Skyline – City of Pittsburgh
PIC QUESTION OF THE WEEK: 9/22/08 Q: Can you summarize the results of the ENHANCE trial and comment on how its findings might affect the treatment of hypercholesterolemia? A: The Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression (ENHANCE) trial compared the effects of simvastatin with placebo or ezetimibe in 720 patients with familial hypercholesterolemia. The 24-month study was conducted to determine the effect of combination therapy (ezetimibe and simvastatin) versus monotherapy (simvastatin and placebo) on the progression of atherosclerosis based on changes in intima-media thickness of the walls of the carotid and femoral arteries. In this study, LDL cholesterol decreased by 58% in patients on combination therapy compared to a 41% decrease in the simvastatin-only group. There was also a 25% greater decrease in C-reactive protein (CRP) levels in the combined treatment group. Combination therapy did not provide a significant decrease in the intima-media thickness of the vessel walls being evaluated. Reduction in the intima-media thickness of these vessels was used as a surrogate endpoint in this trial. Surrogate endpoints allow investigators to conduct smaller and more rapid trials than endpoints utilizing clinical outcomes. In the ENHANCE trial, failure of combination therapy to reduce the size of atherosclerotic lesions was unexpected and contributed to the controversy over the benefits of ezetimibe. There has also been some suggestion that ezetimibe increases the risk of various types of cancer. Although a recent review of three on-going clinical trials did not support an increased risk of cancer, mortality rates were higher in the groups treated with ezetimibe. The FDA is now reviewing available data on the potential risk of cancer in patients treated with ezetimibe and will announce its findings possibly by the end of this year. When monotherapy with statins is insufficient to decrease LDL cholesterol to acceptable levels in high-risk patients, there are a limited number of agents that can subsequently be added. These include nicotinic acid, ezetimibe, and the bile acid sequestrants. At this time, it would appear that ezetimibe is still a viable option for high-risk patients not adequately responding to maximum doses of a statin. Further study is required to determine the role of ezetimibe as a risk factor for cancer. In addition, its usefulness in reducing atherosclerotic lesions must also undergo additional investigation. References: •
Peto R, Emberson J, Landray M, et al. Analyses of cancer data from three ezetimibe trials [published online ahead of print September, 2008]. N Engl J Med DOI:10.1056/NEJMsa0806603. • Ezetimibe revisited. Med Lett Drugs Ther 2008;50:67. • Kastelein JJ, Akdim F, Stroes, ESG, et al. Simvastatin with or without ezetimibe in familial hypercholesterolemia. N Engl J Med 2008;358:1431-43.
Photo by: R-Z: used under Creative Commons License; http://www.flickr.com/photos/r-z/842417078/ (September 16, 2008)
John M. Van Damia and Kristen L. Ridge, Pharm.D. Candidates The PIC Question of the Week is a publication of the Pharmaceutical Information Center, Mylan School of Pharmacy, Duquesne University, Pittsburgh, PA 15282 (412.396.4600).