lowering of LDL, statins alone are unlikely to achieve more stringent LDL targets very often. Clearly, a need exists for a new class of drugs, presumably working through a different mechanism, that could augment the effects of statins and achieve significantly lower plasma levels of cholesterol than can currently be achieved with statins alone. Cholesterol absorption inhibitors offer the potential for more dramatic reductions in cholesterol levels when combined with statins, and ezetimibe, the first agent in this new class of lipid-lowering drugs, recently became available.