Ignite Creation Date:
2024-05-05 @ 5:36 PM
Last Modification Date:
2024-10-26 @ 9:33 AM
Study NCT ID:
NCT00481351
Status:
COMPLETED
Last Update Posted:
2011-01-26
First Post:
2007-05-30
Brief Title:
Effects of Statin and Ezetimibe Association on Kinetics of Artificial Chilomicrons
Sponsor:
University of Sao Paulo
Organization:
University of Sao Paulo
Study Overview
Official Title:
Effects of Statin and Ezetimibe Association on Kinetics of Artificial Chilomicrons in Men With Stable Coronary Heart Disease
Status:
COMPLETED
Status Verified Date:
2007-01
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Effects of statin and ezetimibe association on kinetics of artificial chylomicrons in men with stable coronary heart disease CHD
Background
The rate kinetics of chylomicrons removal from circulation have been correlated with the incidence and severity of atherosclerotic lesions a number of studies demonstrated lower plasmatic clearance of chylomicrons in patients with CHD compared to patients without this condition It was also demonstrated a correlation among LDL-C levels and removal of chylomicrons remnants by a technique employing artificial chylomicrons
The investigators also know that higher doses of more potent statins are more effective in chylomicrons removal than lower doses or less potent statins nevertheless the effect of the isolated use of statin has not been completely studied up to now
Study design
The investigators propose to study 26 outpatients volunteers with chronic CHD followed at the Heart Institute - INCOR - of the School of Medicine University of São Paulo
Following a period of six weeks of washout from any cholesterol reducer the kinetics of chylomicrons removal by a technique of emulsion of radiolabeled artificial chylomicrons will be evaluated Lipid fractions hepatic enzymes and CK will be measured Initially patients will be randomly allocated to receive simvastatin 20 mg day n 13 or ezetimibe 10 mgday n13 for six weeks At the end of this period kinetics of chylomicrons removal and laboratorial measurements will be repeated Period 1
In the next period Period 2 patients will receive simvastatin 20 mg ezetimibe 10 mg n13 or simvastatin 80 mg n13 for additional six weeks at the end of this period the evaluations will be repeated third and last evaluation
The aim of this study is to further understand chylomicrons metabolism in patients with chronic coronary disease receiving cholesterol reducers at different dosage regimes
Background
The rate kinetics of chylomicrons removal from circulation have been correlated with the incidence and severity of atherosclerotic lesions a number of studies demonstrated lower plasmatic clearance of chylomicrons in patients with CHD compared to patients without this condition It was also demonstrated a correlation among LDL-C levels and removal of chylomicrons remnants by a technique employing artificial chylomicrons
The investigators also know that higher doses of more potent statins are more effective in chylomicrons removal than lower doses or less potent statins nevertheless the effect of the isolated use of statin has not been completely studied up to now
Study design
The investigators propose to study 26 outpatients volunteers with chronic CHD followed at the Heart Institute - INCOR - of the School of Medicine University of São Paulo
Following a period of six weeks of washout from any cholesterol reducer the kinetics of chylomicrons removal by a technique of emulsion of radiolabeled artificial chylomicrons will be evaluated Lipid fractions hepatic enzymes and CK will be measured Initially patients will be randomly allocated to receive simvastatin 20 mg day n 13 or ezetimibe 10 mgday n13 for six weeks At the end of this period kinetics of chylomicrons removal and laboratorial measurements will be repeated Period 1
In the next period Period 2 patients will receive simvastatin 20 mg ezetimibe 10 mg n13 or simvastatin 80 mg n13 for additional six weeks at the end of this period the evaluations will be repeated third and last evaluation
The aim of this study is to further understand chylomicrons metabolism in patients with chronic coronary disease receiving cholesterol reducers at different dosage regimes
Detailed Description:
1-INTRODUCTION
11Chylomicron metabolism Chylomicrons are particles formed in the postprandial period and are responsible for transporting blood lipids originating in the diet These lipoproteins are formed mostly by a core of triglycerides about 90 of its weight and small amounts of vitamins and cholesterol esters surrounded by a phospholipid monolayer Its protein portion ie apolipoproteins apo remain adhered to the surface of chylomicrons and do not exceed 2 of their total weight the most common Apo E CII and CIII which modulate the activity of lipolytic enzymes or act as ligands for cell receptors
In the circulation chylomicrons bind to the endothelial surface of capillaries and triglyceride hydrolysis occurs by the action of lipoprotein lipase LPL thereby releasing fatty acids and glycerol to the surrounding cells thus facilitating their absorption and accumulation in various tissues especially adipose and muscle The action of lipase is facilitated by apo CII on the particle surface This mechanism is extremely important for the transit of energy in the body After this initial phase the chylomicron remnants smaller and depleted of triglycerides are kidnapped in the Disse space and bind to receptors via the hepatic apolipoprotein E Among these the investigators may mention the very LDL receptors receptor B E and receiver RLP receptor related protein in LDL Importantly apo B48 the main component of chylomicrons and remnants apoprotéico has only a structural function Chylomicrons and VLDL share common catabolic pathways regarding LPL and at least in part on the mechanisms of cellular uptake
Within the classes of lipoproteins chylomicrons to more rapid removal of plasma and its half life of about 15 minutes in healthy men The speed kinetic removal of chylomicrons from the circulation has been correlated with the incidence and severity of atherosclerotic injury Several studies showed lower plasma clearance of chylomicrons in patients with coronary artery disease compared to individuals without atherosclerosis These findings are found even in normolipemic subjects Chylomicrons participate in the atherosclerotic process by the generation of foam cells by direct deposition of those remaining in the subendothelial space of arterial wall and also interference with the reverse transport of colestero Thus treatments that reduce the plasma concentration of chylomicrons by accelerating its catabolism plasma could be used to prevent atherosclerosis
Among the methods used to evaluate the plasma kinetics of chylomicron the investigators bring the lipid emulsion similar to chylomicrons labeled with radioisotopes They offer an integrated vision and clear steps of the catabolism of chylomicrons in plasma Several studies have shown that the kinetics of chylomicron is altered in patients with dyslipidemia and or coronary artery disease CAD Defects were found both in lipolysis and the removal of chylomicron remnants and in CAD patients these process were slowed5 Other studies have also shown that altered kinetics of chylomicrons is a marker of angiographic progression and a more severe course of CAD
Among the lipid-lowering drugs statins are the more potent and safe drugs in reducing plasma levels of LDL leading to decreased LDL cholesterol by 18-55 They inhibit the hydroxy-methyl-glutaryl coenzyme A reductase HMGCoA-A reductase which acts on the synthesis of cholesterol The enzyme inhibition results in decreased intracellular production of cholesterol by the liver which leads to increased expression of LDL hepatic receptor which increases the removal of LDL from the circulation
The effects of statins on clinical events were studied in several placebo controlled trials randomizing more than 90000 patients for statin therapy or placebo for 3-5 years time These studies showed consistently clinical benefit of statins including reduction of cardiovascular morbidity and mortality overall mortality coronary revascularization procedures and stroke as demonstrated in a recent meta-analysis In this group of drugs the investigators find Simvastatin drug of low cost and high efficacy in reducing cardiovascular events as demonstrated in the study 4S
Studies have shown that increased expression of LDL receptors in the liver caused by statins leads to increased hepatic uptake of chylomicron artificial emulsions In this context it has been demonstrated previously increased plasma removal of chylomicron remnants in patients with coronary disease treated with pravastatin Likewise different doses of atorvastatin 10mg and 40mg were evaluated in relation to intra-vascular metabolism and plasma kinetics of chylomicron emulsion in subjects with dyslipidemia It was demonstrated that atorvastatin significantly accelerates the removal of chylomicron slowed characteristic of these patients a dose-dependent reducing the atherogenic potential of these triglyceride-rich particles in circulation
Ezetimibe a new cholesterol absorption inhibitor emerges as a tool for controlling cholesterol The drug acts by inhibiting the absorption of dietary cholesterol and bile in the brush border of intestinal epithelium without affecting the absorption of triglycerides and vitamins Moreover the glucuronidated ezetimibe undergoes enterohepatic recirculation repeatedly returning the drug to its site of action Recent studies suggest that NPC1L1 Nieman-Pick C1 Like 1 protein has a critical role in intestinal cholesterol absorption being established as a direct target for the action ezetimibe18
Results of several studies in various models have demonstrated the lipid-lowering properties of ezetimibe as monotherapy or in combination with statins In humans ezetimibe at a dose of 10mg per day reduces the level of LDL by 12-14 However when combined with ezetimibe statins show its therapeutic potential because its association with low doses of the latter presents lowering effects similar to the use of maximal doses of those statins Thus the association of low doses of statins with ezetimibe may be an alternative to progressive titration of statin therapy This would be due to the fact that the association by reducing the concentration of an intense intra-hepatic cholesterol increase the expression of LDL receptors on the cell membrane of hepatocytes This fact leads to a higher removal of plasma lipoproteins that bind to these receptors Recently it was shown that the isolated use of ezetimibe increases the plasma clearance of lipoproteins containing apo B100 and VLDL remnants and LDL without however affecting the removal of containing apo B48 chylomicron remnants To date no published study that evaluated the association ezetimibe statin on the kinetics of plasma chylomicrons in research done in medline
2RATIONALE In literature there are already several studies that show that the plasma removal of chylomicron is reduced in subjects with coronary atherosclerosis and that these changes are correlated with greater clinical and angiographic progression of disease
Therapy with statins in several different schemes proved effective in increasing the kinetics of chylomicron removal in subjects with coronary artery disease and this effect is dose-dependent This fact can be explained by the finding that there was an inverse correlation between the plasma clearance of chylomicron remnants and plasma concentrations of LDL-cholesterol However to date there is still not clear what the effects of ezetimibe used alone or in combination with statins on the chylomicrons Another aspect to be evaluated is the comparison of titration of statin versus the effects of ezetimibe and statins in their initial doses of chylomicrons also not previously evaluated
3METHODS The study included 30 patients previously diagnosed with stable chronic coronary ischemia in clinical follow-up at the outpatient clinic of the Unit for Chronic Coronary Disease Heart Institute INCOR-FMUSP
After the initial suspension of statin therapy for 6 weeks washout patients were randomized into three groups 12 patients group 1 treatment with simvastatin 20mgday 13 patients group 2 to therapy with ezetimibe 10mg day and 5 patients for use of simvastatin 20 mg day group 3 In this phase patients were treated with the drug of choice for 06 weeks and assessed for chylomicron kinetics before and after treatment
In a second phase patients received lipid-lowering therapy for optimization of treatment with simvastatin 80 mg day group 1 or simvastatin 20 mg day and ezetimibe 10 mg day group 2 and 3 for 6 weeks Reassessment of the kinetics of chylomicron was held at the end of the second phase
Data were analyzed kinetics of chylomicrons baseline without lipid-lowering therapy for a minimum of 6 weeks after standard-dose monotherapy first phase and optimized combination therapy with statins in maximum therapeutic dose or combination of statin and ezetimibe second phase in patients with established coronary disease
Biochemical analysis as well as evaluations of the kinetics of chylomicron were funded by FAPESP No 0408048-3 entitled Out of free cholesterol from lipoprotein particles and deposition of cholesterol in the arterial wall a new mechanism of atherogenesis The lipid-lowering drugs were supplied by Merck Sharp Dohme simvastatin and ezetimibe
Regarding the suspension of lipid-lowering drug in patients with stable coronary artery disease wash-out for a period of six weeks there is evidence of no increased risk of acute coronary syndrome in the suspension of statin for up to 6 weeks 24
The kinetics study of chylomicrons will be carried out as previously published in the literature The lipid emulsion after preparation shows the following percentage composition Triolein 765 41 free cholesterol 19 03 cholesterol ester 112 30 phospholipids and 104 1 3 and sizes ranging from 80 to 100 nm are made of lipid mixtures emulsified by ultrasonic irradiation and purified by ultracentrifugation in density gradients
C-cholesteryl oleate and H-Triolina are added TG Amershan UK mixture for determination of plasma kinetics The emulsion is then sterilized through a 2μm filter
Patients are instructed to attend to the laboratory at 800 am after fasting for 12 hours to collect blood sample for lipid analysis The radioactively labeled lipid emulsion is injected as a bolus volume 200-300μl containing 74KBp 2μCi 14C and 148KBp 4μCi of 3H by antecubital vein catheterization These concentrations are equivalent to respectively 002 and 00012 mSv SV radioactive cholesterol and triglycerides The contralateral antecubital vein is cannulated to obtain blood samples for measurement of radioactivity saline infusion without heparin infusion was administered slowly to ensure patency of the vein A saline infusion does not exceed 100ml
Thereafter blood samples are collected at predetermined intervals as follows 2 4 6 10 15 20 30 45 and 60 minutes after injection of the emulsion
After collection blood plasma is separated by centrifugation in 1 ml aliquots and then transferred to counters containing 7ml of scintillation solution PPO DM-POPOP Triton X-100toluen 5g 05333 ml667ml The radioactivity in the samples is determined using a Packard 160 TR spectrometer Packard Meridien USA
The estimated time of the metabolism of lipid emulsion is evaluated by compartmental analysis according to the modification of the model proposed by Redgrave and Zench The delipidation index is then calculated as proposed by Redgrave and Zench which represents the depletion of the triglyceride content of lipid emulsion before the capture of chylomicrons from the circulation
The dose of radioactivity even after the three kinetic studies is much lower 00636 mSv maximum annual dose allowed by the International Committee for the Protection of radioactivity 50mSv
11Chylomicron metabolism Chylomicrons are particles formed in the postprandial period and are responsible for transporting blood lipids originating in the diet These lipoproteins are formed mostly by a core of triglycerides about 90 of its weight and small amounts of vitamins and cholesterol esters surrounded by a phospholipid monolayer Its protein portion ie apolipoproteins apo remain adhered to the surface of chylomicrons and do not exceed 2 of their total weight the most common Apo E CII and CIII which modulate the activity of lipolytic enzymes or act as ligands for cell receptors
In the circulation chylomicrons bind to the endothelial surface of capillaries and triglyceride hydrolysis occurs by the action of lipoprotein lipase LPL thereby releasing fatty acids and glycerol to the surrounding cells thus facilitating their absorption and accumulation in various tissues especially adipose and muscle The action of lipase is facilitated by apo CII on the particle surface This mechanism is extremely important for the transit of energy in the body After this initial phase the chylomicron remnants smaller and depleted of triglycerides are kidnapped in the Disse space and bind to receptors via the hepatic apolipoprotein E Among these the investigators may mention the very LDL receptors receptor B E and receiver RLP receptor related protein in LDL Importantly apo B48 the main component of chylomicrons and remnants apoprotéico has only a structural function Chylomicrons and VLDL share common catabolic pathways regarding LPL and at least in part on the mechanisms of cellular uptake
Within the classes of lipoproteins chylomicrons to more rapid removal of plasma and its half life of about 15 minutes in healthy men The speed kinetic removal of chylomicrons from the circulation has been correlated with the incidence and severity of atherosclerotic injury Several studies showed lower plasma clearance of chylomicrons in patients with coronary artery disease compared to individuals without atherosclerosis These findings are found even in normolipemic subjects Chylomicrons participate in the atherosclerotic process by the generation of foam cells by direct deposition of those remaining in the subendothelial space of arterial wall and also interference with the reverse transport of colestero Thus treatments that reduce the plasma concentration of chylomicrons by accelerating its catabolism plasma could be used to prevent atherosclerosis
Among the methods used to evaluate the plasma kinetics of chylomicron the investigators bring the lipid emulsion similar to chylomicrons labeled with radioisotopes They offer an integrated vision and clear steps of the catabolism of chylomicrons in plasma Several studies have shown that the kinetics of chylomicron is altered in patients with dyslipidemia and or coronary artery disease CAD Defects were found both in lipolysis and the removal of chylomicron remnants and in CAD patients these process were slowed5 Other studies have also shown that altered kinetics of chylomicrons is a marker of angiographic progression and a more severe course of CAD
Among the lipid-lowering drugs statins are the more potent and safe drugs in reducing plasma levels of LDL leading to decreased LDL cholesterol by 18-55 They inhibit the hydroxy-methyl-glutaryl coenzyme A reductase HMGCoA-A reductase which acts on the synthesis of cholesterol The enzyme inhibition results in decreased intracellular production of cholesterol by the liver which leads to increased expression of LDL hepatic receptor which increases the removal of LDL from the circulation
The effects of statins on clinical events were studied in several placebo controlled trials randomizing more than 90000 patients for statin therapy or placebo for 3-5 years time These studies showed consistently clinical benefit of statins including reduction of cardiovascular morbidity and mortality overall mortality coronary revascularization procedures and stroke as demonstrated in a recent meta-analysis In this group of drugs the investigators find Simvastatin drug of low cost and high efficacy in reducing cardiovascular events as demonstrated in the study 4S
Studies have shown that increased expression of LDL receptors in the liver caused by statins leads to increased hepatic uptake of chylomicron artificial emulsions In this context it has been demonstrated previously increased plasma removal of chylomicron remnants in patients with coronary disease treated with pravastatin Likewise different doses of atorvastatin 10mg and 40mg were evaluated in relation to intra-vascular metabolism and plasma kinetics of chylomicron emulsion in subjects with dyslipidemia It was demonstrated that atorvastatin significantly accelerates the removal of chylomicron slowed characteristic of these patients a dose-dependent reducing the atherogenic potential of these triglyceride-rich particles in circulation
Ezetimibe a new cholesterol absorption inhibitor emerges as a tool for controlling cholesterol The drug acts by inhibiting the absorption of dietary cholesterol and bile in the brush border of intestinal epithelium without affecting the absorption of triglycerides and vitamins Moreover the glucuronidated ezetimibe undergoes enterohepatic recirculation repeatedly returning the drug to its site of action Recent studies suggest that NPC1L1 Nieman-Pick C1 Like 1 protein has a critical role in intestinal cholesterol absorption being established as a direct target for the action ezetimibe18
Results of several studies in various models have demonstrated the lipid-lowering properties of ezetimibe as monotherapy or in combination with statins In humans ezetimibe at a dose of 10mg per day reduces the level of LDL by 12-14 However when combined with ezetimibe statins show its therapeutic potential because its association with low doses of the latter presents lowering effects similar to the use of maximal doses of those statins Thus the association of low doses of statins with ezetimibe may be an alternative to progressive titration of statin therapy This would be due to the fact that the association by reducing the concentration of an intense intra-hepatic cholesterol increase the expression of LDL receptors on the cell membrane of hepatocytes This fact leads to a higher removal of plasma lipoproteins that bind to these receptors Recently it was shown that the isolated use of ezetimibe increases the plasma clearance of lipoproteins containing apo B100 and VLDL remnants and LDL without however affecting the removal of containing apo B48 chylomicron remnants To date no published study that evaluated the association ezetimibe statin on the kinetics of plasma chylomicrons in research done in medline
2RATIONALE In literature there are already several studies that show that the plasma removal of chylomicron is reduced in subjects with coronary atherosclerosis and that these changes are correlated with greater clinical and angiographic progression of disease
Therapy with statins in several different schemes proved effective in increasing the kinetics of chylomicron removal in subjects with coronary artery disease and this effect is dose-dependent This fact can be explained by the finding that there was an inverse correlation between the plasma clearance of chylomicron remnants and plasma concentrations of LDL-cholesterol However to date there is still not clear what the effects of ezetimibe used alone or in combination with statins on the chylomicrons Another aspect to be evaluated is the comparison of titration of statin versus the effects of ezetimibe and statins in their initial doses of chylomicrons also not previously evaluated
3METHODS The study included 30 patients previously diagnosed with stable chronic coronary ischemia in clinical follow-up at the outpatient clinic of the Unit for Chronic Coronary Disease Heart Institute INCOR-FMUSP
After the initial suspension of statin therapy for 6 weeks washout patients were randomized into three groups 12 patients group 1 treatment with simvastatin 20mgday 13 patients group 2 to therapy with ezetimibe 10mg day and 5 patients for use of simvastatin 20 mg day group 3 In this phase patients were treated with the drug of choice for 06 weeks and assessed for chylomicron kinetics before and after treatment
In a second phase patients received lipid-lowering therapy for optimization of treatment with simvastatin 80 mg day group 1 or simvastatin 20 mg day and ezetimibe 10 mg day group 2 and 3 for 6 weeks Reassessment of the kinetics of chylomicron was held at the end of the second phase
Data were analyzed kinetics of chylomicrons baseline without lipid-lowering therapy for a minimum of 6 weeks after standard-dose monotherapy first phase and optimized combination therapy with statins in maximum therapeutic dose or combination of statin and ezetimibe second phase in patients with established coronary disease
Biochemical analysis as well as evaluations of the kinetics of chylomicron were funded by FAPESP No 0408048-3 entitled Out of free cholesterol from lipoprotein particles and deposition of cholesterol in the arterial wall a new mechanism of atherogenesis The lipid-lowering drugs were supplied by Merck Sharp Dohme simvastatin and ezetimibe
Regarding the suspension of lipid-lowering drug in patients with stable coronary artery disease wash-out for a period of six weeks there is evidence of no increased risk of acute coronary syndrome in the suspension of statin for up to 6 weeks 24
The kinetics study of chylomicrons will be carried out as previously published in the literature The lipid emulsion after preparation shows the following percentage composition Triolein 765 41 free cholesterol 19 03 cholesterol ester 112 30 phospholipids and 104 1 3 and sizes ranging from 80 to 100 nm are made of lipid mixtures emulsified by ultrasonic irradiation and purified by ultracentrifugation in density gradients
C-cholesteryl oleate and H-Triolina are added TG Amershan UK mixture for determination of plasma kinetics The emulsion is then sterilized through a 2μm filter
Patients are instructed to attend to the laboratory at 800 am after fasting for 12 hours to collect blood sample for lipid analysis The radioactively labeled lipid emulsion is injected as a bolus volume 200-300μl containing 74KBp 2μCi 14C and 148KBp 4μCi of 3H by antecubital vein catheterization These concentrations are equivalent to respectively 002 and 00012 mSv SV radioactive cholesterol and triglycerides The contralateral antecubital vein is cannulated to obtain blood samples for measurement of radioactivity saline infusion without heparin infusion was administered slowly to ensure patency of the vein A saline infusion does not exceed 100ml
Thereafter blood samples are collected at predetermined intervals as follows 2 4 6 10 15 20 30 45 and 60 minutes after injection of the emulsion
After collection blood plasma is separated by centrifugation in 1 ml aliquots and then transferred to counters containing 7ml of scintillation solution PPO DM-POPOP Triton X-100toluen 5g 05333 ml667ml The radioactivity in the samples is determined using a Packard 160 TR spectrometer Packard Meridien USA
The estimated time of the metabolism of lipid emulsion is evaluated by compartmental analysis according to the modification of the model proposed by Redgrave and Zench The delipidation index is then calculated as proposed by Redgrave and Zench which represents the depletion of the triglyceride content of lipid emulsion before the capture of chylomicrons from the circulation
The dose of radioactivity even after the three kinetic studies is much lower 00636 mSv maximum annual dose allowed by the International Committee for the Protection of radioactivity 50mSv
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None