Hypercholesterolemia: Clinical and MOA update on ezetimibe

Ezetimibe therapy: mechanism of action and clinical update.

Literature -

Phan BA, Dayspring TD, Toth PP.
Vasc Health Risk Manag. 2012;8:415-27.


There is a clear association between elevated serum cholesterol levels and cardiovascular risk [1,2]. Treatment with statins effectively lowers LDL-C levels and reduces major cardiovascular events [3-7]. More aggressive lowering of LDL-C may increase cardiovascular benefit [8-10], especially in high-risk patients with multiple risk factors [11]. To achieve optimal LDL-C levels, statin therapy alone might not be sufficient. In these patients, combination with other cholesterol-lowering agents is warranted, such as the cholesterol absorption inhibitor ezetimibe.
The mechanism of action, lipid effects, and safety of ezetimibe treatment are described as well as outcome trials that may impact its use in clinical practice.


Ezetimibe inhibits intestinal cholesterol absorption by selectively blocking the Niemann-Pick C1-like protein (NPC1L1) in the jejunal brush border, integral to the uptake of intestinal lumen micelles into the enterocyte [12-15]. It is, either in monotherapy or in combination with statins, effective in lowering cholesterol in several populations, such as insulin resistance, FH and sitosterolemia.
Both the SANDS and VYCTOR trial reported atherosclerosis regression [16-18]. The clinical efficacy of ezetimibe treatment was evaluated in the SEAS study [19] and in the SHARP trial [20], both using ezetimibe plus simvastatin (figure 1).
However, the ENHANCE [21] and ARBITER-6 trial [22] reported negative outcomes, although both trials were methodologically limited in their ability to evaluate the benefit of ezetimibe.
Therefore, the forthcoming results from the IMPROVE-IT trial [23] are highly anticipated. These results may better guide the use of ezetimibe in very high-risk CHD populations.

Figure 1

Proportional reduction in major ischemic events by mean decrease in LDL-C (mmol/L) in the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) trial (tertiles 1, 2, and 3 for severity of aortic valve stenosis) compared to 14 randomized trials in the Cholesterol Treatment Trialists meta-analysis


Yet, ezetimibe is a viable adjunct to statin therapy in the treatment of hypercholesterolemia. Forthcoming results are awaited to better judge its effect in clinical practice.


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23. Cannon CP, Giugliano RP, Blazing MA, et al. Rationale and design of IMPROVE-IT (IMProved Reduction of Outcomes: Vytorin Efficacy International Trial): comparison of ezetimbe/simvastatin versus simvastatin monotherapy on cardiovascular outcomes in patients with acute coronary syndromes. Am Heart J. 2008;156:826–832.


The lowering of low-density lipoprotein cholesterol (LDL-C) is the primary target of therapy in the primary and secondary prevention of cardiovascular events. Although statin therapy is the mainstay for LDL-C lowering, a significant percentage of patients prescribed these agents either do not achieve targets with statin therapy alone or have partial or complete intolerance to them. For such patients, the use of adjuvant therapy capable of providing incremental LDL-C reduction is advised. One such agent is ezetimibe, a cholesterol absorption inhibitor that targets uptake at the jejunal enterocyte brush border. Its primary target of action is the cholesterol transport protein Nieman Pick C1 like 1 protein. Ezetimibe is an effective LDL-C lowering agent and is safe and well tolerated. In response to significant controversy surrounding the use and therapeutic effectiveness of this drug, we provide an update on the biochemical mechanism of action for ezetimibe, its safety and efficacy, as well as the results of recent randomized studies that support its use in a variety of clinical scenarios.

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