Ezetimibe does not slow progression of coronary disease (ENHANCE)

Clinical Question

Does the addition of ezetimibe to simvastatin slow the progression of coronary artery disease?

Bottom Line

Although ezetimibe (Zetia) reduces low-density lipoprotein (LDL) cholesterol, it does not halt the progression of physiologic measurements of vascular disease. The question of whether it contributes to a reduction in cardiovascular disease remains unanswered, but these results do not support a benefit. (LOE = 1b)


Kastelein JJ, Akdim F, Stroes ES, et al, for the ENHANCE Investigators. Simvastatin with or without ezetimibe in familial hypercholesterolemia. N Engl J Med 2008;358:1431-1443.  [PMID:18376000]

Study Design

Randomized controlled trial (double-blinded)






Outpatient (any)


Although ezetimibe reduces LDL cholesterol, it is unknown whether this has any benefit in terms of progression of cardiovascular disease. In this study, 720 patients with familial hyperlipidemia and an LDL >= 210 mg/dL (5.43 mmol/L) were randomized to receive simvastatin 80 mg alone or simvastatin 80 mg plus ezetimibe 10 mg daily. The study began with a 6-week placebo run-in period, followed by baseline measurements and a 24-month study period. The primary outcome was carotid and femoral artery intima thickness, a disease-oriented measure. The study was not powered to detect any differences in clinical outcomes and none were detected. The mean age of patients was 46 years and half were women. Most patients had previously used a statin, which is not surprising given their high baseline LDL (318 mg/dL). Within 1 month, the LDL level had dropped from a mean of 319 to 141 mg/dL in the simvastatin/ezetimibe group, compared with a drop from 318 to 193 mg/dL in the simvastatin-only group. However, there was no difference between groups in the mean carotid or femoral artery intima thickness at any point during the study.