Hayek S, Canepa Escaro F, Sattar A, et al.
Am J Cardiol. 2013 Feb 15;111(4):532-9. doi: 10.1016/j.amjcard.2012.11.002.

Background

Ezetimibe reduces LDL-cholesterol levels without a proportionate improvement in carotid intima-media thickness (CIMT), a measure of atherosclerotic disease (AD) burden [1-3], although 1 trial showed a reduction of major AD events [4]. It is therefore essential to investigate the independent effect of ezetimibe. As there are no data of the effect of ezetimibe on either cardiovascular outcomes or all-cause mortality in the absence of concomitant statin use, this study examined and compared the estimated effect of ezetimibe use and statin use on these events, using data from a large health maintenance organization. A total of 367 new ezetimibe users, aged ≥18 years with no previous statin use, were identified from November 1, 2002, to December 31, 2009. One to 4 statin user matches were identified for each ezetimibe user, resulting in a total of 1,238 statin user matches. The primary outcome was a composite of major AD and all-cause mortality.

Main results

• Ezetimibe use and statin use were associated with reductions in the likelihood of the composite outcome (odds ratio 0.33, 95% CI0.13 to 0.86, and odds ratio 0.61, 95% CI 0.36 to 1.04, respectively). These associations were most significant for cerebrovascular disease events and all-cause death.
• Subgroup analyses showed consistent protective relations for ezetimibe use and statin use, with no statistical significant differences.
• Among women, a significant protective relation was found for ezetimibe use and statin use
• For statin users with history of AD, ezetimibe users without history of AD, and ezetimibe users with history of diabetes a protective association was found.

Conclusion

Ezetimibe appeared to have a protective effect on major AD events and all-cause death that was not significantly different from that observed for statin use. Additional studies of ezetimibe are needed to support these findings, especially those focusing on hard clinical end points rather than uncertain predictive measures of major AD events, such as CIMT.

References

1. Fleg JL, Mete M, Howard BV, et al. Effect of statins alone versus statins plus ezetimibe on carotid atherosclerosis in type 2 diabetes: the SANDS (Stop Atherosclerosis in Native Diabetics Study) trial. J Am Coll Cardiol 2008;52:2198e2205.
2. Kastelein JJ, Akdim F, Stroes ES, et al. Simvastatin with or without ezetimibe in familial hypercholesterolemia. N Engl J Med 2008;358:1431e1443.
3. Taylor AJ, Villines TC, Stanek EJ, et al. Extended-release niacin or ezetimibe and carotid intima-media thickness. N Engl J Med 2009;361:2113e2122.
4. Baigent C, Landray MJ, Reith C, et al. The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): a randomised placebo-controlled trial. Lancet 2011;377:2181e2192.

Abstract

Despite ezetimibe's ability to reduce serum cholesterol levels, there are concerns over its vascular effects and whether it prevents or ameliorates atherosclerotic disease (AD). The aims of this study were to estimate the effect of ezetimibe use on major AD events and all-cause mortality and to compare these associations to those observed for hydroxymethylglutaryl coenzyme A reductase inhibitor (statin) use. A total of 367 new ezetimibe users were identified from November 1, 2002, to December 31, 2009. These subjects were aged ≥18 years and had no previous statin use. One to 4 statin user matches were identified for each ezetimibe user, resulting in a total of 1,238 closely matched statin users. Pharmacy data and drug dosage information were used to estimate a moving window of ezetimibe and statin exposure for each day of study follow-up. The primary outcome was a composite of major AD events (coronary heart disease, cerebrovascular disease, and peripheral vascular disease events) and all-cause death. Ezetimibe use (odds ratio 0.33, 95% confidence interval 0.13 to 0.86) and statin use (odds ratio 0.61, 95% confidence interval 0.36 to 1.04) were associated with reductions in the likelihood of the composite outcome. These protective associations were most significant for cerebrovascular disease events and all-cause death. Subgroup analyses by gender, race or ethnicity, history of AD, diabetes status, and estimated renal function showed consistent estimates across strata, with no significant differences between ezetimibe and statin use. In conclusion, ezetimibe appeared to have a protective effect on major AD events and all-cause death that was not significantly different from that observed for statin use.