In this double-blind, randomized, 24-month trial performed in 720 patients with familial hypercholesterolemia, the effects of simvastatin (80 mg/day) combined with either placebo or ezetimibe (10 mg/day) were assessed. Compared to patients treated with simvastatin alone, patients who were on the combination of simvastatin and ezetimibe showed significant improvements in plasma concentrations of LDL cholesterol (-16.5%), triglycerides (-6.6%), and C-reactive protein (-25.7%). In both arms, HDL cholesterol increased to a similar extent. No significant differences were observed in changes in intima-media thickness (IMT), measured by B-mode ultrasonography, as the primary endpoint. Although the authors provided reasons for why the combination of simvastatin and ezetimibe did not reduce IMT more significantly than simvastatin alone, the causes of these negative findings remain uncertain. This paper was accompanied by two editorials. The first, written by Brown and Taylor, raised the following question: should the results of ENHANCE diminish the medical community’s confidence in ezetimibe, or is the problem more deeply rooted, i.e., has the idea of targeting LDL cholesterol per se become less relevant? In the other editorial, Drazen et al. commented on the context in which the results of ENHANCE were published. They also discussed the potential clinical implications of ENHANCE as more than 34 million ezetimibe prescriptions were written in 2006 in the US alone.
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