LipidSpin - National Lipid Association › sites › default › files › lipidspin › fall_2012.pdfThe Controversy Over Universal Cholesterol Screening for Children — Samuel S

Volume 10 Issue 3 Fall 2012visit www.lipid.org

Official Publication of the National Lipid Association

LipidSpin

Also in this issue: Coping with Statin Adverse Events—Focus on Pharmacokinetics and Pharmacodynamics Primary Hypertriglyceridemia—Treating Triglycerides When It’s Not the Usual Suspects

This issue sponsored by the Northeast Lipid Association

Controversiesin Clinical Lipidology

Cholesterol Screening for ChildrenHDL: Risk Marker or Risk FactorHDL-targeted Therapies

Scientific Meetings

2013 NLA Clinical Lipid Update—FallHosted by the Southeast Lipid Association

and the Northeast Lipid AssociationSeptember 20–22, 2013

Hyatt Regency Baltimore HotelBaltimore, MD

2013 NLA Clinical Lipid Update—SpringHosted by the Southwest Lipid Association

and the Midwest Lipid AssociationFebruary 22–24, 2013The Roosevelt Hotel

New Orleans, LA

2013 National Lipid Association Scientific SessionsHosted by the Pacific Lipid Association

May 30–June 2, 2013Red Rock Hotel Las Vegas, NV

2013National Lipid Association

1

2 From the NLA President An Exciting but Challenging Time—Peter P. Toth, MD, PhD, FNLA*

3 From the NELA PresidentLipid Spin: A Collaborative Effort— Perry J. Weinstock, MD, FNLA*

4 Editor’s CornerPracticing Based on Evidence—Robert A. Wild, MD, PhD, MPH, FNLA*

5 Clinical FeatureHDL and Cardiovascular Disease Risk—Risk Marker or Risk Factor?— Robert S. Rosenson, MD, FNLA

7 EBM Tools for PracticeRisk Reductions— Spencer D. Kroll, MD, PhD*

9 Specialty CornerCoping with Statin Adverse Events—Focus on Pharmacokinetics and Pharmacodynamics—Kenneth A. Kellick, PharmD, CLS, FNLA

13 Practical PearlsPrimary Hypertriglyceridemia—Treating Triglycerides When It’s Not the Usual Suspects —Vanessa L. Milne, MS, NP, CLS

16 Case Study IThe Patient with Family History of Premature Coronary Heart Disease —Merle Myerson, MD, EdD

19 Lipid LuminationsThe Controversy Over Universal Cholesterol Screening for Children— Samuel S. Gidding, MD

21 Case Study IIDoes Gender Matter in Cardiovascular Risk Assessment?—Danielle Duffy, MD—Edward Goldenberg MD, FNLA

24 Member Spotlight —Suneet Verma, MD, FNLA*

25 2012 Scientific Sessions Young Investigator Abstract —Ike Okwuosa, MD

26 News and Notes

27 Education and Meeting Update

28 Events Calendar

29 Foundation Update

30 Guest EditorialHDL-targeted Therapies—Where Do We Go From Here?—Daniel J. Rader, MD, FNLA*—Emil M. deGoma, MD

34 References

37 Patient Tear Sheet

Look for the NLA Community logo to discuss articles online at www.lipid.org

In This Issue: Fall 2012 (Volume 10, Issue 3)

EditorsJAMES A. UNDERBERG, MD, MS, FACPM, FACP, FNLA* Preventive CV Medicine, Lipidology and Hypertension Clinical Assistant Professor of Medicine NYU Medical School and Center for CV Prevention New York, NY

ROBERT A. WILD, MD, PhD, MPH, FNLA* Clinical Epidemiology and Biostatistics andClinical Lipidology ProfessorOklahoma University Health Sciences CenterOklahoma City, OK

Managing EditorMEGAN L. SEERY National Lipid Association

Executive DirectorCHRISTOPHER R. SEYMOUR, MBA National Lipid Association

Contributing EditorKEVIN C. MAKI, PhD, CLS, FNLA

Associate Editor for Patient EducationVANESSA L. MILNE, MS, NP, CLSCardiac Vascular Nurse and Family Nurse PractitionerBellevue Hospital Lipid ClinicNew York, NY

Lipid Spin is published quarterly by the National Lipid Association 6816 Southpoint Parkway, Suite 1000 Jacksonville, FL 32216 Phone: 904-998-0854 | Fax: 904-998-0855

Copyright ©2012 by the NLA. All rights reserved.

Visit us on the web at www.lipid.org.

The National Lipid Association makes every effort to provide accurate information in the Lipid Spin at the time of publication; however, circumstances may alter certain details, such as dates or locations of events. Any changes will be denoted as soon as possible. The NLA invites members and guest authors to provide scientific and medical opinion, which do not necessarily reflect the policy of the Association.

*indicates ABCL Diplomate status

2 LipidSpin

From the NLA President: An Exciting but Challenging Time

It is my privilege to serve as President of the NLA during this coming year. As is always the case, this is both an exciting but also a very challenging time. I would like to tell you about some of the programs and initiatives we are rolling out this year.

In September, we are convening a panel of 13 experts in Charlotte who will generate a consensus statement on Adiposity and Dyslipidemia. The panel will address issues of pathophysiology as well as assess the role/impact of lifestyle modification and the efficacy of pharmacologic intervention in managing this important area of lipidology. Given the negative results of such trials as AIM-HIGH and dal-OUTCOMES, the clinical impact of treating low serum levels of HDL cholesterol has been called into question. In January the NLA is bringing together an international panel of 16 experts in New York to produce a consensus paper on HDL. The document will help to define what we

know about this lipoprotein both clinically and scientifically and will address unresolved issues and controversies.

The NLA will be rolling out a comprehensive slide library on HDL later this fall complete with case studies and speaker’s notes. A series of highly academic newsletters addressing controversial areas of HDL are in production, and will feature articles by Robert Brook, MD, Ben Ansell, MD, and Phillip Barter, MD, PhD, among others.

All of us have been awaiting the release of ATP IV. A number of committees have been formed to help the NLA respond as effectively as possible during the public commentary periods for each of the new guidelines to be issued by the NHLBI.

In the year ahead, you will see the emergence of a strong pediatrics section of the NLA. The members of this group are currently constructing a plan to help invigorate the NLA’s voice in the diagnosis and management of pediatric dyslipidemia. As the NLA Masters in Lipidology course is updated and revised, expect to see a lecture on pediatric lipidology introduced. A mentoring program for young lipidologists will also be rolled out later this year. A new

committee is currently formulating plans to make this helpful and effective.

Outreach to other organizations continues. We will be meeting with representatives of the Preventive Cardiology Nurses Association this November to further explore ways we can work together. We continue to explore potential avenues to work with the American College of Cardiology and the American Academy of Osteopathic Family Physicians on educational programs.

The response of our membership to the 2012 Scientific Sessions was strongly positive. In the next two months, we will begin planning the Sessions for 2013 in Las Vegas. If you would like to recommend a topic and possible speaker, please e-mail me at [email protected]. We have every intention of making next year’s meeting relevant, exciting, and better than the last!

We would like to continue to expand our membership. Introduce a friend to the NLA. If you stopped paying your dues, please take the time to reactivate your membership. Finally, remember to make a donation to the NLA Foundation, which has embarked on multiple programs of good works and deserves your financial support. n

Discuss this article at www.lipid.orgGo to “Topics/Lipid Spin Fall 2012” and look for “From the NLA President.”

PEtER P. toth, MD, PhD, FNLAPresident, National Lipid AssociationDirector of Preventative CardiologyCGH Medical CenterSterling, ILProfessor of Clinical Family and Community MedicineUniversity of Illinois School of MedicinePeoria, ILDiplomate, American Board of Clinical Lipidology

Official Publication of the National Lipid Association 3

From the NELA President: Lipid Spin: A Collaborative Effort

It is my great honor to serve as President of the Northeast Lipid Association (NELA). One of the responsibilities of the President is to choose the topics and invite the authors for Lipid Spin. Accordingly, this edition of Lipid Spin was developed with my suggestions and direct input. I must say that the task, though daunting at first, was made a true labor of love with the help of all the great chapter members who eagerly participated and with the constant support of the editors, Jamie Underberg, MD and Robert Wild, MD, PhD. Most importantly I want to thank Megan Seery from the NLA staff who was an absolute delight to work with from start to finish.

The theme for this Lipid Spin is “Controversies in Clinical Lipidology.” The daily practice of Clinical Lipidology once seemed rather straightforward. If the LDL was high, lower it. If the triglycerides were high, lower them. If the HDL was low, raise it. However, clinical trials have challenged the simplicity of these assumptions by teaching us that nature frequently confounds the best laid plans of man. Thus, we now understand that it matters how you lower LDL. Likewise, although lowering triglycerides is beneficial, our standard therapies may not

produce a mortality benefit. Perhaps most disappointing is the realization that raising HDL is not clearly protective. We are all familiar with the controversy surrounding CETP inhibition with torcetrapib and now dalcetrapib. We seek to explain why AIM-HIGH did not produce the results we anticipated. Now we must account for the findings of a large Mendelian randomization study published a few months ago in Lancet that showed no consistent relationship between individuals with a genetically high HDL and a lower risk of myocardial infarction. In an effort to refocus our energies and move the lipid hypothesis forward, I have turned to the laboratory of Dan Rader, MD, at the University of Pennsylvania to address the issue of targeting HDL as a therapeutic option. Dr. Rader and his colleague Emil deGoma, MD, took on this task with enthusiasm and produced a masterful summary of the state-of-the-art of HDL altering therapy.

Each of the major articles in this edition of Lipid Spin was written by a member of NELA. I believe the quality of the contributions is outstanding and I wish to congratulate the members of NELA for rising to the task despite their summertime

commitments. I hope all the readers of Lipid Spin will agree this is one of the best editions ever. Please share your copy of Lipid Spin with others and let them see firsthand just how relevant and wonderful this publication is for anyone interested in the field of Clinical Lipidology.

I hope you all had a great summer and look forward to seeing you at our Clinical Lipid Update in Charlotte, North Carolina from September 14-16. n

PERRY J. WEINStoCK, MD, FACC, FNLAPresident, Northeast Lipid Association

Chief of CardiologyCooper University Hospital

Associate Professor of MedicineCooper Medical School of Rowan University

Camden, NJDiplomate, American Board of Clinical Lipidology

Discuss this article at www.lipid.orgGo to “Topics/Lipid Spin Fall 2012”

and look for “From the NELA President.”

4 LipidSpin

Editor’s Corner: Practicing Based on Evidence

RoBERt A. WILD, MD, PhD, MPh, FNLAClinical Epidemiology and Biostatistics andClinical Lipidology ProfessorOklahoma University Health Sciences CenterOklahoma City, OKDiplomate, American Board of Clinical Lipidology

One of the NLA’s missions is to move our educational efforts towards practicing based on best evidence. You will be seeing segments of Lipid Spin dedicated to this objective. There are many interesting aspects of lipidology addressed and displayed in a multi-disciplinary fashion in this edition of Lipid Spin. Thanks to Perry Weinstock, MD, as he assembled many contributors for each of us to learn from. There are many types of articles presented in this issue and there are many practical things to learn about. In particular I would like to highlight the articles by Spencer Kroll, MD, PhD, and Merle Myerson, MD, EdD.

The article by Dr. Kroll illustrates an important EBM concept and uses a great example of how to interpret and clinically use relative risk and absolute risk. As consumers of the literature we all need to be knowledgeable about these terms and what they mean and how best to use them. We should all be aware that relative

risk can be used in studies that are analytic (control groups) where data is accrued in a prospective fashion. Understanding the magnitude of the relative risk and the confidence limits around the relative risk is important. The relative risk is helpful in contrasting outcomes (comparing the treatment arms) in clinical trials or in cohort studies that use cumulative incident data—the proportion of new cases of disease during a specific time period. Relative risk is a very useful concept because it focuses on the magnitude of the comparison of the groups. It is helpful in understanding associations and helps move our understanding towards causation.

As clinicians what is most important to us however is understanding the absolute risk for each of the groups being studied but most importantly focusing on what the absolute risk reduction is if there is a difference detected between the comparison groups. Understanding the magnitude of the difference and if it is clinically important is a must. We can quantify this by taking the absolute risk difference and then dividing this into one. That gives us the number needed to treat for benefit or, depending on the context, it gives us the number needed to harm. This is interpreted as the number of

patients needed to prevent one outcome in a specified period of time.

The article by Dr. Myerson is a great illustration of finding evidence and using it to deal with a clinical scenario. Importantly, it points out where there are gaps in evidence, and that finding evidence and evaluating evidence is not by itself ever enough. We need to be able to find out if information available is valid, if it fits our particular patient’s clinical presentation and value system. In short, we need to integrate our decisions as this case illustrates. That is the art of clinical practice. Importantly, as clinicians, we often disagree regarding management when there are gaps in evidence available. We always need to be mindful of the clinical circumstance and the specifics of any given clinical situation. What about likelihood of compliance, for example, in this case with lifestyle management? When is medication indicated? How motivated is the patient in front of us? What other therapies is he or she using besides our counsel?

We are pleased to provide these articles and they are published here with the goal of generating thought, discussion and debate. That’s what is great about the NLA. n

Discuss this article at www.lipid.orgGo to “Topics/Lipid Spin Fall 2012” and look for “Editor’s Corner.”


Clinical Feature: HDL and Cardiovascular Disease Risk—Risk Marker or Risk Factor?

Low HDL cholesterol (HDL-C) is an established biomarker for the future development of atherosclerosis and atherosclerotic cardiovascular disease (CVD) events in population-based observational studies and clinical trials of cholesterol-lowering therapies and this includes coronary heart disease (CHD) patients with low levels of LDL cholesterol (LDL-C) on statin therapy.1-3 Because multiple clinical trials designed to increase HDL-C and reduce CVD risk have not demonstrated efficacy and instead have shown potential harm,4-6 there has been widespread confusion regarding the importance of HDL as a biomarker of risk and as a potential target for therapeutic intervention.7 Confusion around the importance of HDL in atheroprotection has been magnified by a Mendelian randomization study that utilized HDL-C as an intermediary biomarker of CVD risk.8

This perspective discusses the limitations of HDL-C as a biomarker of risk, and misguided attempts to reduce atherosclerosis through effectuating changes in the cholesterol content of HDL particles.

hDL-C: A Biomarker of Atherogenic LipoproteinsLow HDL-C levels are commonly associated with cholesterol-depleted HDL particles and cholesterol-depleted LDL particles.9 Due to conformational changes in apolipoprotein (apoB) on the surface of small LDL particles, these cholesterol-depleted particles have reduced interactions with LDL receptors, which results in delayed hepatic clearance of these atherogenic lipoproteins from the bloodstream. In a primary prevention trial of individuals with reduced HDL-C levels, baseline and on-trial CHD events were linearly related to apoB levels.10 It remains uncertain from current observational and clinical trial data whether the increased CVD risk associated with low levels of HDL-C is anything more than an excess concentration of atherogenic apoB-containing particles.

hDL Particles: A Biomarker of CVD RiskFor 50 years, “reverse cholesterol transport” has been considered the major anti-atherogenic function of HDL.11,12 Only 3-5% of the mass of HDL particles, however, is derived from macrophage cholesterol efflux.13 This reliance on HDL-C has resulted in an

under appreciation of the contribution of protein-enriched, cholesterol-depleted HDL subclasses in modulating critical atheroprotective functions.14 Specifically, certain populations of small HDL particles have stronger anti-oxidant, anti-inflammatory and anti-infective properties than other constituents of HDL.15

Several prospective population studies16-18 and clinical trials of lipid modifying-therapies19,20 have reported that the concentrations of small HDL particles and/or total HDL particles are more robust predictors of CVD risk than total HDL-C. These studies suggest that the protein composition or proteome of certain subpopulations of HDL particles may have more important contributions to HDL-associated CVD risk than can be deduced from the cholesterol carrying capacity of circulating HDL particles alone.

RoBERt S. RoSENSoN, MD, FNLADirector, Cardiometabolic Disorders

Mount Sinai Medical CenterProfessor of Medicine

Mount Sinai School of MedicineNew York, NY


and look for “Clinical Feature.”

6 LipidSpin

Mendelian randomization studies have been considered to provide an “unbiased” evaluation of biomarkers and their association with the development of disease. Two recent GWAS studies provide an example of conflicting conclusions related to HDL associated CVD risk however.8,21 In a combination of five cardiovascular disease case-control studies (4,658 cases and 11,459 controls), two single nucleotide polymorphisms (SNP) in the phospholipid transfer protein (PLTP) gene associated with reduced PLTP activity were associated with reduced CVD risk despite the lack of influence of this enzyme on the cholesterol content of HDL.21 In contrast, the PLTP polymorphism was associated with higher concentrations of small HDL particles and total numbers of HDL particles. In the one Mendelian randomization study that had previously used a genome-wide association approach to identify SNPs that affect blood lipid concentrations,22,23 a polymorphism in the endothelial lipase gene (LIPG Asn396Ser) found in 20 studies (20,913 myocardial infarction cases, 95,407 controls) as well as 14 other pathways (12,482 cases of myocardial infarction and 41,331 controls exclusively associated with HDL-C), were investigated for their association with myocardial infarction.8 Despite having high HDL-C levels, there was no association with CVD risk. In this study, the authors assumed that “plasma HDL-C” was the biomarker “directly involved” in the pathogenesis of CHD, and concluded that inherited variation in plasma HDL-C was a surrogate measure of disease.

The Multi-Ethnic Subclinical Atherosclerosis (MESA) study18 investigated the relative importance of several HDL measures (HDL-C, HDL size and HDL particle concentration) as to risk of subclinical atherosclerosis and incident

CVD events. In multivariate models that included major risk factors, lipids and lipoprotein subclasses, HDL particle concentration but not HDL-C was inversely associated with carotid intima medial thickness and incident CHD events. Two other prospective population studies have reported that HDL-P is a more accurate predictor of CVD events in a subset of metabolic syndrome patients (Multiple Risk Factor Collaboration Trial,16 and the EPIC Norfolk Study).17

Several pharmacological agents are known to increase the cholesterol content of HDL (CETP inhibitors, niacin)24,25 and other agents increase the number of HDL particles, but are less effective in loading the particles with cholesterol (PPAR-a agonists).19 In the Veterans Administration HDL Intervention Trial (VA-HIT), gemfibrozil therapy reduced LDL-P by percent, increased total HDL particles by 10% and small HDL particle subclass by 21%. In the initial report of this trial, on-trial changes in HDL-C explained only 17% of the CVD risk.26 A nested-case control study from VA-HIT investigated the CVD risk associated with baseline and

on-trial changes in lipids and lipoprotein subclasses.20 In multivariate models that included treatment group, conventional risk factors and lipid and lipoprotein concentrations, every one standard deviation change in HDL-C was unrelated to CHD events (p=0.14); whereas HDL-P was inversely related with CHD events at baseline (odds ratio: 0.78 [0.69-0.90] ) and on-trial (odds ratio: 0.71 [0.61-0.81.]19 In an analysis of HDL subclasses, baseline and on-trial risk were associated with small HDL subclasses (0.71[0.60-0.84 and 0.67[0.57-079] respectively) and medium subclasses (0.82[0.70-0.96] and 0.82[0.69-0.97]) but not by large HDL subclasses (0.95 [082-1.11] ) and 0.92 [0.79-1.07] respectively).

From the available data, HDL-C remains a robust marker of elevated apoB-containing lipoproteins and CVD risk; however, HDL-C is not a useful biomarker of HDL functionality. Multiple HDL subclasses are involved in anti-atherogenic mechanisms. HDL-P assessment provides one clinically available measure that appears to more precisely predict CVD risk. From my perspective, future trials that investigate HDL-modifying therapies should assess HDL-P and, in particular, certain functional HDL subclasses. n

Disclosure statement: Dr. Rosenson has received grants from Amgen, Genentech and Hoffman-LaRoche. Dr. Rosenson has been an adviser to Abbott Laboratories, Amarin Corporation, Amgen, Genentech, Hoffman-LaRoche, Kowa Pharmaceuticals America, LipoScience Inc. and Sanofi-Aventis. Dr. Rosenson has stock options in LipoScience Inc.

References listed on page 34.

Certain populations of small HDL particles have

stronger anti-oxidant, anti-inflammatory and anti-infective

properties than other constituents of HDL.


Clinicians are constantly presented with data and results intended to influence the treatment they render to patients. However, in spite of the gravity of the consequences of treatment, we are often not supplied with appropriate and adequate data on which to base our judgment of effectiveness. Such situations become clearer when we see media reports with “relative risk reduction” in treatments rather than statistics on “absolute risk reduction.” The difference in data presentation often makes the treatments appear much better than they actually are. Evidence-based medicine compels us to integrate the best research evidence with our clinical expertise and patient values.

In order for clinicians to make an informed decision in evaluating relative and absolute risk reduction data, they must understand the difference between the two forms of risk and the data upon which it is based. There are two types of risk assessment. Absolute risk reduction (ARR) is risk stated without any context. For example, you have a 50 % chance when flipping a coin of coming up with heads. The 50% probability is independent of other factors and is independent of prior tests. It is not

compared to any other risk. Relative risk reduction (RRR) is a comparison between different risk levels and between treatment effect and the risk without treatment. For example, the relative risk for lung cancer is (approximately) 10 times greater for a smoker compared to a nonsmoker. An important feature of relative risk is that it gives no information about the actual baseline risk but it can be important in evaluating how significant a relative increase might be.

A small increase in risk in a large population can skew the effect and make the result seem larger than it actually is. Simply stated, we often lack a standard by which to judge the superior clinical decision. Whether RRR ‘‘overestimates’’ the effect or ARR ‘‘underestimates’’ the effect is a value judgment because we often lack a gold standard for what is the ‘‘best’’ decision.

Let’s now apply these criteria to some specific situations to gain a better insight. The baseline risk is critical for determining changes in absolute risk. For example, thyroid cancer is diagnosed in slightly less than 1 in 100,000 persons per year,

whereas first myocardial infarction is diagnosed in about 400 in 100,000 people per year. These numbers are based upon absolute risk. If relative risk were applied and a 10% increase occurred, then for thyroid cancer there would be 0.10 x 1 = 0.1 new cases per 100,000 people. On the other hand, a 10% increase in myocardial infarction affects an additional 40 per 100,000 people. Accordingly, if we assume the population of the United States is 300 million (which is 3,000 times 100,000), the small increase in thyroid cancer would result in 0.1 x 3,000 = 300 new cases. By contrast, the same increase in rate using RRR in first myocardial infarction would result in 40 x 3,000 = 120,000 new cases.

To further understand the application of the data presented, we must be informed of the average number of patients that need to be treated for one to benefit as

EBM Tools for Practice: Risk Reductions

SPENCER D. KRoLL, MD, PhDDirector, The Cholesterol Treatment Center

Clinical Lipidologist in Private PracticeMarlboro, NJ

Diplomate, American Board of Clinical Lipidology


and look for “EBM Tools for Practice.”

8 LipidSpin

compared with a control in a clinical trial within a given period of time. This is called Number Needed to Treat (NNT). NNT is a more informative statistic for comparison because it describes the number of patients who must be treated over a set period of time to prevent one person from suffering an event or for seeing a benefit of the treatment. Number needed to treat is the inverse of absolute risk. NNT is derived from absolute risk and does not rely upon relative risk for its calculation. The higher the NNT, the less effective the treatment.

The NNT value is time-specific. For example, if a study ran for five years and the NNT was 100, in one year the NNT would be multiplied by five to estimate a one-year NNT of 500. However this method of calculation is controversial because an effect may not be constant over the full course of measurement. If the slope of the curve from the placebo group in a study remains fairly constant throughout a trial, this method is an acceptable and quick method of adjustment for the study’s duration when evaluating the treatment effect as calculated from NNT. In addition to concerns about extrapolating over time, there is the potential limitation when one randomized controlled trial is compared to another when there is a different baseline risk.

Despite criticism of relative risk, it must be considered that relative risk is a comparator against absolute risk, much like clinical trials examine therapies relative to conventional therapy. Relative risk must be interpreted alongside absolute risk to tell you if the therapy is worth pursuing. Does framing the data in RRR alter the perception of therapeutic effectiveness in physicians? In the Helsinki Heart Study, after five years of treatment with gemfibrozil, 2.73% of patients in the treatment arm experienced a cardiac event comparing to 4.14% in the

placebo arm. Without mentioning the name of the trial or the medication, the results of the Helsinki Heart Study in various formats were distributed among 148 physicians. Physicians’ willingness to prescribe the drug was 77% when the data was presented in terms of RRR while 24% were willing to prescribe the drug when data was expressed in terms of ARR.1 Influence of RRR on physician’s perception of treatment benefits has been reported in several other trials.2,3

Applying the criteria of relative risk and absolute risk to some other lipid trials, we find the following: The ASCOT-LLA Trial was a primary prevention study that examined the benefit of atorvastatin 10mg in patients with hypertension but with no previous cardiovascular disease. Over more than three years, the relative risk of a cardiovascular event was reduced by 36%.4 The absolute risk reduction, however, was much smaller. This study determined that taking atorvastatin for 3.3 years would lead to an absolute risk reduction of only 1.02%. The number needed to treat would then be 99.7 for the 3.3 years period to prevent one cardiovascular event.

Absolute event rates in both the rosuvastatin and placebo group arms of the JUPITER trial were low, but the relative effect was very large.5 The relative risk reduction from the use of rosuvastatin in this population was 44% and even higher if there was a family history of premature CHD. When primary endpoints of MI, stroke, CV death, angina requiring hospitalization and revascularization were defined, the NNT was found to be 25 patients over a 5-year period to prevent one of these endpoints. The absolute risk reduction over the two years of the study is 1.2%, reflecting a significantly lower baseline risk in this population. From the relative risk reduction and from the calculated NNT, statin therapy in patients

with elevated high-sensitivity C-reactive protein and low LDL cholesterol seem to be comparable to many other interventions for primary cardiovascular prevention, but significantly higher than that seen for statin interventions for secondary prevention.* Again, we cannot compare NNT across these populations with very different baseline risks.

Exploitation of “information framing” is a well-recognized strategy in marketing and mass media. Perception of probabilities and outcomes can predictably shift when the same problem is framed in a different way. As for medical interventions when the results are presented in RRR rather than ARR, it appears that the enthusiasm for the intervention increases as both physicians and patients downplay other attributes of the treatment such as side effects.7 Clinicians must be vigilant for this type of data presentation and seek out absolute risk reduction figures. In so doing, we can determine if the absolute benefit of the treatment is large enough to justify its potential risks and costs. n

*Another set of data to emerge from JUPITER was a high relative risk for new onset diabetes. Meta-analysis of 13 statin trials shows a 9% increase in the relative risk of new-onset diabetes.6 This meta-analysis shows that 255 patients have to be treated for four years before one statin-induced case of incident diabetes is seen. However, a composite of nine vascular events (including death, myocardial infarction, stroke, and coronary revascularization) would be avoided by treating 255 patients over the same time period. It is intuitively clear that these risks and benefits are independently derived and each population of 255 patients is an individual set.

Disclosure statement: Dr. Kroll has received honoraria related to speaking from Abbott Laboratories, GlaxoSmithKline and AstraZeneca.



We all see patients in our practice who either have complaints of muscle aches after starting HMG-Co-A Redtucase inhibitors (statins) or have been referred by other health care practitioners for management of dyslipidemia in the presence of suggested diagnosis of statin myopathy. A careful differential diagnosis should take into account many factors:

1) The cause of the muscle pain.

2) The timing of the muscle pain with respect to statin initiation.

3) Confirming laboratory tests along with physical examination.

4) The dose and specific statin used.

5) The pharmacokinetics of the statin.

6) Other concomitant medications.

7) Pharmacodynamics with respect to statin metabolism which may be altered by genetic mutations in certain enzyme systems.

8) Other clinical conditions or implicating factors.

The following article reviews the pharmacokinetic and pharmacodyamic parameters of the statins with a focus on the evidence and clinical aspects of the management of the patient with statin myopathy.

Irrespective of statin use, other causes of myopathy have been noted. Many antibiotics along with cocaine or other illicit drugs have been associated with a focal myopathy. Colchicine, amiodarone, cyclosporine, glucocorticoids, cimetidine along with statins have been implicated in diffuse myopathy. Extreme physical activity has also been linked to severe muscle pain. A careful history, physical and laboratory data is essential to classification of a muscle problem.1-3

Useful laboratory tests include a basic metabolic panel to determine renal function and acid-base or electrolyte abnormalities and a creatinine phospho-kinase (CPK) to categorize the degree of muscle damage. Serum and/or urine myoglobin may be helpful in the diagnosis of rhabdomyolysis.4-6

Specialty Corner: Coping with Statin Adverse Events—Focus on

Pharmacokinetics and Pharmacodynamics

KENNEth A. KELLICK, PharmD, CLS, FNLAVA Western NY Health Care Center

Buffalo, New York

Diplomate, Accreditation Council for Clinical Lipidology


and look for “Specialty Corner.”

tERMS

Myopathy: general term for every potential

muscle problem

Asymptomatic myopathy: ↑ Creatinine

Kinase(CK) without myalgias or weakness

Symptomatic myopathy: presence of myalgia,

weakness or cramps

Rhabdomyolysis: evidence of muscle cell injury

demonstrated by ↑ CK.

Mild ↑ CK: CK levels >normal but <10x ULN

Moderate ↑ CK: CK levels >10x ULN but <50x

Marked CK increase: CK levels > 50x ULN

10 LipidSpin

Factors that pre-dispose the patient to muscle diseases (Table 1) should be taken into account. Common among these are family history of statin muscle pain, recent vigorous exercise and gender. The small frame, elderly female may respond more rigorously to small “pixie-dust” doses of statins than their male counterparts and require appropriate dose adjustments. Hypothyroidsim should be ruled out with thyroid function testing. Polypharmacy and multiple providers put patients at risk for drug interactions. A complete family history is must also be part of any comprehensive evaluation. Single-nucleotide polymorphisms (SNPs) impacting statin associated metabolic pathways have

been implicated in the pathogenesis of statin myopathy.3,12

There are more than 30 different enzyme systems and multiple families of enzymes associated with liver metabolism. Commonly associated with statin interactions are CYP 2C9 and CYP3A4. Additionally, aging is associated with a 20-30% reduction in hepatic size and a 20-50% reduction in hepatic blood flow. Despite this, there is conflicting information regarding the impact of aging on hepatic microsomal enzyme activity. Some patients with active liver disease or nonalcoholic steatohepatitis (NASH) may have altered enzyme activity. There is, however, general

consensus that these patients should be treated with statins due to cardiovascular risk associated with this condition. A recent FDA ruling no longer recommends that liver done routinely before starting statin therapy, certain patients such as those with active liver disease and NASH may require additional monitoring.11,13,18,21

The issue surrounding the drug-drug interactions appears to be related to the serum and or intra-cellular levels of statins. When doses are increased higher levels of the statin acid result and muscle toxicity can occur. This first became evident in the late 1990s when an attempt at approving a 160mg dose of simvastatin was abandoned due to higher levels of myotoxicity. In August 2001, cerivastatin was recalled due to the gemfibrozil-cerivastatin interaction which produced very high serum concentrations of the parent drug and some of its metabolites.19

Recently the FDA, following an analysis of the SEARCH trial, capped the maximal dose of simvastatin at 40mg daily due to the burden of myopathy and rhabdomyolysis at the higher dose of the drug. The latter problem was highest during the first year of treatment. Similarly, in February 2012 the FDA announced similar new labeling for lovastatin. Table 3 summarizes new FDA labeling for lovastatin and simvastatin.20,21

Patient Characteristics Statin Properties

Increasing age, family history of myopathy, extreme physical activity High systemic exposure—dose

Female gender Lipophilicity?

Renal insufficiency High bioavailability

Hepatic dysfunction Limited protein binding

Hypothyroidism p-Glycoprotein interactions

Diet (i.e., grapefruit or pomegranate juice) Potential for drug-drug interactions metabolized by CYP pathways (particu-larly CYP450 3A4)

Polypharmacy Pharmacogenomic (SNPs) changes in other enzymes

Multi-organ diseases

S/p post-operative period

Table 1. Factors that increase the risk of statin-induced myopathy.7-11

Table 2. Examples from the CYP3A4 enzyme system. adapted from 8,19

Substrates Inhibitors Inducersacetaminophen, alfentanil, alprazolam, amiodarone, aminopyrine, amitriptyline, amlodipine, amprenavir, antipyrine, astemizole, atorvastatin, benzphetamine, budesonide, busulfan, cannabinoids, carbamazepine, celecoxib, cisapride, clarithromycin, clindamycin, clomipramine, clozapine, codeine, cortisol, cyclobenzaprine, cyclophosphamide, cyclosporin A, dapsone, delavirdine, dexamethasone, dextromethorphan, diazepam, digoxin,diltiazem, disopyramide, docetaxel, donepezil, doxorubicin, dronabinol, erythromycin, ethinylestradiol, ethosuximide, etopside, felodipine, fentanyl, fexofenadine, flutamide, granisetron, haloperidol, hydrocortisone, ifosfamide, imipramine, indinavir, isradipine, ketoconazole, lansoprazole, lidocaine, loratadine, losartan, lovastatin, methadone, mibefradil, miconazole, midazolam, navelbine, nefazodone, nelfinavir, nicardipine, nifedipine, nimodipine, nisoldipine, omeprazole, ondansetron, paclitaxel, pravastatin, prednisone, propafenone, quinidine, quinine, retinoic acid, rifampin, ritonavir, ropivacaine, saquinavir, sertraline, sufentanil, tacrolimus, tamoxifen, temazepam, teniposide, terfenadine, testosterone, THC, theophylline, triazolam, troleandomycin, verapamil, vinblastine, vincristine, (R)-warfarin

amiodarone, amprenavir, cannabinoids, cimetadine, clarithromycin, clotrimazole, cyclosporin, delavirdine, diltiazem, ethinylestradiol, erythromycin, fluconazole, fluoxetine, fluvoxamine, indinavir, intraconazole, ketoconazole, metronidazole, mibefradil, miconazole, nefazodone, nelfinavir, nicardipine, norfloxacin, propafol, quinine, ritonavir, saquinavir, sertraline, troleandomycin, verapamil, zafirlukast

carbamazepine, dexamethasone, ethosuximide, glutethimide, nevirapine, phenobarbital, phenytoin, primidone, rifabutin, rifampin, St. John’s Wort, sulfadimidine, sulfinpyrazone, troglitazone, troleandomycin

The new hepatitis C drugs, boceprivir and telaprivir, may inhibit the metabolism of simvastatin through CYP 3A4. Grapefruit juice in large quantities inhibits CYP3A4 and hence simvastatin, lovastatin and atorvastatin. Once inhibited the ability of the enzyme takes up to 24 hours to rebound to pre-inhibitory concentrations after withdrawal of the grapefruit juice. HAART regimen with newer or older protease inhibitors(PI) Amprenavir, saquinavir, lopinavir, duranavir and other protease inhibitors increase the risk for atorvastatin, simvastatin and lovastatin myopathy. Changing the statin or changing the PI to an alternative agent may be required. Amiodarone is metabolized

through CYP3A4 and CYP2C8 and dose adjustments with some statins are required when with this agent. The FDA arbitrarily lowered the simvastatin dose cap to 10mg when taken with amiodarone. This was redacted in December 2011 to a maximum simvastatin dose of 20mg due to lack of clinical trial or pharmacokinetic data to support the lower dose.20,21

The inhibition of statin metabolism is not limited to the CYP3A4 enzyme system. Statins and non-statins, such as ezetimibe and gemfibrozil are affected by interacting agents. Inhibitors of CYP2C9 and CYP3A4 will likely increase the area under the concentration-time curve (AUC) as well as peak plasma concentrations of many

statins. These higher drug levels are thought to be directly related to increased incidence statin adverse reactions. Inducers the activity of these enzymes will increase the catabolism of the drug rendering it less effective.3,18,19,22

Uridine diphosphate glucuronosyltrans-ferase (UGT) has been previously implicated in the gemfibrozil–cerivastatin interaction. Ezetimibe undergoes rapid glucuronidation in intestinal mucosa cells by UGT1A1 and UGT1A3 and to a lesser degree, UGT2B15. Both fenofibrate and gemfibrozil can increase levels of ezetimibe due to their interaction with UGT enzyme family. The latter is not thought to be clinically significant.4,22

In addition to liver enzymes, there are a number of transporters responsible for hepatic uptake and clearance of statins. Table 3 lists enzymes that have been implicated in statin myopathy and rhabdomyolysis. P-Glycoprotein (pGp) is an ATP dependent efflux pump member of the ABCB1 transport protein. Its biologic function is to prevent toxins from being absorbed through the GI tract and to actively excrete toxins in the liver and kidney. Drugs that interact with pGp can either inhibit or induce the activity of this protein. This alters transport of the substrate. Examples of common pGp interactions are noted on Table 5.22

PGp interactions are mostly associated with CYP3A4 metabolized drugs. Fluvastatin and pravastatin do not significantly


Table 4. Enzymes, other drugs and statins that may affect hepatocellular uptake.10

Label Changes

Contraindicated with lovastatin:• itraconazole • ketoconazole • posaconazole • erythromycin • clarithromycin • telithromycin • HIV protease inhibitors • boceprevir • telaprevir • nefazodone

Contraindicated with simvastatin:• itraconazole • ketoconazole • posaconazole • erythromycin • clarithromycin • telithromycin • HIV protease inhibitors • nefazodone • gemfibrozil • cyclosporine • danazol

Avoid with lovastatin:• cyclosporine • gemfibrozil• >1qt/day grapefruit juice

Do not exceed 10mg simvastatin daily with:• verapamil • diltiazem

Do not exceed 20mg lovastatin daily with:• danazol • diltiazem • verapamil

Do not exceed 20mg simvastatin daily with:• amlodipine • ranolazine • amiodarone (changed in Dec 2011)

Do not exceed 40mg Lovastatin daily with:• amiodarone

Avoid with simvastatin:• >1qt/day grapefruit juice

Enzyme or Transporter Major Statin Substrate Interacting drugs

CYP2C9 fluvastatin, rosuvastatin ketoconazole, fluconazole

UGT (usually UGT1A1 and UGT1A3) all statins also ezetimibe (UGT1A1) gemfibrozil, rosuvastatin

p-Glycoprotein atorvastatin, lovastatin, simvastatin ritonavir, cyclosporine, verapamil, erythromycin, ketoconazole, itraconazole, quinidine, gemfibrozil

OATP1B1 all statins cyclosporine, rifampicin, gemfibrozil, clarithromycin, erythromycin, ritonavir, indinavir, saquinavir

OATP2 pravastatin

Table 3. June/December 2011 and February 2012 FDA label changes.20,21

12 LipidSpin

inhibit pGp transport. Rosuvastatin has not been shown to be a substrate or inhibitor of pGp or CYP3A4, yet when co-administered with itraconazole or cyclosporine serum concentrations increase. An alternative transporter, such as OATP2 may be responsible for the rosuvastatin-itraconazole interaction. Table 5 shows the effect of commonly given drugs (p-Glycoprotein substrates, inducers and inhibitors) and their effect on statin levels.23

Polymorphisms in additional transport systems may offer an alternative explanation for statin induced myopathy. OATP1B1 is an uptake transporter located on the hepatocyte and is responsible for transport of statins from the portal

circulation to the hepatocyte. In the recent SEARCH trial it was noted that more than 60% of the myopathies were attributed to a noted gene variant in this enzyme system. This SLCO1B1 521T>C polymorphism may be associated with increased of some statins such as simvastatin, but not pravastatin.

When approaching statin-drug interactions, the pharmacokinetics of statins need to be considered (Table 6). Lipophilicity appears to have little role in predicting statin intolerance as does half-life. Synthetic statins may be more tolerable than semi-synthetic statins.

Drug-drug interactions, dosing, patient characteristics, pharmacodynamics and

pharmacogenomics are all players in the picture of statin induced muscle disorders. In many patients statin metabolism is altered producing higher serum drug levels resulting in symptoms of myalgia or myopathy. The science of statin metabolism continues to expand, with the hope that someday a home monitoring test will be available to assist the patient in profiling which drug and or drug combination is most safe and efficacious. n

Disclosure statement: Dr. Kellick has no relevant disclosures.


Drug Atorva Fluva Lova Prava Simva Rosuva

St. John’s Wort NS(20mg) ↓ 2x

Digoxin 1.15 fold↑ (digoxin) NS(40mg) NS(40mg)

Diltiazem 3.5x ↑ NS(20mg) 2-5x↑1.8x ↓ (dilt)

Verapamil NS(40mg) 4-5 fold↑

Itraconazole 1.5-3x↑ NS (40mg) 15-20x↑ NS(40mg) or1.5fx↑(40mg)

10x↑ 1.4x↑(10mg)

Ketoconazole - - - - - NS(80mg)

Grapefruit Juice 1.6-2.5x↑ 2-15x↑ NS (10,40mg) 3.3-16x↑

Cyclosporine 7.4x↑ 3.1x↑ 5x↑ 20x(20mg)↑ 2.5x↑ 7.1x ↑(10mg)

Erythromycin 1.3x ↑ 6.2x↑ NS(80mg)

Clarithromycin 1.8-4x↑ 2x↑ 10x↑

Table 5. P-glycoprotein interacting drugs and statin levels.23

Atorvastatin Simvastatin Lovastatin Pitavastatin Fluvastatin Rosuvastatin Pravastatin

Tmax(H) 2-3 1.3-2.4 2-4 0.6-0.8 0.5-1 3.0-5-0 0.9-1.6

Lipo/Hydrophilic Lipophilic Lipophilic Lipophilic Lipophilic Lipophilic Hydrophilic Hydrophilic

T ½(h) 15-30 2-3 2.9 10 0.5-2.3 20 1.3-2.8

Source Synthetic Semi-synthetic Semi-synthetic Synthetic Synthetic Synthetic Semi-synthetic

Metabolism CPY3A4 CYP3A4 CYP3A4 Glucuronidation (minor CYP2C9 AND CYP2C8)

CYP2C9 Limited hepatic (CYP 2C9 and CYP2C19)

PgP, some hydroxylase

Protein Binding % 80-90 94-98 >95 96 >99 88 43-55

Urine excretion % Little 13 10 Little 6 10 20

Fecal excretion % 70 58 83 90 90 90 71

Table 6. Pharmacokinetics of various statins.8,10,19,22


Hypertriglyceridemia (HTG) is defined as an excess of triglycerides in the blood. Primary HTG is caused by one or more genetic defects leading to triglyceride elevation. Secondary HTG is acquired; the causes are plethoric and can be identified by methodically assessing the factors listed in Table 1. Primary HTG should be suspected if a secondary cause cannot be identified. In addition, an astute clinician should consider primary HTG when the patient with a secondary cause has a fasting triglyceride measurement greater than 300 mg/dL, since primary HTG may not reveal itself without a secondary “insult” added to the clinical milieu.

The National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) guidelines recommend first treating low density lipoprotein cholesterol (LDL-C) to goal and then targeting non-high density lipoprotein cholesterol (non-HDL-C), unless triglycerides are ≥ 500 mg/dL. At a level of ≥ 500 mg/dL, the patient is believed to be at risk for acute pancreatitis and lowering triglycerides is the initial goal.¹ Data on triglyceride levels and their independent correlation

with cardiovascular disease is unclear; however, some types of primary HTG convey higher risk for cardiovascular disease based on the specific lipoprotein elevation. Understanding the types of primary HTG, as well as distinctive responses to differences in treatment, allows the clinician to better assess and manage patient risk for pancreatitis and cardiovascular disease.

EvaluationIt can be challenging to definitively identify the genetic basis of a patient’s primary HTG as genetic testing is not readily available and the diagnostic waters are muddied when a secondary component is involved. However, serum lipid levels, personal and family history, and physical exam may guide the clinician to a likely genetic defect. First, consider the patient’s serum levels. Does the patient have an elevation in triglycerides and total cholesterol or solely triglycerides? Second, does the patient or a family member have a history of pancreatitis or cardiovascular disease? Third, are there any findings on physical exam suggestive of a specific type of primary HTG?

If a Patient has Isolated htG Consider:Familial hyperchylomicronemia (Fredrickson Type 1)—Patients with Familial hyperchylomicronemia have triglycerides > 1000 mg/dL, sometimes exceeding 10,000 mg/dL, but often have normal total cholesterol. The ratio of triglyceride to cholesterol is often cited as being 10:1.2 The severe elevation in fasting chylomicrons results from a genetic mutation causing an absence of Lipoprotein Lipase (LPL), which metabolizes chylomicrons and very low density lipoprotein (VLDL), or a genetic defect in a co factor, protein or enzyme that obliterates LPL activity.3 Pancreatitis is common. Patients with Familial hyperchylomicronemia have low risk for coronary artery disease (CAD) since

Practical Pearls: Primary Hypertriglyceridemia—Treating Triglycerides

When It’s Not the Usual Suspects

VANESSA L. MILNE, MS, NP, CLSCardiac Vascular Nurse and Family Nurse Practitioner

Bellevue Hospital Lipid ClinicNew York, NY

Diplomate, Accreditation Council for Clinical Lipidology


and look for “Practical Pearls.”

14 LipidSpin

the elevated lipoproteins, chylomicrons, carry small amounts of cholesterol. They can exhibit eruptive xanthomas, hepatosplenomegaly and lipemia retinalis. This is a rare disorder and symptoms usually manifest during childhood.

Familial hypertriglyceridemia (Fredrickson Type 4)—Patients have normal to slightly elevated total cholesterol with triglycerides ranging from 200-1000 mg/dL. VLDL is elevated, which may result from a LPL gene mutation that decreases LPL activity. Apo B is normal.2 A secondary component, such as alcohol or high carbohydrate diet, is a common finding. Patients are usually asymptomatic and have low risk for atherogenicity.4

If a Patient has htG and Elevated total Cholesterol Consider: Familial combined hypercholesterolemia (Fredrickson Type 2B)—Patients with Familial combined hypercholesterolemia usually have triglycerides between 150-500 mg/dL and total cholesterol between 200 and 400 mg/dL. A secondary component such as insulin resistance or metabolic syndrome is common. The disorder is thought to be polygenic and large phenotypic variation can exist between family members.5 Apo B is usually elevated (> 120mg/dL), which distinguishes it from Familial hypertriglyceridemia.2 Patients have low risk for pancreatitis, but are at risk for CAD due to LDL and VLDL elevations. They do not have xanthomas.

Dysbetalipoproteinemia (Fredrickson Type 3)—Triglycerides and total cholesterol levels are elevated and equal in a one to one ratio, resulting from the Apolipoprotein (Apo) E isoform Apo E2/E2. Since many people with isoform Apo E2/E2 do not demonstrate dyslipidemia, it is thought that a secondary cause contributes to this phenotype. An elevation in VLDL remnants increases CAD risk.4 It is thought that targeting non-HDL-C, instead

of Apo B, may have more clinical utility.2 Orange palmar xanthomas, elbow and knee tubero-eruptive xanthomas and peripheral vascular disease may be found on exam.

Primary mixed hyperlipidemia (Fredrickson Type 5)—Like Familial hyperchylomicronemia, patients with Primary mixed hyperlipidemia have triglyceride levels >1000 mg/dL. Unlike Familial hyperchylomicronemia, the patient’s total cholesterol levels are also elevated and the disorder usually manifests in adulthood. Chylomicrons and VLDL elevations result from a partial deficiency of LPL or Apo C- II. They are at risk for CAD and pancreatitis. They can exhibit eruptive xanthomas, hepatosplenomegaly and lipemia retinalis.6

The appearance of a patient’s plasma can also aid in diagnosis. If a patient with severe HTG has not responded to medications, plasma should be visually assessed after phlebotomy. If plasma is clear, as opposed to cloudy or lactescent, glycerol kinase deficiency should be considered.7 Glycerol kinase deficiency, an X linked genetic disorder, causes an accumulation of free glycerol in plasma. During triglyceride synthesis, three fatty acids attach to one glycerol molecule. Most labs count glycerol instead of triglycerides when calculating triglyceride levels, thus overestimating triglycerides if free glycerol is elevated. If one suspects glycerol kinase deficiency, the clinician should seek a lab that controls for glycerol concentrations.8

Treatment

Secondary CausesTreating secondary causes of HTG will improve triglyceride levels, thus requiring less medication. Pregnant women with triglycerides > 350 mg/dL should be referred to a high risk obstetrician and lipid specialist since pancreatitis can increase fetal and maternal morbidity and mortality.9 Examining the patient’s prescription list may reveal medicines that increase triglycerides, some of which may be substituted for a lipid neutral medication. For example, the older beta blockers may be replaced by newer beta blockers, carvedilol or nebivolol.

Diet and ExerciseAlcohol abstinence is recommended for the long-term prevention of pancreatitis.10 Fat restriction is extremely important for patients with Familial hyperchylomicronemia, since they may not respond to medications. When hyperchylomicronemia is severe, fat should be restricted to < 15% of total calories per day.¹ Medium-chain triglycerides, available as cooking oil, can provide fat that does not allow chylomicron formation since it bypasses the intestine.11 Since Familial hypertriglyceridemia, Dysbetalipoproteinemia and Familial combined hyperlipidemia can be exacerbated by metabolic disease or poor diet, it is important to counsel patients about alcohol, fat and carbohydrate intake. 2,12,13 Replacing trans-fatty acids with monounsaturated or polyunsaturated fat lowered triglyceride levels in a meta-

Secondary causes

Diseases/states Renal disease, thyroid disease, autoimmune disease, HIV, hepatic disease, pregnancy, diabetes, metabolic syndrome, obesity

Diet and exercise Alcohol, high carbohydrate and/or high fat diet, physical inactivity

Medications Beta blockers, thiazide diuretics, bile acid sequestrants, corticosteroids, estrogen, androgens (rarely), SERMS, antiretrovirals, atypical antipsychotics, isotretinoin

Table 1. Secondary causes of HTG.


analysis of controlled dietary trials.14 A low carbohydrate diet (<50% of calories from carbohydrates) should be recommended.1,2

Dietary fiber and complex carbohydrates should be emphasized and simple carbohydrates should be avoided.1,2 Weight loss, if needed, should be encouraged as a weight loss of 5-10% may result in a 20-30% reduction in triglycerides.15

Exercise increases lipoprotein lipase and decreases hepatic lipase activity, both which lower triglycerides. 16 Unfortunately, patients with primary HTG may not experience the same decrease in triglycerides as someone with secondary HTG. However, an exercise program should still be recommended based on patient age and abilities.

Pharmacologic treatmentWhen a patient’s triglyceride level is < 500 mg/dL, the clinician will first target LDL-C and non-HDL-C. The medications used to lower LDL-C and non-HDL-C also lower triglycerides to varying degrees. Once the patient has met his or her LDL-C and non-HDL-C goals, or if a patient presents with triglycerides > 500 mg/dL, fibric acids, omega-3 fatty acids and niacin, used primarily for triglyceride lowering, should be considered. Fibric acids are often prescribed initially, although omega-3 fatty acids may be favored in women of childbearing age. Doses at or above 4 grams daily of docosahexaenoic acid and eicosapentaenoic acid (DHA/EPA) are usually necessary. If triglycerides are above 400 mg/dL, omega-3 fatty acids and fibric acids can increase LDL-C, although shifting the pattern to larger less dense low density lipoprotein (LDL) particles and still lowering non-HDL-C. Niacin lowers LDL-C and increases high density lipoprotein cholesterol (HDL-C), in addition to lowering triglycerides and non-HDL-C, but should be used with caution in patients who have pre-diabetes

or metabolic syndrome since it can worsen glycemic status.

Orlistat is a gastric and pancreatic lipase inhibitor which is FDA approved for weight loss and maintenance. Dietary fat cannot be hydrolyzed and undigested triglycerides are not absorbed.17 Orlistat has successfully lowered triglycerides in patients with Familial hyperchylomicronemia when used as an adjunct to dietary therapy.18 It has been suggested that the triglyceride-lowering effect of omega-three fatty acids or medium chain triglycerides may be lost if administered simultaneously.18,19

When managing a patient with elevated cholesterol and HTG, it is important to remember that bile acid sequestrants can increase triglycerides and are contraindicated at triglyceride level > 500 mg/dL. Their effect on triglyceride level should be monitored for those with triglycerides > 300 mg/dL.

Does the Diagnosis Matter?If patients with primary HTG are treated to goal, some would argue that the specific genetic defect causing the HTG is not significant. However, the lipoprotein elevation that results from the genetic

defect is significant when cardiovascular disease and pancreatitis risk is considered. If the clinician believes that their patient has an elevation in the atherogenic lipoproteins, chylomicron remnants, VLDL, VLDL remnants and LDL, then the clinician may focus on cardiovascular disease prevention and screening.20 If the clinician suspects an elevation in chylomicrons, then pancreatitis is a great concern. In addition, nuances in dietary and pharmacological treatment affect response between types of primary HTG. Lastly, a discussion with patients about the likelihood of a genetic basis for their disease may compel family members to be tested and treated. n

Disclosure statement: Ms. Milne has received honoraria related to speaking from Kowa Pharmaceuticals America. She has received consulting fees from Amarin Corporation, Aegerion, and Genzyme.


Medication Reduction in triglycerides

Mechanism of action Cautions and contraindications

Fibric acids 20-60% Decreases serum VLDL and increases production of LPL

Renal disease, hepatic disease, gallstones, pregnancy, breastfeeding, caution with simultaneous use of statins (avoid gemfibrozil), may increase LDL-C

Omega-3fatty acids

35-50% Reduction in hepatic triglyceride synthesis, an increase in LPL activity and/or increased hepatic beta oxidation

Fish allergy, may increase LDL-C

Niacin 20-50% Inhibits VLDL and LDL synthesis

Pregnancy, peptic ulcer disease, renal disease, liver disease, pre-diabetes, gout

Table 2. Medications used primarily for triglyceride lowering.

16 LipidSpin

Patient LH, a 39-year-old white male came to me for evaluation as he was concerned about his risk for coronary heart disease (CHD). His father had coronary artery disease at age 46. He had 99% blockage of his right coronary artery and subsequent stent placement. While not first degree relatives, he also has several aunts, uncles, and cousins with early coronary heart disease (defined as women prior to age 55 and women prior to age 65).

On his first visit he stated that he felt very well overall and denied chest pain, pressure, or dyspnea. He is very active. He runs 3 miles a day on weekdays and 5-7 miles a day on weekends, He does not smoke, he has an occasional alcoholic beverage and had states he never used illicit drugs. He admitted to a poor diet and often ate “take-out.” He worked as an

architect and is married with no children. He took no medications. His blood pressure was 125/78. He was 175 cm tall and he weighed 70 kg. A 12-lead EKG showed normal sinus rhythm at 66 beats per minute and no other abnormalities.

the month prior to his first visit the following levels were reported: Total cholesterol 215 mg/dLLDL-C 122 mg/dLHDL-C 45 mg/dLTriglycerides 242 mg/dL

Based on NCEP ATP III, what are the lipid goals for this patient? He only has one traditional risk factor, so this and Framingham Risk Score may not be helpful for this patient. Based on ATP III his LDL-cholesterol (LDL-C) goal is < 160 mg/dL.His triglycerides are elevated but may very well respond to dietary modification. Should I have stopped my evaluation here? What about the “family history?”

Our patients often relate a family history of early CHD which should raise a “red flag.” At present, it is difficult for clinicians to assess and incorporate this information into a management plan.

The independent association of early CHD in a first degree relative and associated risk has been demonstrated in many prospective cohort and case-control studies. In the Atherosclerosis Risk in Communities (ARIC) Study1 it was found that a family history of premature CHD was independent of other risk factors. While many risk factors such as hypertension and dyslipidemia are present in those with early CHD, these risk factors account for only a portion of the aggregate CHD seen in families.2,3

The Framingham Risk Score does not include family history. In a prospective study, Lloyd-Jones and colleagues used the Framingham cohort study data base to investigate risk due to family history. Using validated events, they found that parental cardiovascular disease independently predicted the future of offspring events in middle-aged adults. However, the investigators go on to say that the addition of validated parental data into multivariable functions predicting 10-year absolute risks may only increase the predictive accuracy to a small extent. “The overall C statistic for our multivariable model increased from 0.82 to 0.83.”4

Case Study I: The Patient with Family History of Premature Coronary Heart Disease

MERLE MYERSoN, MD, EdD, FACCDirector, Center for Cardiovascular Disease PreventionDirector, Cardiology Section, Center for Comprehensive Care (HIV) ClinicAttending CadiologistSt. Luke’s-Roosevelt Hospital New York, NY Assistant Professor of Clinical Medicine and Epidemiology Columbia University College of Physicians and SurgeonsNew York, New York

Discuss this article at www.lipid.orgGo to “Topics/Lipid Spin Fall 2012” and look for “Case Study I.”


In 2001, the NCEP ATP III Guidelines stated: “The presence and age of onset of CHD in all first-degree relatives should be assessed. The family history should be considered positive for premature CHD if clinical CHD or sudden death can be documented in first degree male relatives younger than 55 years of age and in first degree female relatives younger than 65 years of age. Because a positive family history of premature CHD provides information about the risk for CHD and the probability of having modifiable risk factors, it should serve important information helpful in making treatment decisions relative to setting and reaching LDL-cholesterol goals in primary prevention.”

The Reynolds Risk Score was introduced in 2007 to focus on risk for women. Thirty-five factors were assessed in healthy women who were 45 years of age or older. “Parental history of MI < age 60” is included in the score.5

More recently, the European Guidelines on Cardiovascular Disease Prevention state “The importance of familial prevalence of early-onset CVD is not yet sufficiently understood in clinical practice.” “Family history is a variable combination of genetics and shared environment.” “Because of the polygenic and polyfactorial determinants of the most common CVDs, the impact of any single polymorphism remains rather modest.” The guidelines do go on to recommend “Familial prevalence of atherosclerotic disease or of major risk factors…should be systematically sought in the first-degree relatives of any patient affected before 55 years in men and 65 years in women.”6

The reason for lack of complete understanding is that “family history” is a general term and does not reflect a particular environmental or genetic abnormality. In an editorial, Christopher J.

O’Donnell of the Framingham Heart Study stated “…what has remained unclear are the pathophysiological/genetic mechanisms of the familial risk, the extent to which familial risk is independent of other risk factors, and the extent to which risk conferred by a positive family history of CHD is modifiable.”7

While we cannot definitively assess whether a positive family history has conferred risk to our patients, many providers use a positive family history to weigh the balance towards aggressive treatment of other risk factors including lipids. Another approach is to perform advanced lipid testing to help assess overall risk and to help determine need for pharmacologic treatment.

Advanced Lipid and Biomarker testing

Lipoprotein (a) [LP(a)]LP(a) has a very strong genetic component—it is under the control of the LP(a) gene. LP(a) is unaffected by diet and most drugs; and has been associated with premature CHD. Lp(a) has positive predictive value that is additive to other lipid and traditional risk factors.

A consensus panel of the European Atherosclerosis Society issued a statement stating that LP(a) should be measured once in all patients at intermediate or high risk of CVD/CHD who present with associated characteristics including family history of premature CVD. The panel goes on to state “For reduction of plasma Lp(a) as a secondary priority after LDL-cholesterol reduction, we recommend a desirable level for LP(a) < 80th percentile (less than about 50 mg/dL). Treatment should primarily be niacin 1-3 g/day…”8

The panel’s recommendation for testing and treating has been criticized by many including Samuel Goldhaber who wrote that “problems with standardization and reporting of Lp(a) assays have persisted without resolution.” More important, there has been no randomized prospective clinical trial of treatment of Lp(a).9

In 2011, an expert panel of the National Lipid Association issued a statement on the clinical utility of advanced lipid testing. Measurement of Lp(a) is reasonable when there is “a very strong family history of vascular events…” The statement outlines that the impact of treatment has yet to be determined by clinical trials, making use of niacin unclear, but other evidence suggests that an elevated Lp(a) should prompt aggressive reduction of LDL-C.10

Residual Risk: Non-hDL Cholesterol, Apolipoprotein B, and LDL Particle NumberThe concept of non-HDL cholesterol was discussed in the NCEP ATP III guidelines. It was recommended that in patients with TG > 200 mg/dL, non-HDL cholesterol (“atherogenic cholesterol”) should be a secondary target of therapy.

Non-HDL cholesterol has also been shown to improve on LDL-C in terms of risk prediction. Some recent investigations have identified LDL-particle number and

The reason for lack of complete understanding is that “family

history” is a general term and does not reflect a particular environmental or

genetic abnormality.

18 LipidSpin

ApoB as even better able to predict risk and targets for therapy as non-HDL11,12,13

however others have not.14,15

The NLA Expert Panel recommends that measuring LDL-P is “reasonable for many patients” with a family history of premature CHD” “When LDL-P is discordantly elevated, consideration should be given to initiating LDL-lowering therapy.” The panel also states that measurement of ApoB is “reasonable for many patients” with a family history of premature CHD based on the fact that “familial combined hyperlipidemia is the most common atherogenic dyslipoproteinemia associated with premature CHD.10

Lp-PLA2This enzyme has shown to independently predict risk for CVD and to also be an active participant in development of atherosclerosis. At present there is no FDA-approved drug to treat Lp-PLA2 but existing lipid-lowering medications have been shown to lower levels. The NLA Expert statement recommends measurement of Lp-PLA2 be “considered for selected patients” with a positive family history.10 Lp-PLA2 is considered reasonable for patients in intermediate risk.

CRPC-reactive protein is a non-specific inflammatory marker that has been extensively studied in terms of risk for CHD. The NLA panel recommends “In patients with a premature family history of CHD…CRP measurement is a reasonable option to help determine if therapy should be started…”10

testing for presence of subclinical atherosclerosisIn addition to advanced lipid and biomarker testing, Coronary artery calcium and carotid intima-media thickness have been used to help risk-stratify patients with intermediate risk. While no guidelines

specifically address their use in an otherwise low-risk patient with family history, these tests can also be considered to help determine risk and management in such patients.16

Follow-UpGiven his high triglycerides and poor diet, I counseled the patient and gave him educational material on a heart-healthy diet. I also ordered another fasting lipid profile and advanced lipid testing. The patient was compliant with the lifestyle modifications and three months later had another blood test. Total cholesterol 187LDL-particle number 1723LDL-C 125HDL-C 43Triglycerides 95Lp (a) 4Glucose 98TSH 4.1 uIU/mLLp-PLA2 155CRP 1 mg/LApolipoprotein B 120 mg/dL

The advanced testing results were all unremarkable with the exception of LDL-particle number and Apolipoprotein B. His TG had improved most likely due to the changes in his diet. His Lp(a), Lp-PLA2, and CRP were low.

Testing showed that there was discordance between the LDL-C and LDL-P and ApoB. While LDL-C and LDL-P are generally correlated, they may also be discordant—meaning one value is high and the other low, or vice versa. In this case, the LDL-C was low and at goal but the LDL-P number was quite high.

As discussed above, LDL-P has been shown to potentially improve risk predication for CHD in groups of individual patients better than LDL-C. Mechanistically, the particles, containing the cholesterol enter

the arterial wall by a gradient-driven process. Once inside, the particles bind to the arterial wall and the process of plaque formation is initiated.17

I reviewed the lab testing with the patient. We discussed imaging studies (stress test, CAC, CIMT), further lifestyle modification, or pharmacologic treatment.

We decided on CAC; his score was zero. With the absence of other risk factors and zero calcium score, we decided to hold off on pharmacologic treatment. He agreed to go for medical nutrition counseling to enforce the improvements in his diet. We will recheck a basic lipid profile and LDL-P in six months. n

Editors’ Note: Question—How many of you would have tried to normalize his lipid particles with medication given his family history and prior stent placement for the 90% occlusion?

Disclosure statement: Dr. Myerson has received consulting fees from LipoScience Inc. and Kowa Pharmaceuticals America. Dr. Myerson has received grants from Medtronic and LipoScience Inc.



In 2011, the NLA and the National Heart Lung and Blood Institute (NHLBI) sponsored expert panel on Integrated Cardiovascular Risk Reduction for Children and Adolescents each recommended universal lipid screening of United States children at age 9-11 years.1,2 Prior reports recommended cholesterol measurement over age 2 years in the presence of a positive family history of heart disease or elevated cholesterol or the presence of a co-morbid condition known to increase cardiovascular risk. This latter recommendation was retained by the NHLBI Integrated Risk Reduction panel. The two guidelines, by design, are essentially identical with regard to formal recommendations; however, the purpose of each is somewhat different. The NLA recommendations are directed towards identifying all children with familial hypercholesterolemia (FH). The Integrated Risk Reduction guideline takes a different approach to cardiovascular risk reduction in youth, integrating risk factor management developmentally across childhood and across all the risk factors to provide comprehensive primordial and primary prevention strategies that consider

the whole child rather than managing individual risk factors independently. Each set of recommendations has generated controversy.

In the NLA consensus-based statement, and for the first time in the United States, FH is considered as a distinct disease entity, separate from epidemiologically based lipid assessment. Thus, increased risk associated with lifelong exposure to severe and genetically elevated cholesterol levels is, finally, given appropriate consideration. The controversy related to the NLA recommendations is international, where many Western countries and some others have embraced cascade screening of identified index cases of FH, often with confirmation by genetic testing, as opposed to universal population screening as recommended in the NLA guideline. For example, in the Netherlands where FH genetic identification is most advanced, probably about 80% of FH carriers have been identified. In the United Kingdom, identification of those with FH between the ages of 40-70 years and subsequent cascade screening with genetic testing and lipid treatment is highly cost effective.3

In fact, if one looks deeply at current cost analyses for FH care, one learns that treating an identified patient with FH is highly cost effective (particularly with generic medications) and gene testing does not substantially worsen these projections (particularly as testing becomes much cheaper in the future). Adverse cost in FH management is largely incurred in case identification. The NLA panel recommended universal screening for FH because of the historic failure of physicians in this country to successfully implement cascade screening, the recognition that family history is an inadequate criterion for youth screening, and the high discrimination in childhood between true cases and unaffected individuals. Genetic testing was not recommended because risk is determined more by LDL cholesterol

Lipid Luminations: The Controversy Over Universal Cholesterol Screening for Children

SAMUEL S. GIDDING, MDCardiology Division Head

A. I. DuPont Hospital for ChildrenNemours Cardiac Center

Wilmington, DE


and look for “Lipid Luminations.”

level than genotype. In contrast, in the rest of the world, universal lipid screening is prohibitively expensive, and index cases are identified at older ages when genetic testing often helps risk stratification. In my view, this discussion is not so much a controversy as a very healthy scientific and public health argument that in the short term will lead to increased recognition and awareness of FH in the medical and general community and, in the long term, to cost effective treatment strategies appropriate to the varied health care systems and resources around the world.

The controversy over the evidence-based NHLBI sponsored Integrated Cardiovascular Risk Reduction Guideline exists mostly within the United States. Concerns are raised about the true benefit in cardiovascular disease risk reduction from early identification, the unknown harms of pharmacologic treatment, and cost. These arguments are not that different from those raised 20 years ago when the first selective screening recommendations were made and are legitimate concerns.4 However, to be frank, I have a hard time accepting these arguments as sufficient. In contrast to the international debate on the best way to recognize and treat FH, this argument has the potential to destroy efforts to prevent heart disease in this country.

The current NHLBI-sponsored 2011 Integrated Guidelines are unique compared to prior expert recommendations. Most important, they are evidence-based and were developed according to the highest recommended process as defined by the Institute of Medicine. 5 The critiques described above were considered in the weighting of evidence (these critiques are actually included in the text of the guideline) and the panel’s conclusion was that the evidence for universal screening far

outweighed the evidence against. In the minds of the panel, the knowledge that atherosclerosis begins in youth and is directly related to risk factors, that genetic disorders of lipid metabolism provide overwhelming and consistent evidence for the benefit of lifelong LDL cholesterol levels below 100 mg/dL, that clinical trials have been conducted that show medium term safety and efficacy of statins with improvement in subclincal atherosclerosis outcomes, and that selective screening strategies fail to identify a significant percentage of those with severe elevations of cholesterol outweighed gaps in evidence related to long term safety and cost.

Perhaps the most radical (and underappreciated) change in the 2011 Integrated Guidelines compared to prior efforts is the fact that they are designed to evaluate all cardiovascular risk factors in every child both developmentally and across all risk factors, as opposed to creating “risk silos” engendered by prior guidelines for individual risk factors. The rationale for this approach comes from recognition of the importance of preventing risk development in the first place (primordial prevention), of the natural history of atherosclerosis and the importance of multiple risk factors to rapid atherosclerosis progression, of the need to tailor recommendations to the age of the child and the needs of the entire family, and of the importance of obesity to the development of multiple cardiovascular risk factors. Additionally, there is a small subset of children who need cardiovascular risk management: those with FH, diabetes, chronic kidney disease, and other high risk conditions. The focus on whether or not to measure cholesterol in children undercuts and deflects from the two more important goals of the 2011 guideline: to improve cardiovascular health across all risk factors before target organ injury is advanced and to make sure that small subgroup of

children at highest risk is identified.

To summarize, it is probably worth considering if universal screening at age 9-11 years is that different from current recommendations. In ATP III, universal screening is recommended at age 20 years, when very few people regularly go to the doctor. Prior youth recommendations would test 60-65% of United States children, largely because of the high prevalence of obesity and positive family history. What these new recommendations do is increase awareness of the importance of healthy lifestyle habits for all, move the cholesterol test up about 10 years for about 35-40% of the population to an age when genetic dyslipidemias can be recognized and at an optimal time for intervention, and allow for dietary intervention at an age when preventive health care is the norm. Is that so bad?. n

Editors’ Note: Dr. Gidding was a member of the NLA and NHLBI expert panels that drafted the lipid screening guidelines.


20 LipidSpin


Case Study IIDoes Gender Matter in Cardiovascular Risk Assessment?

JR is a 69-year-old white female with long-standing, well-controlled hypertension treated with an ACE-inhibitor who comes in for a cardiovascular risk evaluation. She denies a personal history of diabetes, tobacco abuse, psoriasis, collagen vascular disease, or chronic kidney disease. There is no family history of premature vascular disease. She is moderately active and has no clinical symptoms referable to the cardiovascular system. Her medications also include anti-depressants and supplemental thyroid.

Her blood pressure is 135/85. Her physical examination and electrocardiogram are normal. There are no findings of left

ventricular hypertrophy.

Routine chemistries reveal normal renal function, fasting blood glucose, and thyroid stimulating hormone. On fasting lipid profile total cholesterol is 260 mg/dL, triglycerides 156 mg/dL, HDL-C 72 mg/dL, LDL-C 157 mg/dL and non-HDL-C 188 mg/dL.

Does she need an aspirin and what are her lipid goals?

In the Women’s Health Study, 39,856 women over the age of 45 without baseline cardiovascular disease (CVD) were randomized to low dose aspirin versus placebo and followed for an

average of 10 years. In this study, there was no advantage to the use of aspirin 100 mg every other day in the reduction of a combined endpoint of stroke, non- fatal myocardial infarction (MI), or cardiovascular death. However, there was a significant 17% reduction in the risk of stroke. There was a 24% reduction in ischemic stroke risk and a non-statistically significant increase in hemorrhagic stroke risk. In a subgroup analysis of women over the age of 65, aspirin significantly reduced the risk of major cardiovascular events, ischemic stroke, and MI.1

The 2011 American Heart Association (AHA) Effectiveness-Based Guidelines for

DANIELLE DUFFY, MD, FACCAssistant Professor of Medicine, Jefferson Medical College

Director, Cardiovascular Risk Reduction, Jefferson Heart InstitutePhiladelphia, PA

EDWARD GoLDENBERG, MD, FACC, FACP, FNLAMedical Director of Cardiovascular Prevention and Employee Wellness

Christiana Care Health SystemNewark, DE


and look for “Case Study II.”

the Prevention of Cardiovascular Disease in Women recommends the use of aspirin therapy in women 65 years of age or older (81 mg daily or 100 mg every other day) if blood pressure is controlled and the benefit for ischemic stroke and MI prevention is likely to outweigh the risk of gastrointestinal bleeding and hemorrhagic stroke. These guidelines also note that aspirin may be reasonable for women less than 65 years of age for ischemic stroke prevention.2

It is important to note the gender differences in the benefit of aspirin, as the data from the Physicians Health Study, although older, demonstrated a 44% reduction in the risk of MI in men who took 325 mg of aspirin every other day compared with those who received placebo.3 This gender difference in the effectiveness of aspirin may be related to differences in vascular pathophysiology, and is highlighted by demographic trends. In 2008, there were 419,700 women and 392,200 men who died of CVD.4 Death from coronary heart disease (CHD) or MI was more common in men (73% of the men versus 59% of the women). However, death from stroke, hypertension, or congestive heart failure was more common in women (35% of the women versus 26% of the men).4

The 2009 U.S. Preventive Services Task Force (USPSTF) recommends the use of aspirin in women ages 55 to 79 for stroke prevention when the potential benefit outweighs the potential risk of gastrointestinal bleeding. Specifically, for women ages 60-69, aspirin is recommended when the 10 year risk of stroke is 8% or greater.5 For comparison, the USPSTF recommends the use of aspirin for prevention of MI in men ages 45 to 79 years when the potential benefit outweighs the potential harm.5

JR’s risk of developing a stroke in the next ten years is 8%, which exceeds the average risk in the United States of 7.2%.6,7 Based on both the USPSTF recommendations and the AHA Prevention Guidelines for Women, low dose aspirin is a very reasonable recommendation for JR.

How about a statin?

Statins have been proven to reduce the risk of stroke in both primary and secondary prevention trials. In the Heart Protection Study, 20,536 high-risk patients were randomized to moderate-dose statin versus placebo. In this trial, statin use was associated with a 25% relative risk reduction in the occurrence of a first stroke event, regardless of baseline LDL-C level.8 A recent meta-analysis by the Cholesterol Treatment Trialists’ Collaborators also demonstrated a significant reduction in stroke risk with statin use and subsequent LDL-C reduction, regardless of baseline risk level.9

Although stroke risk is lowered with statins, we generally consider the recommendation for statin therapy based on a patient’s overall cardiovascular risk and the benefit of reducing all CVD events.

Based on JR’s traditional Framingham risk factors (age and hypertension, minus one for having an HDL-C > 60 mg/dL), she would fall into the low risk category (0-1 risk factor) with a LDL-C treatment target of less than 160 mg/dL and a non-HDL-C target of less than 190 mg/dL.10 Following the step-wise approach recommended by the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III), we would not be expected to calculate a Framingham risk score. Even if we did, her 10-year risk of coronary death or MI would also fall into the low risk category at 6%, notably lower than her estimated 10-year stroke risk of 8%.

Therefore, JR’s LDL-C of 156 mg/dL seems to be within her treatment goal as does her non-HDL-C. Should we really stop here or are we missing something?

It is now well-recognized that the traditional Framingham risk assessment has limitations and can underestimate risk in women, especially in young women. Some of these limitations include: the focus on short-term (ie.10-year) risk of “hard” coronary outcomes only (MI or CHD death), the lack of inclusion of family history in risk calculators, overestimation or underestimation of risk in nonwhite populations, and the fact that subclinical CVD can have a relatively high prevalence among women who are scored as being at low risk.2 In order to address some of these limitations, alternative risk stratification schemes have been adopted in certain guidelines such as the AHA Prevention Guidelines for Women.2 Indeed the AHA guidelines propose three risk categories: high risk, at risk, and ideal risk. JR would fall into the “at risk” category based on her risk factors of hypertension and elevated total cholesterol. Of note, this “at risk” category also includes non-traditional risk factors, which JR doesn’t have, such as poor exercise capacity, lupus or rheumatoid arthritis, and evidence of subclinical CVD. For “at risk” women, the AHA guidelines do recommend calculating a Framingham risk score using the newest Framingham risk calculator in order to further refine treatment targets.

As noted above, one of the limitations of the traditional Framingham risk calculation is that it only estimates the 10-year risk of CHD death or MI, and does not account for other vascular events. A newer risk assessment model, also based on Framingham data, expands the risk calculation to include all first cardiovascular events such as coronary artery disease, stroke, manifestations

22 LipidSpin

of peripheral vascular disease, or heart failure.11 If we calculate JR’s “general cardiovascular risk score,” she actually falls into the moderate risk category with a 13.7% risk of developing a major vascular event in the next 10 years.11,12 This general CVD risk profile also calculates a “vascular age,” which is a translation of the patient’s general CVD risk points to the equivalent age assuming all other risk factors are optimal. JR’s vascular age is greater than 80, over 10 years older than her biologic age. Based on her general CVD risk score, JR’s LDL-C goal would be less than 130 mg/dL with an optional goal of less than 100 mg/dL, and she would qualify for a statin as first line therapy in addition to lifestyle counseling to achieve her LDL-C target.13 One other important concept for assessing and communicating cardiovascular risk is that of “lifetime risk.” For many patients,

especially young patients, 10-year risk is relatively short term, and the Framingham risk score may be very low unless there are multiple uncontrolled risk factors. Lifetime risk or 30-year risk has emerged as a tool that better reflects the cumulative burden of risk factors over a much longer period of time. A high lifetime risk can identify patients who may be at low short-term risk, but would certainly benefit from additional lifestyle counseling or even preventive pharmacotherapies. Based on data from the Cardiovascular Lifetime Risk Pooling Project, JR’s lifetime risk (to the age of 90) of any event related to atherosclerotic CVD is estimated at 38.7% based on her age and the presence of 2 major risk factors (treated hypertension and total cholesterol greater than 240 mg/dL). For comparison, her risk would be 12.4% if all risk factors were optimal.14

For JR, a statin should be recommended in addition to aspirin to lower her overall risk of CVD, including both coronary events and stroke. Her recommended LDL-C goal should be less than 130 mg/dL with an optional goal of less than 100 mg/dL, and a moderate dose statin should be prescribed to achieve this goal. n

Disclosure statement: Dr. Duffy has received grants from Roche/Genentech, Forest Laboratories, and Abbott Laboratories. Dr. Goldenberg has received honoraria related to speaking from Takeda Pharmaceuticals, Boehinger-Ingelheim, Abbott Laboratories, and Merck & Co. Dr. Goldenberg has received consulting fees from Amarin Corporation.



Learn more at

Phone: 904.309.6250

www.lipidspecialist.org

Strive for ExcellenceDemonstrate Your Expertise by Achieving Certification as a Clinical Lipid Specialist

Accreditation Council for Clinical Lipidology

The ACCL Offers Two Pathways to Recognition:

I. The Clinical Lipid Specialist (CLS) Certification Program is open to allied health professionals with advanced knowledge, experience and/or interest in specializing in lipid management.

II. The Basic Competency in Clinical Lipidology (BCCL) Exam is a competency assessment and credentialing pathway open to any healthcare professional with basic involvement in the lipid field.

Select a pathway that matches your professional goals. ACCL exams will evaluate and validate the specialized knowledge and training required to practice in the dynamic and multifaceted field of lipid management.

"I joined a multidisciplinary team focused on chronic disease management as the lipid specialist and gained a new level of respect from my teammates. Clinicians consult me for the best lipid management tactics and I have increased job security as I am the only registered dietitian certi�ed as a Clinical Lipid Specialist in my state.”

Julie Bolick, RD, MS, CD, CLSSalt Lake City, Utah

24 LipidSpin

When he moved to South Dakota to fulfill a rural medicine requirement, Suneet Verma, MD, never guessed he would become fas-cinated with lipids. A native of Delhi, India, Dr. Verma came to the United States to do his post-graduate training in internal medi-cine at the University of Pittsburgh Medical Center. In South Dakota, he worked as an internist at Avera McKennan University Hospital and also as a Clinical Associate Professor of Medicine at the University of South Dakota School of Medicine, where he taught medical students, internal medicine residents and mid-level providers. Dr. Verma had significant interest in preventive medicine and always enjoyed conducting patient education as part of his treatment strategy. He observed that significant opportunity existed in South Dakota where rural farmers had poor un-derstanding of cardiovascular risks and their eating habits were not necessarily healthy. There was an epidemic of obesity, diabetes, metabolic syndromes and fatty liver issues. Studying fatty liver and how it relates to

other issues led Dr. Verma to take an inter-est in complicated dyslipidemias and the mechanics of atherosclerosis and vascular biology. He searched for resources and began attending NLA meetings to network with others, as there were few lipidologists in South Dakota. As his interest in lipids grew, Dr. Verma became involved with re-search and successfully ran clinical trials at Avera Research Institute, where he served as principal investigator for the Stabiliza-tion of Atherosclerotic Plaque by Initiation of Darapladib Therapy Trial (STABILITY). He participated in area television shows to educate local residents about about genetics, dyslipidemia, cardiovascular risk factors and hypertension. Before long, Dr. Verma was helping colleagues develop lipid clinics as a complimentary service at the hospital. “I was the only lipidologist in Sioux Falls at one time, the next closest one was the Mayo Clinic in Rochester, Minn., and some high risk patients started to Google me and drive in from the remote towns for office visits,” he said. “I was impressed that patients were becoming aware of their risk factors, and I started getting referrals from colleagues and building a little niche in this area.”

After leaving South Dakota, Dr. Verma com-pleted a fellowship at Temple University in Philadelphia. Now a member of the North-

east Lipid Association, he lives with his fam-ily in Cherry Hill, New Jersey. With the move to the Northeast came a new opportunity: this September, Dr. Verma began a position at Fox Chase Cancer Cen-ter, a Temple University affiliate, where he works as an internal medicine physician and also will be developing a geriatric oncology program. “It’s a unique opportunity because cancer patients have unique challenges, especially in regard to their frailty, age, multiple co-morbidities and they often have very com-plicated dyslipidemias and polypharmacy,” he said. While he is looking forward to the future, Dr. Verma credits the NLA with much of his early career success. Dr. Verma is a strong advocate to spread NLA’s mission among the general population and with his colleagues. He has served on several NLA committees and the Midwest Lipid Association Board of Directors.

“This organization offers a very collegial setting and I really like the group of people who started the NLA,” he said. “It is easy to become involved and the NLA has become a trusted source of clinical guidance.” n

Member Spotlight: Suneet Verma, MD

SUNEEt VERMA, MD, FACP, FNLAInternal Medicine PhysicianFox Chase Cancer CenterPhiladelphia, PA


Discuss this article at www.lipid.orgGo to “Topics/Lipid Spin Fall 2012” and look for “Member Spotlight.”


2012 Scientific Sessions Poster AbstractCongratulations to the NLA Young Investigator Ike Okwuosa, MD, who won First Place during the

Young Investigator Competition* during the 2012 Annual Scientific Sessions.

Initiation of Statins in Patients on Hemodialysis: does the evidence support the practice?

Ike Okwuosa, MD; Eric Tuday MD, PhD; Neil Stone, MD

Abstract

Synopsis: Patients with end stage renal disease (ESRD) are at high risk of developing cardiovascular disease (CVD) related complications. Statins have been proven to reduce cardiovascular complications in those at elevated CVD risk and per person meta-analyses of randomized clinical trials have shown statins to be associated with increased survival. The Die Deutsche Diabetes Dialyse Studie (the 4D study) and A Study to Evaluate the Use of Rosuvastatin in Subjects on Regular Hemodialysis: An Assessment of Survival and Cardiovascular Events (AURORA) have both demonstrated no significant benefit compared to placebo if statin therapy was begun in those on hemodialysis. In this study we attempt to assess physician practice patterns in response to the 4D and AURORA study.

Methods: This study was a single center retrospective review of patients with a diagnosis of ESRD on dialysis from 2006 to 2010 at Northwestern Memorial Hospital. The primary end point of this study was to determine if there was a decline in incidence of statin prescriptions following the 4D and AURORA studies.

Results: From 2006 to 2010, 1725 patients were identified as having a diagnosis of ESRD. During this period 905 patients were initiated on a statin and 820 were not. The patients in the statin group were older and had a higher rate of diabetes. In all, 68% of diabetics with ESRD were started on a statin. There was a significant increase in the trend of prescribing statin therapy by year in all patients with ESRD. Amongst ESRD patient with diabetes, there was also a significant increase in the trend of prescribing statin therapy.

Conclusions: Despite the results of the 4D and AURORA studies, two large multicenter randomized trials that demonstrated no survival benefit in initiating statins to patients with ESRD on hemodialysis, the practice remains prevalent. Further studies are needed to determine if there are subgroups that benefit from statin initiation in those on hemodialysis. Moreover, physicians would benefit from guidance from clinical guidelines.

2005 2006 2007 2008 2009 20100

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New Statin RxNew ESRD Dx

# Pa

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Figure 1.

Figure 2.

Figure 3.

Figure 1 – New ESRD diagnoses by year compared with new initiation of statin therapy on or after the new ESRD dianosis. Graphs show a significant increase in statin therapy among ESRD patients. (p<.0001)

Figure 2 – New ESRD diagnoses with a concurrent diagnosis of diabetes by year compared with a new statin therapy. Graphs show a significant increase in statin therapy among ESRD-diabetic patients. (p<.0001)

Figure 3 – Kaplan-Meyer type analysis of time from dialysis initiation to initial or new-continued statin therapy in ESRD patients with diabetes compared to their non-diabetic counterparts. There was a greater number of patients previously on statin therapy, a more rapid onset of statin therapy, and a larger overall percentage of patients on statins in the diabetic group. (p<.0001)

* The NLA Young Investigator Competion was sponsored by LipoScience Inc.

26 LipidSpin

News and Notes

International UpdatesNLA President Peter toth, MD, PhD, will represent the NLA at the Annual Conference of the Polish Lipid Association (PoLA) from September 7-8 in Warsaw, where he will present on the “Current Position of Fibrates in Lipid-lowering Therapy.” NLA member Kevin Maki, PhD, will present updates regarding cholesterol and triglycerides during the “Masters Class in Lipids and Cardiovascular Protection,” a joint initiative of the NLA and the Australian Atherosclerosis Society that will take place in Sydney from October 5-6.

Peter toth, MD, PhD, will be a guest speaker at the World Congress of Clinical Lipidology in Budapest, Hungary, from December 6-9. He will be part of a plenary session on lipid guidelines around the world and will lead a workshop on “Difficult to Treat Hyperlipidemia.”

Important Legal Advice for Members of the NLA In recent weeks the NLA General Counsel has reviewed several contracts in which physicians are to be paid by laboratories to collect and ship specimens and are even furnished the supplies to do so.

NLA members are cautioned to have such contracts reviewed carefully by a health care attorney. Under Counsel Advisory Opinion No 05-08, such arrangements may well run afoul of the Stark Law. A collection fee well in excess of what Medicare would pay for such services may be deemed to

exceed “fair market value,” and often is only obtained by the physician when he or she refers to that particular laboratory. As the Advisory Opinion warns, “Where a laboratory pays a referring physician to perform blood draws, particularly where the amount paid is more than the laboratory receives in Medicare reimbursement, an inference arises that the compensation paid is an inducement to the physician to refer patients to the laboratory.” This is not to say that all such contracts are inherently illegal; it does mean that they should be reviewed.

Fh Foundation Formed to Educate Patients and Family MembersThe FH Foundation is a nonprofit organization developed to raise awareness of FH through education, advocacy, and research and also to establish a patient registry. The FH Foundation is led by patients with FH and by clinicians dedicated to treating them. Their goal is to help FH patients become better educated about their health and that of their families and to direct them to community resources and medical assistance. This organization’s development is seen as a great complement to the Foundation of the NLA and its goals of reaching Americans with information about and solutions for managing FH. For details about the FH Foundation, please visit theFhfoundation.com.

Lipid Spin SupportSpecial thanks go to Wayne Warren, MD, for reviewing articles for this issue.

New Impact Factor for Journal of Clinical LipidologyIn June, the 2011 impact factors were released by Thomson Reuters and the Journal of Clinical Lipidology score went from 1.467 up to 1.583. The Journal’s Editor-in-Chief, W. Virgil Brown, MD, said that “The impact factor is an index of the frequency of papers in our Journal being quoted in the reviewed medical literature. The Journal is growing in quality and in volume of submissions. These are the factors that cause a rising impact factor. Authors are recognizing the Journal as a source of key information that deserves referencing in their publications. We are grateful to a very capable Editorial Board and group of dedicated reviewers who provide critiques that result in accurate assessment of the manuscripts submitted. Their comments almost always help the authors improve the presentation of their data.”

Actor John o’hurley Joins Launch of USAGE SurveyOn Tuesday, June 19, TV personality John o’hurley joined the NLA, Kowa Pharmaceuticals America and Eli Lilly and Company in announcing the results of the USAGE survey, “Understanding Statin use in America and Gaps in Education,” the largest known U.S. cholesterol survey involving more than 10,100 statin users. NLA member Eliot Brinton, MD, is co-spokesperson for the survey with O’Hurley (Seinfeld and Dancing with the Stars), who is one of the 71 million Americans diagnosed with high cholesterol. To visit the USAGE website, please go to StatinUSAGE.com.


Education and Meeting Update

Reducing CVD Risk in the Patient with high triglycerides and Metabolic Syndrome or DM-2 Join harold Bays, MD, Eliot Brinton, MD, W. Virgil Brown, MD, and terry Jacobson, MD, for a new online CME activity that includes faculty presentations from a live symposium held on June 1 in Scottsdale, Arizona. Please visit lipid.org/education/online for more information. highlights from the 2012 NLA Annual Scientific SessionsCheck out multimedia highlights of what you missed if you did not attend the NLA’s Annual Scientific Sessions in Scottsdale, Arizona. The highlights, featuring audio recordings and slides synched in real time, are based on the best-reviewed presentations from the meeting. Selected presentations also include written summaries prepared by Linda Brookes, MSc. Visit lipid.org/highlights for more information. online Version of CLM-SAP Edition 14 Available CLM-SAP Edition #14: Evaluation and Management of Familial Hypercholesterolemia provides a comprehensive, interactive self-assessment that will strengthen your knowledge of the most clinically relevant, evidence-based medicine related to FH. In addition, you will earn up to 3.0 CME/CE credits by participating in the program, which can be applied toward meeting the requirements necessary to be eligible for certification in Clinical Lipidology. The CLM-SAP series is

a complimentary benefit of membership in the NLA. Please visit lipid.realcme.com to access this activity.

Learn from Leading Experts in a City Near You: Join a Lipid Forum This exciting, case-based, audience-driven, interactive CME meeting series will feature world-renowned specialists in lipidology discussing HDL functionality and quantification, residual cardiovascular risk, and the latest clinical trials as well as emerging therapies for HDL modulation, CETP inhibition and reverse cholesterol transport. This activity will be highlighted by “Meet the Experts” breakout sessions that will allow the learner to discuss therapeutic dilemmas, complex topics, and challenging cases in greater detail with all the faculty. For more information, please visit vindicomeded.com/lipidforum.

Preventive Cardiology: Update 2012 Wednesday, September 19 Donald E. Stephens Convention Center5555 North River RoadRosemont, IL Sponsored by the ASPC Make plans to attend Preventive Cardiology: Update 2012, a 4-hour dinner symposium, that will be held on September 19 at the Donald E. Stephens Convention Center in Rosemont, Illinois. This exciting program will feature nationally renowned faculty members exploring cutting-edge topics in preventive cardiology and will include didactic lectures, interactive question-and-answer sessions and panel discussions. This dinner symposium will be held

in conjunction with Pri-Med MidWest 2012. There is no registration fee for the symposium or dinner. For more information or to register, please visit aspconline.org. 4th Annual orange County Symposium on CVD Prevention: Case and Guideline-Based Approaches to Clinical Lipidology, hypertension and obesitySaturday, October 27 Newport Beach, CADon’t miss your chance to attend this comprehensive one-day symposium that will explore practical solutions and strategies for managing challenging patients at risk for cardiovascular disease including the management of lifestyle, Clinical Lipidology, pre-diabetes and hypertension.

Symposium Topics Include:

•ApproachestothePatientwithLowHDL-C

•FamilialHypercholesterolemia:Identification and Awareness with Live Patient Perspective

•TheObesityEpidemic:NewStrategies

•ThePatientwithMultipleCardiometabolic Risk Factors and Severe Hypertriglyceridemia

For more information and to register, please visit leadingstar.com/ocsympo.

28 LipidSpin

Events Calendar

2013 Scientific Meetings 2013 National Lipid AssociationClinical Lipid Update—Spring

Hosted by the Southwest Lipid Association and the Midwest Lipid Association

February 22–24, 2013The Roosevelt HotelNew Orleans, Louisiana

2013 National Lipid Association Scientific Sessions

Hosted by the Pacific Lipid Association May 30–June 2, 2013Red Rock Hotel Las Vegas, Nevada

2013 NLA Clinical Lipid Update—FallHosted by the Southeast Lipid Association and the Northeast Lipid Association

September 20–22, 2013Hyatt Regency Baltimore HotelBaltimore, Maryland

2012 MeetingsLipid Forum 2012 September 22, 2012 JW MarriottWashington, D.C. 4th Annual European Workshop on Lipid Mediators September 27, 2012Pasteur InstituteParis, France PCNA Fall Lecture Series September 29, 2012 Waterfront Plaza Hotel OaklandOakland, California PCNA SIhD Lecture Series September 29, 2012 HotelREDMadison, Wisconsin

PCNA SIhD Lecture SeriesSeptember 29, 2012 Marriott New OrleansNew Orleans, Louisiana

PCNA SIhD Lecture Series September 29, 2012 Renaissance Asheville HotelAsheville, North Carolina Lipid Forum 2012 October 6, 2012 Atlanta, Georgia Lipid Forum 2012 October 20, 2012 Houston, Texas Lipid Forum 2012 November 17, 2012 Anaheim, California

World Congress of Clinical Lipidology December 6–8, 2012Budapest Marriott HotelBudapest, Hungary

Foundation Update

First, I would like to thank everyone who supported the NLA’s 10th Anniversary President’s Gala, which raised almost $10,000 for the Foundation and was our largest fundraiser to-date. More than 200 NLA members and guests attended the gala during the Annual Scientific Sessions this past May in Scottsdale, Arizona, where entertainment was provided by Alan Brown, MD, and his band This End Up. We had a great time supporting a tremendous organization and I thank all of you for your support.

In addition, I would like to thank the sustaining and individual donors who have made almost $24,000 in contributions to the Foundation since January. As the holiday season draws near, please remember us in your year-end contributions. To donate, visit us online at lipidfoundation.org.

In May 2012, the NLA Board of Directors approved a recommendation by the NLA Membership Committee to establish and fund a fellowship/training program by offering a Lifetime Membership option to members. To qualify for Lifetime Membership, one would need to have

maintained membership in the NLA for five or more years, and then would be eligible to pay the $1,500 Lifetime Membership fee. Proceeds from the fee would be distributed between the Foundation and the NLA, with $1,000 of the fee going to the Foundation to fund the fellowship/training program fund. Lifetime Membership will become available in 2013.

In addition, The International Guidelines Center published an FH Pocket Guide in May 2012 based on the NLA’s FH recommendations from 2011. This concise guide is especially helpful to healthcare providers working outside of the field of Clinical Lipidology and who may need a quick reference for diagnosing and treating patients with FH. More than 1,900 copies of the FH Pocket Guide have been sold.

Sharecare.com, a consumer-friendly website that provides a “roundtable” of expert answers to patient questions, has invited the Foundation and the NLA to join as partner organizations, and our first group of representatives will begin answering patient questions in late September. Our involvement with Sharecare is overseen

by the NLA Communications Committee, chaired by James Underberg, MD, and Robert Wild, MD, PhD. Please take a few minutes to visit the Sharecare website and refer it to your patients as a consumer-friendly resource.

Finally, I would like to call your attention to a new non-profit organization developed to raise awareness of FH through education, advocacy, and research and also to establish a patient registry. The FH Foundation is led by patients with FH and by clinicians dedicated to treating them. This organization’s development is seen as a great complement to the Foundation of the NLA and its goals of reaching Americans with information about and solutions for managing FH. For details about the FH Foundation, please visit their website at theFhfoundation.com. n

ANNE C. GoLDBERG, MD, FNLAPresident, Foundation of the National Lipid Association

Associate Professor of MedicineWashington University School of Medicine

St. Louis, MO



Discuss this article at www.lipid.orgGo to “Topics/Lipid Spin Fall 2012” and look for “Foundation Update.”

A recent succession of negative studies—including two randomized, placebo-controlled intervention trials1, 2 and a large genetic association analysis3—calls for a careful re-examination of the approach to HDL-directed therapies. In May 2011 the Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health (AIM-HIGH) trial was stopped early due to futility.4 In the setting of mildly reduced HDL-C levels (mean baseline 35 mg/dL), the addition of extended-release niacin at a daily dose of 1500-2000 mg raised HDL-C by 10 mg/dL (28%), or 5 mg/dL (13%) compared to the control group.1 Despite the observed increase in HDL-C, niacin use was not associated with a lower incidence

of cardiovascular events among patients with stable coronary artery disease (CAD) treated to aggressive LDL-C targets (mean baseline 71 mg/dL, mean on-treatment 65 mg/dL).1 Peculiarities of study design as recently reviewed limit the generalizability of the AIM-HIGH findings.5 More definitive evidence regarding the effect of niacin on clinical outcomes awaits the conclusion of the Heart Protection Study 2: Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE) trial. Dal-OUTCOMES succumbed to a similar fate as AIM-HIGH in May 2012 after interim analysis failed to demonstrate a benefit of dalcetrapib, an inhibitor of cholesteryl ester transfer protein (CETP), on hard cardiovascular endpoints in patients with

acute coronary syndrome (ACS) on optimal medical therapy.2 In phase II studies, dalcetrapib 600 mg daily, the dose used in the outcomes trial, increased HDL-C by an average of 25-31% and did not exhibit adverse off-target hemodynamic or hormonal effects.6 Details regarding the prematurely terminated study remain eagerly anticipated. As noted below, at least two more potent CETP inhibitors are still in clinical development. In addition to these two disappointing clinical trials, a large Mendelian randomization analysis published in May 2012 highlighted the potential for inconsistency between higher HDL-C levels and a lower risk of myocardial infarction (MI).3 Carriers of a single nucleotide polymorphism in the

Guest Editorial: HDL-targeted Therapies—Where Do We Go From Here?

DANIEL J. RADER, MD, FNLADivision of Translational Medicine and Human GeneticsCardiovascular Institute and Institute for Translational Medicine and TherapeuticsPerelman School of Medicine at the University of PennsylvaniaPhiladelphia, PADiplomate, American Board of Clinical Lipidology

EMIL M. deGoMA, MDDivision of Cardiovascular MedicinePerelman School of Medicine at the University of PennsylvaniaPhiladelphia, PADiplomate, American Board of Clinical Lipidology

Discuss this article at www.lipid.orgGo to “Topics/Lipid Spin Fall 2012” and look for “Guest Editorial.”

30 LipidSpin

endothelial lipase gene (LIPG Asn396Ser) exhibited HDL-C levels 5.5 mg/dL higher than non-carriers with no significant difference in LDL-C or other lipids. Observational cohort studies suggest that this modest increment in HDL-C would confer a 13% reduction in MI risk. However, analysis of 20,913 MI cases and 95,407 controls demonstrated no association between LIPG Asn396Ser and MI (odds ratio 0.99, 95% CI 0.88-1.11, p=0.85). Several other variants associated with HDL-C were also found to have no clear association with MI, unless they were also associated with triglyceride or LDL- C levels.

The principal lesson from these recent findings lies in the complexity of the relationship between HDL cholesterol and cardiovascular disease. A wealth of data from traditional epidemiologic studies as well as statin trials support an inverse relationship between HDL-C and coronary events, a powerful association incorporated into most global risk equations including the Framingham risk score.7 However, despite the popularly ingrained concept of HDL-C as the “good” cholesterol, evidence indicates that higher levels of HDL-C are not synonymous with improved outcomes. HDL-C suffers from limitations intrinsic to its static, mass-based measurement.8 First, as a snapshot of the steady-state cholesterol pool, HDL-C does not directly assess the rate of centripetal cholesterol flux from peripheral foam cells to the liver, which is influenced by many factors beyond the mass of HDL-C alone. Second, circulating HDL-C values fail to convey information regarding the anti-inflammatory, antioxidant, anti-thrombotic, and endothelial function promoting benefits of HDL, despite evidence supporting the potential clinical significance of these pleiotropic functions.

Recent publications shed light on promising measures that assess reverse

cholesterol transport, arguably the most critical anti-atherogenic function of HDL, as well as anti-inflammatory activity. One study utilized a validated ex vivo system to quantify cholesterol efflux capacity using incubation of macrophages with apo B-depleted serum.9 Healthy participants exhibited an inverse relationship between efflux capacity and carotid intima-media thickness before and after adjustment for HDL-C. Among subjects who underwent coronary angiography for clinically suspected CAD, efflux capacity remained a strong inverse predictor of coronary disease status after adjustment for traditional risk factors as well as HDL-C (adjusted OR for CAD per 1-SD increase in efflux capacity, 0.75; 95% CI 0.63-0.90) and apo A-I (OR 0.74; 95% CI 0.61-0.89). A second study demonstrated an association between CAD status and HDL inflammatory index (HII), the latter quantified as the ratio of in vitro LDL oxidation of a fluorescein substrate incubated with and without participant HDL.10 Among 193 symptomatic patients undergoing angiography, HII was significantly higher (less antioxidant capacity) among those with acute coronary syndrome (ACS) than those without CAD (1.57 vs 1.17, p 0.005) or with stable CAD (1.57 vs 1.11, p 0.006). Association with ACS remained significant after adjusting for traditional risk factors (OR 3.8 p 0.003).

AIM-HIGH and dal-OUTCOMES additionally suggest that demonstrating incremental clinical benefit above and beyond current optimal medical therapy, inclusive of aggressive LDL-lowering, may be challenging for new therapies. Such a high hurdle may inadvertently weed out effective treatments for individuals unable to achieve ideal targets, including those suffering from medication intolerance (e.g., statin myopathy) or extreme phenotypes (e.g., familial dyslipidemias). This population is not insignificant in

routine clinical practice. With regard to optimal management of dyslipidemia, a recent international study of 9,518 ambulatory patients on lipid-lowering therapy revealed that 34% of high-risk patients and 71% of very high-risk patients do not meet their recommended LDL-C goals.11 Moreover, data from tertiary lipid clinics suggest that the majority of patients referred for complex dyslipidemia fail to achieve target LDL-C levels.12, 13 Broadening the scope of comparative effectiveness research to include populations such as those unable to take high-dose statin therapy addresses considerable unmet need and may also facilitate the development of useful HDL-directed therapies.

Fortunately, now more than ever, a myriad of HDL-targeted drug candidates is available to test new approaches.14 Lipid-poor apo A-I—phospholipid complexes have been studied extensively in animals and in preliminary studies in humans. Preclinical studies have demonstrated that the administration of apo A-I is associated with the inhibition or regression of atherosclerosis, enhanced macrophage-specific reverse cholesterol transport, and the inhibition of vascular inflammatory pathways, endothelial adhesion molecule expression and phospholipid oxidation.15-17 Moreover, short exploratory clinical studies of apoA-I infusion using recombinant apoA-I Milano/phospholipid (MDCO-216),18 purified native apoA-I/phospholipid (CSL-111),19 and autologous delipidated HDL (PDS-2)20 have yielded decreases in coronary atherosclerosis as assessed by coronary imaging.

Two novel compounds enable further testing of the CETP-inhibition strategy. Unlike dalcetrapib, which exerts modest effects on HDL-C alone, anacetrapib and evacetrapib yield significant reductions in atherogenic lipoproteins as well as more potent increases in HDL-C, at least


suggesting a greater potential for clinical benefit. The phase III Determining the Efficacy and Tolerability of CETP Inhibition with Anacetrapib (DEFINE) randomized, placebo-controlled trial examined the effect of 100 mg of anacetrapib administered daily for 18 months to 1623 patients with CAD or at high-risk for CAD events who had achieved LDL-C treatment goals with statin therapy.21, 22 Treatment with anacetrapib was associated with a 40% reduction in LDL-C from 81 mg/dl to 45 mg/dl (P <0.001) and a 138% increase in HDL-C from 41 mg/dl to 101 mg/dl (P <0.001) compared with placebo.22 Lp(a) decreased 36% compared with placebo from 27 nmol/l to 15 nmol/l. No increases in clinic-based blood pressure, serum aldosterone levels, or cardiovascular events were observed following anacetrapib treatment at 76 weeks. Supported by these improvements in LDL, HDL, and Lp(a), as well as an apparently benign safety profile, the Randomized Evaluation of the Effects of Anacetrapib through Lipid-Modification (REVEAL) is underway. This study will examine major coronary events, defined as coronary death, myocardial infarction and coronary revascularization procedures, in 30,000 patients with CAD, cerebrovascular atherosclerotic disease, or peripheral artery disease. The estimated study completion date is January 2017. Evacetrapib administration in daily doses of 30-500 mg decreased LDL-C from 20-51 mg/dL (14-36%) and increased HDL-C from 30-66 mg/dL (54-129%) in a 12-week randomized trial of 398 dyslipidemic patients.23 Addition of evacetrapib 100 mg daily to statin therapy yielded further reductions in LDL-C of 16-21 mg/dL (11-14%) and increments in HDL-C of 41-48 mg/dL (79-89%).23 Effects on lipoprotein(a) were not reported, and no adverse events were observed in the small study. Apparently, a large phase III clinical outcomes trial is planned to elucidate the efficacy and safety of evacetrapib.

Activation of liver X receptors (LXRs) has been demonstrated to promote mobilization of intracellular cholesterol, increase macrophage cholesterol efflux via macrophage ABCA1 and ABCG1, and augment intestinal HDL generation.24-26 Two LXR isoforms have been identified—LXRα and LXRα. Therapeutic development of LXR agonists has been hindered by hepatic steatosis and increased plasma triglyceride concentrations reported in preclinical studies of these drugs.27 Fortunately, dissociating LXR efficacy and toxicity might be possible owing to the differential effects of LXR agonism by receptor isoform and by tissue-specific effects. Administration of a nonselective LXR agonist to LXRα-deficient mice stimulated macrophage ABCA1 expression and cholesterol efflux without inducing fatty liver and with minimal upregulation of hepatic triglyceride synthesis.28 A second approach to safer LXR development might be to selectively activate intestinal LXR. Fatty liver arises from activation of hepatic LXR, which, through upregulation of SREBP1c, stimulates lipogenesis.29 Elevation of triglyceride levels occurs via SREBP1c and the subsequent suppression of apo A-V, which inhibits VLDL synthesis and stimulates VLDL hydrolysis. On the other hand, LXR expression on both macrophages and the small intestine contributes to the regulation of reverse cholesterol transport. An intestine-specific LXRα/β agonist, GW6340, promoted macrophage-specific reverse cholesterol transport, augmenting the fecal excretion of radiolabeled sterol by 52% via increased intestinal HDL production and intestinal excretion of HDL-derived cholesterol.30

Elucidation of posttranscriptional pathways of HDL metabolism has identified additional targets for pharmacotherapeutic intervention. Short non-coding sequences of RNA, termed microRNAs (miRNAs), inhibit gene expression by binding to complementary 3’ untranslated regions

of messenger RNAs (mRNAs) and causing translational repression and/or mRNA destabilization.31 Genome-wide screening identified miR-33, encoded within intron 16 of sterol regulatory element binding transcription factor 2 (SREBF2), from a subset of differentially expressed miRNAs modulated by cellular cholesterol content.32 In vitro and in vivo murine studies demonstrated, in the setting of miR-33 overexpression, suppressed macrophage and hepatocyte expression of ABCA1, reduced circulating HDL-C levels, and attenuated efflux to apoA-I. Conversely, silencing of miR-33 was associated with greater macrophage and hepatocyte expression of ABCA1 and increased HDL-C levels. In a mouse model of atherosclerosis, administration of an antisense oligonucleotide (ASO) to miR-33 significantly increased HDL-C by 35% and promoted macrophage-specific reverse cholesterol transport, augmenting hepatic and fecal delivery of radiolabeled tracer by 42% and 82%, respectively.33 Importantly, these favorable changes in HDL parameters were accompanied by atheroma regression (35% reduction in aortic sinus lesion area compared to baseline and controls) as well as histologic evidence of remodeling toward a more stable plaque phenotype (28% decrease in lipid accumulation, 35% reduction in macrophage content, and 2-fold increase in collagen content).33 In a non-human primate model of dyslipidemia, subcutaneous delivery of anti-miR-33 ASO over a 12-week period increased HDL-C up to 50%.34 Greater macrophage cholesterol efflux was observed following incubation of foam cells with serum obtained from treated monkeys compared to equivalent volumes of serum isolated from control monkeys, correlating with the HDL-C levels in the two groups. Monkeys administered the anti-miR-33 also exhibited attenuated expression of genes involved in fatty acid synthesis, enhanced expression of genes involved in fatty acid oxidation, and a decrement in

32 LipidSpin

VLDL triglycerides of up to 50%, suggesting therapeutic potential for additional metabolic derangements associated with insulin resistance.33 It will be interesting to see if anti-miR-33 approaches are taken into clinical development.

In conclusion, recent negative studies suggest the need for a revised approach to the evaluation of novel HDL-directed therapies. Therapeutic elevation of HDL-C does not necessarily mitigate atherothrombotic risk. Assessment of HDL functionality, particularly reverse cholesterol transport, is important to characterize the potential anti-atherogenic activity of new compounds; however, validation of emerging HDL assays remains critical prior to their use as surrogate measures. Finally, apoA-I mimetics, CETP

inhibitors, LXR agonists, and miR-33 antagonists comprise several HDL-targeted candidate drug classes under current investigation. n

Disclosure statement: Dr. deGoma has no disclosures to report. Dr. Rader has received consulting fees from AstraZeneca, Bristol-Myers Squibb, Daiichi Sankyo Inc., Eli Lilly & Co., GlaxoSmithKline, Johnson and Johnson, Merck & Co., Novartis Pharmaceuticals, Pfizer Inc., Regeneron, Roche, Sanofi, Alnylam, Catabasis, and Omthera.



Dr. BrownAlan S. Brown, MD

Director, Midwest Heart Specialists Prevention Center

Naperville, IL

New Lipid Luminations Programs On ReachMD:

Tune into Lipid Luminations, hosted by Dr. Alan Brown as he

discusses topics such as HDL in Clinical Settings, Particle Number

Testing in the Prevention of Atherosclerosis, Dietary Fats and

Cardiovascular Disease and many more on ReachMD XM160 -

The Channel for Medical Professionals. Download programs at

www.ReachMD.com/Lipids or via ReachMD's MedicalRadio

iPhone app .

Series brought to you by

Introducing a radio host who gives you

the skinnyon fatty acids.

Listen at XM167 or online at ReachMD.com or www.lipid.org/publications

Reaching and teaching medical professionals

34 LipidSpin

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Case Study I References1. Bensen JT, Li R, Hutchinson RG, Province MA, Tyroler HA.

Family history of coronary heart disease and pre-clinical carotid artery atherosclerosis in African-Americans and whites: the ARIC Study: Atherosclerosis Risk in Communities. Genet Epidemiol. 1999;16:165-178.

2. Snowden CB, McNamara PM, Garrison RJ, Feinleib M, Kannel WB, Epstein FH. Predicting coronary heart disease in siblings—a multivariate assessment. The Framingham Study. Am J Epide-miol.1982;115:217-222.

3. Khaw KT, Barrett-Connor E. Family history of heart attack: a modifi-able risk factor: Circulation. 1986;74:239-244.

4. Lloyd-Jones DM, Nam B-H, D’Agostin RB, Levy, D, Murabito JM, Wang TJ, Wilson PWF, O’donnell CJ. Parental cardiovascular disease as a risk factor for cardiovascular disease in middle-aged adults. JAMA. 2004;291:2204-2211.

5. Ridker, PM, Buring JE, Rifai N, Cook NR. Development and valida-tion of improved algorithms for the assessment of global cardiovas-cular risk in women. JAMA. 2007;297:611-619.

6. European guidelines on cardiovascular disease prevention in clinical practice (version 2012). European Heart Journal. 2012;33:1635-1701.

7. O’Donnell CJ. Family History, subclinical atherosclerosis, and coro-nary heart disease risk. Circulation. 2004;110:2074-2076.

8. Nordestgaard BG, et al. Lipoprotein (a) as a cardiovascular risk fac-tor: current status. European Heart Journal. 2010;31:2844-2853.

9. Goldhaber SZ. European atherosclerosis society screening recom-mendations for lipoprotein(a) and high-sensitivity C-reactive protein: double standard or failure of evidence-based medicine? Clinical Chemistry. 2010;56:1544-1546.

10. Davidson MH, et al. Clinical utility of inflammatory markers and ad-vanced lipid testing: advice from an expert panel of lipid specialists. Journal of Clinical Lipidology. 2011;5:338-367.

11. Cromwell WC, Otvos JD, Keyes MJ, Pencina MJ, Sullivan L, Vasan RS, Wilson PWF, D’Agostino RB. LDL particle number and risk of future cardiovascular disease in the Framingham offspring study—implications for LDL management. J Clin Lipidol. 2007;1:583-592.

12. Otvos JD, Mora S, Shalurova I, Greenland P, Mackey RH, Goff DC Jr. Clinical implications of discordance between low-density lipopro-tein cholesterol and particle number. J Clin Lipidol. 2011;5:105-113.

13. St-Pierre AC, Cantin B, Dagenais GR, Despres JP, Lamarche B. Apolipoprotein-B, low-density lipoprotein cholesterol, and the long-term risk of coronary heart disease in men. Am J Cardiol. 2006;97:997-1001.

14. Boekholdt SM, Arsenault BJ, Mora S, et. al. Association of LDL cholesterol, non-HDL cholesterol, and apolipoprotein B levels with risk of cardiovascular events among patients treated with statins: a meta-analysis. JAMA. 2012;307:1302-1309.

15. Parish S, Offer A, Clarke R, et al. Lipids and lipoproteins and risk fo different cardiovascular events in the MRC/BHF Heart Protection Study. Circulation. 2012;125:2469-2478.

16. ACCF/AHA 2007 Clinical expert consensus document on coronary artery calcium scoring by computed tomography in global cardiovas-cular risk assessment and in evaluation of patients with chest pain. J Am Coll Cardiol. 2007;49:378-402.

17. Tabas I, Williams KJ, Boren J. Subendothelial lipoprotein retention as the initiating process in atherosclerosis: update and therapeutic implications. Circulation. 2007;116:1832-1844.

Lipid Luminations References1. Daniels SR, Gidding SS, de Ferranti SD. Pediatric aspects of familial

hypercholesterolemias: recommendations from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. Journal of clinical lipidology. Jun 2011;5(3 Suppl):S30-37.

2. Gidding SS. Familial Hypercholesterolemia: A Decade of Progress, Part 2. J Pediatr. Feb 23 2012.

3. Nherera L, Marks D, Minhas R, Thorogood M, Humphries SE. Prob-abilistic cost-effectiveness analysis of cascade screening for familial hypercholesterolaemia using alternative diagnostic and identification

strategies. Heart. Jul 2011;97(14):1175-1181.4. Newman TB, Garber AM. Cholesterol screening in children and

adolescents. Pediatrics. Mar 2000;105(3 Pt 1):637-638.5. Gidding SS, Daniels SR, Kavey RE. Developing the 2011 Integrated

Pediatric Guidelines for Cardiovascular Risk Reduction. Pediatrics. May 2012;129(5):e1311-1319.

Case Study II References1. Ridker PM, Cook NR, Lee, IM, et al. A randomized trial of low-

dose aspirin in the primary prevention of cardiovascular disease in women. N Engl J Med 2005; 352:1293-1304.

2. Mosca L, Benjamin EJ, Berra K, et. al. Effectiveness-based guidelines for the prevention of cardiovascular disease in women—2011 Update: A Guideline From the American Heart Association. Circula-tion. 2011; 123, 1243-1262.

3. Steering Committee of the Physicians’ Health Study Research Group. Final report on the aspirin component of the ongoing physi-cians’ health study. N Engl J Med. 1989;321:129–135.

4. Heart disease and stroke statistics—2012 update: a report from the American Heart Association. Circulation. 2012;125:e2-e220.

5. Aspirin for the prevention of heart disease. U.S. Preventive Services Task Force. Ann Intern Med 2009;150:396-404.

6. D’Agostino RB, Wolf PA, Belanger AJ, Kannel WB. Stroke risk profile: adjustment for antihypertensive medication. The Framingham Study. Stroke. 1994;25:40–43.

7. Stroke. Framingham Heart Study website. Accessed online at http://www.framinghamheartstudy.org/risk/stroke.html on August 27, 2012.

8. Collins R, Armitage J, Parish S, et. al. Heart Protection Study Col-laborative Group. Effects of cholesterol-lowering with simvastatin on stroke and other major vascular events in 20536 people with cerebrovascular disease or other high-risk conditions. Lancet 2004;363:757-67

9. Cholesterol Treatment Trialists’ (CTT) Collaborators. Mihaylova B, Emberson J, Blackwell L, et. al. The effects of lowering LDL choles-terol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials. Lancet. 2012 Aug 11;380(9841):581-90.

10. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486-2497.

11. D’Agostino RB, Vasan RS, Pencina MJ, Wolf PA, Cobain M, Massaro JM, Kannel WB. General cardiovascular risk profile for use in

primary care. Circulation 2008; 117:743--753.12. General Cardiovascular Risk. Framingham Heart Study website.

Accessed online at http://www.framinghamheartstudy.org/risk/gen-cardio.html on August 27, 2012.

13. Grundy SM, Cleeman JI, Bairey Merz CN, et. al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation. 2004;110:227-239.

14. Berry JD, Dyer A, Cai X, et.al. Lifetime risks of cardiovascular dis-ease. NEJM. 2012; 366(4):321-9.

Guest Editorial References1. Boden WE, Probstfield JL, Anderson T, Chaitman BR, Desvignes-

Nickens P, Koprowicz K, McBride R, Teo K, Weintraub W. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. The New England Journal of Medicine. 2011;365:2255-2267.

2. Roche. (2012). Roche provides update on Phase III study of dalcetra-pib. Retrieved from http://www.roche.com/media/media_releases/med-cor-2012-05-07.htm.

3. Voight BF, Peloso GM, Orho-Melander M, et. al. Plasma HDL cho-lesterol and risk of myocardial infarction: A mendelian randomisa-tion study. Lancet. 2012.

4. NHLBI. Nih stops clinical trial on combination cholesterol treat-ment. 2011;2012.

5. Brinton EA. Search and rescue for hypotheses surviving aim-high, the niacin therapy earthquake: Still problematic after the primary publication. Journal of Clinical Lipidology. 2012;6:312-317.

6. Stein EA, Stroes ES, Steiner G, Buckley BM, Capponi AM, Burgess T, Niesor EJ, Kallend D, Kastelein JJ. Safety and tolerability of dalce-trapib. The American Journal of Cardiology. 2009;104:82-91.

7. Cooney MT, Dudina AL, Graham IM. Value and limitations of existing scores for the assessment of cardiovascular risk: A review for clinicians. Journal of the American College of Cardiology. 2009;54:1209-1227.

8. deGoma EM, deGoma RL, Rader DJ. Beyond high-density lipoprotein cholesterol levels evaluating high-density lipoprotein function as in-fluenced by novel therapeutic approaches. Journal of the American College of Cardiology. 2008;51:2199-2211.

9. Khera AV, Cuchel M, de la Llera-Moya M, Rodrigues A, Burke MF, Jafri K, French BC, Phillips JA, Mucksavage ML, Wilensky RL, Mohler ER, Rothblat GH, Rader DJ. Cholesterol efflux capacity, high-density lipoprotein function, and atherosclerosis. The New England Journal of Mmedicine. 2011;364:127-135.

10. Patel PJ, Khera AV, Jafri K, Wilensky RL, Rader DJ. The anti-oxidative capacity of high-density lipoprotein is reduced in acute coronary

syndrome but not in stable coronary artery disease. Journal of the American College of Cardiology. 2011;58:2068-2075.

11. Chiang CW, Santos RD, Waters DD, Messig M, Tarasenko L, Jukema JW, Ferrieres J, Foody J, Seung KB. Reaching c-reactive protein and low-density lipoprotein cholesterol goals in dyslipidemic patients (from the lipid treatment assessment project [l-tap] 2). The Ameri-can Journal of Cardiology. 2011;107:1639-1643.

12. Klinke JA, Malek F, Gao M, Holmes D, Frohlich JJ. Reaching target lipid levels in patients at high risk of cardiovascular event: The experience of a canadian tertiary care lipid clinic. Central European Journal of Public Health. 2007;15:106-109.

13. Pirro M, Del Giorno R, Lupattelli G, Mannarino MR, Roscini AR, Covelli D, Schillaci G, Pasqualini L, Bagaglia F, Siepi D, Mannarino E. Cardiovascular risk factors and recommended lipid goals attain-ment among patients referred in a tertiary care lipid clinic. Euro-pean Journal of Internal Medicine. 2011;22:412-417.

14. Degoma EM, Rader DJ. Novel hdl-directed pharmacotherapeutic strategies. Nature reviews. Cardiology. 2011;8:266-277.

15. Badimon JJ, Badimon L, Fuster V. Regression of atheroscle-rotic lesions by high density lipoprotein plasma fraction in the cholesterol-fed rabbit. The Journal of Clinical Investigation. 1990;85:1234-1241.

16. Chiesa G, Monteggia E, Marchesi M, et. al. Recombinant apolipoprotein a-i(milano) infusion into rabbit carotid artery rapidly removes lipid from fatty streaks. Circulation Research. 2002;90:974-980.

17. Zhang Y, Zanotti I, Reilly MP, et. al. Overexpression of apolipopro-tein a-i promotes reverse transport of cholesterol from macrophages to feces in vivo. Circulation. 2003;108:661-663.

18. Nissen SE, Tsunoda T, Tuzcu EM, et. al. Effect of recombinant apoa-i milano on coronary atherosclerosis in patients with acute coronary syndromes: A randomized controlled trial. JAMA : the Journal of the American Medical Association. 2003;290:2292-2300.

19. Tardif JC, Gregoire J, L’Allier PL, et. al. Effects of reconstituted high-density lipoprotein infusions on coronary atherosclerosis: A random-ized controlled trial. JAMA : the Journal of the American Medical Association. 2007;297:1675-1682.

20. Waksman R, Torguson R, Kent KM, et. al. A first-in-man, random-ized, placebo-controlled study to evaluate the safety and feasibility of autologous delipidated high-density lipoprotein plasma infusions in patients with acute coronary syndrome. Journal of the American College of Cardiology. 2010;55:2727-2735.

21. Cannon CP, Dansky HM, Davidson M, et. al. Design of the define trial: Determining the efficacy and tolerability of cetp inhibition with anacetrapib. American heart journal. 2009;158:513-519 e513.

22. Cannon CP, Shah S, Dansky HM, et. al. Safety of anacetrapib in patients with or at high risk for coronary heart disease. The New England Journal of Medicine. 2010;363:2406-2415

23. Nicholls SJ. Evacetrapib. Current Cardiology Reports. 2012;14:245-250.

24. Rigamonti E, Helin L, Lestavel S, et. al. Liver x receptor activation controls intracellular cholesterol trafficking and esterification in human macrophages. Circulation Research. 2005;97:682-689.

25. Costet P, Luo Y, Wang N, Tall AR. Sterol-dependent transactivation of the abc1 promoter by the liver x receptor/retinoid x receptor. The Journal of Biological Chemistry. 2000;275:28240-28245.

26. Brunham LR, Kruit JK, Iqbal J, et. al. Intestinal abca1 directly con-tributes to hdl biogenesis in vivo. The Journal of Clinical Investiga-tion. 2006;116:1052-1062.

27. Grefhorst A, Elzinga BM, Voshol PJ, et. al. Stimulation of lipogenesis by pharmacological activation of the liver x receptor leads to produc-tion of large, triglyceride-rich very low density lipoprotein particles. The Journal of Biological Chemistry. 2002;277:34182-34190.

28. Lund EG, Peterson LB, Adams AD, et. al. Different roles of liver x receptor alpha and beta in lipid metabolism: Effects of an alpha-selective and a dual agonist in mice deficient in each subtype. Biochemical Pharmacology. 2006;71:453-463.

29. Yoshikawa T, Shimano H, Amemiya-Kudo M, et. al. Identification of liver x receptor-retinoid x receptor as an activator of the sterol regulatory element-binding protein 1c gene promoter. Molecular and Cellular Biology. 2001;21:2991-3000

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34. Rayner KJ, Esau CC, Hussain FN, et. al. Inhibition of mir-33a/b in non-human primates raises plasma hdl and lowers vldl triglycerides. Nature. 2011;478:404-407.

The National Lipid Association now offers the 2011 Update of the NLA-SAP series — a one-of-a-kind comprehensive, clinical problem-solving program and self-assessment exam. Designed for physicians, physician assistants, nurses, pharmacists, and dietitians managing patients with dyslipidemia, the NLA-SAP serves as an invaluable resource to ensure mastery of this critical content and to prepare you for certification, maintenance of certification, and/or state licensure.

The four-volume NLA-SAP series provides over 750 multiple-choice questions with robust, evidence-based critiques:

• Volume I Basic Lipid and Lipoprotein Metabolism, Diagnosis and Treatment of Dyslipidemia • Volume II Management of Cardiometabolic Risk, Biomarkers of Atherosclerosis, Epidemiology and Statistics, Clinical Trials • Volume III Complex Case Management and Advanced Pharmacology • Volume IV Vascular Biology, Advanced Lipid Metabolism and Lipoprotein Biochemistry

Each Volume of the NLA-SAP consists of a board exam-style Question Book and a separate, referenced Critique Book, providing comprehensive explanations for the correct answers.

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• Earn 32-40 hours of CME credit at the completion of each Volume of the NLA-SAP

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Assess and Maintain Your Clinical Knowledge of the Complete Clinical Lipidology Curriculum.

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Dietary Fats and Heart Disease-Understanding the Di�erence Between the Good and the BadDietary fat is necessary for health, but because many Americans have a high intake of fast and fried foods they eat too much fat and the wrong type of fat. Dietary fat is composed of several di�erent fatty acids which can have a considerable e�ect on cholesterol levels. Unsaturated or “heart healthy” fats are derived mainly from plant and �sh sources and can help to improve lipid levels, whereas saturated fat comes from animal products and can worsen lipid levels and increase the risk for heart disease. Oil, used in cooking or as an ingredient in salad dressings, margarines, and mayonnaise, is a signi�cant source of dietary fat. Unfortunately, selecting the best oil can be confusing.

Limit the Bad Fats Saturated FatFoods high in saturated fat are typically solid at room temperature and come primarily from animal sources, with the exception of palm and coconut oils. Examples of foods high in saturated fat include fatty meats, such as sausage, bacon, and hot dogs, poultry with skin, lunch meats such as bologna and salami, and regular fat dairy products, including whole milk, cheese, butter, and ice cream. It is recommended that we limit saturated fat in our diet to less than 7 percent of total calories, which is approximately 15 grams based on an 1800 calorie diet.

Trans-Fatty AcidsHydrogenation, the addition of hydrogen atoms to an unsaturated fat, can create unnatural trans-fats. The major sources of trans-fatty acids in the U.S. are partially hydrogenated vegetable oils, such as those found in stick margarines and deep fried fast foods. Food manufacturers have used this process to prolong the shelf-life of foods such as crackers, cookies, potato chips, and puddings. Several large studies have shown that trans-fatty acids increase the risk of coronary heart disease (CHD) by raising low density lipoprotein cholesterol (LDL-C) levels and decreasing high density lipoprotein cholesterol (HDL-C) levels. You should look for soft tub margarines and food products that contain zero grams of trans-fats.

Choose the Good FatsPolyunsaturated FatsTwo major categories of polyunsaturated fatty acids (PUFA) are omega-6 and omega-3 fatty acids. Substitution of PUFA for saturated fat in the diet lowers LDL-C and reduces risk for CHD. Vegetable oils such as corn, sun�ower, sa�ower, soybean, cottonseed, and peanut are high in omega-6 fatty acids. These oils provide linoleic acid (LA). Omega-3 fatty acids include eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), as well as alpha-linolenic acid (ALA). EPA and DHA are marine-based fatty acids found in cold water �sh, including tuna, sword�sh, salmon, mackerel, sardines, and herring and may provide cardiac bene�ts. Alpha-linolenic acid is plant-based and found in canola, �axseed and to some extent in soybean oil and walnuts. The American Heart Association advises consumption of �sh

The Facts About FatsThe Facts About Fats

at least twice a week to reduce cardiovascular risk. In patients with evidence of heart disease a daily supplement containing 1000 mg of EPA plus DHA may be recommended by your provider.1

Monounsaturated FatsMonounsaturated fatty acids (MUFA) contain one double bond; oleic acid is the most common dietary form. Oils high in oleic acid include canola and olive oil. Other dietary sources of MUFA include avocados and nuts. Epidemiologic evidence from the Mediterranean region, where diets are rich in MUFA, has demonstrated a lower incidence of CHD. Short term clinical trials of a Mediterranean-style diet have shown improvement in a number of risk factors, including lowering serum triglycerides and reduction of in�ammatory markers, such as C-reactive protein. Provision of some calories from MUFA that might otherwise be provided from carbohydrates or saturated fatty acids can lower LDL-C without lowering HDL-C or raising triglyceride levels.

Cooking with Fats and OilsIt is impossible to completely eliminate all saturated and trans-fats from your diet, but you should try to eat as little as possible. When cooking choose the oil with the lowest amount of saturated fat that will provide the particular �avor that you desire. Heating oil changes its characteristics, so it is equally important to select cooking oil based on its intended use. Corn, sun�ower or sa�ower oil, because of their high smoke points, are best used for deep frying, a cooking method that should be used very infrequently. Canola, extra virgin olive, sesame, and peanut oil are best used for baking, oven cooking or stir frying. Since all fats are equally caloric, however, limited use in food preparation is advised to maintain a reasonable body weight. —Fran Burke, MS, RD

Reference1. Kris-Etherton PM, Harris WS, Apper LJ. Fish consumption, fish oil, omega-3 fatty acids, and cardiovascular disease. Circulation. 2002;106:2747-2757.

F O R Y O U R P A T I E N T S

Fat Composition of Oils/Fats

MonounsaturatedPolyunsaturatedSaturated

0% 20% 40% 60%

Percent Fat

butter

lard

margarine

soybean

corn

peanut

sesame

canola

olive

80% 100%

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LipidSpin - National Lipid Association › sites › default › files › lipidspin › fall_2012.pdfThe Controversy Over Universal Cholesterol Screening for Children — Samuel S