LDL LoweringShould Ezetimibe Ever Be Used?
Abstract & Commentary
By Harold L. Karpman, MD, FACC, FACP, Clinical Professor of Medicine, UCLA School of Medicine. Dr. Karpman reports no financial relationship to this field of study.
Synopsis: Lifestyle changes such as improving diet and exercise are always the first important approach for the treatment of hyperlipidemia however, if the target LDL-C level is not achieved using statins and niacin, fibrates, and/or resins, at this time, ezetimibe should definitely be utilized to achieve these target goals if there are no specific contraindications to the use of the drug in each individual patient.
Source: Brown BG, et al. Curr Opin Lipidol. 2006;17:631-636.
Lower is better had been the battle cry with respect to LDL-cholesterol (LDL-C) for close to 20 years since most controlled clinical trials of statins have demonstrated the validity of that conclusion because of both the clinical and imaging cardiovascular benefits which had been widely reported to occur when LDL-C is adequately lowered.1 In fact, it would even appear that the magnitude of the event reduction is a function of the extent of LDL-C lowering.8 However, since administration of even the highest approved dosage of statin drugs used for LDL-C lowering not infrequently offered less than optimal lowering of the LDL-C and/or were, on occasion, associated with an increased incidence of side effects,2 other drugs which further reduced LDL-C levels either alone or when added to statin therapy were sought for and eventually developed. Ezetimibe is such a drug which acts by inhibiting cholesterol absorption from the gastrointestinal tract resulting in lower cholesterol and LDL-C levels. It has frequently been combined with statin drugs in clinical practice and has been demonstrated to provide further incremental reduction of LDL-C levels of 12-19%3-4 beyond the levels of LDL-C reduction obtained with statin drugs alone
Kastelein and his colleagues for the ENHANCE (ie, the Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression trial) investigators5 sought to determine over a two-year period of time whether daily therapy with 80 mg of simvastatin plus either placebo or 10 mg of ezetimibe could reduce the progression of atherosclerosis in patients with familial hypercholesterolemia as assessed by measurement of arterial intima-media thickness. The rationale for studying patients with familial hypercholesterolemia was that these patients have a greatly increased risk of premature coronary artery disease6 and an increased rate of progression of intima-media thickness starting in childhood.7 The study demonstrated that, in patients with familial hypercholesterolemia, combined-therapy with ezetimibe and simvastatin did not result in a significant difference in changes in intima-media thickness, as compared with simvastatin alone, despite decreases in levels of LDL-C and C- reactive protein.
Commentary
Intima-media thickness has been well validated as a surrogate marker for atherosclerotic vascular disease in published results from large epidemiologic studies which have demonstrated strong associations between intima-media thickness and stroke, angina pectoris, and myocardial infarction.6,7 Considering the results of the ENHANCE study, should we conclude that the addition of ezetimibe to a high-dose statin is very effective in lowering LDL-C but had no added value in the therapy of atherosclerosis and presumably therefore has no clinical benefits? Before answering this important question, it is important to recognize that over the past two decades most patients with familial hypercholesterolemia will have received statins, resins, ezetimibe or various combinations of these agents with increasing intensity starting at early ages. It should also be recognized that any long-term drug therapy which had been given before entering a trial may have favorably altered the atherosclerotic plaque resulting in plaque stability and clinical quiescence9 and therefore, only minimal changes in plaque thickness might be expected with subsequent ezetimibe therapy although it should be noted that the 19% of patients who were not receiving statins at the time of ENHANCE enrollment did not have a better response with the combined regimen of simvastatin plus ezetimibe compared to those receiving simvastatin alone. In further support of the influence of previous statin therapy on the progression of intimamedia thickness in the carotid artery, it had previously been reported that progression of media thickness in the carotid artery decreased to only 0.005 mm per year during long-term daily therapy with 80 mg of atorvastatin, a finding that contrasts with the substantial reductions in intima-media thickness which had occurred during the first two years of the trial.10 Finally, the RADIANCE 1 study11 in a similar group of patients revealed a similar pattern of change in the intima-media thickness in patients receiving a mean daily dose of 57 mg of atorvastatin raising the possibility that there may be limits to the extent to which the lowering of LDL-C levels can result in a further decrease or in the progression of intima-media thickness in the group of patients who had received previous statin therapy and who have only a modest baseline intima-media thickness to begin with.
Ongoing clinical trials such as the Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) will hopefully help to define the role of ezetimibe in the treatment of hypercholesterolemia and should also provide insight into the biology of LDL-C lowering and the use of carotid intima-media thickness as a surrogate indicator of coronary events. However, the results of the IMPROVE-IT trial will not be available until at least 2011 and therefore, in the interim, clinicians should continue to evaluate and treat their patients by first determining the target LDL-C that they want to achieve in a particular patient based upon the clinical picture and risk factors presented by that patient. The National Cholesterol Education Program Adult Treatment Panel-III targeted the optimal LDL-C levels for patients with coronary heart disease (CHD) or CHD risk equivalents (ie, diabetes, peripheral or cerebral vascular disease and/or predicted 10 year CHD risk of greater than 20%) at less than 100 mg/dL (12) and the National Institutes of Health's National Cholesterol Education Program recommended that the-LDL-C level should be reduced to below 70 mg/dL in patients who have suffered a myocardial infarction or who were considered to be at high risk for the development of symptomatic CHD. It should be noted that these current guidelines may be replaced by the end of this calendar year by revised ACC/AHA lipid-management guidelines that reflect the results of the ENHANCE trial.
How should the prudent physician use ezetimibe at the present time in his hypercholesterolemic patients? Of course, life style changes such as improving diet and exercise are always the most important first approach for the treatment of hyperlipidemia however, if the target LDL-C level is not achieved using statins and niacin, fibrates, and/or resins, ezetimibe which is relatively safe and extremely effective at lowering LDL-C levels should still definitely be utilized to achieve the target LDL-C goal if there are no specific contraindications to the use of the drug in any individual patient.
References
1. Brown BG, et al. Curr Opin Lipidol. 2006;17:631-636.
2. Armitage J. The safety of statins in clinical practice. Lancet. 2007;370:1781-1790.
3. Ballantyne CM, et al. Circulation. 2003;107:2409-2415.
4. Davidson MH, et al. J Am Coll Cardiol. 2002;40:2125-2134.
5. Kastelein JJP, et al. N Engl J Med. 2008;358:1431-1433.
6. Rader DJ, et al. J Clin Invest. 2003;111:1795-1803.
7. Wiegman A, et al. Lancet. 2004;363:3690-370.
8. Sacks FM, et al. Circulation. 2000;102:1893-1900.
9. Brown BG, et al. Circulation. 1993 87:1781-1791.
10. van Wissen S, et al. Am J Card. 2005;95:264-266.
11. Kastelein JJP, et al. N Engl J Med. 2007;356:1620-1630.
12. Leeper NJ, et al. Circulation. 2007;116:613-618.
Lifestyle changes such as improving diet and exercise are always the first important approach for the treatment of hyperlipidemia however, if the target LDL-C level is not achieved using statins and niacin, fibrates, and/or resins, at this time, ezetimibe should definitely be utilized to achieve these target goals if there are no specific contraindications to the use of the drug in each individual patient.You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
- Award-winning Medical Content
- Latest Advances & Development in Medicine
- Unbiased Content