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

Peter J Meikle,Gerard Wong,Ricardo Tan,Philippe Giral,Paul Robillard,Alexina Orsoni,Neil Hounslow,Dianna J Magliano,Jonathan E Shaw,Joanne E Curran,John Blangero,Bronwyn A Kingwell,M.John Chapman

doi:10.1194/jlr.p061143

Abstract

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.

Highlights

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
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 statininduced T2D than those without, thereby suggesting a Abbreviations: AusDiab, Australian Diabetes, Obesity and Lifestyle study; FPG, fasting plasma glucose; HDL-C, HDL-cholesterol; HOMAIR, homeostasis model of insulin resistance; IDF, International Diabetes Federation; LDL-C, LDL-cholesterol; MetS, metabolic syndrome; SAFHS, San Antonio Family Heart Study; SBP, systolic blood pressure
In the CAPITAIN trial, an open label study, we evaluated this hypothesis through analysis of the plasma lipidome in male patients with the above phenotype at baseline and after pitavastatin (4 mg/ day) treatment for a period of 6 months; subjects acted as their own controls

Summary

Introduction

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. 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 statininduced T2D than those without, thereby suggesting a Abbreviations: AusDiab, Australian Diabetes, Obesity and Lifestyle study; FPG, fasting plasma glucose; HDL-C, HDL-cholesterol; HOMAIR, homeostasis model of insulin resistance; IDF, International Diabetes Federation; LDL-C, LDL-cholesterol; MetS, metabolic syndrome; SAFHS, San Antonio Family Heart Study; SBP, systolic blood pressure. Journal of Lipid Research Volume 56, 2015 2381 predisposition [5, 6] 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]; 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, 9]. As 95% or more of plasma lipids are transported in lipoproteins, which facilitate exchange and net transfer of lipids with cells of the circulation, tissues, and organs, the complement of individual lipid molecular species in plasma, i.e., the lipidome, has the potential to reflect chronic disorders of lipid metabolism, such as those implicated in prediabetes and T2D

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Conclusion