Differences in synthesis and absorption of cholesterol of two effective lipid-lowering therapies

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.

Figures

Figure 1.. Box-plots (median, 25th and 75th percentiles) for plasma levels of campesterol (A), β-sitosterol (B), and desmosterol (C) at baseline and at the end of the study according to treatment. Baseline values were comparable between groups. Rosuvastatin did not modify these parameters over time. Subjects treated with simvastatin/ezetimibe presented a reduction of plasma levels of campesterol and β-sitosterol (P < 0.0001 vs baseline for both, Wilcoxon test), and an increase of desmosterol (P = 0.012 vs baseline, Wilcoxon test). Plasma campesterol and β-sitosterol levels were lower at the end of the study (P < 0.0001 for both, Mann-Whitney test) in subjects receiving simvastatin/ezetimibe compared to individuals receiving rosuvastatin, whereas desmosterol levels were higher (P = 0.007, Mann-Whitney test).

Figure 2.. Box-plots (median, 25th and 75th percentiles) of the campesterol/cholesterol (A), β-sitosterol/cholesterol (B) and desmosterol/cholesterol (C) ratios at baseline and at the end of the study according to treatment. Baseline values were comparable between groups. Rosuvastatin increased all of these ratios (P < 0.002 vs baseline for all, Wilcoxon test). Treatment with simvastatin/ezetimibe promoted a significant decrease of the campesterol/cholesterol ratio (P = 0.008 vs baseline, Wilcoxon test), but not of the β-sitosterol/cholesterol ratio (P = NS). Conversely, the desmosterol/cholesterol ratio increased 3-fold after treatment with simvastatin/ezetimibe (P < 0.0001). Comparison of the effects of treatments showed that campesterol/cholesterol and β-sitosterol/cholesterol ratios were lower at the end of treatment in patients receiving simvastatin/ezetimibe than in those treated with rosuvastatin (P < 0.0001, Mann-Whitney test), whereas the desmosterol/cholesterol ratio was higher in patients treated with simvastatin/ezetimibe (P < 0.0001).