Snowden Stuart G, Grapov Dmitry, Settergren Magnus, D'Alexandri Fabio Luiz, Haeggström Jesper Z, Fiehn Oliver, Hyötyläinen Tuulia, Pedersen Theresa L, Newman John W, Orešič Matej, Pernow John, Wheelock Craig E
Department of Medical Biochemistry & Biophysics, Division of Physiological Chemistry II, Karolinska Institutet, Stockholm, Sweden.
NIH West Coast Metabolomics Center, University of California.
Circ Cardiovasc Genet. 2014 Dec;7(6):955-964. doi: 10.1161/CIRCGENETICS.114.000606.
Statins are the frontline in cholesterol reduction therapies; however, their use in combination with agents that possess complimentary mechanisms of action may achieve further reductions in low-density lipoprotein cholesterol. Thirty-nine patients were treated with either 80 mg simvastatin (n=20) or 10 mg simvastatin plus 10 mg ezetimibe (n=19) for 6 weeks. Dosing was designed to produce comparable low-density lipoprotein cholesterol reductions, while enabling assessment of potential simvastatin-associated pleiotropic effects. Baseline and post-treatment plasma were analyzed for lipid mediators (eg, eicosanoids and endocannabinoids) and structural lipids by liquid chromatography tandem mass spectrometry. After statistical analysis and orthogonal projections to latent structures multivariate modeling, no changes were observed in lipid mediator levels, whereas global structural lipids were reduced in response to both monotherapy (R(2)Y=0.74; Q(2)=0.66; cross-validated ANOVA P=7.0×10(-8)) and combination therapy (R(2)Y=0.67; Q(2)=0.54; cross-validated ANOVA P=2.6×10(-5)). Orthogonal projections to latent structures modeling identified a subset of 12 lipids that classified the 2 treatment groups after 6 weeks (R(2)Y=0.65; Q(2)=0.61; cross-validated ANOVA P=5.4×10(-8)). Decreases in the lipid species phosphatidylcholine (15:0/18:2) and hexosyl-ceramide (d18:1/24:0) were the strongest discriminators of low-density lipoprotein cholesterol reductions for both treatment groups (q<0.00005), whereas phosphatidylethanolamine (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.
他汀类药物是降低胆固醇治疗的一线用药；然而，将其与具有互补作用机制的药物联合使用可能会进一步降低低密度脂蛋白胆固醇水平。39名患者接受了为期6周的治疗，其中20名患者服用80毫克辛伐他汀，19名患者服用10毫克辛伐他汀加10毫克依折麦布。给药方案旨在使低密度脂蛋白胆固醇降低程度相当，同时能够评估辛伐他汀可能的多效性作用。通过液相色谱串联质谱法分析基线和治疗后血浆中的脂质介质（如类花生酸和内源性大麻素）及结构脂质。经过统计分析和正交投影到潜在结构多元建模后，脂质介质水平未观察到变化，而单一疗法（R(2)Y=0.74；Q(2)=0.66；交叉验证方差分析P=7.0×10(-8)）和联合疗法（R(2)Y=0.67；Q(2)=0.54；交叉验证方差分析P=2.6×10(-5)）均使整体结构脂质减少。正交投影到潜在结构建模确定了12种脂质的一个子集，可在6周后区分两个治疗组（R(2)Y=0.65；Q(2)=0.61；交叉验证方差分析P=5.4×10(-8)）。磷脂酰胆碱（15:0/18:2）和己糖神经酰胺（d18:1/24:0）的减少是两个治疗组低密度脂蛋白胆固醇降低的最强判别指标（q<0.00005），而磷脂酰乙醇胺（36:3e）对区分治疗组贡献最大（q=0.017）。高剂量辛伐他汀和辛伐他汀/依折麦布联合疗法的脂质组成变化相似，但降低幅度与辛伐他汀剂量有关。辛伐他汀治疗不影响脂质介质的循环水平，表明多效性作用与类花生酸生成无关。只有高剂量辛伐他汀降低了鞘磷脂和神经酰胺相对于磷脂酰胆碱的相对比例（q=0.008），提示存在一种先前与降低心血管疾病风险相关的多效性作用。
