Comparison of the Effects of Simvastatin vs. Rosuvastatin vs. Simvastatin/Ezetimibe on Parameters of Insulin Resistance

E. Moutzouri; E. Liberopoulos; D. P. Mikhailidis; M. S. Kostapanos; A. A. Kei; H. Milionis; M. Elisaf

Disclosures

Int J Clin Pract. 2011;65(11):1141-1148. 

In This Article

Methods

Study Population

Consecutive patients with primary hypercholesterolemia (n = 160) attending the Outpatient Lipid and Obesity Clinic of the University Hospital of Ioannina, Ioannina, Greece participated in the present study.

Inclusion criteria were LDL-C levels above those recommended by the National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP III) based on each patient risk factors following a 3-month period of lifestyle changes.[14]

Exclusion criteria were known CVD, symptomatic carotid artery disease, peripheral arterial disease, abdominal aortic aneurysm, diabetes mellitus, triglycerides > 500 mg/dl (5.65 mmol/l), renal disease (serum creatinine levels > 1.6 mg/dl; 141.4 lmol/l), hypothyroidism [thyroid stimulating hormone (TSH) > 5 IU/ml] and liver disease [alanine aminotranferase and/or aspartate aminotranferase levels > 3-fold upper limit of normal (ULN) in two consecutive measurements], neoplasia as well as clinical and laboratory evidence of an inflammatory or infectious condition. Patients with hypertension were included in the study if they were on stable medication for at least 3 months and their blood pressure was adequately controlled (no change in their treatment was allowed during the study). Patients currently taking lipid-lowering drugs or having stopped them less than 4 weeks before study entry were excluded.

Study Protocol

Before randomisation to study treatment, all patients underwent a 12-week dietary intervention in accordance with the NCEP-ATP-III guidelines.[14] After 12 weeks, patients who continued to meet the inclusion criteria were randomly allocated to receive open-label simvastatin 40 mg or rosuvastatin 10 mg or simvastatin/ezetimibe 10/10 mg for 12 weeks. Patients were instructed to follow the same diet guidelines during drug treatment. Randomisation was performed by means of a computer-generated sequence of random numbers.

All participants gave their written informed consent before any clinical or laboratory evaluations were performed. The study protocol was approved by the institutional ethics committee.

Primary and Secondary End Points

The primary end point was change in the homeostasis model assessment of insulin resistance (HOMAIR) after 3 months of treatment among the three study groups. Secondary end points included changes in fasting plasma glucose (FPG), fasting insulin, glycosylated haemoglobin (HbA1c), the HOMA of b-cell function (HOMA-B) (a marker of basal insulin secretion by pancreatic b-cells), serum lipid parameters and high sensitivity C-reactive protein (hsCRP) among the three study groups. Tolerability was assessed by questioning patients about adverse effects and monitoring relevant laboratory parameters [creatine kinase (CK), liver function tests].

Compliance with study medication was assessed at week 12 by tablet counts; patients were considered compliant if they took 80–100% of the prescribed number of tablets.

Clinical and Laboratory Assessments

Visits took place at baseline, after the 12-week dietary intervention period and at 12 weeks after drug treatment commenced.

Blood samples were obtained after a 14 h overnight fast and were blindly assessed with regard to treatment allocation. All laboratory measurements were performed at the Laboratory of Biochemistry of the University Hospital of Ioannina. Fasting insulin levels were measured using an AxSym microparticle enzyme immunoassay on an AxSym analyzer (Abbott Diagnostics, Abbott Park, IL, USA). HOMA-IR was calculated as follows: fasting insulin (mU/l) · fasting glucose (mg/dl)/405. HOMA-B was calculated as follows: (360· fasting insulin [mU/l])/(fasting glucose [mg/dl] )63). HbA1c (expressed as percentage of the total haemoglobin concentration) was determined using a latex agglutination inhibition assay (Randox Laboratories Ltd., Crumlin, UK). The analytical range for total Hb is 7–23 g/dl. The range of the HbA1c assay is approximately 0.25–2.4 g/dl. The analytical range for %HbA1c is the concentration that corresponds to the level 6 HbA1c calibrator (2.40 g/dl HbA1c, 17.1% HbA1c at a total Hb of 14 g/dl). The minimum detectable concentration of HbA1c with an acceptable level of precision was determined as 0.25 g/dl. The inter- and intra-assay % coefficient of variation (CV) for all other measurements was < 5.0%. Accuracy and precision was surveyed by both, internal quality controls and external quality control assurance.

Concentrations of FPG, total cholesterol (TC), triglycerides (TGs) and high-density lipoprotein cholesterol (HDL-C) were determined enzymatically on the Olympus AU 600 clinical chemistry analyzer (Olympus Diagnostica, Hamburg, Germany). HDL-C was determined using a direct assay (Olympus Diagnostica). LDL-C was calculated with the Friedewald formula.

Apolipoproteins (apo) A-I and apoB and apoE, as well as lipoprotein a [Lp(a)] were measured using a Behring Nephelometer BN100 and with reagents (antibodies and calibrators) from Dade Behring Holding GmbH (Liederbach, Germany). The apoA-I and apoB assays were calibrated according to the International Federation of Clinical Chemistry standards. Serum creatinine, liver and muscle enzymes as well as thyroid function tests were measured using conventional methods. Serum concentrations of hsCRP were measured using the high sensitivity CRP method (Dade Behring, Marburg, Germany) based on particle enhanced immunonephelometry; the reference range is 0.175–55 mg/l.

Statistical Analysis

It was estimated that a sample size of 150 would give a 90% power to detect a 15% difference in the change of HOMA-IR between the three groups at a two-sided alpha of 0.05. Parametric and non-parametric data are presented as mean (SD) and media (range) respectively. The chi-square test was used to compare categorical variables. Continuous variables were tested for lack of normality using the Kolmogorov–Smirnov test, and logarithmic transformations were performed for non-parametric variables. The paired-samples t test was used to assess the effects of treatment in each group. Analysis of covariance (ANCOVA), adjusted for baseline values, was used for comparisons between groups.

After log-transforming non-Gaussian variables, Pearson correlation coefficients were used to describe the relationship of post-treatment change in the HOMA-IR with baseline HOMA-IR, age, gender as well as with waist circumference, body mass index (BMI), hsCRP, lipid and apolipoprotein levels and changes in these parameters at the end of follow up (univariate analysis).

Statistical significance was set at p < 0.05 (two-tailed). Analyses were performed using spss version 15.0 (SPSS Inc., Chicago, IL, USA).

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