Comparison of Simvastatin Versus Simvastatin/Ezetimibe on Small Dense Low -Density Lipoprotein (LDL)
Information source: University of Ioannina
ClinicalTrials.gov processed this data on August 23, 2015 Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Hypercholesterolemia
Intervention: SIMVASTATIN 40 mg (Drug); SIMVASTATIN/EZETIMIBE 10/10 mg (Drug)
Phase: Phase 4
Status: Completed
Sponsored by: University of Ioannina
Summary
Both simvastatin 40 mg and simvastatin/ezetimibe 10/10 mg result in low-density lipoprotein
cholesterol (LDL-C) reductions of approximately the same magnitude. However, the
differential effects of these two treatment options on small dense LDL-C (sdLDL-C)
concentration have not been assessed.
The aim of the present study is to compare the effects of simvastatin 40 mg versus
simvastatin/ezetimibe 10/10 mg on sdLDL-C concentration. The primary efficacy endpoint will
be changes in LDL subfraction profile (i. e. mean LDL particle size, sdLDL-C levels) at 3
months after treatment initiation.
Clinical Details
Official title: THE EFFECT OF SIMVASTATIN VERSUS COMBINED SIMVASTATIN/EZETIMIBE TREATMENT ON THE CONCENTRATION OF SMALL DENSE LOW-DENSITY LIPOPROTEIN PARTICLES IN PATIENTS WITH PRIMARY HYPERCHOLESTEROLEMIA
Study design: Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
Primary outcome: Changes in Small Dense Low-density Lipoprotein Cholesterol (sdLDL-C) Levels
Secondary outcome: Changes in Low-density Lipoprotein Cholesterol (LDL-C)
Detailed description:
Hypercholesterolemia is a major risk factor for atherosclerosis and coronary heart disease
(CHD).[1] Epidemiological and clinical studies have demonstrated that aggressive lowering of
low-density lipoprotein cholesterol (LDL-C) reduces morbidity and mortality in patients with
or without CHD.[1-3] LDL consists of an heterogeneous population of particles with respect
to size, density and chemical composition. Several studies have shown that small, dense LDL
(sdLDL) particles are more atherogenic than large, buoyant ones[4, 5] and thus associated
with increased risk for coronary artery disease[6] or stroke.[7] Statins, the mainstay of
lipid lowering therapy, achieve significant reductions in LDL-C levels and are suggested to
lower all LDL subfractions, possibly as a result of the statin-induced stimulation of
LDL-receptor-mediated catabolism.[8] Moreover, several studies have shown that abnormalities
in LDL subfraction profile are amenable to correction with statins.[9] Ezetimibe monotherapy
has also been found to significantly reduce concentrations of all LDL subfractions.[10] The
combination of ezetimibe with low dose of a statin results in similar LDL-C lowering
compared with high dose of the same statin. A recent study demonstrated that
ezetimibe/simvastatin combination was more effective than ezetimibe and simvastatin
monotherapy in reducing atherogenic lipoprotein subfractions in patients with primary
hypercholesterolemia.[11] However, in this study ezetimibe/simvastatin combination was more
potent in reducing LDL-C levels compared with either monotherapy.[11] In another study, the
addition of ezetimibe in patients already receiving atorvastatin decreased LDL-C values
exclusively by reducing the concentrations of large, buoyant LDL subfractions.[12] It is so
far unknown whether high-dose of a statin would reduce sdLDL-C level more than low-dose
statin plus ezetimibe therapy for the same degree of LDL-C lowering.
Both simvastatin 40 mg and simvastatin/ezetimibe 10/10 mg result in LDL-C reductions of
approximately the same magnitude.[13,14] However, the differential effects of these two
treatment options on sdLDL-C concentration have not been assessed.
Study design Randomized, open label study.
Aim of the study The aim of the present study is to compare the effects of simvastatin 40 mg
versus simvastatin/ezetimibe 10/10 mg on sdLDL-C concentration.
Materials and Methods Study population Consecutive patients with primary
hypercholesterolemia (n=100) attending the Outpatient Lipid and Obesity Clinic of the
University Hospital of Ioannina, Ioannina, Greece will participate in the present study.
All subjects will receive dietary instructions according to National Cholesterol Education
Program Adult Treatment Panel III (NCEP-ATP III) by a clinical nutritionist. If LDL-C is
still above recommended levels after 3 months of appropriate lifestyle changes, patients
will be randomly allocated to open-label simvastatin 40 mg (n=50) or simvastatin/ezetimibe
10/10 mg (n=50) daily.
Enrollment will be completed in a period of 1 year. Follow-up visit will be scheduled at 3
months after treatment initiation.
The study protocol will be approved by the Ethics Committee of the University Hospital of
Ioannina and all participants will be asked to give their written informed consent.
Laboratory measurements
Blood analyses will be carried out after an overnight fast (12 hours) and will include:
- Glucose, insulin, creatinine, uric acid, aspartate aminotransferase (AST), alanine
aminotransferase (ALT), gamma glutamyl transpeptidase (γ-GT), alkaline phosphatase
(ALP)
- Total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C) and triglyceride
levels, whereas LDL-C levels will be assessed using the Friedewald equation (LDL-C =
TC-HDL-C-triglycerides/5)
- high-sensitivity C-reaction protein (hs-CRP) levels
- Apolipoproteins A-I, A-II, A-V, B, E, C-II, C-III, lipoprotein (a)[Lp(a)]
- Lipoprotein-associated phospholipase A2 (Lp-PLA2) activity in plasma
Methods LDL subclass analysis Electrophoresis will be performed using high resolution 3%
polyacrylamide tube gel and the Lipoprint LDL System (Quantimetrix, Redondo Beach, CA)
according to the manufacturer's instructions.[16, 17, 18] Briefly, 25 μl of sample will be
mixed with 200 μl of Lipoprint Loading Gel and placed upon the upper part of the 3%
polyacrylamide gel. After 30 min of photopolymerization at room temperature, electrophoresis
will be performed for 60 min with 3 mA for each gel tube. Each electrophoresis chamber will
involve 2 quality controls (sample provided by the manufacturer). For quantification,
scanning will be performed with a ScanMaker 8700 digital scanner (Mikrotek Co, USA) and iMac
personal computer (Apple Computer Inc, USA). After scanning, electrophoretic mobility (Rf)
and the area under the curve (AUC) will be calculated qualitatively and quantitatively with
the Lipoprint LDL system Template and the Lipoware software (Quantimetrix Co, Redondo Beach,
CA), respectively. The LDL subfraction will be calculated using the Rf between the very
low-density lipoprotein (VLDL) fraction (Rf 0. 0) and the HDL fraction (Rf 1. 0). LDL is
distributed from Rf 0. 32 to Rf 0. 64 as 7 bands, whose Rfs are 0. 32, 0. 38, 0. 45, 0. 51, 0. 56,
0. 6 and 0. 64 (LDL1 to LDL7, respectively). LDL1 and LDL2 are defined as large, buoyant LDL
and LDL3 to LDL7 are defined as sd-LDL. The cholesterol concentration (in mg/dl) of each LDL
subfraction is determined by multiplying the relative AUC of each subfraction by the TC
concentration of the sample (the TC concentration of the sample is measured independently).
The proportion of sd-LDL-cholesterol (sd-LDL%) will be defined as the percentage of the
LDL-cholesterol carried in sd-LDL (i. e. bands 3 to 7). LDL peak particle diameter (LDL-PPD)
(nm) will be determined using the Rf of the highest peak of the LDL bands according to the
following equation proposed: LDL-PPD = (1. 429-Rf)*25. Moreover, the Lipoprint LDL System
provides a mean LDL particle size (nm) and uses a size of 26. 8 nm as a cut-off point to
classify individuals into phenotypes A (absence of sd-LDL particles) and non-A (presence of
sd-LDL particles).
Measurement of plasma Lp-PLA2 activity Lp-PLA2 activity in total plasma, in apo B-depleted
plasma, after the sedimentation of all apo B-containing lipoproteins with dextran
sulfate-magnesium chloride (HDL-Lp-PLA2 activity) as well as in lipoprotein subfractions,
will be determined by the trichloroacetic acid precipitation procedure using
[3H]-platelet-activating factor (PAF) (100 μM final concentration) as a substrate.[16] The
reaction will be performed for 10 min at 37°C and Lp-PLA2 activity will be expressed as nmol
PAF degraded per min per ml of plasma or mg of LDL subfraction protein. The non-HDL-Lp-PLA2
activity will be calculated by subtracting the HDL-Lp-PLA2 activity from the total plasma
enzyme activity. Lp-PLA2 specific activity will be expressed as a ratio of the enzyme
activity to the enzyme mass (nmol/ng/min).
Serum apolipoproteins measurement Serum apolipoproteins A-I, A-II, AV, B, E, C-II, C-III
and Lp(a) will be measured by immunonephelometry on a Behring Nephelometer BN ProSpec
(Dade-Behring, Lieberbach, Germany).
Determination of plasma hs-CRP levels Plasma concentrations of CRP will be measured with a
high sensitivity immunonephelometric assay (Beckman Instruments, Fullerton, CA). The
reference range of this assay is 1. 0 to 80 mg/l. The detection limit is 1. 0 mg/l.
Routine laboratory determinations Routine laboratory determinations will be carried out by
automated chemical analysis in the laboratory of the University Hospital of Ioannina using
an Olympus AU 600 analyzer (Olympus Diagnostica GmbH, Hamburg, Germany). Glucose will be
measured by the hexokinase method and serum insulin levels by the AxSYM Insulin assay, which
is based on the Microparticle Enzyme Immunoassay technology (Abbott Laboratories, Diagnostic
Division, Abbott Park, IL, USA).
Statistical analysis All parameters will be checked for normality with the
Kolmogorov-Smirnov test and non-normal-distributed variables will be log-transformed. Linear
regression analysis will be used for the assessment of the relationships between study
variables, whereas multivariate analysis will be used for the determination of the
independent predictors of study parameter change. The paired-samples t-test will be used for
assessing the effect of treatment in each group. Analysis of covariance (ANOVA), adjusted
for baseline values, will be used for comparisons between treatment groups. Significance
will be defined as p<0. 05 and Bonferroni correction will be applied in the case of multiple
comparisons. All analyses will be carried out with SPSS 13. 0 (SPSS Inc., 1989-2004, Chicago,
IL). It was estimated that a sample size of 90 would give a 94% power to detect a 15%
difference in the reduction of sdLDL-C concentration between the 2 groups at a 2-sided alpha
of 0. 05. We will include 100 patients allowing for a drop-out rate of ~10%.
Eligibility
Minimum age: N/A.
Maximum age: N/A.
Gender(s): Both.
Criteria:
Inclusion Criteria:
- 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.
Exclusion Criteria:
- Triglycerides >500 mg/dL, renal disease (serum creatinine levels >1. 6 mg/dL),
hypothyroidism [thyroid stimulating hormone (TSH) >5 IU/mL] and liver disease (ALT
and/or AST levels >3-fold upper limit of normal in 2 consecutive measurements).
- Patients with hypertension will be included in the study if they are on stable
medication for at least 3 months and their blood pressure is adequately controlled
(no change in their treatment will be made during the study period).
- Patients currently taking lipid lowering drugs or having stopped them less than 4
weeks before study entry will be excluded
Locations and Contacts
University Hospital of Ioannina, Ioannina 45 110, Greece
Additional Information
2nd Department of Internal Medicine, University Hospital of Ioannina
Starting date: June 2009
Last updated: August 17, 2011
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