Statin action favors normalization of the plasma lipidome in the atherogenic mixed dyslipidemia of MetS: potential relevance to statin-associated dysglycemia

The impact of statin treatment on the abnormal plasma lipidome of mixed dyslipidemic patients with metabolic syndrome (MetS), a group at increased risk of developing diabetes, was evaluated. Insulin-resistant hypertriglyceridemic hypertensive obese males (n = 12) displaying MetS were treated with pitavastatin (4 mg/day) for 180 days; healthy normolipidemic age-matched nonobese males (n = 12) acted as controls. Statin treatment substantially normalized triglyceride (−41%), remnant cholesterol (−55%), and LDL-cholesterol (−39%), with minor effect on HDL-cholesterol (+4%). Lipidomic analysis, normalized to nonHDL-cholesterol in order to probe statin-induced differences in molecular composition independently of reduction in plasma cholesterol, revealed increment in 132 of 138 lipid species that were subnormal at baseline and significantly shifted toward the control group on statin treatment. Increment in alkyl- and alkenylphospholipids (plasmalogens) was prominent, and consistent with significant statin-induced increase in plasma polyunsaturated fatty acid levels. Comparison of the statin-mediated lipidomic changes in MetS with the abnormal plasma lipidomic profile characteristic of prediabetes and T2D in the Australian Diabetes, Obesity, and Lifestyle Study and San Antonio Family Heart Study cohorts by hypergeometric analysis revealed a significant shift toward the lipid profile of controls, indicative of a marked trend toward a normolipidemic phenotype. Pitavastatin attenuated the abnormal plasma lipidome of MetS patients typical of prediabetes and T2D. The impact of statin treatment on the abnormal plasma lipidome of mixed dyslipidemic patients with metabolic syndrome (MetS), a group at increased risk of developing diabetes, was evaluated. Insulin-resistant hypertriglyceridemic hypertensive obese males (n = 12) displaying MetS were treated with pitavastatin (4 mg/day) for 180 days; healthy normolipidemic age-matched nonobese males (n = 12) acted as controls. Statin treatment substantially normalized triglyceride (−41%), remnant cholesterol (−55%), and LDL-cholesterol (−39%), with minor effect on HDL-cholesterol (+4%). Lipidomic analysis, normalized to nonHDL-cholesterol in order to probe statin-induced differences in molecular composition independently of reduction in plasma cholesterol, revealed increment in 132 of 138 lipid species that were subnormal at baseline and significantly shifted toward the control group on statin treatment. Increment in alkyl- and alkenylphospholipids (plasmalogens) was prominent, and consistent with significant statin-induced increase in plasma polyunsaturated fatty acid levels. Comparison of the statin-mediated lipidomic changes in MetS with the abnormal plasma lipidomic profile characteristic of prediabetes and T2D in the Australian Diabetes, Obesity, and Lifestyle Study and San Antonio Family Heart Study cohorts by hypergeometric analysis revealed a significant shift toward the lipid profile of controls, indicative of a marked trend toward a normolipidemic phenotype. Pitavastatin attenuated the abnormal plasma lipidome of MetS patients typical of prediabetes and T2D. The HMG-CoA reductase inhibitors, or statins, act to stabilize vulnerable lipid-rich atherosclerotic plaques and to reduce cardiovascular morbidity and mortality as a consequence of their marked lowering of circulating levels of atherogenic apoB-containing lipoproteins, and notably of LDL-cholesterol (LDL-C) (1. Baigent C. Blackwell L. Emberson J. Holland L. E. Reith C. Bhala N. Peto R. Barnes E. H. Keech A. Simes J. et al. 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Libby P. Glynn R. J. Cardiovascular benefits and diabetes risks of statin therapy in primary prevention: an analysis from the JUPITER trial. Lancet. 2012; 380: 565-571Abstract Full Text Full Text PDF PubMed Scopus (610) Google Scholar). Importantly, post hoc analyses of the Treating to New Targets (TNT), IDEAL, and JUPITER trials indicate that subjects with preexisting risk factors for development of T2D, such as hyperglycemia, hypertriglyceridemia, hypertension, and elevated BMI, are more susceptible to statin-induced T2D than those without, thereby suggesting a predisposition (5. Ridker P. M. Pradhan A. MacFadyen J. G. Libby P. Glynn R. J. Cardiovascular benefits and diabetes risks of statin therapy in primary prevention: an analysis from the JUPITER trial. Lancet. 2012; 380: 565-571Abstract Full Text Full Text PDF PubMed Scopus (610) Google Scholar, 6. Waters D. D. Ho J. E. Boekholdt S. M. DeMicco D. A. Kastelein J. J. Messig M. Breazna A. Pedersen T. R. Cardiovascular event reduction versus new-onset diabetes during atorvastatin therapy: effect of baseline risk factors for diabetes. J. Am. Coll. Cardiol. 2013; 61: 148-152Crossref PubMed Scopus (142) Google Scholar). Each of these risk factors is a component of the cluster characteristic of the metabolic syndrome (MetS), a prediabetic state characterized by elevated cardiovascular risk (7. Alberti G. Zimmet P. Shaw J. Grundy S. M. The IDF consensus worldwide definition of the metabolic sybdrome. IDF Communications. 2006; http: //www. idf. org/webdata/docs/IDFMetadeffinal. pdfGoogle Scholar) ; atherogenic mixed dyslipidemia, characterized by elevated levels of triglyceride-rich lipoproteins and subnormal concentrations of HDL-cholesterol (HDL-C), contributes significantly to such risk (8. Chapman M. J. Ginsberg H. N. Amarenco P. Andreotti F. J. et lipoproteins and cholesterol in patients at risk of cardiovascular and for Heart J. 2011; PubMed Scopus Google Scholar, N. 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IDF Communications. 2006; http: //www. idf. org/webdata/docs/IDFMetadeffinal. pdfGoogle Scholar). subjects atherogenic mixed with plasma participants were to as a two or or treatment for with a treatment with a or plasma from healthy control subjects (n = 12) were from the these nonobese subjects were a with their these subjects were for were hypertensive = = or dyslipidemic of cardiovascular or of dyslipidemic participants with MetS and of the effect of statin treatment for 180 in the with the healthy control from significant from significant from from significant from in a The plasma lipid of the participants and control subjects are in baseline of and in participants in the were M. J. A. P. N. P. of pitavastatin on in patients at elevated risk of new-onset from the and Med. 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The are to lipid as in a with a fatty acid and a of the two fatty acid the the fatty the of the of and the of the of fatty is these species by the and of plasma levels of lipid in control MetS subjects at baseline and MetS subjects treatment lipid of healthy control versus versus MetS versus control as by were significant for by the of MetS as by were significant for by the of MetS control as by were significant for by the of lipid of healthy control control as by were significant for by the of MetS as MetS control as in a of molecular lipid species were by the of species to the of the or as J. M. G. A. L. Shaw J. et lipid in a 2013; Full Text Full Text PDF PubMed Scopus Google Scholar). of lipid were from the of the lipid species The and were to to the plasma and T2D P. J. G. J. M. L. 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A. et lipid with prediabetes and 2013; PubMed Scopus Google Scholar). the lipid concentrations in the and in the were normalized to and the with T2D in the and were to for the effect of pitavastatin in atherogenic cholesterol levels and to in the plasma lipidome that were of the primary in were to the of the the of associated with with the lipid was by pitavastatin treatment potential The of the the of associated with and the lipid was by pitavastatin treatment potential was analysis was to of lipid species that were significantly associated with T2D in the The in these from pitavastatin treatment in the was was of on subjects from the were the was significant analyses of the changes by pitavastatin treatment were the to to pitavastatin treatment that were associated with T2D. The MetS of was hypertriglyceridemic as with in the control = and a significantly to the control group = in MetS subjects (n = revealed a baseline of was significantly than that of the control group P. S. Chapman M. J. A. syndrome is associated with elevated and displaying PubMed Scopus Google Scholar). levels in MetS were to the of by IDF for males with cholesterol = = and = levels were in the MetS group to control indicative of their with for subjects a = with elevated = and to controls. group a of of M. J. A. P. N. P. of pitavastatin on in patients at elevated risk of new-onset from the and Med. PubMed Scopus Google as a group in the P. A. F. F. A. and the metabolic syndrome in a effect of and 2013; PubMed Scopus Google Scholar). low levels of as by on statin treatment. and remnant cholesterol levels as plasma cholesterol and to the cholesterol of triglyceride-rich and their in the were by pitavastatin treatment = = and = such that levels significantly from triglyceride levels = significantly than of a of on treatment in levels are typical for of the statin such effects to to in and are and P. J. G. S. J. of on a to changes in analysis of the 2010; Full Text Full Text PDF PubMed Scopus Google Scholar). were (n = two subjects were and significant changes from baseline in and the were in subjects at a trend to a in levels and was on statin treatment baseline at at baseline at increase in at with the baseline was as M. J. A. P. N. P. of pitavastatin on in patients at elevated risk of new-onset from the and Med. PubMed Scopus Google Scholar). effects were of the of pitavastatin in atherogenic lipid levels. the plasma lipidome of the MetS group at baseline significantly levels of = and = and = in to = to the control the MetS group significantly baseline levels of = = as well as = and = 180 of pitavastatin significant in the baseline elevated plasma levels of and and toward concentrations in the control group were and for elevated levels of the lipid in MetS subjects at were statin treatment. concentrations of and the alkyl- and were significantly of were elevated in MetS as with controls, were to the control group statin treatment. lipid levels were than at baseline were statin and Importantly, these analyses the more differences in composition or the changes in the of lipid molecular species from pitavastatin treatment. order to these independently of baseline plasma cholesterol levels and changes in those normalized lipid and species to and the MetS and controls, and in the MetS and and analyses revealed significantly = and = to in MetS in to controls, consistent with the in MetS lipid the alkyl- and levels to in the MetS group with the control statin treatment for 180 the in and that in significant in the concentrations of lipid and to and in the alkyl- and were in a of the lipidomic profile in the MetS group toward that of the control subjects such that of the lipid and that were significantly baseline MetS and controls, significantly the and differences plasma levels of lipid to in controls, MetS subjects and MetS treatment lipid of healthy control group versus versus MetS versus control as by were significant for by the of MetS as by were significant for by the of MetS control as by were significant for by the of lipid of healthy control group control as by were significant for by the of MetS as MetS control as in a the molecular lipid species the were to the by statin and species were was in the and the levels of species acid and were elevated over = and = the species of the species acid and = and = than the species effects of pitavastatin treatment on lipid species acid and acid were in the of the species a to treatment an species to an increase or fatty the species that the treatment at fatty acid effect was with the species in the to the and molecular species a and effects of statin on of lipid and fatty acid order to the potential impact of statin-induced in the plasma lipidome on risk for T2D, a hypergeometric to the in associated with T2D on the and those significantly by statin treatment on the of those changes in the of lipid metabolic and of to for control for the effect of levels of apoB-containing lipoproteins and the reduction of plasma from statin hypergeometric analysis was on lipid that normalized to lipid and species were at baseline in the MetS group normalized to as with the control the concentrations of these species increased toward to statin treatment. a significant of the that were associated with T2D to to those that were their concentrations by pitavastatin treatment were these data were with those in the = and cohorts = with of the in the in the that were associated with T2D were significantly in the of that were by statin treatment were two lipid species that were significantly in to pitavastatin treatment analysis was to of lipid species that with a to the of these data The the lipid in those of and The a more with of the in of were those from statin treatment changes in and species with of lipid species in the and analysis of statin-induced in the abnormal plasma lipid profile in MetS subjects in the a shift toward that in healthy normolipidemic controls. marked statin-induced shift in circulating levels of molecular lipid species toward levels in the control group that pitavastatin therapy reduce risk of and T2D associated with the atherogenic mixed characteristic of and lipidomic analysis of the impact of statin treatment on mixed dyslipidemic subjects with MetS a prediabetic state at baseline impact on circulating atherogenic apoB-containing lipoproteins and thereby of lipid levels are by plasma lipid and are significant statin-induced in of plasma lipid and and in of molecular lipid were Moreover, lipid of the plasma lipidome associated with and prediabetic elevated levels of and and concentrations of the alkyl- and species of and M. J. M. A. at the of the of therapy with statins, and Heart J. 2010; PubMed Scopus Google and was in in the MetS participants to the healthy controls. The shift in the of plasma lipid and statin treatment changes in the lipid composition of for normalized plasma lipid data to lipid species in plasma levels to pitavastatin thereby to cholesterol to control and MetS baseline differences in plasma lipid profile and the shift in lipid toward the lipidome of control normolipidemic subjects statin treatment. levels of the and species were elevated over in MetS subjects to at were in to statin such that were significantly to changes in the and elevated in the MetS group to were statin treatment and were significantly to reduction in concentrations The of these more to the of the statin than to that of lipid The analysis lipid species to a to fatty acid The of lipid levels treatment for the lipid that pitavastatin a effect at the lipid to the or plasma fatty acid of the of the statin-mediated changes in the plasma lipidome in to risk of T2D. on cohorts with a lipid profile associated with T2D P. J. G. J. M. L. 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F. of by 2002; PubMed Scopus Google of are to atherosclerotic of the lipid species that were associated with T2D in the and by pitavastatin were the were species of and and of or polyunsaturated fatty species were associated with T2D in the a potential for these lipid species in the and are to potential effects on differences in the of species of and to statin treatment to effects on the metabolic of of to by by metabolic is to for polyunsaturated species of G. and of and and plasma in 2011; Full Text Full Text PDF PubMed Scopus Google and to the and progression of and to of 2013; PubMed Scopus Google Scholar). the or of pitavastatin on the to effect on the plasma lipidome in prediabetes and with potential for a or effect on risk of development of T2D. to these are of and T2D associated with statin is a and in group G. S. Chapman M. J. P. et for the of the for the of of the of and the Heart J. 2011; PubMed Scopus Google Scholar). randomized of for potential effects in patients at diabetes risk are in order to in the the of a statin data to that for pitavastatin are for of in subjects displaying mixed and the that the effects on the plasma lipidome are to are to The to was in by of a group of patients a consistent mixed dyslipidemia, of M. J. A. P. N. P. of pitavastatin on in patients at elevated risk of new-onset from the and Med. PubMed Scopus Google Scholar). of and plasma and were in a on the in order to potential for on the to potential in lipid and in to or the patients acted as their in mechanistic is to effects to differences in and baseline to a that to the in to of treatment effects in the of a control to these the of the lipidomic analysis with the to lipid species and that were significantly in to statin with for the data to that from two clinical for these data in a in an of mixed dyslipidemic to and a statin The M. for in clinical P. and at the of for and and A. for The by the Heart and the The are to the participants of the with Australian Diabetes, and Lifestyle plasma HDL-cholesterol of LDL-cholesterol metabolic syndrome San Antonio Family Heart Study