Ezetimibe: from pharmacology to clinical trials

LDL-cholesterol (LDL-C) is a key factor in primary and secondary prevention of coronary heart disease. Statins have become a mainstay in the first-line treatment of hypercholestorelomia. Nevertheless, in clinical practice, there is a major gap between treatment guidelines and real life treatment patterns. It is not uncommon that statins lack sufficient efficacy in the most severe cases of dyslipidemia, even when the highest doses are used. Therapy combining statins with other cholesterol-lowering agents is often used, although it may be poorly tolerated. These limitations have directed research towards new mechanisms of action, additive to those of statins which inhibit the hepatic biosynthesis of cholesterol. Ezetimibe is the first once-daily potent and selective inhibitor of cholesterol absorption which has been shown to reduce the overall delivery to the liver, with a subsequent reduction of serum LDL-C. As monotherapy, mean decrease in LDL-C with ezetimibe was 19.1% versus placebo, whereas in addition to ongoing statin therapy, there was a 21.8% incremental reduction of LDL-C (p<0.001) and a 11.1% of triglycerides (p<0.001) with an increase of HDL-C of about 1.7% (p<0.05). Phase III factorial co-administration studies with various statins at increasing dosages have shown a mean supplementary decrease of LDL-C (-12.1 to -13.8%) and triglycerides (-7.4 to -10.5%) and raising HDL-C (+1.4 to 4.5%) (versus pooled statins). Co-administration of ezetimibe (10 mg once a day) with a statin permits a degree of LDL-C lowering similar to that achieved with the highest doses of statins. The efficacy of ezetimibe has also been demonstrated in familial homozygous hypercholesterolemia and sistosterolemia. In both monotherapy and combination studies, clinical and biological safety of ezetimibe was good.