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Abstract
Statins are widely prescribed for reducing LDL-cholesterol (C) and risk for cardiovascular disease (CVD), but there is considerable variation in therapeutic response. We used a gas chromatography-time-of-flight mass-spectrometry-based metabolomics platform to evaluate global effects of simvastatin on intermediary metabolism. Analyses were conducted in 148 participants in the Cholesterol and Pharmacogenetics study who were profiled pre and six weeks post treatment with 40 mg/day simvastatin: 100 randomly selected from the full range of the LDL-C response distribution and 24 each from the top and bottom 10% of this distribution (“good” and “poor” responders, respectively). The metabolic signature of drug exposure in the full range of responders included essential amino acids, lauric acid (p<0.0055, q<0.055), and alpha-tocopherol (p<0.0003, q<0.017). Using the HumanCyc database and pathway enrichment analysis, we observed that the metabolites of drug exposure were enriched for the pathway class amino acid degradation (p<0.0032). Metabolites whose change correlated with LDL-C lowering response to simvastatin in the full range responders included cystine, urea cycle intermediates, and the dibasic amino acids ornithine, citrulline and lysine. These dibasic amino acids share plasma membrane transporters with arginine, the rate-limiting substrate for nitric oxide synthase (NOS), a critical mediator of cardiovascular health. Baseline metabolic profiles of the good and poor responders were analyzed by orthogonal partial least square discriminant analysis so as to determine the metabolites that best separated the two response groups and could be predictive of LDL-C response. Among these were xanthine, 2-hydroxyvaleric acid, succinic acid, stearic acid, and fructose. Together, the findings from this study indicate that clusters of metabolites involved in multiple pathways not directly connected with cholesterol metabolism may play a role in modulating the response to simvastatin treatment.Trial RegistrationClinicalTrials.gov NCT00451828
Highlights
Statins are HMG-CoA reductase inhibitors that are used to reduce low-density lipoprotein (LDL)-cholesterol (LDL-C) and, thereby, to reduce cardiovascular disease (CVD) risk [1]
A pattern of higher levels of essential amino acids appears when considering that 2-ketoisocaproic acid (p,0.027, q,0.12) and 2-aminoadipic acid (p,0.039, q,0.13), intermediates in the degradation of leucine and lysine respectively, were both increased by simvastatin treatment (Table 1)
An increase in dibasic amino acids was correlated with response to simvastatin, again not a random set of amino acids, but those transported by the cystinuria and arginine transporters
Summary
Statins are HMG-CoA reductase inhibitors that are used to reduce LDL-cholesterol (LDL-C) and, thereby, to reduce CVD risk [1]. This class of drugs exhibits a broad spectrum of biological effects that may impact on CVD risk, including improvement of endothelial function by upregulation of endothelial NO synthase (eNOS), decrease in proliferation of vascular smooth muscle cells and macrophages, reduction of platelet activity, stabilization of atherosclerotic plaques, and antioxidant, anti-inflammatory and immunomodulatory effects [2]. Variation in response to statins can be affected by genetic and environmental influences. There is increasing interest in the role of gut bacteria in the metabolism of drugs [8], and recent data suggest that secondary bile acids produced by gut microbiome contribute to variation of LDL lowering response to simvastatin [9]
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