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The Effect of Rosuvastatin on Low-Density Lipoprotein Subfractions in Patients With Impaired Fasting Glucose Christos V. Rizos, Michael S. Kostapanos, Evangelos C. Rizos, Alexandros D. Tselepis and Moses S. Elisaf J CARDIOVASC PHARMACOL THER published online 18 September 2014 DOI: 10.1177/1074248414549419 The online version of this article can be found at: http://cpt.sagepub.com/content/early/2014/09/18/1074248414549419.1

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Original Article

The Effect of Rosuvastatin on Low-Density Lipoprotein Subfractions in Patients With Impaired Fasting Glucose

Journal of Cardiovascular Pharmacology and Therapeutics 1-8 ª The Author(s) 2014 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/1074248414549419 cpt.sagepub.com

Christos V. Rizos, MD1, Michael S. Kostapanos, MD1, Evangelos C. Rizos, MD1, Alexandros D. Tselepis, MD2, and Moses S. Elisaf, MD, FASA, FRPSH1

Abstract Background: Prediabetes substantially increases cardiovascular risk. We examined the effect of rosuvastatin on the quantity and quality of low-density lipoprotein cholesterol (LDL-C) in patients with dyslipidemia having impaired fasting glucose (IFG) compared to normoglycemic patients with dyslipidemia. Methods: This was a prospective observational study including patients with dyslipidemia and IFG (IFG group, n ¼ 49) matched with normoglycemic patients with dyslipidemia (control group, n ¼ 64). Study participants, following dietary intervention, were prescribed rosuvastatin 10 or 20 mg/d to achieve LDL-C goals. Baseline as well as 24 weeks posttreatment changes in the serum lipid profile were evaluated. Moreover, analysis of the LDL subfraction profile was conducted using a polyacrylamide tube gel electrophoresis method. Results: Similar effects were observed in lipid profile in both treatment groups. Patients with IFG experienced a greater decrease in the cholesterol concentration of small dense LDL particles (65.7%, P < .001 vs baseline) compared to controls (38.5%, P < .001 vs baseline; P ¼ .018 vs patients with IFG). There was no significant difference in the changes of cholesterol concentration of large and buoyant LDL particles in the IFG group when compared to the control group. A greater increase in the mean LDL particle size (þ1.5%, P < .001 vs baseline) was noted in the IFG group compared to the control group at 24 weeks (þ0.4%, P ¼ .028 vs baseline; P ¼ .008 vs IFG group). Conclusion: Targeting dyslipidemia with rosuvastatin was associated with more favorable changes in the LDL subfraction profile in patients with IFG compared to normoglycemic ones. Keywords rosuvastatin, prediabetes, impaired fasting glucose, low-density lipoprotein cholesterol, low-density lipoprotein cholesterol subfractions

Introduction Hypercholesterolemia is an independent risk factor for the development and progression of cardiovascular (CV) disease, which is among the leading causes of mortality globally.1 Raised low-density lipoprotein cholesterol (LDL-C) levels proportionally increase the risk of CV events. However, this risk cannot be entirely predicted by LDL-C levels.2 Several lipid contributors associated with the ‘‘residual’’ CV risk include atherogenic dyslipidemia (elevated triglycerides [TGs] together with low high-density lipoprotein cholesterol [HDLC] levels) and the distribution of low-density lipoprotein (LDL) particles.3 Moreover, the quality of HDL-C plays an important role in the development of CV disease.4 Low-density lipoprotein is not homogenous but consists of multiple subfractions with different size, density, and chemical composition.5 Small dense LDLs (sdLDLs) are particles that appear to possess most of the atherogenic potential of LDL.6 This is mostly attributed to their capacity to penetrate the vessel wall and undergo oxidative modification.7

Statins are the cornerstone of hypercholesterolemia treatment. Among statins, rosuvastatin is considered the most potent in beneficially modifying the serum lipid profile8 and altering LDL subfraction distribution.9,10 We have previously shown that rosuvastatin can reduce the cholesterol content of both large-buoyant LDL (lbLDL) and sdLDL.11,12 Also, rosuvastatin can increase LDL size, especially in patients with raised TG levels at baseline.11,12 On

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Department of Internal Medicine, Medical School, University of Ioannina, Ioannina, Greece 2 Laboratory of Biochemistry, School of Chemistry, University of Ioannina, Ioannina, Greece Manuscript submitted: June 14, 2014; accepted: August 1, 2014. Corresponding Author: Moses S. Elisaf, Department of Internal Medicine, Medical School, University of Ioannina, Ioannina 45110, Greece. Email: [email protected]

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Journal of Cardiovascular Pharmacology and Therapeutics

the other hand, statin treatment has been associated with the development of new-onset diabetes mellitus.13 As a result, the safety and the strength of intervention with statin treatment could be questioned in the subgroup of prediabetic patients who already have a high risk of diabetes development. It is estimated that at least one-third of patients with impaired fasting glucose (IFG) or impaired glucose tolerance (IGT; or more when IFG coexists with IGT) will eventually progress to overt diabetes in the next decade following the primary diagnosis. However, a careful evaluation of the potential risks and benefits with statin administration should be considered. Compared with the CV protection provided by statins, their effect on glucose metabolism is relatively small. In addition, multiple CV risk factors are common among patients with IFG who also frequently fulfill the diagnostic criteria of metabolic syndrome. To date, it is unclear whether statin intervention in patients with dyslipidemia having IFG better modifies the serum lipid profile as well as the quality synthesis of LDL particles. In this study, we examined the potentially differential effect of rosuvastatin on the quantity and quality of LDL-C in patients with dyslipidemia having IFG compared with normoglycemic patients with dyslipidemia.

Methods Patients Consecutive patients with dyslipidemia (LDL-C levels >160 mg/dL [4.14 mmol/L]) who attended the Outpatient Lipid and Metabolic Control Clinic of the University Hospital of Ioannina, Greece, from December 2011 to December 2012, were recruited. Patients were excluded if they had any of the following: (1) history of diabetes (fasting plasma glucose >125 mg/dL [7 mmol/L] in 2 consecutive measurements or use of antidiabetic drugs), (2) established CV disease, (3) TG >400 mg/dL (4.52 mmol/L), (4) renal disease (estimated glomerular filtration rate according to the Modification of Diet in Renal Disease [MDRD] formula 5 IU/mL), (6) liver dysfunction (alanine aspartate aminotransferase and/or aspartate aminotransferase activity greater than 3 the upper limit of normal), (7) active lipid-lowering or antihypertensive treatment in the last 3 months prior to recruitment; and (8) childbearing potential (for women). According to the American Diabetes Association (ADA) criteria, prediabetes is defined as IFG with fasting plasma glucose levels between 100 and 125 mg/dL (5.6-6.9 mmol/L) or impaired glucose tolerance (IGT) with 2-hour glucose levels between 140 and 199 mg/dL (7.8-11.0 mmol/L) following an oral glucose tolerance test with 75 g glucose, or both of them.14 Eligible patients with IFG were compared to a group of patients with dyslipidemia who had normal fasting plasma glucose. All participants gave written informed consent, and the study protocol was approved by our institutional ethics committee.

Study Design This was a prospective observational study. No extramural funding was used to support this work. The authors are solely responsible for the design and conduct of this study, all study analyses, and drafting and editing of the article. All patients (n ¼ 127) received a 12-week dietary intervention in accordance with the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) guidelines.15 Patients who continued to meet the inclusion criteria after the dietary intervention period (n ¼ 113; 49 with IFG and 64 controls) were prescribed rosuvastatin 10 or 20 mg/d to achieve the NCEP ATP III LDL-C goals. Adherence with study medication was assessed at week 24 by counting the tablets taken; patients were considered adherent if they took >80% of the prescribed number of tablets. The primary outcome was the differential change in the LDL subfraction profile in the subgroup of patients with dyslipidemia having IFG compared to those with normal glucose levels, following rosuvastatin treatment for 24 weeks.

Biochemical Parameters All laboratory determinations were carried out after a 12-hour overnight fasting. Clinical investigators were blinded to laboratory results. Levels of fasting plasma glucose, total cholesterol (TC), HDL-C, and TGs were determined enzymatically in the laboratory of the University Hospital of Ioannina using an Olympus AU 600 analyzer (Olympus Diagnostica GmbH, Hamburg, Germany). Low-density lipoprotein cholesterol was calculated using the Friedewald formula (LDL-C ¼ TC  TG/5  HDL; provided that TGs were

The effect of rosuvastatin on low-density lipoprotein subfractions in patients with impaired fasting glucose.

Prediabetes substantially increases cardiovascular risk. We examined the effect of rosuvastatin on the quantity and quality of low-density lipoprotein...
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