High Dose Simvastatin Exhibits Enhanced Lipid Lowering Effects Relative to Simvastatin/Ezetimibe Combination Therapy

摘要

Statins are the frontline in cholesterol reduction therapies; however use in combination with agents that possess complimentary mechanisms of action may achieve further reductions in LDL-C. Thirty-nine patients were treated with either 80mg simvastatin (n=20) or 10mg simvastatin plus 10mg ezetimibe (n=19) for 6 weeks. Dosing was designed to produce comparable LDL-C reductions, while enabling assessment of potential simvastatin-associated pleiotropic effects. Baseline and post-treatment plasma were analyzed for lipid mediators (e.g., eicosanoids, endocannabinoids) and structural lipids by liquid chromatography tandem mass spectrometry. Following statistical analysis and orthogonal projections to latent structures (OPLS) multivariate modeling, no changes were observed in lipid mediator levels, while global structural lipids were reduced in response to both mono- (R²Y=0.74, Q²=0.66, CV-ANOVA p=7.0×10^-8) and combination therapy (R²Y=0.67, Q²=0.54, CV-ANOVA p=2.6×10⁻⁵). OPLS modeling identified a subset of 12 lipids that classified the two treatment groups after 6 weeks (R²Y=0.65, Q²=0.61, CV-ANOVA p=5.4×10⁻⁸). Decreases in the lipid species PC(15:0/18:2) and HexCer(d18:1/24:0) were the strongest discriminators of LDL-C reductions for both treatment groups (q<0.00005), while PE(36:3e) contributed most to distinguishing treatment groups (q=0.017). Shifts in lipid composition were similar for high-dose simvastatin and simvastatin/ezetimibe combination therapy, but the magnitude of the reduction was linked to simvastatin dosage. Simvastatin therapy did not affect circulating levels of lipid mediators, suggesting that pleiotropic effects are not associated with eicosanoid production. Only high-dose simvastatin reduced the relative proportion of sphingomyelin and ceramide to phosphatidylcholine (q=0.008), suggesting a pleiotropic effect previously associated with a reduced risk of cardiovascular disease.