Hypercholesterolemia is an important cardiovascular risk factor leading to atherosclerosis. Reduction of cholesterol levels leads to a significant reduction of cardiovascular morbidity and mortality. Statins are state of the art medication when life style changes and low-fat diet cannot reduce low density lipoprotein-cholesterol (LDL-C) levels beyond target concentrations. Statins positively influence acute coronary syndromes, myocardial infarction and ischemic stroke. Cardiovascular risk reduction with statins has prompted the development of target LDL-C concentrations in patients with coronary artery disease (CAD). Reaching LDL-C target concentrations is still difficult even with statin treatment. In patients with known CAD, only 18% reach the LDL-C goal of <100mg/dl with a statin. The cholesterol uptake inhibitor ezetimibe represents a new therapeutic concept for lipid lowering.
Mechanism of action
Ezetimib is a selective inhibitor of cholesterol absorption and results in a decreased absorption of cholesterol and phytosterols in the small bowl. A hepatic reduction of cholesterol levels leads to a reduced hepatic cholesterol storage, decreased LDL production and finally, to a reduction of LDL-C (Fig.2). Importantly, the decreased cholesterol-uptake through the bowl is followed by a compensatory increase of endogenous cholesterol production (89% compared to placebo). A monotherapy with ezetimib leads to a reduction of LDL-C of 20.4% and to total cholesterol level of 15.1%.
The compensatory increase in endogenous cholesterol after ezetimib treatment is the pathophysiological explanation for the recommended combined use of a fix dosage of ezetimib (10mg/day) together with a statin.
Several mono and combination-studies with ezetimib and statins on more than 2380 patients have underlined the safety and efficacy of this new therapeutical concept1;2;4;5. Interestingly, no significant further side effects beyond the known side effects of a statin therapy have been put forward up to date.
In patients with primary hypercholesterolemia and LDL-C levels beyond the target concentration, 71.5% on ezetimib and statin vs. 18.9% on statin and placebo reached the target LDL-C after 8 weeks2. An additional LDL-C reduction of 25.1% vs. 3.7% compared to placebo and statin was achieved. Similar results were obtained in additional combination studies with an average LDL-C reduction of 21% when compared to a statin monotherapy1;2;4.
In contrast to primary hypercholesterolemia, treatment of the homozygous forms of familiar hypercholesterolemia show no significant LDL-C reductions with statin treatment. The effect of a combination therapy of ezetimib and statin in patients with familiar homozygous hypercholesterolemia was investigated in a double-blind study on 50 patients3. Ezetimib in combination with 40mg and 80mg statin resulted in a significant reduction of LDL-C compared to 80mg statin (-20.7% vs. –6.7%, p=0.007).
Inhibition of cholesterol resorption from the small bowl is a novel concept of LDL-C reduction. Clinical indications for a therapy with ezetimibe and a statin are the homozygous form of familiar hypercholesterolemia and the refractory primary hypercholesterolemia under adequate statin therapy. A monotherapy with ezetimibe is restricted to the rare sitosterolemia6. Ezetimib should be combined with statins in a fix dosage of 10mg/day due to its pharmacological properties. Further prospective studies will have to evaluate, whether a combination therapy results in a significant improvement of clinical endpoints. Until the publication of these results, statins remain the first-choice therapy in patients with hypercholesterolemia.
The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.