The effects of ezetimibe on LDL-cholesterol: quantitative or qualitative changes?

Ezetimibe represents the first of a new class of agents, the cholesterol absorption inhibitors, able to reduce low-density lipoproteins (LDL)-cholesterol by 15-25% from baseline in monotherapy and on top of statins and fibrates. To-date all the data regarding the efficacy of ezetimibe comes from the studies of its lipid-lowering power. Yet, recent findings from the ENHANCE study on atherosclerosis progression showed that the addition of ezetimibe to simvastatin in patients with heterozygous familial hypercholesterolemia did not affect the mean change in carotid intima-media thickness, although a significant reduction in LDL-cholesterol levels was present. Therefore, we cannot exclude that ezetimibe is treating mainly LDL-cholesterol and not the underlying dyslipidemia. Reviewing all available evidences on the effects on atherogenic small, dense LDL, it seems that ezetimibe produce quantitative rather than qualitative changes in LDL, with small net effects on LDL subclass distribution. Yet, we cannot exclude that clinical and laboratory factors influenced this result. We found important differences in the methodology used to measure LDL size and subfractions and this represents a crucial point, since these methods cannot be fully used interchangeably. In addition, it is reasonable to imagine that ezetimibe may be more effective on small, dense LDL in subjects with hypertriglyceridemia. Further formal cardiovascular event outcome trials are underway and this will provide additional insights into the long-term effects of ezetimibe. Future prospective studies are also needed to clarify to which extent ezetimibe is able to reduce atherogenic dyslipidemia, beyond LDL-cholesterol levels.