From the Department of Cardiology, Division of Heart and Lungs, University Medical Center Utrecht, University of Utrecht, The Netherlands (D.K., F.W.A.); Department of Cardiology (R.N.E., W.H.v.G., P.v.d.H.), Department of Internal Medicine (S.J.L.B.), and Department of Endocrinology, University Medical Center Groningen (R.P.F.D.), University of Groningen, The Netherlands; Durrer Center for Cardiogenetic Research, ICIN-Netherlands Heart Institute, Utrecht (P.v.d.H., F.W.A.); and Institute of Cardiovascular Science, Faculty of Population Health Sciences, University College London, United Kingdom (F.W.A.).
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Background—Statins lower cholesterol by inhibiting HMG-CoA reductase, the rate-limiting enzyme of the metabolic pathway that produces cholesterol and other isoprenoids. Little is known about their effects on metabolite and lipoprotein subclass profiles. We, therefore, investigated the molecular changes associated with pravastatin treatment compared with placebo administration using a nuclear magnetic resonance–based metabolomics platform.Methods and Results—We performed metabolic profiling of 231 lipoprotein and metabolite measures in the PREVEND IT (Prevention of Renal and Vascular End-stage Disease Intervention Trial) study, a placebo-controlled randomized clinical trial designed to test the effects of pravastatin (40 mg once daily) on cardiovascular risk. Metabolic profiles were assessed at baseline and after 3 months of treatment. Pravastatin lowered low-density lipoprotein cholesterol (change in SD units [95% confidence interval]: −1.01 [−1.14, −0.88]), remnant cholesterol (change in SD units [95% confidence interval]: −1.03 [−1.17, −0.89]), and apolipoprotein B (change in SD units [95% confidence interval]: −0.98 [−1.11, −0.86]) with similar effect magnitudes. In addition, pravastatin globally lowered levels of lipoprotein subclasses, with the exception of high-density lipoprotein subclasses, which displayed a more heterogeneous response pattern. The lipid-lowering effect of pravastatin was accompanied by selective changes in lipid composition, particularly in the cholesterol content of very-low-density lipoproteinparticles. In addition, pravastatin reduced levels of several fatty acids but had limited effects on fatty acid ratios.Conclusions—These randomized clinical trial data demonstrate the widespread effects of pravastatin treatment on lipoprotein subclass profiles and fatty acids.Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT03073018.