Using Apolipoprotein B to Manage Dyslipidemic Patients: Time for a Change?
2010; Elsevier BV; Volume: 85; Issue: 5 Linguagem: Inglês
10.4065/mcp.2009.0517
ISSN1942-5546
AutoresCharles R. Harper, Terry A. Jacobson,
Tópico(s)Cancer, Lipids, and Metabolism
ResumoLow-density lipoprotein cholesterol (LDL-C) concentration has been established as an independent risk factor for the development of atherosclerosis; consequently, multiple practice guidelines recognize LDL-C as the primary target of therapy.1Grundy SM Cleeman JL Mercz CN National Heart, Lung, and Blood Institute American College of Cardiology Foundation American Heart Association et al.Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines [published correction appears in Circulation. 2004;110(6):763].Circulation. 2004; 110: 227-239Crossref PubMed Scopus (5067) Google Scholar, 2Genest J McPherson R Frohlich J et al.2009 Canadian Cardiovascular Society/Canadian guidelines for the diagnosis and treatment of dyslipidemia and prevention of cardiovascular disease in the adult-2009 recommendations.Can J Cardiol. 2009; 25: 567-579Abstract Full Text PDF PubMed Scopus (624) Google Scholar For decades, considerable effort has been committed to educating physicians and the general public about the importance of lowering LDL-C levels. Despite the extensive data relating LDL-C to atherosclerosis, some have suggested that focusing only on LDL-C may not be an optimal strategy.3Mudd JO Borlaug BA Johnston PV et al.Beyond low-density lipoprotein cholesterol: defining the role of low-density lipoprotein heterogeneity in coronary artery disease.J Am Coll Cardiol. 2007; 50: 1735-1741Abstract Full Text Full Text PDF PubMed Scopus (103) Google Scholar Several limitations exist for an approach that focuses only on LDL-C: (1) evidence is increasing that triglyceride-rich lipoproteins, including very low-density lipoproteins (VLDL) and intermediate-density lipoproteins (IDL) (Figure 1)4Blaha MJ Blumenthal RS Brinton EA Jacobson TA National Lipid Association Taskforce on Non-HDL Cholesterol The importance of non-HDL cholesterol reporting in lipid management.J Clin Lipidol. 2008; 2: 267-273Abstract Full Text Full Text PDF PubMed Scopus (131) Google Scholar are also atherogenic5Austin MA Hokanson JE Edwards KL Hypertriglyceridemia as a cardiovascular risk factor.Am J Cardiol. 1998; 81: 7B-12BAbstract Full Text Full Text PDF PubMed Scopus (918) Google Scholar, 6Hokanson JE Austin MA Plasma triglyceride level is a risk factor for cardiovascular disease independent of high-density lipoprotein cholesterol level: a meta-analysis of population-based prospective studies.J Cardiovasc Risk. 1996; 3: 213-219Crossref PubMed Google Scholar; and (2) a substantial percentage of patients with atherosclerotic vascular disease have LDL-C in the optimal range.7Sachdeva A Cannon CP Deedwania PC et al.Lipid levels in patients hospitalized with coronary artery disease: an analysis of 136,905 hospitalizations in Get with the Guidelines.Am Heart J. 2009; 157: 111-117Abstract Full Text Full Text PDF Scopus (227) Google Scholar Furthermore, many patients who receive treatment and achieve recommended LDL-C goals even lower than 70 mg/dL (to convert to mmol/L, multiply by 0.0259) still develop the complications of atherosclerotic vascular disease, which is referred to as residual risk.8Libby P The forgotten majority: unfinished business in cardiovascular risk reduction.J Am Coll Cardiol. 2005; 46: 1225-1228Abstract Full Text Full Text PDF Scopus (321) Google Scholar One explanation for these discrepancies is the mismatch that has been described in many patients between the LDL-C concentration reported on a basic lipid panel and the number of atherogenic lipid particles, which is often expressed as low-density lipoprotein (LDL) particle number or the number of apolipoprotein B (apo B)–containing lipoproteins.9Barter PJ Ballantyne CM Carmena R et al.Apo B versus cholesterol in estimating cardiovascular risk and in guiding therapy: report of the thirty-person/ten-country panel.J Intern Med. 2006; 259: 247-258Crossref PubMed Scopus (385) Google Scholar The reason for this mismatch is that LDL particles are extremely heterogeneous with respect to the amount of cholesterol contained in the LDL particle core.10Chapman MJ Laplaud PM Luc G et al.Further resolution of the low density lipoprotein spectrum in normal human plasma: physicochemical characteristics of discrete subspecies separated by density gradient ultracentrifugation.J Lipid Res. 1988; 29: 442-458Google Scholar Patients with a predominance of cholesterol-depleted LDL particles (also called small dense LDL-C) may have a low LDL "cholesterol" concentration as reported on the standard lipid panel but still have a large number of circulating atherogenic LDL particles.11Berneis KK Krauss RM Metabolic origins and clinical significance of LDL heterogeneity.J Lipid Res. 2002; 43: 1363-1379Crossref Scopus (684) Google Scholar For example, 2 patients with the same LDL-C concentration on a basic lipid panel may have markedly different LDL particle numbers and different cardiovascular risk (Figure 2).12Otvos JD Jeyarajah EJ Cromwell WC Measurement issues related to lipoprotein heterogeneity.Am J Cardiol. 2002; 90: 22i-29iAbstract Full Text Full Text PDF PubMed Scopus (208) Google Scholar Extrapolating information concerning the number of atherogenic LDL particles from the LDL-C content is an unreliable strategy.FIGURE 2Same low-density lipoprotein cholesterol (LDL-C) levels, different cardiovascular risk. apo = apolipoprotein. SI conversion factors: To convert LDL-C value to mmol/L, multiply by 0.0259.Show full captionAdapted from Am J Cardiol,12Otvos JD Jeyarajah EJ Cromwell WC Measurement issues related to lipoprotein heterogeneity.Am J Cardiol. 2002; 90: 22i-29iAbstract Full Text Full Text PDF PubMed Scopus (208) Google Scholar with permission.View Large Image Figure ViewerDownload (PPT) Adapted from Am J Cardiol,12Otvos JD Jeyarajah EJ Cromwell WC Measurement issues related to lipoprotein heterogeneity.Am J Cardiol. 2002; 90: 22i-29iAbstract Full Text Full Text PDF PubMed Scopus (208) Google Scholar with permission. Recently, some expert panels and national organizations have proposed using apo B in conjunction with standard lipid testing to address the aforementioned limitations.13Brunzell JD Davidson M Furberg CD et al.Lipoprotein management in patients with cardiometabolic risk: consensus conference report from the American Diabetes Association and the American College of Cardiology Foundation.J Am Coll Cardiol. 2008; 51: 1512-1524Abstract Full Text Full Text PDF PubMed Scopus (428) Google Scholar Apo B is a key structural component of all the atherogenic lipoprotein particles, including LDL, VLDL, and IDL. Each of these atherogenic particles carries only one apo B molecule; thus, the total apo B level represents the total number of circulating atherogenic lipoprotein particles and provides the clinician a more accurate picture of a patient's risk of cardiovascular events.13Brunzell JD Davidson M Furberg CD et al.Lipoprotein management in patients with cardiometabolic risk: consensus conference report from the American Diabetes Association and the American College of Cardiology Foundation.J Am Coll Cardiol. 2008; 51: 1512-1524Abstract Full Text Full Text PDF PubMed Scopus (428) Google Scholar Other advantages to the measurement of apo B include the fact that it does not require a fasting specimen, its relative low cost, and the existence of a World Health Organization–approved standard. Alternatively, some experts advocate calculating and using non–high-density lipoprotein cholesterol (non–HDL-C) instead of LDL-C to improve risk prediction in certain groups of patients, particularly in those with elevated triglyceride values.1Grundy SM Cleeman JL Mercz CN National Heart, Lung, and Blood Institute American College of Cardiology Foundation American Heart Association et al.Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines [published correction appears in Circulation. 2004;110(6):763].Circulation. 2004; 110: 227-239Crossref PubMed Scopus (5067) Google Scholar The National Cholesterol Education Program (NCEP)/Adult Treatment Panel (ATP) III guidelines recommend that, in patients with triglyceride levels of 200 mg/dL or higher, non–HDL-C should be calculated and the goal set at 30 mg/dL higher than the LDL-C goal (Table1).1Grundy SM Cleeman JL Mercz CN National Heart, Lung, and Blood Institute American College of Cardiology Foundation American Heart Association et al.Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines [published correction appears in Circulation. 2004;110(6):763].Circulation. 2004; 110: 227-239Crossref PubMed Scopus (5067) Google Scholar Substantial evidence supports the idea that non–HDL-C is clearly superior to LDL-C for cardiovascular disease risk prediction. Non–HDL-C is calculated by subtracting the HDL-C from the total cholesterol, and it represents the cholesterol concentration of all atherogenic lipoproteins.14Cui Y Blumenthal RS Flaws JA et al.Non-high-density lipoprotein cholesterol level as a predictor of cardiovascular disease mortality.Arch Intern Med. 2001; 161: 1413-1419Crossref Scopus (525) Google Scholar, 15Frost PH Havel RJ Rationale for use of non-high-density lipoprotein cholesterol rather than low-density lipoprotein cholesterol as a tool for lipoprotein cholesterol screening and assessment of risk and therapy.Am J Cardiol. 1998; 81: 26B-31BAbstract Full Text Full Text PDF Scopus (175) Google Scholar Although non–HDL-C is a good surrogate measure of apo B, it does not measure the same thing. Non–HDL-C measures the "cholesterol" content of all atherogenic lipoproteins (LDL, IDL, and VLDL), whereas apo B represents the total number of circulating atherogenic particles. Although substantial evidence supports the idea that non–HDL-C is clearly superior to LDL-C for cardiovascular disease risk prediction, strong evidence shows that apo B may be superior to both LDL-C and non–HDL-C for both risk stratification and determination of goal attainment during therapy.TABLE 1ATP III LDL-C Goals and Cutpoints for Drug TherapyaATP = Adult Treatment Panel; CHD = coronary heart disease; LDL-C = low-density lipoprotein cholesterol; non–HDL-C = non–high-density lipoprotein cholesterol.From JAMA,1Grundy SM Cleeman JL Mercz CN National Heart, Lung, and Blood Institute American College of Cardiology Foundation American Heart Association et al.Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines [published correction appears in Circulation. 2004;110(6):763].Circulation. 2004; 110: 227-239Crossref PubMed Scopus (5067) Google Scholar with permission.Goal (mg/dLbSI conversion factors: To convert LDL-C and non–HDL-C values to mmol/L, multiply by 0.0259.)Risk categoryLDL-CNon-HDL-CVery high riskcVery high risk is defned as the presence of established cardiovascular disease plus diabetes, or plus multiple poorly controlled risk factors, or multiple risk factors of the metabolic syndrome (especially high triglyc-erides >200 mg/dL), or patients with acute coronary syndrome.<100 (optional <70)<130 (optional 50% obstruction of carotid artery), diabetes, and ≥2 risk factors with 10-y risk of hard CHD >20%.<100 140/90 mm Hg or antihypertensive medication), low HDL-C ( 45 y in men, >55 y in women). (10-y risk, 10%–20%)6Hokanson JE Austin MA Plasma triglyceride level is a risk factor for cardiovascular disease independent of high-density lipoprotein cholesterol level: a meta-analysis of population-based prospective studies.J Cardiovasc Risk. 1996; 3: 213-219Crossref PubMed Google Scholar<130 (optional <100)160 (optional 140/90 mm Hg or antihypertensive medication), low HDL-C ( 45 y in men, >55 y in women). (10-y risk 200 mg/dL), or patients with acute coronary syndrome.d CHD includes history of myocardial infarction, unstable angina, coronary artery procedures (bypass or angioplasty), or evidence of clinically important myocardial ischemia.e CHD risk equivalents are defned as clinical manifestations of noncoro-nary atherosclerotic disease, including peripheral arterial disease, abdominal aortic aneurysm, and carotid artery disease (transient ischemic attacks or stroke of carotid origin or >50% obstruction of carotid artery), diabetes, and ≥2 risk factors with 10-y risk of hard CHD >20%.f Risk factors include cigarette smoking, hypertension (blood pressure, >140/90 mm Hg or antihypertensive medication), low HDL-C ( 45 y in men, >55 y in women). Open table in a new tab In this commentary, we propose how apo B might be used by clinicians involved in the primary and secondary prevention of coronary heart disease. First, we briefly discuss the evidence that suggests the superiority of apo B as arisk predictor compared to non–HDL-C and LDL-C. Then, we suggest certain patient populations in whom clinicians may wish to target apo B because of demonstrated superiority to LDL-C, including those with diabetes and those receiving statin therapy. Finally, we discuss current recommendations for apo B goals of therapy and the evidence for these goals. Multiple epidemiological and clinical trials support the superiority of apo B for risk prediction compared to both LDL-C and non–HDL-C (Table 2).16Walldius G Jungner I Holme I Aastveit AH Kolar W Steiner E High apolipoprotein B, low apolipoprotein A-I, and improvement in the prediction of fatal myocardial infarction (AMORIS study): a prospective study.Lancet. 2001; 358: 2026-2033Abstract Full Text Full Text PDF PubMed Scopus (1054) Google Scholar, 17McQueen MJ Hawken S Wang X et al.Lipids, lipoproteins, and apolipoproteins as risk markers of myocardial infarction in 52 countries (the INTERHEART study): a case-control study.Lancet. 2008; 372: 224-233Abstract Full Text Full Text PDF PubMed Scopus (636) Google Scholar, 18Hsia SH Pan D Berookim P Lee ML A population-based, cross-sectional comparison of lipid-related indexes for symptoms of atherosclerotic disease.Am J Cardiol. 2006; 98: 1047-1052Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar, 19Holme I Cater NB Faergeman O et al.Lipoprotein predictors of cardiovascular events in statin-treated patients with coronary heart disease: insights from the incremental decrease in end-points through aggressive lipid-lowering trial (IDEAL).Ann Med. 2008; 40: 456-464Crossref PubMed Scopus (42) Google Scholar, 20Simes RJ Marschner IC Hunt D et al.Relationship between lipid levels and clinical outcomes in the Long-term Intervention with Pravastatin in Ischemic Disease (LIPID) Trial: to what extent is the reduction in coronary events with pravastatin explained by on-study lipid levels?.Circulation. 2002; 105: 1162-1169Crossref PubMed Scopus (244) Google Scholar, 21Chien KL Hsu HC Su TC Chen MF Lee YT Hu FB Apolipoprotein B and non-high density lipoprotein cholesterol and the risk of coronary heart disease in Chinese.J Lipid Res. 2007; 48: 2499-2505Crossref Scopus (83) Google Scholar, 22Gotto Jr, AM Whitney E Stein EA et al.Relation between baseline and on-treatment lipid parameters and first acute major coronary events in the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS).Circulation. 2000; 101: 477-484Crossref PubMed Scopus (498) Google Scholar, 23Bruno G Merletti F Biggeri A et al.Effect of age on the association of non-high-density-lipoprotein cholesterol and apolipoprotein B with cardiovascular mortality in a Mediterranean population with type 2 diabetes: the Casale Monferrato study.Diabetologia. 2006; 49: 937-944Crossref PubMed Scopus (31) Google Scholar, 24van Lennep JE Westerveld HT van Lennep HW Zwinderman AH Erkelens DW van der Wall EE Apolipoprotein concentrations during treatment and recurrent coronary artery disease events.Arterioscler Thromb Vasc Biol. 2000; 20: 2408-2413Crossref Scopus (140) Google Scholar, 25Pischon T Girman CJ Sacks FM Rifai N Stampfer MJ Rimm EB Non-high-density lipoprotein cholesterol and apolipoprotein B in the prediction of coronary heart disease in men.Circulation. 2005; 112: 3375-3383Crossref PubMed Scopus (408) Google Scholar Recently, the large epidemiological study AMORIS (Apolipoprotein related Mortality Risk) recruited more than 175,000 Swedish men and women and monitored them for more than 5 years.16Walldius G Jungner I Holme I Aastveit AH Kolar W Steiner E High apolipoprotein B, low apolipoprotein A-I, and improvement in the prediction of fatal myocardial infarction (AMORIS study): a prospective study.Lancet. 2001; 358: 2026-2033Abstract Full Text Full Text PDF PubMed Scopus (1054) Google Scholar Total cholesterol, apo B, and apo A1 levels were measured, and LDL-C values calculated. The association between death from acute myocardial infarction and initial values for apo B, apo A1, and LDL-C was analyzed. In multivariate analysis, apo B was a stronger predictor of risk than LDL-C. Apo B also demonstrated a higher sensitivity and specificity than LDL-C as a predictive variable in both men and women irrespective of whether the data were adjusted for age.TABLE 2Epidemiological Studies and Clinical Trials in which Apo B Levels are Superior to LDL-C and Non–HDL-C LevelsStudy nameStudy typeNo. of patientsSexPatient populationAMORIS16Walldius G Jungner I Holme I Aastveit AH Kolar W Steiner E High apolipoprotein B, low apolipoprotein A-I, and improvement in the prediction of fatal myocardial infarction (AMORIS study): a prospective study.Lancet. 2001; 358: 2026-2033Abstract Full Text Full Text PDF PubMed Scopus (1054) Google ScholarEpi175,553M+FAsymptomaticINTERHEART17McQueen MJ Hawken S Wang X et al.Lipids, lipoproteins, and apolipoproteins as risk markers of myocardial infarction in 52 countries (the INTERHEART study): a case-control study.Lancet. 2008; 372: 224-233Abstract Full Text Full Text PDF PubMed Scopus (636) Google ScholarEpi31,465M+FPost-MINHANES18Hsia SH Pan D Berookim P Lee ML A population-based, cross-sectional comparison of lipid-related indexes for symptoms of atherosclerotic disease.Am J Cardiol. 2006; 98: 1047-1052Abstract Full Text Full Text PDF PubMed Scopus (54) Google ScholarEpi9500M+FAsymptomaticIDEAL19Holme I Cater NB Faergeman O et al.Lipoprotein predictors of cardiovascular events in statin-treated patients with coronary heart disease: insights from the incremental decrease in end-points through aggressive lipid-lowering trial (IDEAL).Ann Med. 2008; 40: 456-464Crossref PubMed Scopus (42) Google ScholarCT8888M+FPost-MILIPID20Simes RJ Marschner IC Hunt D et al.Relationship between lipid levels and clinical outcomes in the Long-term Intervention with Pravastatin in Ischemic Disease (LIPID) Trial: to what extent is the reduction in coronary events with pravastatin explained by on-study lipid levels?.Circulation. 2002; 105: 1162-1169Crossref PubMed Scopus (244) Google ScholarCT4502M+FCHDChinese Heart study21Chien KL Hsu HC Su TC Chen MF Lee YT Hu FB Apolipoprotein B and non-high density lipoprotein cholesterol and the risk of coronary heart disease in Chinese.J Lipid Res. 2007; 48: 2499-2505Crossref Scopus (83) Google ScholarEpi3586M+FAsymptomaticAFCAPS/TexCAPS22Gotto Jr, AM Whitney E Stein EA et al.Relation between baseline and on-treatment lipid parameters and first acute major coronary events in the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS).Circulation. 2000; 101: 477-484Crossref PubMed Scopus (498) Google ScholarEpi3301M+FAsymptomaticCasale Monferrato23Bruno G Merletti F Biggeri A et al.Effect of age on the association of non-high-density-lipoprotein cholesterol and apolipoprotein B with cardiovascular mortality in a Mediterranean population with type 2 diabetes: the Casale Monferrato study.Diabetologia. 2006; 49: 937-944Crossref PubMed Scopus (31) Google ScholarEpi1565M+FDiabetesLeiden Heart study24van Lennep JE Westerveld HT van Lennep HW Zwinderman AH Erkelens DW van der Wall EE Apolipoprotein concentrations during treatment and recurrent coronary artery disease events.Arterioscler Thromb Vasc Biol. 2000; 20: 2408-2413Crossref Scopus (140) Google ScholarCT848MCHDHealth Professionals Follow-up study25Pischon T Girman CJ Sacks FM Rifai N Stampfer MJ Rimm EB Non-high-density lipoprotein cholesterol and apolipoprotein B in the prediction of coronary heart disease in men.Circulation. 2005; 112: 3375-3383Crossref PubMed Scopus (408) Google ScholarEpi532MAsymptomaticAMORIS = Apolipoprotein related Mortality Risk; AFCAPS/Tex-CAPS = Air Force/Texas Coronary Atherosclerosis Prevention Study; Apo B = apolipoprotein B; CHD = coronary heart disease; CT = clinical trial; Epi = epidemiological study; IDEAL = Incremental Decrease in End Points through Aggressive Lipid Lowering; NHANES = National Health and Nutrition Examination Survey; LIPID = Long-term Intervention with Pravastatin in Ischemic Disease; LDL-C = low-density lipoprotein cholesterol; non–HDL-C = non–high-density lipoprotein cholesterol; post-MI = post myocardial infarction. Open table in a new tab AMORIS = Apolipoprotein related Mortality Risk; AFCAPS/Tex-CAPS = Air Force/Texas Coronary Atherosclerosis Prevention Study; Apo B = apolipoprotein B; CHD = coronary heart disease; CT = clinical trial; Epi = epidemiological study; IDEAL = Incremental Decrease in End Points through Aggressive Lipid Lowering; NHANES = National Health and Nutrition Examination Survey; LIPID = Long-term Intervention with Pravastatin in Ischemic Disease; LDL-C = low-density lipoprotein cholesterol; non–HDL-C = non–high-density lipoprotein cholesterol; post-MI = post myocardial infarction. Another example is the INTERHEART study. INTERHEART is a large standardized case-control study of acute myocardial infarction in more than 12,000 cases and more than 14,000 age-matched and sex-matched controls from 52 countries and several ethnic groups. Apo B had the highest odds ratio of any single measure for the prediction of risk of coronary heart disease and was superior to non–HDL in all ethnic groups.17McQueen MJ Hawken S Wang X et al.Lipids, lipoproteins, and apolipoproteins as risk markers of myocardial infarction in 52 countries (the INTERHEART study): a case-control study.Lancet. 2008; 372: 224-233Abstract Full Text Full Text PDF PubMed Scopus (636) Google Scholar Diabetic patients and patients with multiple cardiometabolic risk factors (obesity, insulin resistance, and hypertension) are populations in whom apo B measurement may be most advantageous. Focusing on the basic lipid panel and LDL-C alone may result in an underestimation of cardiovascular risk. Diabetic dyslipidemia is frequently characterized by multiple lipoprotein abnormalities, including elevated levels of triglyceride-rich lipoproteins such as VLDL and IDL, increased numbers of small dense LDL particles, and low levels of HDL-C.13Brunzell JD Davidson M Furberg CD et al.Lipoprotein management in patients with cardiometabolic risk: consensus conference report from the American Diabetes Association and the American College of Cardiology Foundation.J Am Coll Cardiol. 2008; 51: 1512-1524Abstract Full Text Full Text PDF PubMed Scopus (428) Google Scholar Because there is one apo B molecule perparticle of VLDL and IDL, apo B measurement could be used as an effective marker for elevations in these atherogenic triglyceride-rich lipoproteins and a more accurate predictor of cardiovascular risk. Support is increasing for measurement of apo B to improve the assessment of "residual risk" in patients being treated with lipid-lowering drugs. Patients receiving therapy still have significant residual cardiovascular risk even with treatment to reach aggressive LDL-C goals. Factors that contribute to residual risk include elevated levels of atherogenic lipoprotein particles other than LDL, such as IDL and VLDL, and the presence of small dense LDL particles not detected in a basic lipid panel. Measurement of apo B detects the presence of all atherogenic particles and has led some experts to recommend monitoring apo B along with LDL-C to better determine residual risk and therapeutic effectiveness. This recommendation has led some experts to suggest monitoring of apo B to better determine "residual" cardiovascular risk in patients receiving therapy and to target both LDL-C and apo B for monitoring therapeutic effectiveness.13Brunzell JD Davidson M Furberg CD et al.Lipoprotein management in patients with cardiometabolic risk: consensus conference report from the American Diabetes Association and the American College of Cardiology Foundation.J Am Coll Cardiol. 2008; 51: 1512-1524Abstract Full Text Full Text PDF PubMed Scopus (428) Google Scholar In fact, several clinical trials have demonstrated the superiority of apo B to LDL-C in monitoring patients receiving statin therapy for residual risk. One such trial is AFCAPS/TexCAPS (Air Force/Texas Coronary Atherosclerosis Prevention Study).22Gotto Jr, AM Whitney E Stein EA et al.Relation between baseline and on-treatment lipid parameters and first acute major coronary events in the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS).Circulation. 2000; 101: 477-484Crossref PubMed Scopus (498) Google Scholar This post hoc analysis of the 6600 participants receiving lovastatin for 1 year was performed to identify lipid variables related to an acute major coronary event. At baseline, the association between LDL-C and apo B levels and the risk of a major coronary event was similar. However, after 1 year of treatment, the association between LDL-C and the risk of a major coronary event was not significant (P=.162). In contrast, after 1 year of treatment, apo B was a strong predictor of major coronary events (P=.001). In another post hoc analysis, data were combined from 2 prospective secondary prevention trials: TNT (Treating to New Targets) and IDEAL (Incremental Decrease in EndPoints through Aggressive Lipid Lowering). The strengths of associations of LDL-C, non–HDL-C, and apo B with the occurrence of major cardiovascular events while patients were receiving treatment were analyzed. The hazard ratios (HRs) were significant for LDL-C (HR, 1.15; 95% confidence interval [CI], 1.10-1.20), non–HDL-C (HR, 1.19; 95% CI, 1.14-1.25), and apo B level (HR, 1.19; CI, 1.14-1.24). In pair-wise comparisons, LDL-C was not significant as a predictor when combined with the apo B level or the non–HDL-C level, whereas apo B and non–HDL-C remained significant at HRs of 1.24 and 1.31, respectively. Thus, in statin-treated patients in TNT and IDEAL, levels of apo B and non–HDL-C were more closely associated with cardiovascular outcome than levels of LDL-C while patients were receving treatment.26Kastelein JJP van der Steeg WA Holme I et al.Lipids, apolipoproteins, and their ratios in relation to cardiovascular events with statin treatment.Circulation. 2008; 117: 3002-3009Crossref PubMed Scopus (375) Google Scholar One of the reasons apo B may be superior to LDL-C in assessing the cardiovascular risk of patients receiving statin therapy is that statin therapy reduces LDL-C levels by a greater percentage than it does apo B levels; thus, it alters the association of LDL-C (LDL cholesterol content) to LDL particle number, resulting in many patients reaching their LDL-C goal but continuing to have a high number of LDL particles. This concept of a mismatch between LDL-C and LDL particle number is illustrated in the MERCURY (Measuring Effective Reductions in Cholesterol Using Rosuvastatin therapY) II trial, a 16-week trial consisting of more than 1900 patients at high risk of coronary heart disease or recurrent cardiac events.27Ballantyne CM Bertolami M Hernandez Garcia HR et al.Achieving LDL cholesterol, non-HDL cholesterol, and apolipoprotein B target levels in high-risk patients: Measuring Effective Reductions in Cholesterol Using Rosuvastatin therapY (MERCURY) II.Am Heart J. 2006; 151: 975.e1-975.e9Abstract Full Text Full Text PDF Scopus (97) Google Scholar Patients were randomized to treatment with rosuvastatin, atorvastatin, or simvastatin to compare the efficacy and safety of the most widely prescribed statins. In untreated patients, an LDL-C level of 100 mg/dL was approximately equivalent to an apo B level of 90 mg/dL. However, in patients receiving treatment with statins, the association between LDL-C and apo B was altered. In patients treated with a statin to an LDL-C goal of less than 100 mg/dL, only 48% reached their apo B goal of less than 90 mg/dL, thus underscoring that a significant number of patients have elevated apo B levels despite achievement of LDL-C goals. To consistently reach an apo B goal of less than 90 mg/dL required achievement of an LDL-C goal of less than 70 mg/dL (for patients with a high triglyceride level at baseline) or less than 80 mg/dL (for patients with a low triglyceride level at baseline). Results similar to MERCURY II were observed in an analysis by Sniderman28Sniderman AD Differential response of cholesterol and particle measures of atherogenic lipoproteins to LDL-lowering therapy: implications for clinical practice.J Clin Lipidol. 2008; 2: 36-42Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar of 11 statin trials representing more than 17,000 patients. While patients were receiving treatment, the mean LDL-C concentration was 99.2 mg/dL, representing the 21st percentile of the population, whereas the mean apo B concentration was 101.6 mg/dL, representing the 55th percentile (Table 3).28Sniderman AD Differential response of cholesterol and particle measures of atherogenic lipoproteins to LDL-lowering therapy: implications for clinical practice.J Clin Lipidol. 2008; 2: 36-42Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar Thus, a clear discordance between population percentiles for achieved LDL and apo B goals was again noted. This discordance illustrates how patients with optimal LDL-C levels may still be at high risk of cardiovascular events secondary to an undetected high number of LDL or apo B particles. Identifying patients with optimal or near optimal LDL-C levels yet high LDL particle number could result in more effective prevention of cardiovascular events.TABLE 3Effectiveness of Statin Therapy at Decreasing LDL-C, Non–HDL-C, and Apo B Levels in 11 Statin TrialsaApo B = apolipoprotein B; LDL-C = low-density lipoprotein cholesterol; non–HDL-C = non–high-density lipoprotein cholesterol.,bSI conversion factors: To convert apo B to g/L, multiply by 0.01; to convert LDL-C and non–HDL-C to mmol/L, multiply by 0.0259.Adapted from J Clin Lipidology,28Sniderman AD Differential response of cholesterol and particle measures of atherogenic lipoproteins to LDL-lowering therapy: implications for clinical practice.J Clin Lipidol. 2008; 2: 36-42Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar with permission.% Reduction on therapyMean on-treatment concentration (mg/dL)Mean on-treatment population (%)LDL-C42.199.221Non-HDL-C39.6127.029Apo B33.1101.655a Apo B = apolipoprotein B; LDL-C = low-density lipoprotein cholesterol; non–HDL-C = non–high-density lipoprotein cholesterol.b SI conversion factors: To convert apo B to g/L, multiply by 0.01; to convert LDL-C and non–HDL-C to mmol/L, multiply by 0.0259. Open table in a new tab The American Diabetes Association/American College of Cardiology (ADA/ACC) Consensus Conference Report (Table 4)13Brunzell JD Davidson M Furberg CD et al.Lipoprotein management in patients with cardiometabolic risk: consensus conference report from the American Diabetes Association and the American College of Cardiology Foundation.J Am Coll Cardiol. 2008; 51: 1512-1524Abstract Full Text Full Text PDF PubMed Scopus (428) Google Scholar and the Canadian Cardiovascular Society2Genest J McPherson R Frohlich J et al.2009 Canadian Cardiovascular Society/Canadian guidelines for the diagnosis and treatment of dyslipidemia and prevention of cardiovascular disease in the adult-2009 recommendations.Can J Cardiol. 2009; 25: 567-579Abstract Full Text PDF PubMed Scopus (624) Google Scholar have suggested apo B goals for treatment of dyslipidemia and prevention of cardiovascular disease.13Brunzell JD Davidson M Furberg CD et al.Lipoprotein management in patients with cardiometabolic risk: consensus conference report from the American Diabetes Association and the American College of Cardiology Foundation.J Am Coll Cardiol. 2008; 51: 1512-1524Abstract Full Text Full Text PDF PubMed Scopus (428) Google Scholar The ADA/ACC consensus report recommends, in addition to an LDL-C and non–HDL-C goal of 70 mg/dL and 100 mg/dL, respectively, an apo B goal of 80 mg/dL for patients with either established cardiovascular disease or diabetes with one riskfactor.13Brunzell JD Davidson M Furberg CD et al.Lipoprotein management in patients with cardiometabolic risk: consensus conference report from the American Diabetes Association and the American College of Cardiology Foundation.J Am Coll Cardiol. 2008; 51: 1512-1524Abstract Full Text Full Text PDF PubMed Scopus (428) Google Scholar In patients without cardiovascular disease but with 2 cardiometabolic risk factors, the ADA/ACC recommends an apo B goal of 90 mg/dL. For patients with coronary heart disease, the Canadian Cardiovascular Society recommends an apo B goal of 80 mg/dL.2Genest J McPherson R Frohlich J et al.2009 Canadian Cardiovascular Society/Canadian guidelines for the diagnosis and treatment of dyslipidemia and prevention of cardiovascular disease in the adult-2009 recommendations.Can J Cardiol. 2009; 25: 567-579Abstract Full Text PDF PubMed Scopus (624) Google ScholarTABLE 4ADA/ACC Consensus Report Treatment Goals in Patients with Lipoprotein AbnormalitiesaACC = American College of Cardiology; ADA = American Diabetes Association; apo B = apolipoprotein B; CVD = cardiovascular disease; LDL-C = low-density lipoprotein cholesterol; non–HDL-C = non–high-density lipoprotein cholesterol.Adapted from J Am Coll Cardiol,13Brunzell JD Davidson M Furberg CD et al.Lipoprotein management in patients with cardiometabolic risk: consensus conference report from the American Diabetes Association and the American College of Cardiology Foundation.J Am Coll Cardiol. 2008; 51: 1512-1524Abstract Full Text Full Text PDF PubMed Scopus (428) Google Scholar with permission from Elsevier.Goals (mg/dLbSI conversion factors: To convert apo B to g/L, multiply by 0.01; to convert LDL-C and non–HDL-C to mmol/L, multiply by 0.0259.)Risk categoryLDL-Cnon-HDL-Capo BHighest-risk patients, including those with (1) known CVD or (2) diabetes plus ≥1 additional major CVD risk factor<70<100<80High-risk patients, including those with (1) no diabetes or known clinical CVD but ≥2 additional major CVD risk factors or (2) diabetes but no other major risk factorcOther major risk factors (beyond dyslipoproteinemia) include smoking, hypertension, and family history of premature coronary artery disease.<100<130<90a ACC = American College of Cardiology; ADA = American Diabetes Association; apo B = apolipoprotein B; CVD = cardiovascular disease; LDL-C = low-density lipoprotein cholesterol; non–HDL-C = non–high-density lipoprotein cholesterol.b SI conversion factors: To convert apo B to g/L, multiply by 0.01; to convert LDL-C and non–HDL-C to mmol/L, multiply by 0.0259.c Other major risk factors (beyond dyslipoproteinemia) include smoking, hypertension, and family history of premature coronary artery disease. Open table in a new tab Data from recent clinical trials, including PROVE IT (Pravastatin or Atorvastatin Evaluation and Infection Therapy) and CARDS (Collaborative Atorvastatin Diabetes Study), lend support to an apo B goal of less than 80 mg/dL for high-risk patients. In PROVE IT, more than 4000 patients recently hospitalized for an acute coronary syndrome with a baseline median apo B level near 100 mg/dL were randomized to receive treatment either with pravastatin at 40 mg(moderate therapy) or with atorvastatin at 80 mg (intensive therapy).29Ray KK Cannon CP Cairns R Morrow DA Ridker PM Braunwald E Prognostic utility of apoB/AI, total cholesterol/HDL, non-HDL cholesterol, or hs-CRP as predictors of clinical risk in patients receiving statin therapy after acute coronary syndromes: results from PROVE IT-TIMI 22.Arterioscler Thromb Vasc Biol. 2009; 29: 424-430Crossref PubMed Scopus (130) Google Scholar At the end of the trial, the median apo B level for the moderate therapy arm was 90 mg/dL, whereas the median for the aggressive therapy arm was 67 mg/dL. The aggressive therapy arm experienced a 16% reduction in the HR for death or a major cardiovascular event (P=.005; 95% CI, 5%-26%) compared with the moderate therapy arm. In CARDS, more than 2800 diabetic patients without documentation of previous cardiovascular disease were randomized to atorvastatin, 10 mg, or placebo.30Charlton-Menys V Betteridge DJ Colhoun H et al.Targets of statin therapy: LDL cholesterol, non-HDL cholesterol, and apolipoprotein B in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS).Clin Chem. 2009; 55: 473-480Crossref PubMed Scopus (78) Google Scholar Mean baseline LDL-C, non–HDL-C, and apo B values were 117 mg/dL, 152 mg/dL, and 117 mg/dL, respectively. Median duration of follow-up was 3.9 years. Compared with placebo, atorvastatin treatment at 1 year lowered LDL-C concentration by a mean of 40.9% (95% CI, 40.1%-41.6%), whereas atorvastatin treatment decreased the non–HDL-C concentration by 38.1% (95% CI, 37.2%-39%) and the apo B concentration by 24.3% (95% CI, 23.4%-25.2%) (all P <.001). There was a 37% risk reduction in the primary end point of major cardiovascular events (95% CI, 52%-17%; P=.001). The mean apo B level after 1 year of therapy with atorvastatin was 71.5 mg/dL. Although these trials, which demonstrated significant cardiovascular event reductions, were not designed to test specific apo B targets, the levels of apo B that were achieved in these studies are consistent with the ADA/ACC apo B goals of less than 80 mg/dL for patients with known cardiovascular disease or with diabetes and one risk factor. There has been much discussion regarding the appropriate apo B goals of therapy. Some experts advocate using apo B goals equivalent to LDL-C in terms of population percentiles from databases such as the Framingham Offspring study (Table 5).31Contois JH McConnell JP Sethi AA et al.Apolipoprotein B and cardiovascular disease risk: position statement from the AACC Lipoproteins and Vascular Diseases Division Working Group on Best Practices.Clin Chem. 2009; 55: 407-419Crossref Scopus (250) Google Scholar If this approach is applied to the updated NCEP III guidelines, high-risk patients requiring an LDL-C level of 100 mg/dL, which is the 20th percentile, should have an apo B goal of 78 mg/dL (Table 3). Likewise, patients at very high risk of coronary heart disease would require an LDL goal of 70 mg/dL, which is the second percentile, and the corresponding apo B level would be 54 mg/dL.TABLE 5Population Distributions of LDL-C, non–HDL-C, and Apo B in the Framingham Offspring StudyaUnit is mg/dL. Apo B = apolipoprotein B; LDL-C = low-density lipoprotein cholesterol; non–HDL-C = non–high-density lipoprotein cholesterol.Adapted from Clin Chem,31Contois JH McConnell JP Sethi AA et al.Apolipoprotein B and cardiovascular disease risk: position statement from the AACC Lipoproteins and Vascular Diseases Division Working Group on Best Practices.Clin Chem. 2009; 55: 407-419Crossref Scopus (250) Google Scholar with permission.%LDL-Cnon-HDL-Capo B2708354578946210881046920100119783011113285401201439150130153976013916310370149175110801601871189017620513095191224140bSI conversion factors: To convert apo B to g/L, multiply by 0.01; to convert LDL-C and non–HDL-C to mmol/L, multiply by 0.0259.a Unit is mg/dL. Apo B = apolipoprotein B; LDL-C = low-density lipoprotein cholesterol; non–HDL-C = non–high-density lipoprotein cholesterol. Open table in a new tab bSI conversion factors: To convert apo B to g/L, multiply by 0.01; to convert LDL-C and non–HDL-C to mmol/L, multiply by 0.0259. In our view, using the same population percentile cut-points for LDL-C and apo B is probably unnecessary. These apo B targets are not currently supported by any clinical trial evidence, and their use may result in unachievable goals with even 2 or 3 lipid-lowering drugs. Thus, the medical necessity and practical feasibility of decreasing apo B levels to less than 60 mg/dL (the second percentile) are questionable. In the EXPLORER (Examination of Potential Lipid Modifying Effects of Rosuvastatin in Combination With Ezetimibe versus Rosuvastatin) trial, patients were treated with the highest dose of the most potent statin, rosuvastatin at 40 mg, in conjunction with ezetimibe at 10 mg.32Ballantyne CM Weiss R Moccetti T et al.Efficacy and safety of rosuvastatin 40 mg alone or in combination with ezetimibe in patients at high risk of cardiovascular disease (results from the EXPLORER study).Am J Cardiol. 2007; 99: 673-680Abstract Full Text Full Text PDF PubMed Scopus (161) Google Scholar The mean baseline LDL-C and apo B values were 189 mg/dL and 176 mg/dL, respectively. Although this combination resulted in a 70% reduction in LDL-C levels, the apo B reduction was significantly lower at 56%. At the end of the trial, LDL-C and apo B values were 57 mg/dL and 76 mg/dL, respectively. This trial highlights the difficulty in achieving apo B goals lower than 60 mg/dL. For patients in the EXPLORER trial to achieve an apo B goal of 54 mg/dL (the 2nd percentile), a third and possibly a fourth drug would have been needed. A substantial number of patients with atherosclerotic vascular disease have LDL-C levels in the recommended range but still have significant residual risk. This discrepancy exists because many of these patients have elevated LDL particle numbers despite having normal LDL-C concentrations. The calculation of non–HDL-C may improve risk prediction and assessment of goal attainment in many of these patients; however, the total body of evidence suggests that apo B is a better marker for total atherogenic particle number. The available evidence supports the superiority of apo B over LDL-C and non–HDL-C in both risk stratification and monitoring of the effectiveness of statin therapy. Although NCEP III is built on the strong foundations of LDL-C1Grundy SM Cleeman JL Mercz CN National Heart, Lung, and Blood Institute American College of Cardiology Foundation American Heart Association et al.Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines [published correction appears in Circulation. 2004;110(6):763].Circulation. 2004; 110: 227-239Crossref PubMed Scopus (5067) Google Scholar and non–HDL-C,4Blaha MJ Blumenthal RS Brinton EA Jacobson TA National Lipid Association Taskforce on Non-HDL Cholesterol The importance of non-HDL cholesterol reporting in lipid management.J Clin Lipidol. 2008; 2: 267-273Abstract Full Text Full Text PDF PubMed Scopus (131) Google Scholar consideration should be given to the use of additional markers that may further aid in better risk stratification and in greater reductions in residual risk.
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