To verify that the observed lipoprotein, fatty acid, and metabolite changes are due to the effects of statins, the results were corroborated via Mendelian randomization by using a genetic variant in the HMGCR gene as a proxy for the pharmacological action of statins 18, 19, 20. We aimed to determine comprehensive metabolic effects of statin therapy by conducting metabolomic profiling at 2 time points in 4 population-based cohorts. This high-throughput profiling simultaneously quantifies numerous other biomarkers, which, in concert, provide a fine-grained snapshot of systemic metabolism 5, 17. Direct assaying of remnant cholesterol, that is, the cholesterol in very-low-density lipoprotein (VLDL) and intermediate-density lipoprotein (IDL) particles, has recently become feasible as part of the lipoprotein subclass profiling provided by nuclear magnetic resonance (NMR) metabolomics (16). Of particular importance are the effects on triglycerides and remnant cholesterol, because these measures have been causally linked to the development of coronary heart disease 13, 14, 15. Although the vascular event rate reduction follows a linear relationship with LDL-C lowering (9), the cardioprotective abilities of statins may also partly be attributed to other lipids 10, 11, 12. Statins have been proposed to possess various pleiotropic properties such as reducing inflammation and improving endothelial function 7, 8, yet it remains unclear whether such effects would manifest in the systemic metabolic profile. Nearly 30% of Americans 45 years of age and older were receiving statins from 2007 to 2010 (2), and many more are eligible for treatment under the 2013 American College of Cardiology/American Heart Association cardiovascular prevention guidelines 3, 4.ĭespite widespread use of statin therapy, their effects on many lipids and other metabolic biomarkers of cardiovascular risk, such as circulating fatty acids and amino acids 5, 6, have not been assessed in large studies. Statins have become first-line therapy for managing dyslipidemia and cardiovascular disease (CVD) risk, making them the most widely prescribed drug class worldwide. HMG-CoA reductase (HMGCR) inhibitors, commonly known as statins, reduce low-density lipoprotein cholesterol (LDL-C) levels leading to proportionate reduction in cardiovascular risk (1).
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