- Email: [email protected]
Measuring HDL: The Effect of Current HDL-Raising Therapies on HDL Levels and Subfractions
S8
Journal of Clinical Lipidology, Vol 5, No 6, December 2011
presentation. Radar DJ. J Clin Lipidol. 2011; 5(6). Accessible at http://lipidjournal.com.
protocol), nevertheless it has been shown epidemiologically and in a post-hoc analysis of the Treating to New Targets (TNT) LDL lipid-lowering trial that a low serum HDL cholesterol level is predictive of risk of coronary heart disease (CHD) events, regardless of baseline, or therapeutically achieved, LDL cholesterol levels. Therefore at the present time, attempting to raise serum HDL cholesterol appears to be the best next step in the search for the optimal treatment strategy for treating dyslipidemic atherosclerotic disease. This Journal of Clinical Lipidology open-source eCME activity (accessed at http://multimedia.lipidjournal. com/2011/HDL) details the most promising new approach to this treatment stratagem: inhibition of the cholesterolester transfer protein (CETP), which catalyzes transfer of cholesterol out of the largest, ‘‘full’’ HDL particles back to the very-low-density lipoprotein (VLDL)/LDL particles for recirculation in the normal physiologic manner. Although the first candidate CETP inhibitor, torcetrapib, spectacularly failed its clinical outcomes trial (and its imaging trials), both the theory of CETP inhibition and the explanations for the failure of torcetrapib, as well as description of the later, newer, apparently effective CETP inhibitors (there are two) currently in clinical trials, are discussed in this review. Barter PJ. J Clin Lipidol. 2011; 5(6). Accessible at http://lipidjournal.com.
doi: 10.1016/j.jacl.2011.10.012
eCME Multimedia Activity HDL Proteomics and Lipidomics M. John Chapman, BS, PhD, DSc
ABSTRACT Recent research has shown that the spectrum of HDL particles is far more complex than the simple array of LDL particles. As with LDL particles, the spectrum of HDL particles can be characterized by size and density, as a measure of the quantity of cholesterol they distribute; this categorization is based chiefly on the early analytic methods, however, and it fails to recognize that unlike LDL particles, the different HDL particles perform qualitatively different biologic functions, depending on their composition. This diversity is caused by both the protein components of the particle’s structure, the proteome, and the lipid contents of the particle, the lipidome. This Journal of Clinical Lipidology open-source eCME activity (accessed at http://multimedia.lipidjournal. com/2011/HDL) examines the variety in the components of the proteome and the contents of the lipidome that account for the spectrum of atheroprotective effects of HDL particles, as well as their known antiinflammatory effects and their less-known anti-diabetic effects (protective effects on the pancreatic b cells), as well as a contribution to the innate immune reaction. In this comprehensive review of the components and functions of HDL particles, two concepts are detailed: (1) that the functions of HDL particles reflect the integrated biological activities of their lipid (lipidome) and protein (proteome) components, and (2) that the dynamic intravascular metabolism of the lipid and protein components of HDL particles may be perturbed in cardiometabolic diseases (dyslipidemia, inflammation, and premature CVD), resulting in alterations in the atheroprotective function(s) of the HDL. Chapman J. J Clin Lipidol. 2011; 5(6). Accessible at http://lipidjournal.com. doi: 10.1016/j.jacl.2011.10.013
eCME Multimedia Activity The Current Status and Future Development of CETP Inhibitors Philip J. Barter, MD, PhD
ABSTRACT Although difficult to test prospectively (because proof would require enrollment of large numbers of patients who fail maximal lowering of low-density lipoprotein [LDL] cholesterol to ,70 mg/dL, followed by success in a high-density lipoprotein [HDL]-raising treatment
doi: 10.1016/j.jacl.2011.10.014
eCME Multimedia Activity Measuring HDL: The Effect of Current HDL-Raising Therapies on HDL Levels and Subfractions Ernst J. Schaefer, MD, FNLA
ABSTRACT Although lacking prospective controlled clinical trial evidence to prove the hypothesis, nevertheless it has been firmly established observationally that there is both a substantial gradient of risk associated with low HDL levels and a degree of protection associated with high HDL levels. However, whereas LDL particles present a relatively simplistic size spectrum, ranging from large, buoyant and less harmful, to the small, dense, and readily oxidized and infiltrative into the arterial wall and atherosclerotic plaques, the spectrum of HDL particle sizes is rather more complex, although in one dimension the size spectrum can be considered as simply the amount of cholesterol that has accumulated to fill the HDL particle. In line with this analysis, this Journal of Clinical Lipidology open-source eCME activity (accessed at http://multimedia.lipidjournal.com/2011/HDL) describes the smallest pre-b HDL1 and HDL3-4 particles as the ‘‘empty dump trucks that gradually are filled to become the large, HDL1 particles. As discussed in this article, the ways in which these different particles sizes correlate with different risk factors (gender, age, disease severity, etc.) and the ways
Translating HDL Science to Clinical Practice in which different HDL-affecting therapies (statins, niacin, CETP inhibitors) affect the different particle sizes in this spectrum, provide a more complex and complete understanding of HDL metabolism. Schaefer EJ. J Clin Lipidol. 2011; 5(6). Accessible at http://lipidjournal.com. doi: 10.1016/j.jacl.2011.10.015
eCME Multimedia Activity Unraveling HDL-Associated Risk: Current Challenges and Future Directions Robert S. Rosenson, MD, FNLA
ABSTRACT High-density lipoprotein (HDL) cholesterol is gaining more attention as an important risk factor and as important
S9 biomarker in cardiovascular disease (CVD). This Journal of Clinical Lipidology open-source eCME activity (accessed at http://multimedia.lipidjournal.com/2011/HDL) summarizes the many issues that this raises: the unacceptably high variance in direct HDL assays; the importance of considering low-density lipoprotein (LDL) particle number in the evaluation of HDL cholesterol-associated residual risk; the conflicting CVD risk factor associations, depending on whether measuring serum HDL cholesterol levels or HDL particles in models that include LDL-P; and assessment of HDL ‘‘functionality.’’ The article concludes with reference to the recently published article that attempts to establish a standardized nomenclature for HDL that addresses and tries to resolve some of these areas of confusion. Rosenson RS. J Clin Lipidol. 2011; 5(6). Accessible at http://lipidjournal.com. doi: 10.1016/j.jacl.2011.10.016
S9.e1
Journal of Clinical Lipidology, Vol 5, No 6, December 2011
Activity Overview
National Lipid Association designates this enduring material for a maximum of 1.0 AMA PRA Category 1 CreditÔ. Physicians should only claim credit commensurate with the extent of their participation in the activity.
To provide an enduring record of the most important contents from the live HDL Highlights Symposium: Translating HDL Science to Clinical Practice, held in New York City in May 2011, the National Lipid Association has partnered with Elsevier to publish an open-access, journalindexed Internet activity, with optional CME/CE credit, presented as a slide-driven narrative with edited text for each figure interpolated from the audio presentations. This online publication from the Journal of Clinical Lipidology provides the opportunity to access the contents visually, acoustically, and via the peer-reviewed text, as presented during this key opinion leader symposium.
Target Audience This journal publication is designed for a broader audience of healthcare professionals including lipidologists, cardiologists, endocrinologists, internists, primary care physicians, pharmacists, nurse practitioners, physician assistants, nurses, and registered dietitians.
Learning Objectives Upon completion of this activity, participants should be able to: Evaluate the role of HDL-C in reducing cardiovascular events and rates of atherosclerotic disease progression; Describe the metabolic pathways of HDL and the roles that HDL and inflammation play in the development of atherosclerosis; Distinguish those patients who remain at risk for CV events despite having an acceptable LDL level; Identify appropriate current treatment options including concomitant drug therapy to minimize residual CV risk; Summarize recent lipid-related research on raising HDL cholesterol and emerging treatment options, and clinical implications for patient management.
Sponsorship This activity is sponsored by the National Lipid Association.
Commercial Support This activity is supported by an educational grant from Genentech.
Accreditation CME credit provided by the National Lipid Association
Physicians The National Lipid Association is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. The
Physician Assistants NCCPA accepts AMA PRA Category 1 CreditÔ from organizations accredited by ACCME. CE credit provided by AKH Inc., Advancing Knowledge in Healthcare
Pharmacists AKH Inc. is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. AKH Inc. approves this KNOWLEDGE/APPLICATION-based activity for 1.0 contact hour(s) (0.1 CEUs). UAN 0077-9999-11-035-H04-P. Initial release date October 1, 2011.
Nurses AKH Inc. is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center’s COA. AKH Inc. designates this educational activity for 1.0 contact hour(s) (0.1 CEU). Accreditation applies solely to educational activities and does not imply approval or endorsement of any commercial product by the ANCC-COA.
Dietitians AKH Inc. is a Continuing Professional Education (CPE) Accredited Provider with the Commission on Dietetic Registration (CDR). Registered dietitians (RDs) and dietetic technicians, registered (DTRs) will receive 1.0 continuing professional education units (CPEUs) for completion of this program/material. CDR Accredited Provider #AN008. The focus of this activity is rated Level 2. Learners may submit evaluations of program/materials quality to the CDR at www.cdrnet.org.
Disclosure of Conflict of Interest Statements Disclosure Declaration: It is the policy of NLA and AKH Inc. to ensure independence, balance, objectivity, scientific rigor, and integrity in all of its continuing education activities. The faculty must disclose to the participants any significant relationships with commercial interests whose products or devices may be mentioned in the activity or with the commercial supporter of this continuing education activity. Identified conflict of interest is resolved by NLA and AKH prior to accreditation of the activity. NLA and AKH planners and reviewers have no relevant financial relationships to disclose. Daniel J. Rader, MD, FNLA, Professor of Medicine, University of Pennsylvania, Philadelphia, PA. Consultant: AstraZeneca; Bristol-Myers Squibb; Daiichi Sankyo, Inc.; Eli Lilly and Company; Merck & Co., Inc.; Novartis Pharmaceuticals; Roche Pharmaceuticals.
Translating HDL Science to Clinical Practice
S9.e2
M. John Chapman, BS, PhD, DSc, President, European Atherosclerosis Society, Director, INSERM (Dyslipidemia and Atherosclerosis Research), Paris, France; Contracted Research: Danone; Kowa Pharmaceuticals America, Inc.; Merck & Co., Inc.; Pfizer Inc.
Heart, New York, NY; Advisory Board: Abbott Laboratories, Inc.; Amgen; Genentech; Grain Foods Foundation; LipoScience, Inc.; Sanofi-aventis; Sticares InterACT; Contracted Research: Amgen; Genentech; LipoScience, Inc.; Roche Pharmaceuticals; Stock: LipoScience, Inc.
Philip J. Barter, MD, PhD, The Heart Research Institute, Sydney, Australia; Advisory Board: AstraZeneca; GlaxoSmithKline; Merck & Co., Inc.; Novartis Pharmaceuticals; Pfizer Inc.; Roche Pharmaceuticals; Speakers Bureau: AstraZeneca; GlaxoSmithKline; Merck & Co., Inc.; Pfizer Inc.; Roche Pharmaceuticals.
Staff and Reviewers Disclosures: AKH Inc., Advancing Knowledge in Healthcare staff, planners and reviewers have no financial relationships to disclose. National Lipid Association staff, planners and reviewers have no financial relationships to disclose.
Ernst J. Schaefer, MD, FNLA, Tufts University School of Medicine, Boston, MA; Consultant: Amarin; AstraZeneca; DuPont; Merck & Co., Inc.; Roche Pharmaceuticals; Unilever; Speakers Bureau:Merck & Co., Inc.; Stock: Boston Heart Lab.
Peer Review
Robert S. Rosenson, MD, FNLA, Mt Sinai School of Medicine, Director, Cardiometabolic Disorders, Mt Sinai
Sponsorship
This CME Multimedia Activity has been peer-reviewed by the Journal of Clinical Lipidology.
There is no fee to participate in this CME-certified activity.
Journal of Clinical Lipidology, Vol 5, No 6, December 2011
presentation. Radar DJ. J Clin Lipidol. 2011; 5(6). Accessible at http://lipidjournal.com.
protocol), nevertheless it has been shown epidemiologically and in a post-hoc analysis of the Treating to New Targets (TNT) LDL lipid-lowering trial that a low serum HDL cholesterol level is predictive of risk of coronary heart disease (CHD) events, regardless of baseline, or therapeutically achieved, LDL cholesterol levels. Therefore at the present time, attempting to raise serum HDL cholesterol appears to be the best next step in the search for the optimal treatment strategy for treating dyslipidemic atherosclerotic disease. This Journal of Clinical Lipidology open-source eCME activity (accessed at http://multimedia.lipidjournal. com/2011/HDL) details the most promising new approach to this treatment stratagem: inhibition of the cholesterolester transfer protein (CETP), which catalyzes transfer of cholesterol out of the largest, ‘‘full’’ HDL particles back to the very-low-density lipoprotein (VLDL)/LDL particles for recirculation in the normal physiologic manner. Although the first candidate CETP inhibitor, torcetrapib, spectacularly failed its clinical outcomes trial (and its imaging trials), both the theory of CETP inhibition and the explanations for the failure of torcetrapib, as well as description of the later, newer, apparently effective CETP inhibitors (there are two) currently in clinical trials, are discussed in this review. Barter PJ. J Clin Lipidol. 2011; 5(6). Accessible at http://lipidjournal.com.
doi: 10.1016/j.jacl.2011.10.012
eCME Multimedia Activity HDL Proteomics and Lipidomics M. John Chapman, BS, PhD, DSc
ABSTRACT Recent research has shown that the spectrum of HDL particles is far more complex than the simple array of LDL particles. As with LDL particles, the spectrum of HDL particles can be characterized by size and density, as a measure of the quantity of cholesterol they distribute; this categorization is based chiefly on the early analytic methods, however, and it fails to recognize that unlike LDL particles, the different HDL particles perform qualitatively different biologic functions, depending on their composition. This diversity is caused by both the protein components of the particle’s structure, the proteome, and the lipid contents of the particle, the lipidome. This Journal of Clinical Lipidology open-source eCME activity (accessed at http://multimedia.lipidjournal. com/2011/HDL) examines the variety in the components of the proteome and the contents of the lipidome that account for the spectrum of atheroprotective effects of HDL particles, as well as their known antiinflammatory effects and their less-known anti-diabetic effects (protective effects on the pancreatic b cells), as well as a contribution to the innate immune reaction. In this comprehensive review of the components and functions of HDL particles, two concepts are detailed: (1) that the functions of HDL particles reflect the integrated biological activities of their lipid (lipidome) and protein (proteome) components, and (2) that the dynamic intravascular metabolism of the lipid and protein components of HDL particles may be perturbed in cardiometabolic diseases (dyslipidemia, inflammation, and premature CVD), resulting in alterations in the atheroprotective function(s) of the HDL. Chapman J. J Clin Lipidol. 2011; 5(6). Accessible at http://lipidjournal.com. doi: 10.1016/j.jacl.2011.10.013
eCME Multimedia Activity The Current Status and Future Development of CETP Inhibitors Philip J. Barter, MD, PhD
ABSTRACT Although difficult to test prospectively (because proof would require enrollment of large numbers of patients who fail maximal lowering of low-density lipoprotein [LDL] cholesterol to ,70 mg/dL, followed by success in a high-density lipoprotein [HDL]-raising treatment
doi: 10.1016/j.jacl.2011.10.014
eCME Multimedia Activity Measuring HDL: The Effect of Current HDL-Raising Therapies on HDL Levels and Subfractions Ernst J. Schaefer, MD, FNLA
ABSTRACT Although lacking prospective controlled clinical trial evidence to prove the hypothesis, nevertheless it has been firmly established observationally that there is both a substantial gradient of risk associated with low HDL levels and a degree of protection associated with high HDL levels. However, whereas LDL particles present a relatively simplistic size spectrum, ranging from large, buoyant and less harmful, to the small, dense, and readily oxidized and infiltrative into the arterial wall and atherosclerotic plaques, the spectrum of HDL particle sizes is rather more complex, although in one dimension the size spectrum can be considered as simply the amount of cholesterol that has accumulated to fill the HDL particle. In line with this analysis, this Journal of Clinical Lipidology open-source eCME activity (accessed at http://multimedia.lipidjournal.com/2011/HDL) describes the smallest pre-b HDL1 and HDL3-4 particles as the ‘‘empty dump trucks that gradually are filled to become the large, HDL1 particles. As discussed in this article, the ways in which these different particles sizes correlate with different risk factors (gender, age, disease severity, etc.) and the ways
Translating HDL Science to Clinical Practice in which different HDL-affecting therapies (statins, niacin, CETP inhibitors) affect the different particle sizes in this spectrum, provide a more complex and complete understanding of HDL metabolism. Schaefer EJ. J Clin Lipidol. 2011; 5(6). Accessible at http://lipidjournal.com. doi: 10.1016/j.jacl.2011.10.015
eCME Multimedia Activity Unraveling HDL-Associated Risk: Current Challenges and Future Directions Robert S. Rosenson, MD, FNLA
ABSTRACT High-density lipoprotein (HDL) cholesterol is gaining more attention as an important risk factor and as important
S9 biomarker in cardiovascular disease (CVD). This Journal of Clinical Lipidology open-source eCME activity (accessed at http://multimedia.lipidjournal.com/2011/HDL) summarizes the many issues that this raises: the unacceptably high variance in direct HDL assays; the importance of considering low-density lipoprotein (LDL) particle number in the evaluation of HDL cholesterol-associated residual risk; the conflicting CVD risk factor associations, depending on whether measuring serum HDL cholesterol levels or HDL particles in models that include LDL-P; and assessment of HDL ‘‘functionality.’’ The article concludes with reference to the recently published article that attempts to establish a standardized nomenclature for HDL that addresses and tries to resolve some of these areas of confusion. Rosenson RS. J Clin Lipidol. 2011; 5(6). Accessible at http://lipidjournal.com. doi: 10.1016/j.jacl.2011.10.016
S9.e1
Journal of Clinical Lipidology, Vol 5, No 6, December 2011
Activity Overview
National Lipid Association designates this enduring material for a maximum of 1.0 AMA PRA Category 1 CreditÔ. Physicians should only claim credit commensurate with the extent of their participation in the activity.
To provide an enduring record of the most important contents from the live HDL Highlights Symposium: Translating HDL Science to Clinical Practice, held in New York City in May 2011, the National Lipid Association has partnered with Elsevier to publish an open-access, journalindexed Internet activity, with optional CME/CE credit, presented as a slide-driven narrative with edited text for each figure interpolated from the audio presentations. This online publication from the Journal of Clinical Lipidology provides the opportunity to access the contents visually, acoustically, and via the peer-reviewed text, as presented during this key opinion leader symposium.
Target Audience This journal publication is designed for a broader audience of healthcare professionals including lipidologists, cardiologists, endocrinologists, internists, primary care physicians, pharmacists, nurse practitioners, physician assistants, nurses, and registered dietitians.
Learning Objectives Upon completion of this activity, participants should be able to: Evaluate the role of HDL-C in reducing cardiovascular events and rates of atherosclerotic disease progression; Describe the metabolic pathways of HDL and the roles that HDL and inflammation play in the development of atherosclerosis; Distinguish those patients who remain at risk for CV events despite having an acceptable LDL level; Identify appropriate current treatment options including concomitant drug therapy to minimize residual CV risk; Summarize recent lipid-related research on raising HDL cholesterol and emerging treatment options, and clinical implications for patient management.
Sponsorship This activity is sponsored by the National Lipid Association.
Commercial Support This activity is supported by an educational grant from Genentech.
Accreditation CME credit provided by the National Lipid Association
Physicians The National Lipid Association is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. The
Physician Assistants NCCPA accepts AMA PRA Category 1 CreditÔ from organizations accredited by ACCME. CE credit provided by AKH Inc., Advancing Knowledge in Healthcare
Pharmacists AKH Inc. is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. AKH Inc. approves this KNOWLEDGE/APPLICATION-based activity for 1.0 contact hour(s) (0.1 CEUs). UAN 0077-9999-11-035-H04-P. Initial release date October 1, 2011.
Nurses AKH Inc. is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center’s COA. AKH Inc. designates this educational activity for 1.0 contact hour(s) (0.1 CEU). Accreditation applies solely to educational activities and does not imply approval or endorsement of any commercial product by the ANCC-COA.
Dietitians AKH Inc. is a Continuing Professional Education (CPE) Accredited Provider with the Commission on Dietetic Registration (CDR). Registered dietitians (RDs) and dietetic technicians, registered (DTRs) will receive 1.0 continuing professional education units (CPEUs) for completion of this program/material. CDR Accredited Provider #AN008. The focus of this activity is rated Level 2. Learners may submit evaluations of program/materials quality to the CDR at www.cdrnet.org.
Disclosure of Conflict of Interest Statements Disclosure Declaration: It is the policy of NLA and AKH Inc. to ensure independence, balance, objectivity, scientific rigor, and integrity in all of its continuing education activities. The faculty must disclose to the participants any significant relationships with commercial interests whose products or devices may be mentioned in the activity or with the commercial supporter of this continuing education activity. Identified conflict of interest is resolved by NLA and AKH prior to accreditation of the activity. NLA and AKH planners and reviewers have no relevant financial relationships to disclose. Daniel J. Rader, MD, FNLA, Professor of Medicine, University of Pennsylvania, Philadelphia, PA. Consultant: AstraZeneca; Bristol-Myers Squibb; Daiichi Sankyo, Inc.; Eli Lilly and Company; Merck & Co., Inc.; Novartis Pharmaceuticals; Roche Pharmaceuticals.
Translating HDL Science to Clinical Practice
S9.e2
M. John Chapman, BS, PhD, DSc, President, European Atherosclerosis Society, Director, INSERM (Dyslipidemia and Atherosclerosis Research), Paris, France; Contracted Research: Danone; Kowa Pharmaceuticals America, Inc.; Merck & Co., Inc.; Pfizer Inc.
Heart, New York, NY; Advisory Board: Abbott Laboratories, Inc.; Amgen; Genentech; Grain Foods Foundation; LipoScience, Inc.; Sanofi-aventis; Sticares InterACT; Contracted Research: Amgen; Genentech; LipoScience, Inc.; Roche Pharmaceuticals; Stock: LipoScience, Inc.
Philip J. Barter, MD, PhD, The Heart Research Institute, Sydney, Australia; Advisory Board: AstraZeneca; GlaxoSmithKline; Merck & Co., Inc.; Novartis Pharmaceuticals; Pfizer Inc.; Roche Pharmaceuticals; Speakers Bureau: AstraZeneca; GlaxoSmithKline; Merck & Co., Inc.; Pfizer Inc.; Roche Pharmaceuticals.
Staff and Reviewers Disclosures: AKH Inc., Advancing Knowledge in Healthcare staff, planners and reviewers have no financial relationships to disclose. National Lipid Association staff, planners and reviewers have no financial relationships to disclose.
Ernst J. Schaefer, MD, FNLA, Tufts University School of Medicine, Boston, MA; Consultant: Amarin; AstraZeneca; DuPont; Merck & Co., Inc.; Roche Pharmaceuticals; Unilever; Speakers Bureau:Merck & Co., Inc.; Stock: Boston Heart Lab.
Peer Review
Robert S. Rosenson, MD, FNLA, Mt Sinai School of Medicine, Director, Cardiometabolic Disorders, Mt Sinai
Sponsorship
This CME Multimedia Activity has been peer-reviewed by the Journal of Clinical Lipidology.
There is no fee to participate in this CME-certified activity.