The recent development of the cholesterol absorption inhibitor ezetimibe provides an additional option in the treatment of lipoprotein disorders.
6 Ezetimibe is the first drug that specifically blocks absorption of intestinal cholesterol. This action effectively reduces plasma LDL-C levels, because intestinal absorption may account for up to 50% of the cholesterol found in the circulating lipoproteins.
13 Ezetimibe inhibits as much as 54% of all intestinal cholesterol absorption without affecting uptake of triglycerides or lipid-soluble vitamins.
13 The mechanism of action of the statin-ezetimibe coadministration is attractive: the site of action and its alteration of lipid metabolism for both drugs are well characterized. Coadministration of ezetimibe and a statin reduces both intestinal cholesterol absorption and hepatic cholesterol synthesis, resulting in a significant reduction of the plasma LDL-C level.
5
Lipid lowering with ezetimibe coadministered with low-dose statins is similar to that of high-dose statin monotherapy as LDL-C reductions up to 55% to 60% have been demonstrated.
13 Ezetimibe (10 mg/d) plus simvastatin (10 mg/d) improved lipid profiles as effectively as simvastatin (80 mg/d). This coadministration therapy obviates the need for high statin doses.
14,15 Davidson et al
14 demonstrated that coadministration of ezetimibe and simvastatin resulted in significantly greater reductions in LDL-C (13.8%) than simvastatin alone (
P<.01). Similarly, Goldberg et al
15 noted that coadministration of ezetimibe and simvastatin was more effective than simvastatin (10 mg/d, 20 mg/d, 40 mg/d, or 80 mg/d) alone in reducing LDL-C levels (–53.1% vs –38.3%). In addition, 82.4% of patients in whom the two agents were coadministered achieved an LDL-C target level less than or equal to 100 mg/dL, compared with 42.9% of patients receiving simvastatin monotherapy.
15
Further evidence supporting the ability of ezetimibe and simvastatin in helping patients to achieve their National Cholesterol Education Program (NCEP) target levels comes from a study of 769 patients who failed to achieve goal despite ongoing statin therapy.
16 The addition of ezetimibe to statin therapy resulted in an additional 21.4% reduction in LDL-C (
P<.001 vs statin). The greater LDL-C reduction elicited by coadministration of ezetimibe and statin allowed 71.5% of patients to achieve their LDL-C goal compared with 18.9% of those who received statin plus placebo.
16 Two recent trials confirmed this finding.
17,18 The Ezetimibe Add-on to Statin for Effectiveness (EASE) trial
17 demonstrated that coadministration of the two agents provided a 25% greater reduction in LDL-C than statin plus placebo for all CHD risk categories. The combination also significantly increased the percentage of patients reaching ATP III target levels compared with statin alone (
Table 1). Similarly, Feldman and colleagues
18 reported that coadministration of ezetimibe (10 mg) and any dose of simvastatin produced greater reductions in LDL-C and allowed more patients at high risk to achieve their ATP III target goal (<100 mg/dL after 5 weeks of therapy (
P<.001) than monotherapy with simvastatin (20 mg).
The safety profile for ezetimibe coadministered with a statin is similar to that of statin monotherapy (
Table 2), but in some patients, hypersensitivity reactions, including angioedema and rash, were reported in postmarketing experience.
19