Ezetimibe: a novel cholesterol-lowering agent that highlights novel physiologic pathways

Abstract

Ezetimibe is a US Food and Drug Administration-approved novel drug that targets the absorption of cholesterol in the intestine. The identification of this drug has also led to the elucidation of the dietary cholesterol receptor. Ezetimibe is efficacious as a plasma cholesterol-lowering agent as monotherapy, but its greatest utility seems to be as a combination with a low-dose statin, where it results in cholesterol lowering that is equivalent to using maximum-dose statins. It has a very favorable side-effect profile, as well as a lack of drug-drug interactions. In addition, it prevents the absorption of noncholesterol sterols, such as plant sterols. In clinical studies, it has been shown to be highly efficacious in lowering plant sterols in a rare genetic disorder, sitosterolemia. Both the disease, as well as this therapeutic agent, have led to the concept that ezetimibe may be also useful in dissecting the role of these noncholesterol sterols in the pathogenesis of atherosclerosis.

Figure 1

The basis for action of ezetimibe and ezetimibe/statin combination. A, Upon treatment with the cholesterol inhibitor (and in general any modality that reduces dietary cholesterol absorption), less dietary cholesterol is delivered to the pool of cholesterol to the liver. This may result in the liver sensing this reduced delivery and will upregulate mechanisms to maintain its pools; synthesis and low-density lipoprotein (LDL) receptors will be upregulated and the latter will result in a modest fall in plasma LDL cholesterol. B, In contrast, if a statin is co-administered, the ability to upregulate cholesterol synthesis is impaired by the statin drug, resulting in the liver increasing further upregulation of both the receptors, as well as synthetic enzymes. The latter may restore the cholesterol balance in the liver, but the former will result in an enhanced clearance of LDL cholesterol particles from the blood. Only a small amount of statin is needed to greatly up-regulate these mechanisms and thus the greater efficacy and lower side-effect profiles. (Adapted from Dietschy [15••].)