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From the Editor: What should be our target of treatment?
Journal of Clinical Lipidology (2016) 10, 1055–1056
Foreword
From the Editor: What should be our target of treatment? In this issue of the Journal, Dr Allan Sniderman has provided a very interesting and timely analysis of the data comparing our clinical use of 3 well-studied measures of plasma lipoproteins that are highly predictive of future cardiovascular events in population-based studies and in cohorts of patients in clinical trials. It is of particular interest to this Journal and the National Lipid Association (NLA) because he has chosen to make his scientific points in a comparative format to an official position statement of the NLA published in this Journal in 2015. The editorial entitled ‘‘An Evidence-Based Analysis of the National Lipid Association Recommendations Concerning nonHDL-C and ApoB’’ was invited by this editor after personal discussions with Dr Sniderman regarding his belief that the time had come to take a different approach in choosing a target of treatment for reducing atherogenic lipoprotein concentrations and achieving a more effective intervention strategy in reducing vascular events. He has provided data from his own clinical studies and multiple analyses of a variety of data sets from many community-based studies and clinical intervention studies pointing out that the blood plasma quantitation of apolipoprotein B (apoB) provides the most accurate measure of risk and when reduced by treatment, the most accurate predictor of event rate reduction for atherosclerotic vascular disease. Sniderman’s current editorial reflects his concern that the NLA in its most recent guideline statement entitled ‘‘National Lipid Association recommendations for patientoriented management of dyslipidemia: part I - full report’’ (J Clin Lipid. Vol 9; p 129–169) placed major emphasis on the measurement of cholesterol content of lipoproteins, not the particles themselves. The great body of evidence developed over the past 50 years has pointed clearly to the fact that the source of atherosclerotic plaque depends on how cholesterol is carried in the blood, not the cholesterol itself. The obvious difference between the effect of the cholesterol in low-density lipoprotein (LDL) and in high-density lipoprotein (HDL) is only one example of this fact. However, it is difficult to escape the message that managing cholesterol is the appropriate clinical endeavor. Our entire experience with clinical guidelines has been focused on lowering cholesterol in one species of lipoproteins, namely 1933-2874/Ó 2016 National Lipid Association. All rights reserved. http://dx.doi.org/10.1016/j.jacl.2016.08.009
LDL-cholesterol (LDL-C), with the basic assumption that this is a uniform particle with a fixed size and structure. This has continued although we have known for years that there are complex systems exchanging lipids between all lipoprotein species and that these can be significantly altered by lifestyle and medications. The concept of particle number, measured by a variety of means, has been demonstrated to have value over simply measuring total cholesterol in major groupings of lipoproteins. This is now well developed in the basic and clinical research literature discussed by Sniderman. The reason we have not used this effectively in the clinic is that our well-meaning experts have been focused on the application of basic recommendations from 1988 with the publication of the first report of the Adult Treatment Panel of the National Cholesterol Education Program. Although there has been evolution, the basic idea is that LDL-C should be reduced as much as possible consistent with the findings of more and more aggressive clinical trials of lipid-lowering drugs. The benefits of this effort have delayed change. Partial success has been dramatic with continuing dietary recommendations and new drug interventions. We have seen vascular disease rates decline from this approach as well as efforts in blood pressure control and smoking cessation. Statins have provided a most dramatic and successful intervention and there the LDL-C reduction seemed to be confirmed by the use of a drug that was focused on enhancing the specific receptor for this lipoprotein, speeding LDL removal from the blood. We forget that the statin effect is actually an enhancement of the receptor-apoB interaction and is not a direct cholesterol effect. In 2013, the NLA was very concerned when a dramatic change was recommended in ‘‘cholesterol guidelines’’ by the American College of Cardiology in collaboration with the American Heart Association (J Am Coll Cardiol. Vol 63; p 2889–2934). Concern was expressed by many clinical organizations including the NLA. This resulted from the seeming removal of the emphasis on a target of treatment although it was implied throughout that LDL-C remained the focus. The central theme seemed to be that statins were the only evidenced-based treatment that was truly successful in preventing clinical disease and documented by
1056
Journal of Clinical Lipidology, Vol 10, No 5, October 2016
double-blind controlled clinical trials. The response of the clinician in planning therapy was to be focused on the dose of the statin and the choice of the appropriate patient who represented those included in cohorts of the statin trials. Total risk estimates defined those who needed treatment with the exception of those who were too young or too old to have been recruited for the randomized controlled trials. LDL-C itself was considered elevated and treatable as a ‘‘stand alone factor’’ if it was over 190 mg/dL. The concept of LDL-C or non-HDL-C as definable targets and of worthy of defined goals of therapy were left out of these guidelines. Consideration of elevated very low density lipoprotein (VLDL) cholesterol and its relationship to alterations of HDL and LDL composition was ignored. There seemed no place for considering non-HDL-C or apoB as targets although they were taking center stage in many new population studies. Most disturbing to some of us was the concept that physicians were treating cohorts of patients and that little attention was paid to the clinical experience of finding patients who had many risk factors that were not defined in trials and were not a part of the guidelines. These included the patient’s family history, detailed vascular history, a history of therapeutic responses, and other measures such as lipoprotein (a) or markers of inflammation. The NLA undertook to provide a set of guidelines that were focused on individual patients with a broader concept of vascular risk and the issues of lipoprotein contribution in addition to LDL-C such as elevated triglycerides and large numbers of less cholesterol-rich LDL particles. The problem of launching a totally new central focus on LDL particle number or apoB was discussed, and it was decided that this would be unacceptable when so much work was needed to get back to a focus on defining targets of treatment and justifying goals of the therapy. At that time, the most promising new target of treatment was apoB. As pointed out by Sniderman, much evidence already existed that apoB was documented to be at least as good as LDL-C or non-HDL-C in risk prediction, but the consideration of attempting to gain acceptance of this as a target of treatment was unlikely to be successful when the newly published American College of Cardiology/American Heart Association guidelines had placed most emphasis on choosing who to treat and the appropriate dose of statins. Since that time, new drugs such as the proprotein convertase subtilisin/kexin type 9 inhibitors and antisense oligonucleotides have been developed and have revised the need to define the target and goal. These ideas immediately come to mind for physicians and health care systems since apoB as well as cholesterol content of LDL and VLDL can now be driven far below previous therapeutic objectives. Longer term studies with clinical
endpoints will soon help in defining new targets and in setting goals. In anticipation of these changes, the American College of Cardiology working with the NLA and others has recently published new guidelines for the use of several of these drugs in conjunction with statins or alone (J Clin Lipid. Vol 10; p 458–461). We believe that this collaborative approach will improve our ability to reduce our patient’s risk. Population genetics has demonstrated that many genes play a role in the development of atherosclerosis, and only some of these are known to be determinants of lipoprotein cholesterol content. The potential for managing hypertriglyceridemia in a more effective way has been demonstrated by lowering apolipoprotein CIII with antisense oligonucleotides that inhibit apoCIII production. ApoB production can be inhibited by similar methodology. Inhibiting lipid loading of VLDL inhibits apoB delivery into the plasma. More evidence has developed to support the risk relationships with Lp(a), and efforts are underway to develop new treatments for high plasma concentrations of this lipoprotein. All these very recent changes must now open our minds to planning based on the biology of lipoprotein metabolism, of seriously considering issues such as discordance of measures and the application of these concepts in our guidelines for individual patient management. New data are on the horizon regarding the vascular effects of lowering LDL-C and apoB to values well below 50 mg/dL. In the light of this information, we need to reexamine the most appropriate measures of both risks in those already on statins and the best markers for goal setting. Our goals should define the upper limit of the range of values for the best target of treatment in our quest to achieve maximum benefit with regard to diminishing myocardial infarction, stroke, and peripheral vascular disease. We must also consider the time horizon that should provide for more effective intervention. It is clear that an earlier start in reducing causative risk factors will have greater impact. Studies to define the means of diagnosing early occult vascular disease and high-risk patients must then consider treating lipoprotein values well below those found in familial hypercholesterolemia. In this new world, it seems appropriate to seriously consider recommending apoB as a primary focus in risk prediction, in choice of treatment and in the definition of goals of therapy. William Virgil Brown, MD Editor Emory University School of Medicine Atlanta, GA, USA E-mail addresses: [email protected]; [email protected]
Foreword
From the Editor: What should be our target of treatment? In this issue of the Journal, Dr Allan Sniderman has provided a very interesting and timely analysis of the data comparing our clinical use of 3 well-studied measures of plasma lipoproteins that are highly predictive of future cardiovascular events in population-based studies and in cohorts of patients in clinical trials. It is of particular interest to this Journal and the National Lipid Association (NLA) because he has chosen to make his scientific points in a comparative format to an official position statement of the NLA published in this Journal in 2015. The editorial entitled ‘‘An Evidence-Based Analysis of the National Lipid Association Recommendations Concerning nonHDL-C and ApoB’’ was invited by this editor after personal discussions with Dr Sniderman regarding his belief that the time had come to take a different approach in choosing a target of treatment for reducing atherogenic lipoprotein concentrations and achieving a more effective intervention strategy in reducing vascular events. He has provided data from his own clinical studies and multiple analyses of a variety of data sets from many community-based studies and clinical intervention studies pointing out that the blood plasma quantitation of apolipoprotein B (apoB) provides the most accurate measure of risk and when reduced by treatment, the most accurate predictor of event rate reduction for atherosclerotic vascular disease. Sniderman’s current editorial reflects his concern that the NLA in its most recent guideline statement entitled ‘‘National Lipid Association recommendations for patientoriented management of dyslipidemia: part I - full report’’ (J Clin Lipid. Vol 9; p 129–169) placed major emphasis on the measurement of cholesterol content of lipoproteins, not the particles themselves. The great body of evidence developed over the past 50 years has pointed clearly to the fact that the source of atherosclerotic plaque depends on how cholesterol is carried in the blood, not the cholesterol itself. The obvious difference between the effect of the cholesterol in low-density lipoprotein (LDL) and in high-density lipoprotein (HDL) is only one example of this fact. However, it is difficult to escape the message that managing cholesterol is the appropriate clinical endeavor. Our entire experience with clinical guidelines has been focused on lowering cholesterol in one species of lipoproteins, namely 1933-2874/Ó 2016 National Lipid Association. All rights reserved. http://dx.doi.org/10.1016/j.jacl.2016.08.009
LDL-cholesterol (LDL-C), with the basic assumption that this is a uniform particle with a fixed size and structure. This has continued although we have known for years that there are complex systems exchanging lipids between all lipoprotein species and that these can be significantly altered by lifestyle and medications. The concept of particle number, measured by a variety of means, has been demonstrated to have value over simply measuring total cholesterol in major groupings of lipoproteins. This is now well developed in the basic and clinical research literature discussed by Sniderman. The reason we have not used this effectively in the clinic is that our well-meaning experts have been focused on the application of basic recommendations from 1988 with the publication of the first report of the Adult Treatment Panel of the National Cholesterol Education Program. Although there has been evolution, the basic idea is that LDL-C should be reduced as much as possible consistent with the findings of more and more aggressive clinical trials of lipid-lowering drugs. The benefits of this effort have delayed change. Partial success has been dramatic with continuing dietary recommendations and new drug interventions. We have seen vascular disease rates decline from this approach as well as efforts in blood pressure control and smoking cessation. Statins have provided a most dramatic and successful intervention and there the LDL-C reduction seemed to be confirmed by the use of a drug that was focused on enhancing the specific receptor for this lipoprotein, speeding LDL removal from the blood. We forget that the statin effect is actually an enhancement of the receptor-apoB interaction and is not a direct cholesterol effect. In 2013, the NLA was very concerned when a dramatic change was recommended in ‘‘cholesterol guidelines’’ by the American College of Cardiology in collaboration with the American Heart Association (J Am Coll Cardiol. Vol 63; p 2889–2934). Concern was expressed by many clinical organizations including the NLA. This resulted from the seeming removal of the emphasis on a target of treatment although it was implied throughout that LDL-C remained the focus. The central theme seemed to be that statins were the only evidenced-based treatment that was truly successful in preventing clinical disease and documented by
1056
Journal of Clinical Lipidology, Vol 10, No 5, October 2016
double-blind controlled clinical trials. The response of the clinician in planning therapy was to be focused on the dose of the statin and the choice of the appropriate patient who represented those included in cohorts of the statin trials. Total risk estimates defined those who needed treatment with the exception of those who were too young or too old to have been recruited for the randomized controlled trials. LDL-C itself was considered elevated and treatable as a ‘‘stand alone factor’’ if it was over 190 mg/dL. The concept of LDL-C or non-HDL-C as definable targets and of worthy of defined goals of therapy were left out of these guidelines. Consideration of elevated very low density lipoprotein (VLDL) cholesterol and its relationship to alterations of HDL and LDL composition was ignored. There seemed no place for considering non-HDL-C or apoB as targets although they were taking center stage in many new population studies. Most disturbing to some of us was the concept that physicians were treating cohorts of patients and that little attention was paid to the clinical experience of finding patients who had many risk factors that were not defined in trials and were not a part of the guidelines. These included the patient’s family history, detailed vascular history, a history of therapeutic responses, and other measures such as lipoprotein (a) or markers of inflammation. The NLA undertook to provide a set of guidelines that were focused on individual patients with a broader concept of vascular risk and the issues of lipoprotein contribution in addition to LDL-C such as elevated triglycerides and large numbers of less cholesterol-rich LDL particles. The problem of launching a totally new central focus on LDL particle number or apoB was discussed, and it was decided that this would be unacceptable when so much work was needed to get back to a focus on defining targets of treatment and justifying goals of the therapy. At that time, the most promising new target of treatment was apoB. As pointed out by Sniderman, much evidence already existed that apoB was documented to be at least as good as LDL-C or non-HDL-C in risk prediction, but the consideration of attempting to gain acceptance of this as a target of treatment was unlikely to be successful when the newly published American College of Cardiology/American Heart Association guidelines had placed most emphasis on choosing who to treat and the appropriate dose of statins. Since that time, new drugs such as the proprotein convertase subtilisin/kexin type 9 inhibitors and antisense oligonucleotides have been developed and have revised the need to define the target and goal. These ideas immediately come to mind for physicians and health care systems since apoB as well as cholesterol content of LDL and VLDL can now be driven far below previous therapeutic objectives. Longer term studies with clinical
endpoints will soon help in defining new targets and in setting goals. In anticipation of these changes, the American College of Cardiology working with the NLA and others has recently published new guidelines for the use of several of these drugs in conjunction with statins or alone (J Clin Lipid. Vol 10; p 458–461). We believe that this collaborative approach will improve our ability to reduce our patient’s risk. Population genetics has demonstrated that many genes play a role in the development of atherosclerosis, and only some of these are known to be determinants of lipoprotein cholesterol content. The potential for managing hypertriglyceridemia in a more effective way has been demonstrated by lowering apolipoprotein CIII with antisense oligonucleotides that inhibit apoCIII production. ApoB production can be inhibited by similar methodology. Inhibiting lipid loading of VLDL inhibits apoB delivery into the plasma. More evidence has developed to support the risk relationships with Lp(a), and efforts are underway to develop new treatments for high plasma concentrations of this lipoprotein. All these very recent changes must now open our minds to planning based on the biology of lipoprotein metabolism, of seriously considering issues such as discordance of measures and the application of these concepts in our guidelines for individual patient management. New data are on the horizon regarding the vascular effects of lowering LDL-C and apoB to values well below 50 mg/dL. In the light of this information, we need to reexamine the most appropriate measures of both risks in those already on statins and the best markers for goal setting. Our goals should define the upper limit of the range of values for the best target of treatment in our quest to achieve maximum benefit with regard to diminishing myocardial infarction, stroke, and peripheral vascular disease. We must also consider the time horizon that should provide for more effective intervention. It is clear that an earlier start in reducing causative risk factors will have greater impact. Studies to define the means of diagnosing early occult vascular disease and high-risk patients must then consider treating lipoprotein values well below those found in familial hypercholesterolemia. In this new world, it seems appropriate to seriously consider recommending apoB as a primary focus in risk prediction, in choice of treatment and in the definition of goals of therapy. William Virgil Brown, MD Editor Emory University School of Medicine Atlanta, GA, USA E-mail addresses: [email protected]; [email protected]