Abstract
Effective statin therapy is associated with a marked reduction of cardiovascular events. However, the explanation for full benefits obtained for LDL cholesterol targets by combined lipid-lowering therapy is controversial. Our study compared the effects of two equally effective lipid-lowering strategies on markers of cholesterol synthesis and absorption. A prospective, open label, randomized, parallel design study, with blinded endpoints, included 116 subjects. We compared the effects of a 12-week treatment with 40 mg rosuvastatin or the combination of 40 mg simvastatin/10 mg ezetimibe on markers of cholesterol absorption (campesterol and β-sitosterol), synthesis (desmosterol), and their ratios to cholesterol. Both therapies similarly decreased total and LDL cholesterol, triglycerides and apolipoprotein B, and increased apolipoprotein A1 (P < 0.05 vs baseline for all). Simvastatin/ezetimibe increased plasma desmosterol (P = 0.012 vs baseline), and decreased campesterol and β-sitosterol (P < 0.0001 vs baseline for both), with higher desmosterol (P = 0.007) and lower campesterol and β-sitosterol compared to rosuvastatin, (P < 0.0001, for both). In addition, rosuvastatin increased the ratios of these markers to cholesterol (P < 0.002 vs baseline for all), whereas simvastatin/ezetimibe significantly decreased the campesterol/cholesterol ratio (P = 0.008 vs baseline) and tripled the desmosterol/cholesterol ratio (P < 0.0001 vs baseline). The campesterol/cholesterol and β-sitosterol/cholesterol ratios were lower, whereas the desmosterol/cholesterol ratio was higher in patients receiving simvastatin/ezetimibe (P < 0.0001 vs rosuvastatin, for all). Pronounced differences in markers of cholesterol absorption and synthesis were observed between two equally effective lipid-lowering strategies.
Highlights
A recent meta-analysis has shown that marked reductions in LDL cholesterol with statins are related to a greater absolute decrease in major cardiovascular events [1]
Biochemical analyses including lipid profile and apolipoproteins did not differ between groups (Table 2)
AST, ALT and creatine kinase (CK) were slightly increased after the treatments, but remained within the normal range. highly sensitive C-reactive protein (hs-CRP) levels decreased in each treatment group (Table 3)
Summary
A recent meta-analysis has shown that marked reductions in LDL cholesterol with statins are related to a greater absolute decrease in major cardiovascular events [1]. The most appropriate strategies for achieving greater effectiveness in cholesterol reduction include the use of high doses of potent statins or the combination of lipid-lowering drugs [2,3]. Reduction in the endogenous synthesis of cholesterol by statins can be accompanied by increased intestinal sterol absorption [6]. Ezetimibe, an inhibitor of dietary and biliary intestinal cholesterol absorption, has been extensively used as a lipid-lowering agent, but its role in endogenous cholesterol synthesis is less studied, especially when combined with a statin [7]. Differences in the pharmacokinetic properties of statins may account for the effectiveness of cholesterol synthesis inhibition as well as for the stimuli of cholesterol absorption. Ezetimibe has an estimated half-life of approximately 22 h [8], while simvastatin was reported to have a relatively short half-life of less than 3 h [9]
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