Effect of Simvastatin and Ezetimibe on Lipid and Inflammation
Condition: Prediabetes; Hypercholesterolemia; Inflammation; Cardiovascular Risk
MeSH terms: Hypercholesterolemia; Prediabetic State; Glucose Intolerance; Inflammation
Study type: Interventional

Summary: 
      Ezetimibe specifically blocks the absorption of dietary and biliary cholesterol and plant
      sterols. Synergism of ezetimibe-statin therapy on LDL-cholesterol has been demonstrated, but
      data concerning the pleiotropic effects of this combination are controversial. We tested the
      hypothesis that the combination of simvastatin and ezetimibe would induce improvement in
      inflammatory status, as reflected by leukocyte count and CRP, IL-6 and TNF-a levels. This
      open-label trial evaluated whether this combination results in a synergistic effect the
      pro-inflammatory status of pre-diabetic subjects. Fifty pre-diabetic subjects were randomly
      assigned to one of 2 groups, one receiving ezetimibe (10 mg/d), the other, simvastatin (20
      mg/d) for 12 weeks, followed by an additional 12-week period of combined therapy.
    

Detailed description: 
      Long-term benefits of statins on prevention of cardiovascular events have been consistently
      shown in several populations. It has been demonstrated that, with particular regard to
      subjects at high risk, the lower LDL-cholesterol levels, the lower the incidence of
      cardiovascular outcomes. Beneficial effects of statins can be attributed to their
      lipid-lowering ability as well as to additional benefits. The so-called pleiotropic effects
      on low grade inflammation status have been described in subsets of subjects with different
      cardiovascular profiles. The most common inflammatory marker used in clinical practice is the
      high-sensitivity C-reactive protein (CRP) level, but a number of others has also been
      investigated.

      Disturbances of glucose metabolism accompanied by insulin resistance are pro-inflammatory
      conditions which may accelerate atherosclerosis. Diabetic populations are at high
      cardiovascular risk and strict control of lipoprotein concentrations is recommended. Several
      recent studies showed the efficacy of statins on primary and secondary prevention of
      cardiovascular events in diabetic populations. The goal of 100 mg/dL for LDL-cholesterol may
      be too elevated for subjects at very high risk for whom a target of 70 mg/dl has been
      suggested. High statin doses may be necessary, which increases its adverse effects. Given
      that statin monotherapy may be insufficient for the desirable reduction in LDL levels, a
      combination of lipid-lowering agents has become frequent in clinical practice. In particular,
      statin and ezetimibe combination has been shown to be very effective in reducing total and
      LDL cholesterol levels.

      Ezetimibe is a specific cholesterol absorption inhibitor that acts at the brush border of the
      small intestine, blocking the absorption of dietary and biliary cholesterol and plant
      sterols, resulting in intracellular cholesterol depletion via the Niemann-Pick C1-like
      transporter. Adding ezetimibe to statin therapy induces a 15% reduction in LDL levels
      compared with only 6% achieved by doubling the dose of statins. Data concerning the
      pleiotropic effects of this combination are controversial. One study, in which CRP level was
      used as the inflammatory marker, found that a combination of simvastatin and ezetimibe
      produced an incremental effect in lowering CRP, independently of the improvement in
      lipoprotein concentrations. Although few studies have confirmed this finding, as far as we
      know, data regarding simvastatin-ezetimibe combination induced-changes in serum interleukin-6
      (IL-6) and tumor necrosis factor alpha (TNF-a) levels are lacking. We tested the hypothesis
      that this combination would induce improvement in inflammatory status, as reflected by
      leukocyte count and CRP, IL-6 and TNF-α levels.

      Therefore, this study evaluates whether the combination of lipid-lowering effects of
      low-to-moderate dose of simvastatin and ezetimibe also results in a synergistic effect that
      reduces the pro-inflammatory status of pre-diabetic subjects with mild-to-moderate
      hypercholesterolemia.

      Subjects and Methods:

      Participants were selected from the Federal University of São Paulo outpatient clinics. The
      study was approved by the institutional ethical committee and all participants were provided
      with written informed consent.

      Eligible subjects were men and women, aged from 18 to 75 years, with a body mass index (BMI)
      ranging from 25 to 40 kg/m2 and pre-diabetes (impaired glucose tolerance or impaired fasting
      glucose). Entry criteria required triglyceride levels ≤ 350 mg/dl and LDL cholesterol ≤ 200
      mg/dl, stable blood pressure and no evidence of cardiovascular, hepatic or renal diseases.
      Subjects were not taking anti-inflammatory agents or others interfering with lipid or glucose
      metabolism. Eligible participants were recruited from June 2005 to May 2006.
      Two-hundred-ninety subjects with weight excess, with or without family history of diabetes,
      were screened for the interventional protocol and 50 with impaired glucose tolerance (IGT) or
      impaired fasting glucose (IFG) were randomly assigned to 2 groups that would receive
      ezetimibe 10 mg/d (n = 25) or simvastatin 20 mg/d (n = 25), preceded by a 2-week run-in
      period. Monotherapies were maintained for 12 weeks; thereafter the drugs were combined in
      each group for an additional 12-week period. All participants received individual counseling
      for a healthy lifestyle and had monthly visits. Treatment was to be discontinued prematurely
      if transaminases exceeded 3 times the upper limit of reference or creatine phosphokinase
      (CPK) 10 times, but no subject met these criteria. One of the ezetimibe group dropped out due
      to non-compliance.

      Baseline, 12-week and 24-week blood samples were drawn in the morning, after a 12-hour fast,
      for glucose, lipid profile, including apolipoprotein A-I and B, leukocyte count and
      inflammatory markers were made. A LDL-cholesterol goal of 100 mg/dl was used in the present
      study (8,22).

      Laboratory analysis: Plasma glucose, transaminases, CPK and creatinine were determined by
      routine methods. Serum lipid levels (total cholesterol, HDL-cholesterol, and triglycerides)
      were analyzed by commercially available tests (Roche Diagnostics GmbH, Mannheim, Germany).
      Blood samples were stored at -20ºC until determinations of apolipoproteins and inflammatory
      markers. Apolipoprotein A-I and B were measured by immunoturbidimetry (Olympus Life and
      Material Science Europa GmbH, Lismeeham, Ireland), with an intra-assay coefficient of
      variability (CV) of 1.26-1.30% and 0.93-1.17% respectively, and an inter-assay CV of
      1.43-1.55% and 1.10-1.46%, respectively. High-sensitivity CRP (Immulite - DPC, Los Angeles,
      CA, USA), TNF-α and IL-6 (Immulite - Euro/DPC, Llanberis, Gwynedd, UK) were determined by
      chemiluminescent immunometric assay. The sensitivity of CRP assay was 0.01 mg/dL (intra-assay
      CV 4.2-6.4% and inter-assay CV 4.8-10%), of TNF-α assay 1.7 pg/mL (intra-assay CV 2.6-3.6%,
      inter-assay CV 4.0-6.5%) and of IL-6 assay was 2.0 pg/mL (intra-assay CV 3.5-6.2%,
      inter-assay CV 5.1-7.5%).

      Statistical analysis: Data were expressed as mean values and standard errors or deviations.
      Unpaired Student's t test was used to compare groups at baseline and chi-square to assess
      differences between qualitative data. One-way ANOVA for repeated measures was used to
      evaluate the effect of drugs over time and to compare data between groups of subjects
      according to the type of therapy. Pairwise contrasts were made by comparing least-square mean
      estimates, and P values adjusted for multiple comparisons using the Bonferroni Holm method.
      The level of significance was set at P < 0.05. Correlation between variables was tested by
      the Pearson coefficient, also employed to assess whether changes in variables over time were
      correlated. Data analysis was performed using Statistical Analysis System software, version
      8.2 (SAS Institute, Cary, NC).
    

Intervention name(s): Simvastatin; Ezetimibe; Combination Simvastatin plus Ezetimibe
Intervention type(s): Drug; Drug; Drug
Intervention description(s): Tablets of simvastatin 20 mg administered once a day for 12 weeks; Tablets of ezetimibe 10 mg administered once a day for 12 weeks; Simvastatin 20 mg, once a day, was administered for an additional 12-week period for the subset of individuals who took the initial monotherapy with ezetimibe 10 mg (12 week duration).
Ezetimibe 10 mg, once a day, was administered for an additional 12-week period for the subset of individuals who took the initial monotherapy with simvastatin 20 mg (12 week duration).
This Combination represents the experimental period of the present study.
Other intervention name(s): Statin; Lipid-lowering drug; Simvastatin; Statin; Ezetimibe; Lipid-lowering drugs
Intervention MeSH terms: Simvastatin; Ezetimibe; Hypolipidemic Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Prediabetes; Statin; Ezetimibe; Pleiotropic effects; Cardiometabolic risk