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Our mission: To promote excellence in research, practice, education and policy in cardiovascular health, primary and secondary prevention.
Our goal is to reduce the burden in cardiovascular disease in Europe through percutaneous cardiovascular interventions.
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OUR MISSION: TO REDUCE THE BURDEN OF CARDIOVASCULAR DISEASE
Dr. Nicolas Werner
Prof. Michael Bohm
Hyperlipidemia is an important cardiovascular risk factor. Reaching LDL target concentrations is difficult even with a statin. Ezetimibe effectively lowers LDL in familiar hypercholesterolemia and refractory primary hypercholesterolemia.
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.
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.
1. Ballantyne CM, Houri J, Notarbartolo A, Melani L, Lipka LJ, Suresh R, Sun S, LeBeaut AP, Sager PT, Veltri EP. Effect of ezetimibe coadministered with atorvastatin in 628 patients with primary hypercholesterolemia: a prospective, randomized, double-blind trial. Circulation. 2003;107:2409-2415. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12719279&dopt=Abstract
2. Gagne C, Bays HE, Weiss SR, Mata P, Quinto K, Melino M, Cho M, Musliner TA, Gumbiner B. Efficacy and safety of ezetimibe added to ongoing statin therapy for treatment of patients with primary hypercholesterolemia. Am J Cardiol. 2002;90:1084-1091. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12486428&dopt=Abstract
3. Gagne C, Gaudet D, Bruckert E. Efficacy and safety of ezetimibe coadministered with atorvastatin or simvastatin in patients with homozygous familial hypercholesterolemia. Circulation. 2002;105:2469-2475. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12423708&dopt=Abstract
4. Kerzner B, Corbelli J, Sharp S, Lipka LJ, Melani L, LeBeaut A, Suresh R, Mukhopadhyay P, Veltri EP. Efficacy and safety of ezetimibe coadministered with lovastatin in primary hypercholesterolemia. Am J Cardiol. 2003;91:418-424.
5. Knopp RH, Gitter H, Truitt T, Bays H, Manion CV, Lipka LJ, LeBeaut AP, Suresh R, Yang B, Veltri EP. Effects of ezetimibe, a new cholesterol absorption inhibitor, on plasma lipids in patients with primary hypercholesterolemia. Eur Heart J. 2003;24:729-741.
6. Salen G, von Bergmann K, Kwiterovitch P. Ezetimibe is an effective treatment for homozygous sitosterolemia. Circulation. 2002;106:185-186.
Dr N. Werner and Prof. M. Böhm Homburg-Saar, Germany Nucleus member of the ESC Working Group on Heart Failure
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