Complementary effects ezetimibe on potent statins
Effects of ezetimibe added to statin therapy on markers of cholesterol absorption and synthesis and LDL-C lowering in hyperlipidemic patients.Thongtang N, Lin J, Schaefer EJ, Lowe RS, Tomassini JE, Shah AK, Tershakovec AM.
Atherosclerosis. 2012;225:388-96. doi: 10.1016/j.atherosclerosis.2012.09.001.
A substantial number of patients treated with statin therapy still have LDL-C levels above guideline-recommended targets [1-4]. Statins not only have a direct inhibitory effect on cholesterol synthesis, but also reduce markers of cholesterol synthesis, such as lathosterol, which can reveal subsequent increases in markers of cholesterol absorption [5-9], dependent on statin dose and type of statin. Ezetimibe is a selective cholesterol absorption inhibitor blocking transport of cholesterol and phytosterols across the intestinal wall, thereby significantly reducing LDL-C levels by 15-20% [10,11].
Co-administration of ezetimibe together with a statin inhibits cholesterol absorption and synthesis , producing significantly greater reductions in LDL-C than either drug alone [11,13,14]. In this post hoc analysis of the EASE (Ezetimibe Add-on to Statin for Effectiveness) study the effects of adding ezetimibe 10 mg to different statins and doses on plasma lipid-lowering effects and non-cholesterol sterol levels were evaluated. Comparison of subjects was based on statin type or potency (low, medium, high) subgroups. The low-potency statin group included subjects receiving simvastatin ≤10 mg/day, lovastatin ≤20 mg/day, pravastatin ≤20 mg/day, and fluvastatin ≤40 mg/day. The medium-potency statin group included subjects receiving simvastatin > 10-≤40 mg/day, atorvastatin ≤ 20 mg/day, lovastatin > 20-80 mg/day, pravastatin > 20-80 mg/day, and fluvastatin > 40-80 mg/day. The high-potency statin group included subjects receiving simvastatin > 40-80 mg/ day, and atorvastatin > 20-80 mg/day.
Lipid and non-cholesterol sterol data from the ezetimibe arm of this study were used to test the hypothesis that ezetimibe, when added to statin therapy, would be most effective in LDL-C lowering in subjects on high-potency statins and that these effects would be related to alterations in markers of cholesterol absorption (b-sitosterol, b-sitosterol/cholesterol) and synthesis (lathosterol, lathosterol/cholesterol).
- Statin type and dose are significantly associated with levels of cholesterol synthesis and absorption markers
- The addition of ezetimibe to all statin types resulted in significant reductions from baseline in total C, LDL-C, non-HDL-C, Apo B, and total C/HDL-C, with no between-type differences (fig. 1).
- Add-on ezetimibe therapy resulted in significant increases in cholesterol synthesis markers and significant reductions in cholesterol absorption markers from baseline for each statin type and statin potency level.
These results highlight the complementary effects of statins and ezetimibe on modulating markers of cholesterol synthesis and absorption. Patients on (high-potency) statins may be good candidates for ezetimibe therapy if additional LDL-C lowering is required to reach LDL-C goals.
Figure 1.Percent change in lipid values from statin-treated baseline after ezetimibe add-on therapy (adjusted for values from the placebo arm of EASE).
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Statins inhibit cholesterol synthesis but can upregulate cholesterol absorption, with higher doses producing larger effects. Ezetimibe inhibits cholesterol absorption but also upregulates synthesis. We tested whether ezetimibe added to on-going statin therapy would be most effective in lowering LDL-cholesterol (LDL-C) in subjects on high-potency statins and whether these effects would be related to alterations in cholesterol absorption (β-sitosterol) and synthesis (lathosterol) markers.
Hypercholesterolemic subjects (n = 874) on statins received ezetimibe 10 mg/day. Plasma lipids, lathosterol, and β-sitosterol were measured at baseline and on treatment. Subjects were divided into low- (n = 133), medium- (n = 582), and high- (n = 159) statin potency groups defined by predicted LDL-C-lowering effects of each ongoing statin type and dose (reductions of ∼20-30%, ∼31-45%, or ∼46-55%, respectively).
The high-potency group had significantly lower baseline lathosterol (1.93 vs. 2.58 vs. 3.17 μmol/l; p < 0.001) and higher baseline β-sitosterol values (6.21 vs. 4.58 vs. 4.51 μmol/l, p < 0.001) than medium-/low-potency groups. Ezetimibe treatment in the high-potency group produced significantly greater reductions from baseline in LDL-C than medium-/low-potency groups (-29.1% vs. -25.0% vs. -22.7%; p < 0.001) when evaluating unadjusted data. These effects and group differences were significantly (p < 0.05) related to greater β-sitosterol reductions and smaller lathosterol increases. However, LDL-C reduction differences between groups were no longer significant after controlling for placebo effects, due mainly to modest LDL-C lowering by placebo in the high-potency group.
Patients on high-potency statins have the lowest levels of cholesterol synthesis markers and the highest levels of cholesterol absorption markers at baseline, and the greatest reduction in absorption markers and the smallest increases in synthesis markers with ezetimibe addition. Therefore, such patients may be good candidates for ezetimibe therapy if additional LDL-C lowering is needed.