A Supplement to

Managing Atherosclerotic Risk With a Particle Focus

New Recommendations and Emerging Data

The lipoprotein particles that carry cholesterol and triglycerides in the bloodstream are the direct mediators of the atherosclerotic process.

Moderator

W. VIRGIL BROWN, MD

Panelists

Rachel H. Mackey, PHD, MPH, FAHA

Robert S. Rosenson, MD

James A. Underberg, MD, MS, FACPM, FACP, FASH, FNLA

Richard Wright, MD, FACC

A ROUNDTABLE DISCUSSION

This supplement is supported by an educational grant from LipoScience, Inc.

REPRINTED FROM

REVISED COVER.indd 1 11/30/11 2:25 PM

2 Managing Atherosclerotic Risk With a Particle Focus: New Recommendations and Emerging Data

President, IMNG Medical MediaAlan J. Imhoff

National Account Manager, Family Practice News and Internal Medicine NewsPeter Messina

National Account Manager, Cardiology NewsCourtney Leonard

Art Director Louise Koenig

Production SpecialistRebecca Slebodnik

This educational supplement to Cardiology News, Family Practice News, and Internal Medicine News was sponsored by

This supplement was produced by the customized publication department of International Medical News Group, LLC. Neither Cardiology News, Family Practice News, Internal Medicine News, the Editorial Advisory Board, northe reporting staff reviewed orcontributed to its contents. The ideas and opinions expressed in this supplement are those of the faculty and do not necessarily reflect the views of the supporter or the Publisher.

Copyright © 2011 International Medical News Group LLC. All rights reserved. No part of this publication may be reproduced or transmitted in any form, by any means, without prior written permission of the Publisher. IMNG, LLC, will not assumeresponsibility for damages, loss,or claims of any kind arising fromor related to the informationcontained in this publication,including any claims related tothe products, drugs, or servicesmentioned herein.

Moderator

W. Virgil Brown, MDCharles Howard Candler Professor of Medicine Emeritus Emory University School of Medicine Atlanta, GAEditor-in-Chief, Journal of Clinical Lipidology

Panelists

Rachel H. Mackey, PhD, MPH, FAHAAssistant Professor of EpidemiologyDepartment of EpidemiologyUniversity of Pittsburgh Graduate School of Public HealthPittsburgh, PA

Robert S. Rosenson, MDProfessor, Department of Medicine/CardiologyDirector, Cardiometabolic Disorders Mount Sinai School of MedicineNew York, NY

James A. Underberg, MD, MS, FACPM, FACP, FASH, FNLAPreventive Cardiovascular Medicine, Lipidology and HypertensionClinical Assistant Professor of Medicine at New York University School of MedicineDirector, Bellevue Hospital Lipid ClinicNew York, NY

Richard Wright, MD, FACCResearch Director and Director of the Heart Failure CenterPacific Heart InstituteSanta Monica, CAVice Chair of the American College of Cardiology

2

Managing Atherosclerotic Risk With a Particle Focus

New Recommendations and Emerging Data

A RoundtAble discussion

Faculty DisclosuresDr W. Virgil Brown has received consulting fees from Abbott Laboratories, Amgen, Anthera, Genzyme, Pfizer, LipoScience, and Merck & Co. He has received honoraria related to speaking from Abbott Laboratories, LipoScience, and Merck & Co.

Dr Rachel H. Mackey has received a research grant from LipoScience.

Dr Robert S. Rosenson has received grants and research support from Amgen and Genentech. He has received consulting fees from Abbott Laboratories, Amarin, Amgen, AstraZeneca, Grain Foods Advisory Board, LipoScience, Roche/Genentech, and sanofi-aventis. He is a shareholder in LipoScience.

Dr James A. Underberg has received consulting fees from Genzyme and LipoScience. He received honoraria related to speaking from Abbott Laboratories, AstraZeneca, Lilly, Kowa Pharmaceuticals, Merck & Co., Diadexus, LipoScience, Forest Pharmaceuticals, Daiichi Sankyo, and GlaxoSmithKline.

Dr Richard Wright has received research support from Novartis, Atritech, and St. Jude Medical. He has received consulting fees from Novartis, Paragon Health, St. Jude Medical, Centers for Medicare and Medicaid Services–Medicare, Palmetto GBA–Medicare, LipoScience, American College of Cardiology and American Medical Association Relative Value Scale Update Committee. He has received honoraria related to speaking from Novartis, Boehringer Ingelheim, Boston Scientific, Forest Pharmaceuticals, GlaxoSmithKline, and LipoScience. He owns stock in Leading Cardiologists of America.

Managing Atherosclerotic Risk With a Particle Focus: New Recommendations and Emerging Data 3

For decades, low-density lipoprotein (LDL) management has been the primary focus of clinical practice for reducing the risk of cardiovascular disease (CVD). In that time frame,

LDL cholesterol concentration (LDL-C) has become a standard measure of a patient’s LDL-attributable CVD risk. This clinical use of LDL-C is so entrenched that the terms LDL and LDL-C tend to be used interchangeably (for a clarifi cation of terminology, see Table 1). In actuality, however, they are not equivalent. LDL-C is a surrogate measure that provides only an estimate of LDL levels. Evidence suggests that LDL-C can either overestimate or underestimate the LDL-related risk of some patients. This defi ciency helps account for the high number of cardiovascular events that occur in people with “normal” or “low” levels of LDL-C.1-4

Lipoprotein particles carry cholesterol and triglycerides (TG) in the bloodstream and are direct mediators of the atherosclerotic process. LDL particles and, to a lesser extent, very-low-density lipoprotein (VLDL) particles, cause atherosclerosis by entering the artery wall and starting the cascade of events that lead to formation of atherosclerotic plaque (Figure 1). The greater the number of LDL particles in the bloodstream, the greater is the likelihood they will penetrate the arterial wall, become altered by oxidation or other mechanisms, induce an infl ammatory response, and eventually deposit their lipid contents in the growing atherosclerotic lesion.2 By contrast, high-density lipoprotein (HDL) particles can prevent or retard atherosclerosis in the artery wall by several mechanisms, including inhibiting oxidation and infl ammation and helping remove cholesterol from plaque in a process called “reverse cholesterol transport.” Again, the more HDL particles in the bloodstream, the greater will be the number in the arterial wall, and the greater will be the protection against atherosclerotic disease.5 HDL consists of many types of particles, and their relationships with atherosclerosis are complex. The mechanisms of the protective effect of HDL are under intense study, and it is clear that the cholesterol content of HDL does not fully explain the relationships with vascular disease. Overall, CVD risk depends in great part on the balance between the disease-producing LDL (and VLDL) particles and the protective HDL particles. Traditionally, this lipoprotein balance has been assessed by measuring the cholesterol content of a patient’s LDL (LDL-C) and HDL (HDL-C) because there were no readily available

analytic methods available to measure the lipoprotein particles themselves.6 Today, newer measures have been introduced into clinical use that can precisely quantify the numbers of LDL and HDL in the blood, providing a more accurate refl ection of a patient’s risk for atherosclerosis and subsequent CVD events. LDL-C and HDL-C levels provide only an approximation of the number of LDL and HDL particles in the bloodstream. The cholesterol content of LDL (and HDL) particles is not constant but varies widely from patient to patient. Some patients have predominantly large, cholesterol-rich LDL particles, while others have smaller, relatively cholesterol-poor LDL. At a given level of LDL-C, the patients with large, cholesterol-rich

LDL particles will have fewer LDL particles, and the patients with smaller, cholesterol-poor LDL will have more particles. The same goes for HDL; the metabolic modulators of the size and cholesterol content of LDL particles have a similar infl uence on the size and cholesterol content of HDL particles. A laboratory method using nuclear magnetic resonance (NMR) spectroscopy “counts” lipoprotein particles and enables LDL and HDL to be quantifi ed not on the basis of cholesterol content but particle number. This capability enables clinical comparisons to be made between LDL-C and LDL particle number (LDL-P) and HDL-C and HDL particle number (HDL-P). Most of the research to

FIGURE 1. LDL Particles Cause Plaque2

This image is hand-drawn and owned by LipoScience.

The higher the number of LDL particles, the greater the likelihood they will enter the arterial wall and deposit their contents, forming atherosclerotic plaque. Measurement of LDL-C on traditional lipid panels does not reflect the LDL particle number.

Plaque Progression: More LDL Particles = More Plaque

“One can easily be lulled into complacency thinking that a chosen

medical regimen is adequate if it is based solely on traditional lipid profile

targets such as LDL-C and HDL-C. It is critical to test

LDL-P, particularly in patients with a family history of heart disease or diabetes,

or in those patients who have metabolic syndrome.”

DR WRIGHT

4 Managing Atherosclerotic Risk With a Particle Focus: New Recommendations and Emerging Data

LDL Low-density lipoproteins: Spherical particles coated with a monolayer of phospholipid and apolipoprotein B that contain cholesterol ester and triglyceride molecules. High levels of LDL are associated with an increased risk of atherosclerosis and coronary heart disease.

HDL High-density lipoproteins: Spherical particles that regulate cholesterol accumulation in the vessel wall, remove cholesterol from within the artery, and transport it back to the liver for excretion or re-utilization. High levels are associated with a decreased risk of atherosclerosis and coronary heart disease.

VLDL Very-low-density lipoproteins: Precursor lipoproteins to LDL that are considered the “very bad” cholesterol; the most atherogenic of all lipoproteins.

TG Triglycerides: Refers to the triacylglycerol concentration within all of the TG-trafficking lipoproteins in a deciliter of plasma.

Measures of LDL for Managing Cardiovascular Disease (CVD) Risk

LDL-C LDL cholesterol concentration or LDL cholesterol mass concentration (represents an approximation of the concentration of cholesterol within the LDL particles in milligrams per deciliter). LDL-C is often incorrectly referred to simply as LDL.

LDL-P LDL particle number: An analytic measure of LDL (represents the actual number of LDL particles, in molar terms, per liter).

Apo B The primary apolipoprotein of LDL particles; an alternative measure of LDL particle number.

Non-HDL-C

Reflects the sum of serum cholesterol carried by all of the potentially atherogenic lipoproteins and can be calculated by subtracting HDL-C from total cholesterol (TC).

Measures of HDL for Managing Cardioprotection

HDL-C HDL cholesterol concentration or HDL cholesterol mass concentration (represents an approximation of the concentration of cholesterol within the HDL particles in milligrams per deciliter). HDL-C is often incorrectly referred to simply as HDL.

HDL-P HDL particle number: An analytic measure of HDL (represents the actual number of HDL particles, in molar terms, per liter).

date has focused on the LDL comparison, with results consistently showing LDL-P to be related more strongly to atherosclerotic outcomes than is LDL-C. Emerging evidence suggests that the same is true for the particle versus cholesterol measures of HDL.3,4,6,7

The clearest and most compelling evidence that LDL-C levels rarely adequately refl ect the magnitude of a patient’s LDL-related risk comes from studies examining subsets of individuals who have LDL-C and LDL-P levels that do not agree (ie, are discordant). In such cases of discordance, which is common, CVD risk tracks more closely with LDL-P than with LDL-C. Specifi cally, when a patient with low LDL-C has a level of LDL-P that is not equally low, there is higher “residual” CVD risk that would indicate that more aggressive LDL-lowering treatment is warranted to achieve additional risk reduction. Conversely, a patient with low LDL-P but higher LDL-C has lower LDL risk than expected. Such a patient may not require LDL treatment that might otherwise have been considered necessary based on the elevated LDL-C.3,4

A roundtable discussion was held on August 28 at the close of the 2011 National Lipid Association (NLA) clinical update meeting, where new recommendations regarding the clinical utility of infl ammatory markers and advanced lipoprotein testing were reviewed. A group of lipid experts addressed the current and future implications of lipoprotein testing, including LDL-P and apolipoprotein B (Apo B), as well as emerging evidence regarding HDL-P.

ldl Particle number for cardiovascular disease Risk Management

Dr Brown: I have been joined by three highly experienced lipidologists with research and clinical experience in using today’s lipoprotein measures, including LDL-P, Apo B and HDL-P, and an epidemiologist who has studied thousands of individuals in a large community-based study using these measures and quantifying their relationships to the incidence of cardiovascular events. They have agreed to share their experience with us to help understand the full implications of the new recommendations on the assessment and on-treatment management of LDL-related risk made by the NLA, recently published in Journal of Clinical Lipidology.8

Measures of LDL: � e Issue of Discordance and Residual RiskDr Rosenson: Discordance is an important issue with high clinical relevance. Many patients with diabetes and/or CVD have traditional lipid profi les that fall within recommended lipid targets. However, when you measure LDL particle number as LDL-P or Apo B, the results

TABLE 1. Currently Used Terminology in CVD Risk Management

Managing Atherosclerotic Risk With a Particle Focus: New Recommendations and Emerging Data 5

reveal that the majority of these patients have an elevated LDL particle number that would put them into a high-risk or very high-risk category. Identifi cation of residual risk has important clinical implications and allows physicians to manage these patients more aggressively.

Dr Mackey: From a community perspective, there’s quite a lot of data to show where LDL particle number, when compared with LDL-C, is a stronger predictor of cardiovascular events. Analysis of large data sets such as the Multi-Ethnic Study of Atherosclerosis (MESA) has given us the ability to separately examine groups with concordant or discordant levels of LDL-C and LDL-P (Figure 2). In people with low LDL-C but elevated LDL-P, we see both increased carotid intima-media thickness (IMT) and incident CVD events. Clearly, these CVD outcomes track with LDL-P, not LDL-C, when the two measures of LDL disagree.3,4

Clinical Signi� cance of Disagreement Between LDL-C and LDL-PRecent data from Framingham and MESA highlight the fl aws in the clinical performance of LDL-C, in that it can overestimate or underestimate LDL-related risk.3,4

The Framingham Study: During a 15-year follow-up among participants in the Framingham Offspring Study, the risk of future CVD events was shown to be substantially greater in those with high versus low LDL-P (measured by NMR spectroscopy). Among discordant individuals, the high-risk group had high LDL-P, despite low LDL-C, while the low-risk group had low LDL-P but higher LDL-C (Figure 3).3

The MESA Trial: The issue of discordance is further validated in the MESA cohort—an ongoing National Institutes of Health–sponsored trial looking at more than 6,000 ethnically diverse individuals. The population characteristics lend themselves to

FIGURE 2. Cumulative Incidence of Cardiovascular Events in Subgroups With Low LDL-C and/or Low LDL-P, From Proportional Hazards Models Adjusted for Age and Gender. Low LDL-C and LDL-P values were defined as <100 mg/dL and <1060 nmol/L, respectively (<30th percentile). Adapted with permission from Journal of Clinical LipidologyData from Otvos JD, Mora S, Shalaurova I, Greenland P, Mackey RH, Goff DC Jr: “Clinical implications of discordance between LDL cholesterol and LDL particle number,” Figure 3. J Clin Lipidol. 2011;5(2):105-113. Copyright 2011, National Lipid Association.

FIGURE 3. Event-Free Survival Among Participants With LDL Cholesterol (LDL-C) and LDL Particle Number (LDL-P) Above or Below the Median. Median values were 131 mg/dL for LDL-C and 1414 nmol/L for LDL-P.Adapted with permission from Journal of Clinical LipidologyData from Cromwell WC, Otvos JD, Keyes MJ, et al: “LDL particle number and risk for future cardiovascular disease in the Framingham Offspring Study—Implications for LDL management,” Figure 2. J Clin Lipidol. 2007;1:583-592. Copyright 2007, National Lipid Association.

Low: <30th percentileLDL-C<100 mg/dLLDL-P<1060 nmol/L

Not Low: ≥30th percentileLDL-C≥100 mg/dLLDL-P≥1060 nmol/L

Low LDL-P;Low LDL-C(n=1,249)

Low LDL-P;High LDL-C

(n=284)

High LDL-P;Low LDL-C(n=282)

High LDL-P;High LDL-C(n=1,251)

0.06

0.04

0.02

0.0

1.00

0.98

0.96

0.94

0.92

0.90

0.88

0.86

0.84

0.82

0.80

0.78

0.76

0.74

0 1 2 3 4 5

0 2 4 6 8 10 12 14 16

LDL-P LDL-C (n)

Not Low Low (516)

Not Low Not Low (3,414)

Low Low (1,115)

Low Not Low (553)Cum

ulat

ive

Inci

denc

ePr

obab

ility

of E

vent

-Fre

e Su

rviv

al

Follow-Up (years)

Years of Follow-Up

6 Managing Atherosclerotic Risk With a Particle Focus: New Recommendations and Emerging Data

contemporary questions regarding the associations of biomarkers with subclinical and clinical outcomes (Figure 4).4

Additional Data to Support LDL Particle Number as a More Accurate Predictor of Risk Dr Underberg: The fi rst thing that piqued my interest was the data from the Veterans Affairs HDL Intervention Trial (VA-HIT), which were published in 2006. These data showed that men with low HDL-C who received a

fi brate, gemfi brozil, had a signifi cant reduction in stroke and nonfatal myocardial infarction (MI) with changes in HDL-C and TG, but no change at all in LDL-C. A subsequent nested case-control analysis of stored serum samples from VA-HIT showed that the on-trial LDL-P and HDL-P were the best predictors of risk in that particular cohort of patients, outpredicting both LDL-C, non-HDL-C, and even Apo B.9 There are many other retrospective analyses of earlier prospective studies that demonstrate that LDL-P outperforms LDL-C in terms of strength of association with cardiovascular outcomes. Much of this relates to the concept that if you examine patients having events, a great many who suffer MI have relatively normal LDL-C levels. Most recently, this was surprisingly proven by an analysis of the “Get With The Guidelines” data, where 136,905 lipid panels done on patients with ischemic cardiovascular events showed their average LDL-C to be 104.9 ± 38.9 mg/dL. These patients, on the other hand, have low HDL-C and high TG, but LDL-C clearly isn’t predicting the risk in those patients with cardiovascular events.10

Further analysis of studies such as the Framingham Offspring Study and MESA—looking at carotid IMT and coronary vascular events—have reinforced my view that, in patients for whom LDL-C is unlikely to correlate with risk, it is better to look at lipoprotein particle measures, specifi cally LDL-P.

treatment implications and Management strategies for discordance

Dr Wright: In general, all of the traditional agents and methodologies we use to lower LDL-C have some ability to lower LDL-P. However, there are some differences. Some agents are more likely to affect particle number than cholesterol content of the particles, but as a general rule, the initial therapy has been and remains statins (Table 2).

Dr Underberg: It’s important to understand the differing effects that therapies will have on LDL-C and LDL-P. Interventions that will lower LDL-C more than LDL-P

FIGURE 4. Cumulative Incidence of Cardiovascular Events in Subgroups With Concordant or Discordant Levels of LDL-C and LDL-P, From Proportional Hazards Models Adjusted for Age, Gender, and Race. Mean levels of LDL-P and LDL-C are adjusted for age, gender, and race.Adapted with permission from Journal of Clinical LipidologyData from Otvos JD, Mora S, Shalaurova I, Greenland P, Mackey RH, Goff DC Jr: “Clinical implications of discordance between LDL cholesterol and LDL particle number,” Figure 2. J Clin Lipidol. 2011;5(2):105-113. Copyright 2011, National Lipid Association.

LDL-P>LDL-CConcordantLDL-P<LDL-C

0.08

0.06

0.04

0.02

0.0 0 1 2 3 4 5

LDL-P LDL-C

1372 104

1249 117

1117 130

nmol/L mg/dLCum

ulat

ive

Inci

denc

e

Follow-Up (years)

LDL-P may aid in determining treatment strategies and clinical decision-making for personalized LDL management.

If you need to: You should consider:

Lower LDL-P Statin

Lower LDL-P further Titrate statin dosage or use a more potent statin (or)Statin + ezetimibe/bile acid sequestrants (or)Statin + ezetimibe + niacin

Any of the above + lower triglycerides ADD niacin, omega-3 fatty acid, fenofibrate

Any of the above + increase HDL-C ADD niacin, fenofibrate, omega-3 fatty acid

TABLE 2. Therapies to Achieve LDL-P Targets12 Adapted with permission from AtherosclerosisData from Rosenson RS, Davidson MH, Pourfarzib R: “Underappreciated opportunities for low-density lipoprotein management in patients with cardiometabolic residual risk,” Table 4. Atherosclerosis. 2010; 213(1):1-7. Copyright 2010, European Atherosclerosis Society, International Atherosclerosis Society, and the Society of Atherosclerosis Imaging and Prevention.

Managing Atherosclerotic Risk With a Particle Focus: New Recommendations and Emerging Data 7

include statins, estrogen replacement therapy, some antiretrovirals, and a low-fat, high-carbohydrate diet. Interventions that lower LDL-P more than LDL-C include fi brates, niacin, pioglitazone, omega-3 fatty acids, exercise, and a Mediterranean, low-carbohydrate diet. Bile acid sequestrants or ezetimibe monotherapy provide similar changes in LDL-C and LDL-P.11,12

Dr Wright: Using LDL-P as a management target allows you to adjust the statin dose more accurately or, frankly, even to determine whether statins are warranted. One thing we haven’t brought up is the concept that people who might be considered at intermediate risk, based on their LDL-C, might actually be at low risk, based on their LDL-P particle. Discordant individuals are not just those with a high LDL-P number and lower LDL-C. There are also people who are discordant because LDL-P is lower than LDL-C. In those patients, you may be able to use lipoprotein particle tests to justify avoiding therapy that perhaps the patient is not that interested in embarking upon.

Dr Rosenson: Even though statins may be the most effective agents for lowering LDL-P, they are more effective at lowering LDL-C. Therefore, one can’t be complacent by just assuming that getting somebody to their LDL-C target means that their LDL-P target will be met. In COMETS (A COmparative study with rosuvastatin in subjects with METabolic Syndrome), an international multicenter placebo-controlled trial comparing the effi cacy of rosuvastatin and atorvastatin in patients with metabolic syndrome, we found that 10- to 20-mg dosages of both rosuvastatin and atorvastatin were very effective in getting individuals to their LDL-C target but left many individuals well above their LDL-P target.13

Our current therapies—despite how good they may be for lowering LDL-C—are not quite as effective for lowering LDL-P. Statins are the most effi cacious agents for lowering LDL—both the cholesterol content and the particle number. However, for many people, including those with metabolic syndrome or diabetes, statins are insuffi cient. There are other therapies that can be used in individual patients to lower LDL-P and bring it down to a lower percentile value and a lower-risk category. The focus on surrogate markers LDL-C and HDL-C is really inadequate for managing dyslipidemia in today’s population because of the explosion of metabolic syndrome and diabetes in our society. Discordance between LDL-C and LDL-P is most common in these patient types. Utilizing LDL-P makes a difference in how we evaluate risk in an individual patient and how we approach treatment in those patients.

Setting Goals for LDL-PDr Underberg: Initially, we try to reduce LDL-P to the equivalent population-based cut points that we would use for our LDL-C goals—less than 70 mg/dL, or less than 100 mg/dL in our high-risk or very high-risk individuals. Equivalent population-based cut points for LDL-P would be in the range of 700 to 800 nmol/L for very high-risk patients or around 1000 nmol/L for the high-risk patients. We try to reduce LDL-P to those equivalent cut points only because I believe that, left untreated, a patient would retain the residual risk that we often see in patients who continue to have events despite being treated and achieving very low LDL-C levels. We’ve seen this paradox in many statin trials over the years.1,14,15

current nlA expert Panel Recommendations: Avoiding Missed opportunities

Dr Brown: We’ve been well served by the measurement of classical risk factors and have worked for more than 20

years with guidelines regarding lipoprotein, cholesterol, and triglycerides. Now, a group of newer lipoprotein particle measures has been identifi ed that shows promise in refi ning and making our management of cardiovascular risk more accurate. At the 2011 annual combined meeting of the Southeast Lipid Association and Midwest Lipid Association, those present were given a preview of a consensus paper now published in Journal of Clinical Lipidology regarding a group of newer tests now available to increase the predictive power of risk assessment for atherosclerosis.8 In developing this statement, the NLA convened a panel of 16 experts, who spent several days discussing the evidence regarding the potential contribution that

these measurements might make to our traditional methods of assessing risk and managing patients. The result of this discussion is recommendations intended to provide practical advice to clinicians for clinical assessment and on-treatment management of patients. In weighing their impact, several important questions were asked:

• Which tests have suffi cient data to be considered?

• Is there enough evidence to add these measurements in clinical practice?

• When and in which types of patients are they useful? To date, we have been almost totally focused on the cholesterol measurements, LDL-C and HDL-C, with some attention given to TG. Other measures of lipoproteins have been made in community-based studies and clinical trials, and these have provided insights into the relationship of these alternate measures to CVD incidence and prevalence. The expert panel considered several such measures and chose to

“Getting patients to their LDL-C and non-HDL-C targets

can mislead us that these individuals are well managed, when they may still be at

high residual risk as identified by LDL-P.”

DR ROSENSON

8 Managing Atherosclerotic Risk With a Particle Focus: New Recommendations and Emerging Data

evaluate six of them: two infl ammation markers and four lipid-related measures. The lipid-related measures are:

• LDL-P• Apo B• The measurement of subfractions of

LDL and HDL• Lipoprotein (a) [Lp(a)]

The experts looked at various patient subtypes and risk categories and developed recommendations for both initial patient assessment and on-treatment management of CVD risk (Table 3). The recommendations fall into four categories:

1. Recommended for routine measurement in this population

2. Reasonable for many patients

Apo, apolipoprotein; CHD, coronary heart disease; CRP, C-reactive protein; HDL, high-density lipoprotein; Lp-PLA2, lipoprotein-associated phospholipase A2; LDL, low-density lipoprotein; LDL-P, LDL particle number/concentration; Lp(a), lipoprotein (a).

NLA Expert Panel Summary Recommendations

CRP Lp-PLA2 Apo B LDL-P Lp(a)HDL or LDL subfractions

Low risk (<5% 10-year CHD event risk)

Not recommended

Not recommended

Not recommended

Not recommended

Not recommended

Not recommended

Intermediate risk(5%-20% 10-year CHD event risk)

Recommended for routine measurement

Consider for selected patients

Reasonable for many patients

Reasonable for many patients

Consider for selected patients

Not recommended

CHD or CHD equivalent

Consider for selected patients

Consider for selected patients

Consider for selected patients

Consider for selected patients

Consider for selected patients

Not recommended

Family history Reasonable for many patients

Consider for selected patients

Reasonable for many patients

Reasonable for many patients

Reasonable for many patients

Not recommended

Recurrent events Reasonable for many patients

Consider for selected patients

Reasonable for many patients

Reasonable for many patients

Reasonable for many patients

Not recommended

On-Treatment Management Decisions

CRP Lp-PLA2 Apo B LDL-P Lp(a)HDL or LDL subfractions

Low risk (<5% 10-year CHD event risk)

Not recommended

Not recommended

Not recommended

Not recommended

Not recommended

Not recommended

Intermediate risk(5%-20% 10-year CHD event risk)

Reasonable for many patients

Not recommended

Reasonable for many patients

Reasonable for many patients

Not recommended

Not recommended

CHD or CHD equivalent

Reasonable for many patients

Not recommended

Reasonable for many patients

Reasonable for many patients

Consider for selected patients

Not recommended

Family history Consider for selected patients

Not recommended

Consider for selected patients

Consider for selected patients

Consider for selected patients

Not recommended

Recurrent events Reasonable for many patients

Not recommended

Reasonable for many patients

Reasonable for many patients

Consider for selected patients

Not recommended

TABLE 3. Summary Recommendations for Measurement of Inflammatory Markers and Advanced Lipoprotein/Subfraction Testing in Initial Clinical Assessment and On-Treatment Management Decisions8

Adapted with permission from Journal of Clinical LipidologyData from Davidson MH, Ballantyne CM, Jacobson TA, et al: “Clinical utility of inflammatory markers and advanced lipoprotein testing: Advice from an expert panel of lipid specialists,” Table 1. J Clin Lipidol. 2011;5(5):338-367. Copyright 2011, National Lipid Association.

Managing Atherosclerotic Risk With a Particle Focus: New Recommendations and Emerging Data 9

3. Consider for selected patients4. Not recommended

Five clinical scenarios were considered by the panel that account for the vast majority of patients in whom clinicians would consider the use of biomarkers. These scenarios were defi ned as follows:

1. Patients at low risk (10-year risk of a coronary heart disease [CHD] event <5%)

2. Patients at intermediate risk (10-year risk of a CHD event of 5%-20%)

3. Patients with CHD or CHD equivalent4. Patients with a family history of CHD5. Patients with recurrent CVD events

Of the lipid-related measures, Apo B and LDL-P were recommended for consideration in many patients for both initial assessment and on-treatment decision-making.

Putting the new Recommendations into Practice

Dr Underberg: My initial assessment is based on the individual patient. Understanding that my clinical practice is a lipid-focused referral population often at increased risk of CHD, more often than not my initial assessment includes measuring LDL-P. In many cases, even when I do see a patient who has not been evaluated elsewhere, if they fall into risk categories where discordance is likely to exist between LDL-C and LDL-P, I will measure LDL-P at the outset.

Dr Wright: When you’re treating patients one at a time, you have to make a decision as to the test that’s most likely to help guide your hand therapeutically and provide more complete information on that particular patient. There are many patients in whom the traditional lipid profi le is going to be misleading. These include patients with metabolic syndrome or diabetes, obese patients who perhaps don’t meet all the criteria for metabolic syndrome, and patients who have already experienced events. As a cardiologist, many of the patients I see fall into those categories. For those patients, if you just rely on the lipid profi le in the traditional manner, you can be misled about their lipoprotein-attributable risk. I think in those people, actually going directly to a more precise test that measures particle number is a better strategy.

Dr Underberg: The recommendations from the NLA expert panel provide a nice framework to think about some of these additional tests that are available to primary care providers. Understanding the role for LDL-P and Apo B in initial risk assessment and for on-treatment decision-making is important. We fi nally have

some very well thought out evaluations of these tools that give guidance to anyone trying to prevent cardiovascular events. In all patients except those at low risk for CHD events, there is a recommendation now for LDL-P testing that is either reasonable for many, or to be considered for selected patients. Patients at intermediate risk—those with CHD or CHD risk equivalence, a family history of CHD, or recurrent events—should be considered for this testing. I think these recommendations are a great resource for those who are looking for guidance.

Dr Brown: For the primary care physician who is doing an initial assessment, starting in the classical ways is reasonable, but you’re going to get clues really quickly. In patients where the classical risk assessment using the Framingham risk model would say they’re low-risk, you may fi nd cause to look more deeply into their risk factors, perhaps using LDL-P or Apo B as an additional tool for assessment.

Dr Underberg: While Apo B and LDL-P seem to be equally predictive of risk, clinical data—such as that in the VA-HIT study—show that the ability to correlate Apo B in a heterogeneous particle population with LDL-P may not always be what we would like it to be. In such a case, LDL-P seemed to best predict risk, with HDL-P adding to that.

Future clinical utility: the Role of Hdl Particles

While HDL biomarkers were not considered by the NLA expert panel, HDL-C as a treatment target has garnered a lot a recent attention. The epidemiologic evidence is clear that individuals with higher levels of HDL-C are relatively protected from CVD, while those with low HDL-C levels (<40 mg/dL or about 1 nmol/L) have increased rates of heart disease.16 However, there is not yet conclusive clinical

trial evidence that raising levels of HDL-C has clinical benefi t attributable specifi cally to the HDL-C increase. Some emerging evidence suggests that increasing HDL-C without increasing HDL-P may have little or no clinical benefi t, while increasing HDL-P may be more helpful. The former possibility is suggested by the results of the AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides: Impact on Global Health) study, with HDL-C increases induced by niacin treatment not translating to the expected clinical benefi t.17 The latter is supported by VA-HIT, which showed that increasing low HDL-P with a fi brate produced clinical benefi t out of proportion

“At the end of the day, HDL-P is the most robust HDL

predictor of cardiovascular events,

as shown in clinical

studies, and is the most important static

measure we have right now.”

DR ROSENSON

10 Managing Atherosclerotic Risk With a Particle Focus: New Recommendations and Emerging Data

provide robust data directly comparing HDL-C and HDL-P in relation to cardiovascular risk. Meanwhile, existing data from the European Prospective Investigation Into Cancer Norfolk cohort (EPIC-Norfolk) and Initiating Dialysis Early and Late (IDEAL) studies show that, at a given level of Apo A-I and Apo B, HDL-C does not add to cardiovascular risk prediction, and at high levels, HDL-C is associated with increased cardiac events.18 In contrast, HDL-P remains signifi cantly and independently associated with cardiac events regardless of Apo B and TG levels.19

Dr Underberg: The more I learn about HDL-C, the less I’m convinced I can rely on it. Certainly, the number of HDL particles is an important part of evaluating the overall HDL benefi t. I think the more we are able to look at HDL-P, the better direction it will give us as to our ability to intervene.

conclusion: driving toward new clinical standards of care

Dr Rosenson: The worldwide trends toward obesity and diabetes suggest that the conventional lipid profi le is a less appropriate tool. It creates a false sense

of security that people may be low-risk based on the cholesterol numbers versus lipoprotein concentrations that would indicate otherwise. Unless you’re measuring particles, you’re going to miss these opportunities to provide optimal medical care for today’s patients.

Dr Wright: As science has continued to advance, we now have diagnostic tools in our armamentarium that can measure

CVD Outcomes Studies Endpoints Subjects Subject Type

Clinical Implications of Discordance Between LDL Cholesterol and LDL Particle Number (MESA)Otvos et al. J Clin Lipidology. 2011

Incident MI, stroke, CVD death, angina

n=5,598 Healthy men and women

Women’s Health Study (WHS)Mora et al. Circulation. 2009

MI, stroke, CVD death

n=27,673 Healthy women

Women’s Health Initiative Hormone TrialsHsia et al. Arterioscler Thromb Vasc Biol. 2008

MI, coronary death

n=708 Healthy women

Framingham Offspring StudyCromwell et al. J Clin Lipidology. 2007

Incident MI, stroke, CVD death, angina

n=3,066 Healthy men and women

Multi-Ethnic Study of Atherosclerosis (MESA)Mora et al. Atherosclerosis. 2007

Carotid intima-media thickness (IMT)

n=5,538 Healthy men and women

European Prospective Investigation Into Cancer and Nutrition (EPIC)-NorfolkEl Harchaoui et al. J Am Coll Cardiol. 2007

Fatal or nonfatal CAD

n=2,888 Healthy men and women

Veterans Affairs HDL Intervention Trial (VA-HIT)Otvos et al. Circulation. 2006

Nonfatal MI or CHD death

n=1,061 Men with known CHD and low HDL-C

Pittsburgh Epidemiology of Diabetes Complications StudySoedamah-Muthu et al. Diabetologia. 2003

MI, CHD death, coronary revascularization

n=118 Type 1 diabetic men and women

Cardiovascular Health Study (CHS)Kuller et al. Arterioscler Thromb Vasc Biol. 2002

Incident MI or angina

n=1,175 Elderly

Pravastatin Limitation of Atherosclerosis in Coronary Arteries (PLAC-1)Rosenson et al. Am J Cardiol. 2002

Angiographic minimumlumen diameter

n=241 Patients with known CHD

To date, more than 200 papers have been published in peer-reviewed journals including:Journal of the American Medical Association • New England Journal of Medicine • American Journal of Cardiology • Circulation

CVD Outcomes StudiesThe NMR LipoProfile test has been used to study over 48,000 subjects in 10 cardiovascular outcomes studies using LDL-P and other lipoprotein particle concentrations as indicators of outcomes.

TABLE 4. The Weight of Evidence Supporting LDL-P by NMR

to the modest increase in HDL-C, possibly because HDL-P was increased more.9 Comparative relations of HDL-C and NMR-measured HDL-P with carotid atherosclerosis and incident CVD events have recently been examined in the MESA cohort by Mackey and coinvestigators.

Dr Mackey: When published, the MESA results will

Managing Atherosclerotic Risk With a Particle Focus: New Recommendations and Emerging Data 11

particle number and offer us a more precise and accurate way of predicting attributable risks of lipid abnormalities.

Dr Brown: In contrast to measuring immunonephelometry of Apo B, when you do an NMR spectrum analysis of lipoproteins, you also get information about HDL. Of the two tests used to measure lipoprotein particles, would you choose Apo B or LDL-P by NMR?

Dr Wright: In our practice, we use particle number measured by NMR. It’s more reproducible. It’s very accurate. It’s not an expensive test. We believe that it’s a superior methodology. I believe the HDL-P is a risk stratifi er—no question about it, so there is value in having that information.

� e Weight of Evidence Supporting LDL-P by NMRThe NMR LipoProfi le test has been used to study more than 48,000 subjects in 10 cardiovascular outcomes studies with LDL-P and other lipoprotein particle concentrations as indicators of CVD outcomes. In each of these studies, LDL-P consistently remained a signifi cant and independent indicator of cardiovascular endpoints (Table 4).

Additionally, new recommendations support the use of LDL-P as reasonable for both assessment and on-treatment management of many patients, based on suffi cient evidence for use in clinical practice. “It is the consensus of the NLA Biomarkers Expert Panel that there are a substantial number of patients for whom LDL-C may not accurately refl ect CVD risk. On the basis of the data showing that discordantly elevated LDL-P is more strongly associated with incident CVD risk than LDL-C, measurement of LDL-P is thought to be reasonable for many patients (or should be considered for select patients). When LDL-P is discordantly elevated, consideration should be given to initiating or intensifying LDL lowering therapy.” A high proportion of patients with diabetes or metabolic syndrome, obesity, hypertriglyceridemia, or low HDL-C are discordant.8 HDL-P is an emerging area of interest and, based on epidemiologic studies, appears to be an important measure for CVD risk assessment.7,9 Evidence continues to mount that, with HDL-P and HDL-C, as in measures of LDL, risk tracks with particle number. The NMR LipoProfi le test is the only available test today that provides direct measurements of both LDL-P and HDL-P.

1. Contois JH, McConnell JP, Sethi AA, et al. Apolipo-protein B and cardiovascular disease risk: Position statement from the AACC Lipoproteins and Vascular Diseases Division Working Group on Best Practices. Clin Chem. 2009;55:407-419.

2. Otvos JD, Jeyarajah EJ, Cromwell WC, et al. Mea-surement issues related to lipoprotein heterogeneity. Am J Cardiol. 2002;90(suppl):22i-29i.

3. Cromwell WC, Otvos JD, Keyes MJ, et al. LDL particle number and risk for future cardiovascular disease in the Framingham Offspring Study—Implications for LDL management. J Clin Lipidol. 2007;1:583-592.

4. Otvos JD, Mora S, Shalaurova I, Greenland P, Mackey RH, Goff DC Jr. Clinical implications of discordance between LDL cholesterol and LDL particle number. J Clin Lipidol. 2011;5(2):105-113.

5. Cromwell WC. High-density lipoprotein associations with coronary heart disease: Does measurement of cholesterol content give the best result? J Clin Lipidol. 2007;1(1):57-64.

6. Jeyarajah EJ, Cromwell WC, Otvos JD. Lipoprotein par-ticle analysis by nuclear magnetic resonance spectros-copy. Clin Lab Med. 2006;26(4):847-870.

7. Mackey RH, Greenland P, Goff DC, et al. The rela-tionship of HDL cholesterol and HDL particles to ca-rotid atherosclerosis and incident cardiovascular events: The Multi-Ethnic Study of Atherosclerosis (MESA). Presented at the American Heart Association

Cardiovascular Disease Epidemiology and Prevention Scientifi c Sessions, March 22-25, 2011, Atlanta, GA.

8. Davidson MH, Ballantyne CM, Jacobson TA, et al. Clinical utility of infl ammatory markers and advanced lipoprotein testing: Advice from an expert panel of lipid specialists. J Clin Lipidol. 2011;5(5):338-367.

9. Otvos JD, Collins D, Freedman DS, et al. LDL and HDL particle subclasses predict coronary events and are favorably changed by gemfi brozil therapy in the Veterans Affairs HDL intervention trial (VA-HIT). Circulation. 2006;113:1556-1563.

10. Sachdeva A, Cannon CP, Deedwania PC, et al. Lipid levels in patients hospitalized with coronary artery dis-ease: An analysis of 136,905 hospitalizations in Get With The Guidelines. Am Heart J. 2009;157(1):111-117.

11. Cromwell WC, Barringer TA. Low-density lipoprotein and apolipoprotein B: Clinical use in patients with coro-nary heart disease. Curr Cardiol Rep. 2009;11:468-475.

12. Rosenson RS, Davidson MH, Pourfarzib R. Underap-preciated opportunities for low-density lipoprotein management in patients with cardiometabolic residual risk. Atherosclerosis. 2010;213(1):1-7.

13. Rosenson RS, Otvos JD, Hsia J. Effects of rosuvastatin and atorvastatin on LDL and HDL particle concen-trations in patients with metabolic syndrome: A ran-domized, double-blind, controlled study. Diabetes Care. 2009;32(6):1087-1091.

14. LaRosa JC, Grundy SM, Waters DD, et al; the Treating

to New Targets (TNT) Investigators. Intensive lipid low-ering with atorvastatin in patients with stable coronary disease. N Engl J Med. 2005;352:1425-1435.

15. Shepard J, Barter P, Carmena R, et al; the Treating to New Targets Investigators. Effect of lowering LDL cholesterol substantially below currently recommended levels in patients with coronary heart disease and diabe-tes: The Treating to New Targets (TNT) study. Diabetes Care. 2006;29(6):120-126.

16. Toth PP. The “good cholesterol.” High-density lipopro-tein. Circulation. 2005;111(5): e89-e91.

17. AIM-HIGH Investigators. The role of niacin in rais-ing high-density lipoprotein cholesterol to reduce car-diovascular events in patients with atherosclerotic car-diovascular disease and optimally treated low-density lipoprotein cholesterol: Rationale and study design. The Atherothrombosis Intervention in Metabolic syn-drome with low HDL/high triglycerides: Impact on Global Health outcomes (AIM-HIGH). Am Heart J. 2011;161:471-477.

18. Van der Steeg WA, Holme I, Boekholdt SM, et al. High-density lipoprotein cholesterol, high-density lipoprotein particle size, and apolipoprotein A-I: Signifi cance for cardiovascular risk: The IDEAL and EPIC-Norfolk studies. J Am Coll Cardiol. 2008;51:634-642.

19. El Harchaoui K, Arsenault BJ, Franssen R, et al. High-density lipoprotein particle size and concentration and coronary risk. Ann Intern Med. 2009;150:84-93.

About LipoScienceLipoScience is a highly innovative, diagnostic company focused on changing the way heart disease, diabetes, and other metabolic diseases are assessed and managed. Through the use of NMR—information-rich technology that produces a digital representation of the molecules present in a simple blood sample—we can directly measure lipoprotein particles to provide physicians and their patients more information to manage their risk for heart disease and diabetes. For more information, visit www.theparticletest.com.

References

Reprinted with permissions from International Medical News Group. Copyright 2011. All rights reserved. For more information on the use of this content, contact Wright’s Media at 877-652-5295. 82851

REVISED COVER.indd 2 11/30/11 2:25 PM

Managing Atherosclerotic Risk With a Particle Focus

New Recommendations and Emerging Data

This supplement is supported by an educational grant from LipoScience, Inc.

81-255-01R1.0

A Supplement to