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Effect of dalcetrapib plus pravastatin on lipoprotein metabolism and high-density lipoprotein composition and function in dyslipidemic patients: Results of a phase IIb dose-ranging study

Background Cholesteryl ester transfer protein (CETP) is involved in high-density lipoprotein (HDL) remodeling and transfer of lipids between HDL particles and other lipoproteins. Epidemiologic studies show that both elevated HDL-cholesterol (HDL-C) and reduced CETP activity attenuate cardiovascular... Full description

Journal Title: The American heart journal 2012, Vol.163 (3), p.515-521.e3
Main Author: Ballantyne, Christie M., MD
Other Authors: Miller, Michael, MD , Niesor, Eric J., PhD , Burgess, Tracy, MSc , Kallend, David, MBBS , Stein, Evan A., MD, PhD
Format: Electronic Article Electronic Article
Language: English
Subjects:
Quelle: Alma/SFX Local Collection
Publisher: United States: Elsevier Inc
ID: ISSN: 0002-8703
Link: https://www.ncbi.nlm.nih.gov/pubmed/22424025
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title: Effect of dalcetrapib plus pravastatin on lipoprotein metabolism and high-density lipoprotein composition and function in dyslipidemic patients: Results of a phase IIb dose-ranging study
format: Article
creator:
  • Ballantyne, Christie M., MD
  • Miller, Michael, MD
  • Niesor, Eric J., PhD
  • Burgess, Tracy, MSc
  • Kallend, David, MBBS
  • Stein, Evan A., MD, PhD
subjects:
  • Adolescent
  • Adult
  • Aged
  • Analysis
  • Anticholesteremic Agents - administration & dosage
  • Antilipemic agents
  • Blood lipids
  • Cardiovascular
  • Cardiovascular disease
  • Cholesterol
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Drug Therapy, Combination
  • Dyslipidemias - blood
  • Dyslipidemias - drug therapy
  • Electrophoresis, Polyacrylamide Gel
  • Female
  • Follow-Up Studies
  • Humans
  • Lipids
  • Lipoproteins, HDL - blood
  • Lipoproteins, HDL - drug effects
  • Low density lipoprotein
  • Magnetic Resonance Spectroscopy
  • Male
  • Middle Aged
  • Physiological aspects
  • Pravastatin
  • Pravastatin - administration & dosage
  • Product development
  • Sulfhydryl Compounds - administration & dosage
  • Treatment Outcome
  • Young Adult
ispartof: The American heart journal, 2012, Vol.163 (3), p.515-521.e3
description: Background Cholesteryl ester transfer protein (CETP) is involved in high-density lipoprotein (HDL) remodeling and transfer of lipids between HDL particles and other lipoproteins. Epidemiologic studies show that both elevated HDL-cholesterol (HDL-C) and reduced CETP activity attenuate cardiovascular risk, making inhibition or modulation of CETP a potential therapeutic target. This study analyzed the effect of dalcetrapib on lipoprotein profile, CETP activity, and cellular cholesterol efflux when co-administered with pravastatin in patients with low or average HDL-C. Methods Patients were randomized in a double-blind fashion to receive placebo or dalcetrapib 300, 600, or 900 mg once daily for 12 weeks. All patients were concomitantly treated to their low-density lipoprotein cholesterol target with pravastatin. Lipoprotein profile was analyzed by nuclear magnetic resonance spectroscopy and polyacrylamide gradient gel electrophoresis. Composition of the HDL fraction was assessed after polyethylene glycol precipitation. Contribution of this fraction to cholesterol efflux was assessed using radiolabeled donor cells. Results Co-administration of dalcetrapib with pravastatin increased HDL-C, apolipoproteins (apo) A-I and A-II, and CETP mass, and decreased CETP activity. A relative increase in large HDL and low-density lipoprotein subparticle fractions was observed. High-density lipoprotein composition showed increased association of esterified cholesterol, free cholesterol, phospholipids, apo A-I, and apo E. Adenosine 5′-triphosphate–binding cassette A1- and scavenger receptor type BI–mediated cholesterol efflux increased. Conclusions Dalcetrapib up to 600 mg, combined with pravastatin, increased HDL-C and altered lipoprotein profile, HDL composition, and HDL function, with little further change at a 900-mg dose. The impact on cardiovascular events in dyslipidemic patients is being evaluated.
language: eng
source: Alma/SFX Local Collection
identifier: ISSN: 0002-8703
fulltext: fulltext
issn:
  • 0002-8703
  • 1097-6744
url: Link


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titleEffect of dalcetrapib plus pravastatin on lipoprotein metabolism and high-density lipoprotein composition and function in dyslipidemic patients: Results of a phase IIb dose-ranging study
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creatorBallantyne, Christie M., MD ; Miller, Michael, MD ; Niesor, Eric J., PhD ; Burgess, Tracy, MSc ; Kallend, David, MBBS ; Stein, Evan A., MD, PhD
creatorcontribBallantyne, Christie M., MD ; Miller, Michael, MD ; Niesor, Eric J., PhD ; Burgess, Tracy, MSc ; Kallend, David, MBBS ; Stein, Evan A., MD, PhD
descriptionBackground Cholesteryl ester transfer protein (CETP) is involved in high-density lipoprotein (HDL) remodeling and transfer of lipids between HDL particles and other lipoproteins. Epidemiologic studies show that both elevated HDL-cholesterol (HDL-C) and reduced CETP activity attenuate cardiovascular risk, making inhibition or modulation of CETP a potential therapeutic target. This study analyzed the effect of dalcetrapib on lipoprotein profile, CETP activity, and cellular cholesterol efflux when co-administered with pravastatin in patients with low or average HDL-C. Methods Patients were randomized in a double-blind fashion to receive placebo or dalcetrapib 300, 600, or 900 mg once daily for 12 weeks. All patients were concomitantly treated to their low-density lipoprotein cholesterol target with pravastatin. Lipoprotein profile was analyzed by nuclear magnetic resonance spectroscopy and polyacrylamide gradient gel electrophoresis. Composition of the HDL fraction was assessed after polyethylene glycol precipitation. Contribution of this fraction to cholesterol efflux was assessed using radiolabeled donor cells. Results Co-administration of dalcetrapib with pravastatin increased HDL-C, apolipoproteins (apo) A-I and A-II, and CETP mass, and decreased CETP activity. A relative increase in large HDL and low-density lipoprotein subparticle fractions was observed. High-density lipoprotein composition showed increased association of esterified cholesterol, free cholesterol, phospholipids, apo A-I, and apo E. Adenosine 5′-triphosphate–binding cassette A1- and scavenger receptor type BI–mediated cholesterol efflux increased. Conclusions Dalcetrapib up to 600 mg, combined with pravastatin, increased HDL-C and altered lipoprotein profile, HDL composition, and HDL function, with little further change at a 900-mg dose. The impact on cardiovascular events in dyslipidemic patients is being evaluated.
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languageeng
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subjectAdolescent ; Adult ; Aged ; Analysis ; Anticholesteremic Agents - administration & dosage ; Antilipemic agents ; Blood lipids ; Cardiovascular ; Cardiovascular disease ; Cholesterol ; Dose-Response Relationship, Drug ; Double-Blind Method ; Drug Therapy, Combination ; Dyslipidemias - blood ; Dyslipidemias - drug therapy ; Electrophoresis, Polyacrylamide Gel ; Female ; Follow-Up Studies ; Humans ; Lipids ; Lipoproteins, HDL - blood ; Lipoproteins, HDL - drug effects ; Low density lipoprotein ; Magnetic Resonance Spectroscopy ; Male ; Middle Aged ; Physiological aspects ; Pravastatin ; Pravastatin - administration & dosage ; Product development ; Sulfhydryl Compounds - administration & dosage ; Treatment Outcome ; Young Adult
ispartofThe American heart journal, 2012, Vol.163 (3), p.515-521.e3
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5Stein, Evan A., MD, PhD
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descriptionBackground Cholesteryl ester transfer protein (CETP) is involved in high-density lipoprotein (HDL) remodeling and transfer of lipids between HDL particles and other lipoproteins. Epidemiologic studies show that both elevated HDL-cholesterol (HDL-C) and reduced CETP activity attenuate cardiovascular risk, making inhibition or modulation of CETP a potential therapeutic target. This study analyzed the effect of dalcetrapib on lipoprotein profile, CETP activity, and cellular cholesterol efflux when co-administered with pravastatin in patients with low or average HDL-C. Methods Patients were randomized in a double-blind fashion to receive placebo or dalcetrapib 300, 600, or 900 mg once daily for 12 weeks. All patients were concomitantly treated to their low-density lipoprotein cholesterol target with pravastatin. Lipoprotein profile was analyzed by nuclear magnetic resonance spectroscopy and polyacrylamide gradient gel electrophoresis. Composition of the HDL fraction was assessed after polyethylene glycol precipitation. Contribution of this fraction to cholesterol efflux was assessed using radiolabeled donor cells. Results Co-administration of dalcetrapib with pravastatin increased HDL-C, apolipoproteins (apo) A-I and A-II, and CETP mass, and decreased CETP activity. A relative increase in large HDL and low-density lipoprotein subparticle fractions was observed. High-density lipoprotein composition showed increased association of esterified cholesterol, free cholesterol, phospholipids, apo A-I, and apo E. Adenosine 5′-triphosphate–binding cassette A1- and scavenger receptor type BI–mediated cholesterol efflux increased. Conclusions Dalcetrapib up to 600 mg, combined with pravastatin, increased HDL-C and altered lipoprotein profile, HDL composition, and HDL function, with little further change at a 900-mg dose. The impact on cardiovascular events in dyslipidemic patients is being evaluated.
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31Treatment Outcome
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titleEffect of dalcetrapib plus pravastatin on lipoprotein metabolism and high-density lipoprotein composition and function in dyslipidemic patients: Results of a phase IIb dose-ranging study
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1Adult
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7Cardiovascular
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9Cholesterol
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17Follow-Up Studies
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0Ballantyne, Christie M., MD
1Miller, Michael, MD
2Niesor, Eric J., PhD
3Burgess, Tracy, MSc
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atitleEffect of dalcetrapib plus pravastatin on lipoprotein metabolism and high-density lipoprotein composition and function in dyslipidemic patients: Results of a phase IIb dose-ranging study
jtitleThe American heart journal
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date2012
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abstractBackground Cholesteryl ester transfer protein (CETP) is involved in high-density lipoprotein (HDL) remodeling and transfer of lipids between HDL particles and other lipoproteins. Epidemiologic studies show that both elevated HDL-cholesterol (HDL-C) and reduced CETP activity attenuate cardiovascular risk, making inhibition or modulation of CETP a potential therapeutic target. This study analyzed the effect of dalcetrapib on lipoprotein profile, CETP activity, and cellular cholesterol efflux when co-administered with pravastatin in patients with low or average HDL-C. Methods Patients were randomized in a double-blind fashion to receive placebo or dalcetrapib 300, 600, or 900 mg once daily for 12 weeks. All patients were concomitantly treated to their low-density lipoprotein cholesterol target with pravastatin. Lipoprotein profile was analyzed by nuclear magnetic resonance spectroscopy and polyacrylamide gradient gel electrophoresis. Composition of the HDL fraction was assessed after polyethylene glycol precipitation. Contribution of this fraction to cholesterol efflux was assessed using radiolabeled donor cells. Results Co-administration of dalcetrapib with pravastatin increased HDL-C, apolipoproteins (apo) A-I and A-II, and CETP mass, and decreased CETP activity. A relative increase in large HDL and low-density lipoprotein subparticle fractions was observed. High-density lipoprotein composition showed increased association of esterified cholesterol, free cholesterol, phospholipids, apo A-I, and apo E. Adenosine 5′-triphosphate–binding cassette A1- and scavenger receptor type BI–mediated cholesterol efflux increased. Conclusions Dalcetrapib up to 600 mg, combined with pravastatin, increased HDL-C and altered lipoprotein profile, HDL composition, and HDL function, with little further change at a 900-mg dose. The impact on cardiovascular events in dyslipidemic patients is being evaluated.
copUnited States
pubElsevier Inc
pmid22424025
doi10.1016/j.ahj.2011.11.017