Cholesterol Lowering and Ezetimibe

Jeffrey M. Drazen, M.D., John A. Jarcho, M.D., Stephen Morrissey, Ph.D., and Gregory D. Curfman, M.D.
In this issue of the Journal, we publish the results of the Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression (ENHANCE) trial,1 which addresses the question of whether additional lowering of low-density lipoprotein (LDL) cholesterol with ezetimibe beyond the level achieved with simvastatin beneficially affects the progression of atherosclerosis. As a surrogate clinical marker for such progression, the study used imaging of the intima–media thickness of the carotid and femoral arteries. In contrast to statins, which lower LDL cholesterol by increasing its clearance, ezetimibe selectively inhibits the absorption of cholesterol by binding to Niemann–Pick C1-like 1 (NPC1L1) protein, which is involved in cholesterol processing. When administered in combination, ezetimibe and a statin lower plasma LDL cholesterol below the level that can be achieved with a statin alone.
The ENHANCE trial was conducted in patients with familial hypercholesterolemia, a condition characterized by high levels of LDL cholesterol. Patients were randomly assigned to receive either simvastatin alone or a combination of simvastatin plus ezetimibe. Combination therapy resulted in LDL cholesterol levels that were 27% lower than those achieved with monotherapy, and C-reactive protein levels were also significantly lower with combination therapy. Unexpectedly, however, the trial showed that despite increased lowering of LDL cholesterol in the group that received ezetimibe, the rate of progression of atherosclerotic disease, as measured by intima–media thickness, was the same in the two study groups. It is this paradox, which is at odds with our traditional understanding of the relationship between LDL cholesterol and atherosclerosis, that has puzzled investigators and clinicians alike. The paradox and other important questions that are raised by the trial, including the rationale for the use of carotid intima–media thickness as a surrogate end point, are discussed in detail by Brown and Taylor in an accompanying editorial.2
........
Until such data are available, it seems prudent to encourage patients whose LDL cholesterol levels remain elevated despite treatment with an optimal dose of a statin to redouble their efforts at dietary control and regular exercise. Niacin, fibrates, and resins should be considered when diet, exercise, and a statin have failed to achieve the target, with ezetimibe reserved for patients who cannot tolerate these agents.
/.../