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Official Publication of the National Association LipidSpin

Controversies in Clinical Lipidology

Cholesterol Screening for Children HDL: Risk Marker or Risk Factor HDL-targeted Therapies

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

This issue sponsored by the Northeast Lipid Association

Volume 10 Issue 3 Fall 2012 visit www.lipid.org ional Lipid Associat Nat 2013 ion

Scientific Meetings 2013 National Lipid Association Scientific Sessions Hosted by the Pacific Lipid Association May 30–June 2, 2013 Red Rock Hotel Las Vegas, NV 2013 NLA Clinical Lipid Update—Spring 2013 NLA Clinical Lipid Update—Fall Hosted by the Southwest Lipid Association Hosted by the Southeast Lipid Association and the Midwest Lipid Association and the Northeast Lipid Association February 22–24, 2013 September 20–22, 2013 The Roosevelt Hotel Hyatt Regency Baltimore Hotel New Orleans, LA Baltimore, MD In This Issue: Fall 2012 (Volume 10, Issue 3)

Editors 2 From the NLA President JAMES A. UNDERBERG, MD, MS, FACPM, FACP, FNLA* An Exciting but Challenging Time Preventive CV Medicine, Lipidology and Hypertension —Peter P. Toth, MD, PhD, FNLA* Clinical Assistant Professor of Medicine NYU Medical School and Center for CV Prevention New York, NY 3 From the NELA President Look for the NLA logo to discuss articles online at www.lipid.org ROBERT A. WILD, MD, PhD, MPH, FNLA* Lipid Spin: A Collaborative Effort Clinical and and — Perry J. Weinstock, MD, FNLA* Clinical Lipidology Professor Oklahoma University Health Sciences Center Editor’s Corner Oklahoma City, OK 4 21 Case Study II Practicing Based on Evidence Does Gender Matter in Managing Editor —Robert A. Wild, MD, PhD, MPH, FNLA* MEGAN L. SEERY Cardiovascular Risk Assessment? National Lipid Association —Danielle Duffy, MD 5 Clinical Feature —Edward Goldenberg MD, FNLA Executive Director CHRISTOPHER R. SEYMOUR, MBA HDL and National Lipid Association Risk—Risk Marker or Risk Factor? 24 Member Spotlight — Robert S. Rosenson, MD, FNLA ­—Suneet Verma, MD, FNLA* Contributing Editor KEVIN C. MAKI, PhD, CLS, FNLA EBM Tools for Practice Associate Editor for Patient Education 7 25 2012 Scientific Sessions Young VANESSA L. MILNE, MS, NP, CLS Risk Reductions Investigator Abstract Cardiac Vascular Nurse and Family Nurse Practitioner — Spencer D. Kroll, MD, PhD* Bellevue Hospital Lipid Clinic ­—Ike Okwuosa, MD New York, NY 9 Specialty Corner 26 News and Notes Lipid Spin is published quarterly by the Coping with Statin Adverse Events— National Lipid Association Focus on Pharmacokinetics and 6816 Southpoint Parkway, Suite 1000 27 Education and Meeting Update Jacksonville, FL 32216 Pharmacodynamics Phone: 904-998-0854 | Fax: 904-998-0855 —Kenneth A. Kellick, PharmD, CLS, FNLA Events Calendar Copyright ©2012 by the NLA. 28 All rights reserved. Practical Pearls 13 29 Foundation Update Visit us on the web at www.lipid.org. Primary Hypertriglyceridemia— Treating Triglycerides When It’s Not The National Lipid Association makes every effort to 30 Guest Editorial provide accurate information in the Lipid Spin at the the Usual Suspects time of publication; however, circumstances may alter ­—Vanessa L. Milne, MS, NP, CLS HDL-targeted Therapies—Where Do certain details, such as dates or locations of events. We Go From Here? Any changes will be denoted as soon as possible. —Daniel J. Rader, MD, FNLA* The NLA invites members and guest authors to 16 Case Study I —Emil M. deGoma, MD provide scientific and medical opinion, which do not necessarily reflect the policy of the Association. The Patient with Family History of Premature Coronary Heart Disease 34 References ­—Merle Myerson, MD, EdD 37 Patient Tear Sheet 19 Lipid Luminations The Controversy Over Universal Screening for Children *indicates ABCL Diplomate status — Samuel S. Gidding, MD

1 From the NLA President: An Exciting but Challenging Time

Peter P. Toth, MD, PhD, FNLA President, National Lipid Association Director of Preventative Cardiology CGH Medical Center Sterling, IL Professor of Clinical Family and Community Medicine University of Illinois School of Medicine Peoria, IL Diplomate, American Board of Clinical Lipidology

know about this both clinically committee is currently formulating plans to and scientifically and will address unresolved make this helpful and effective. issues and controversies. Outreach to other organizations continues. Discuss this article at www.lipid.org The NLA will be rolling out a comprehensive We will be meeting with representatives of Go to “Topics/Lipid Spin Fall 2012” and look for “From the NLA President.” slide library on HDL later this fall complete the Preventive Cardiology Nurses Association with case studies and speaker’s notes. this November to further explore ways we A series of highly academic newsletters can work together. We continue to explore It is my privilege to serve as President of the addressing controversial areas of HDL are potential avenues to work with the American NLA during this coming year. As is always in production, and will feature articles by College of Cardiology and the American the case, this is both an exciting but also a Robert Brook, MD, Ben Ansell, MD, and Academy of Osteopathic Family Physicians very challenging time. I would like to tell you Phillip Barter, MD, PhD, among others. on educational programs. about some of the programs and initiatives we are rolling out this year. All of us have been awaiting the release The response of our membership to the of ATP IV. A number of committees have 2012 Scientific Sessions was strongly In September, we are convening a panel of been formed to help the NLA respond as positive. In the next two months, we will 13 experts in Charlotte who will generate effectively as possible during the public begin planning the Sessions for 2013 in Las a consensus statement on Adiposity and commentary periods for each of the new Vegas. If you would like to recommend a . The panel will address issues guidelines to be issued by the NHLBI. topic and possible speaker, please e-mail me of pathophysiology as well as assess the at [email protected]. We have every role/impact of lifestyle modification and the In the year ahead, you will see the intention of making next year’s meeting efficacy of pharmacologic intervention in emergence of a strong pediatrics section relevant, exciting, and better than the last! managing this important area of lipidology. of the NLA. The members of this group Given the negative results of such trials as are currently constructing a plan to help We would like to continue to expand our AIM-HIGH and dal-OUTCOMES, the clinical invigorate the NLA’s voice in the diagnosis membership. Introduce a friend to the NLA. impact of treating low serum levels of HDL and management of pediatric dyslipidemia. If you stopped paying your dues, please take cholesterol has been called into question. As the NLA Masters in Lipidology course the time to reactivate your membership. In January the NLA is bringing together an is updated and revised, expect to see a Finally, remember to make a donation to international panel of 16 experts in New lecture on pediatric lipidology introduced. the NLA Foundation, which has embarked York to produce a consensus paper on HDL. A mentoring program for young lipidologists on multiple programs of good works and The document will help to define what we will also be rolled out later this year. A new deserves your financial support. n

2 LipidSpin From the NELA President: Lipid Spin: A Collaborative Effort

PERRY J. WEINSTOCK, MD, FACC, FNLA President, Northeast Lipid Association Chief of Cardiology Cooper University Hospital Associate Professor of Medicine Cooper Medical School of Rowan University Camden, NJ Diplomate, American Board of Clinical Lipidology

It is my great honor to serve as President produce a mortality benefit. Perhaps most of the Northeast Lipid Association (NELA). disappointing is the realization that raising One of the responsibilities of the President HDL is not clearly protective. We are all is to choose the topics and invite the familiar with the controversy surrounding authors for Lipid Spin. Accordingly, this CETP inhibition with torcetrapib and Discuss this article at www.lipid.org edition of Lipid Spin was developed with now dalcetrapib. We seek to explain why Go to “Topics/Lipid Spin Fall 2012” my suggestions and direct input. I must say AIM-HIGH did not produce the results and look for “From the NELA President.” that the task, though daunting at first, was we anticipated. Now we must account made a true labor of love with the help of for the findings of a large Mendelian all the great chapter members who eagerly randomization study published a few commitments. I hope all the readers of participated and with the constant support months ago in Lancet that showed no Lipid Spin will agree this is one of the best of the editors, Jamie Underberg, MD and consistent relationship between individuals editions ever. Please share your copy of Robert Wild, MD, PhD. Most importantly with a genetically high HDL and a lower Lipid Spin with others and let them see I want to thank Megan Seery from the risk of myocardial infarction. In an effort firsthand just how relevant and wonderful NLA staff who was an absolute delight to to refocus our and move the this publication is for anyone interested in work with from start to finish. lipid hypothesis forward, I have turned to the field of Clinical Lipidology. the laboratory of Dan Rader, MD, at the The theme for this Lipid Spin is University of Pennsylvania to address the I hope you all had a great summer and look “Controversies in Clinical Lipidology.” issue of targeting HDL as a therapeutic forward to seeing you at our Clinical Lipid The daily practice of Clinical Lipidology option. Dr. Rader and his colleague Emil Update in Charlotte, North Carolina from once seemed rather straightforward. deGoma, MD, took on this task with September 14-16. n If the LDL was high, lower it. If the enthusiasm and produced a masterful triglycerides were high, lower them. If the summary of the state-of-the-art of HDL HDL was low, raise it. However, clinical altering therapy. trials have challenged the simplicity of these assumptions by teaching us that Each of the major articles in this edition nature frequently confounds the best laid of Lipid Spin was written by a member plans of man. Thus, we now understand of NELA. I believe the quality of the that it matters how you lower LDL. contributions is outstanding and I wish Likewise, although lowering triglycerides is to congratulate the members of NELA for beneficial, our standard therapies may not rising to the task despite their summertime

Official Publication of the National Lipid Association 3 Editor’s Corner: Practicing Based on Evidence

ROBERT A. WILD, MD, PhD, MPH, FNLA Clinical Epidemiology and Biostatistics and Clinical Lipidology Professor Oklahoma University Health Sciences Center Oklahoma City, OK Diplomate, American Board of Clinical Lipidology

risk can be used in studies that are analytic patients needed to prevent one outcome in a (control groups) where data is accrued specified period of time. in a prospective fashion. Understanding the magnitude of the relative risk and the The article by Dr. Myerson is a great Discuss this article at www.lipid.org confidence limits around the relative risk illustration of finding evidence and using it Go to “Topics/Lipid Spin Fall 2012” is important. The relative risk is helpful to deal with a clinical scenario. Importantly, and look for “Editor’s Corner.” in contrasting outcomes (comparing the it points out where there are gaps in treatment arms) in clinical trials or in cohort evidence, and that finding evidence and One of the NLA’s missions is to move studies that use cumulative incident data— evaluating evidence is not by itself ever our educational efforts towards practicing the proportion of new cases of disease during enough. We need to be able to find out if based on best evidence. You will be seeing a specific time period. Relative risk is a very information available is valid, if it fits our segments of Lipid Spin dedicated to this useful concept because it focuses on the particular patient’s clinical presentation and objective. There are many interesting aspects magnitude of the comparison of the groups. value system. In short, we need to integrate of lipidology addressed and displayed in a It is helpful in understanding associations our decisions as this case illustrates. That multi-disciplinary fashion in this edition of and helps move our understanding towards is the art of clinical practice. Importantly, Lipid Spin. Thanks to Perry Weinstock, causation. as clinicians, we often disagree regarding MD, as he assembled many contributors for management when there are gaps in each of us to learn from. There are many As clinicians what is most important to evidence available. We always need to be types of articles presented in this issue and us however is understanding the absolute mindful of the clinical circumstance and the there are many practical things to learn risk for each of the groups being studied specifics of any given clinical situation. What about. In particular I would like to highlight but most importantly focusing on what about likelihood of compliance, for example, the articles by Spencer Kroll, MD, PhD, the absolute risk reduction is if there is a in this case with lifestyle management? and Merle Myerson, MD, EdD. difference detected between the comparison When is medication indicated? How groups. Understanding the magnitude of the motivated is the patient in front of us? What The article by Dr. Kroll illustrates an difference and if it is clinically important is other therapies is he or she using besides our important EBM concept and uses a great a must. We can quantify this by taking the counsel? example of how to interpret and clinically absolute risk difference and then dividing use relative risk and absolute risk. As this into one. That gives us the number We are pleased to provide these articles and consumers of the literature we all need needed to treat for benefit or, depending on they are published here with the goal of to be knowledgeable about these terms the context, it gives us the number needed generating thought, discussion and debate. and what they mean and how best to use to harm. This is interpreted as the number of That’s what is great about the NLA. n them. We should all be aware that relative

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

Robert S. Rosenson, MD, FNLA Director, Cardiometabolic Disorders Mount Sinai Medical Center Professor of Medicine Mount Sinai School of Medicine New York, NY

Low HDL cholesterol (HDL-C) is an HDL-C: A Biomarker of Atherogenic established biomarker for the future development of atherosclerosis and Low HDL-C levels are commonly associated atherosclerotic cardiovascular disease with cholesterol-depleted HDL particles 9 (CVD) events in -based and cholesterol-depleted LDL particles. Discuss this article at www.lipid.org observational studies and clinical trials Due to conformational changes in Go to “Topics/Lipid Spin Fall 2012” of cholesterol-lowering therapies and (apoB) on the surface of and look for “Clinical Feature.” this includes coronary heart disease small LDL particles, these cholesterol- (CHD) patients with low levels of LDL depleted particles have reduced under appreciation of the contribution cholesterol (LDL-C) on statin therapy.1-3 interactions with LDL receptors, which of -enriched, cholesterol-depleted Because multiple clinical trials designed results in delayed hepatic clearance of HDL subclasses in modulating critical to increase HDL-C and reduce CVD risk these atherogenic lipoproteins from the atheroprotective functions.14 Specifically, have not demonstrated efficacy and instead bloodstream. In a primary prevention trial certain of small HDL have shown potential harm,4-6 there has of individuals with reduced HDL-C levels, particles have stronger anti-oxidant, anti- been widespread confusion regarding the baseline and on-trial CHD events were inflammatory and anti-infective properties importance of HDL as a biomarker of risk linearly related to apoB levels.10 It remains than other constituents of HDL.15 and as a potential target for therapeutic uncertain from current observational and intervention.7 Confusion around the clinical trial data whether the increased Several prospective population studies16-18 importance of HDL in atheroprotection CVD risk associated with low levels of and clinical trials of lipid modifying- has been magnified by a Mendelian HDL-C is anything more than an excess therapies19,20 have reported that the randomization study that utilized HDL-C as concentration of atherogenic apoB- concentrations of small HDL particles and/ an intermediary biomarker of CVD risk.8 containing particles. or total HDL particles are more robust predictors of CVD risk than total HDL-C. This perspective discusses the limitations HDL Particles: A Biomarker of CVD Risk These studies suggest that the protein of HDL-C as a biomarker of risk, For 50 years, “reverse cholesterol composition or proteome of certain and misguided attempts to reduce transport” has been considered the subpopulations of HDL particles may have atherosclerosis through effectuating major anti-atherogenic of more important contributions to HDL- changes in the cholesterol content of HDL HDL.11,12 Only 3-5% of the mass of HDL associated CVD risk than can be deduced particles. particles, however, is derived from from the cholesterol carrying capacity of macrophage cholesterol efflux.13 This circulating HDL particles alone. reliance on HDL-C has resulted in an

Official Publication of the National Lipid Association 5 Mendelian randomization studies have CVD events. In multivariate models that on-trial changes in and lipoprotein been considered to provide an “unbiased” included major risk factors, lipids and subclasses.20 In multivariate models that evaluation of biomarkers and their lipoprotein subclasses, HDL particle included treatment group, conventional association with the development of concentration but not HDL-C was inversely risk factors and lipid and lipoprotein disease. Two recent GWAS studies provide associated with carotid intima medial concentrations, every one standard an example of conflicting conclusions thickness and incident CHD events. Two deviation change in HDL-C was unrelated related to HDL associated CVD risk other prospective population studies have to CHD events (p=0.14); whereas HDL-P however.8,21 In a combination of five reported that HDL-P is a more accurate was inversely related with CHD events at cardiovascular disease case-control studies predictor of CVD events in a subset of baseline (odds ratio: 0.78 [0.69-0.90] ) (4,658 cases and 11,459 controls), two metabolic syndrome patients (Multiple and on-trial (odds ratio: 0.71 [0.61-0.81.]19 single nucleotide polymorphisms (SNP) Risk Factor Collaboration Trial,16 and the In an analysis of HDL subclasses, baseline in the transfer protein EPIC Norfolk Study).17 and on-trial risk were associated with (PLTP) gene associated with reduced PLTP small HDL subclasses (0.71[0.60-0.84 activity were associated with reduced and 0.67[0.57-079] respectively) and CVD risk despite the lack of influence of Certain populations medium subclasses (0.82[0.70-0.96] and this on the cholesterol content of 0.82[0.69-0.97]) but not by large HDL HDL.21 In contrast, the PLTP polymorphism of small HDL subclasses (0.95 [082-1.11] ) and 0.92 was associated with higher concentrations [0.79-1.07] respectively). of small HDL particles and total numbers particles have of HDL particles. In the one Mendelian From the available data, HDL-C remains a randomization study that had previously stronger anti-oxidant, robust marker of elevated apoB-containing used a genome-wide association approach lipoproteins and CVD risk; however, to identify SNPs that affect blood lipid anti-inflammatory HDL-C is not a useful biomarker of HDL concentrations,22,23 a polymorphism in the and anti-infective functionality. Multiple HDL subclasses are endothelial lipase gene (LIPG Asn396Ser) involved in anti-atherogenic mechanisms. found in 20 studies (20,913 myocardial properties than other HDL-P assessment provides one clinically infarction cases, 95,407 controls) as well available measure that appears to more as 14 other pathways (12,482 cases of constituents of HDL. precisely predict CVD risk. From my myocardial infarction and 41,331 controls perspective, future trials that investigate exclusively associated with HDL-C), were HDL-modifying therapies should assess investigated for their association with Several pharmacological agents are known HDL-P and, in particular, certain functional myocardial infarction.8 Despite having high to increase the cholesterol content of HDL subclasses. n HDL-C levels, there was no association HDL (CETP inhibitors, niacin)24,25 and Disclosure statement: Dr. Rosenson has received with CVD risk. In this study, the authors other agents increase the number of grants from Amgen, Genentech and Hoffman- assumed that “plasma HDL-C” was the HDL particles, but are less effective in LaRoche. Dr. Rosenson has been an adviser to Abbott Laboratories, Amarin Corporation, Amgen, Genentech, biomarker “directly involved” in the loading the particles with cholesterol Hoffman-LaRoche, Kowa Pharmaceuticals America, pathogenesis of CHD, and concluded that (PPAR-a agonists).19 In the Veterans LipoScience Inc. and Sanofi-Aventis. Dr. Rosenson has stock options in LipoScience Inc. inherited variation in plasma HDL-C was a Administration HDL Intervention Trial (VA- References listed on page 34. surrogate measure of disease. HIT), gemfibrozil therapy reduced LDL-P by percent, increased total HDL particles The Multi-Ethnic Subclinical by 10% and small HDL particle subclass Atherosclerosis (MESA) study18 by 21%. In the initial report of this trial, investigated the relative importance of on-trial changes in HDL-C explained only several HDL measures (HDL-C, HDL size 17% of the CVD risk.26 A nested-case and HDL particle concentration) as to risk control study from VA-HIT investigated of subclinical atherosclerosis and incident the CVD risk associated with baseline and

6 LipidSpin EBM Tools for Practice: Risk Reductions

SPENCER D. KROLL, MD, PhD Director, The Cholesterol Treatment Center Clinical Lipidologist in Private Practice Marlboro, NJ Diplomate, American Board of Clinical Lipidology

Clinicians are constantly presented with compared to any other risk. Relative risk data and results intended to influence reduction (RRR) is a comparison between the treatment they render to patients. different risk levels and between treatment However, in spite of the gravity of the effect and the risk without treatment. For consequences of treatment, we are often example, the relative risk for lung cancer Discuss this article at www.lipid.org not supplied with appropriate and adequate is (approximately) 10 times greater for Go to “Topics/Lipid Spin Fall 2012” data on which to base our judgment of a smoker compared to a nonsmoker. An and look for “EBM Tools for Practice.” effectiveness. Such situations become important feature of relative risk is that clearer when we see media reports with it gives no information about the actual whereas first myocardial infarction is “relative risk reduction” in treatments baseline risk but it can be important diagnosed in about 400 in 100,000 people rather than statistics on “absolute risk in evaluating how significant a relative per year. These numbers are based upon reduction.” The difference in data increase might be. absolute risk. If relative risk were applied presentation often makes the treatments and a 10% increase occurred, then for appear much better than they actually are. A small increase in risk in a large thyroid cancer there would be 0.10 x 1 = Evidence-based medicine compels us to population can skew the effect and make 0.1 new cases per 100,000 people. On the integrate the best research evidence with the result seem larger than it actually is. other hand, a 10% increase in myocardial our clinical expertise and patient values. Simply stated, we often lack a standard infarction affects an additional 40 per by which to judge the superior clinical 100,000 people. Accordingly, if we assume In order for clinicians to make an informed decision. Whether RRR ‘‘overestimates’’ the population of the United States is 300 decision in evaluating relative and absolute the effect or ARR ‘‘underestimates’’ the million (which is 3,000 times 100,000), risk reduction data, they must understand effect is a value judgment because we often the small increase in thyroid cancer would the difference between the two forms of lack a gold standard for what is the ‘‘best’’ result in 0.1 x 3,000 = 300 new cases. By risk and the data upon which it is based. decision. contrast, the same increase in rate using There are two types of risk assessment. RRR in first myocardial infarction would Absolute risk reduction (ARR) is risk Let’s now apply these criteria to some result in 40 x 3,000 = 120,000 new cases. stated without any context. For example, specific situations to gain a better insight. you have a 50 % chance when flipping a The baseline risk is critical for determining To further understand the application of coin of coming up with heads. The 50% changes in absolute risk. For example, the data presented, we must be informed probability is independent of other factors thyroid cancer is diagnosed in slightly of the average number of patients that and is independent of prior tests. It is not less than 1 in 100,000 persons per year, need to be treated for one to benefit as

Official Publication of the National Lipid Association 7 compared with a control in a clinical trial placebo arm. Without mentioning the name with elevated high-sensitivity C-reactive within a given period of time. This is called of the trial or the medication, the results of protein and low LDL cholesterol seem to Number Needed to Treat (NNT). NNT is a the Helsinki Heart Study in various formats be comparable to many other interventions more informative statistic for comparison were distributed among 148 physicians. for primary cardiovascular prevention, but because it describes the number of patients Physicians’ willingness to prescribe the significantly higher than that seen for statin who must be treated over a set period of drug was 77% when the data was presented interventions for secondary prevention.* time to prevent one person from suffering in terms of RRR while 24% were willing to Again, we cannot compare NNT across an event or for seeing a benefit of the prescribe the drug when data was expressed these populations with very different treatment. Number needed to treat is the in terms of ARR.1 Influence of RRR on baseline risks. inverse of absolute risk. NNT is derived physician’s perception of treatment benefits from absolute risk and does not rely upon has been reported in several other trials.2,3 Exploitation of “information framing” is a relative risk for its calculation. The higher well-recognized strategy in marketing and the NNT, the less effective the treatment. Applying the criteria of relative risk and mass media. Perception of probabilities absolute risk to some other lipid trials, and outcomes can predictably shift when The NNT value is time-specific. For we find the following: The ASCOT-LLA the same problem is framed in a different example, if a study ran for five years and Trial was a primary prevention study that way. As for medical interventions when the the NNT was 100, in one year the NNT examined the benefit of atorvastatin 10mg results are presented in RRR rather than would be multiplied by five to estimate a in patients with hypertension but with ARR, it appears that the enthusiasm for the one-year NNT of 500. However this method no previous cardiovascular disease. Over intervention increases as both physicians of calculation is controversial because an more than three years, the relative risk of a and patients downplay other attributes effect may not be constant over the full cardiovascular event was reduced by 36%.4 of the treatment such as side effects.7 course of measurement. If the slope of The absolute risk reduction, however, was Clinicians must be vigilant for this type of the curve from the placebo group in a much smaller. This study determined that data presentation and seek out absolute study remains fairly constant throughout taking atorvastatin for 3.3 years would lead risk reduction figures. In so doing, we can a trial, this method is an acceptable and to an absolute risk reduction of only 1.02%. determine if the absolute benefit of the quick method of adjustment for the study’s The number needed to treat would then be treatment is large enough to justify its duration when evaluating the treatment 99.7 for the 3.3 years period to prevent one potential risks and costs. n effect as calculated from NNT. In addition cardiovascular event. to concerns about extrapolating over time, *Another set of data to emerge from JUPITER was a high relative risk for new onset diabetes. there is the potential limitation when one Absolute event rates in both the Meta-analysis of 13 statin trials shows a 9% randomized controlled trial is compared to rosuvastatin and placebo group arms of the increase in the relative risk of new-onset another when there is a different baseline JUPITER trial were low, but the relative diabetes.6 This meta-analysis shows that 255 risk. effect was very large.5 The relative risk patients have to be treated for four years before one statin-induced case of incident diabetes is reduction from the use of rosuvastatin seen. However, a composite of nine vascular Despite criticism of relative risk, it must in this population was 44% and even events (including death, myocardial infarction, be considered that relative risk is a higher if there was a family history of stroke, and coronary revascularization) would be avoided by treating 255 patients over the same comparator against absolute risk, much like premature CHD. When primary endpoints time period. It is intuitively clear that these risks clinical trials examine therapies relative to of MI, stroke, CV death, angina requiring and benefits are independently derived and each conventional therapy. Relative risk must be hospitalization and revascularization were population of 255 patients is an individual set. interpreted alongside absolute risk to tell defined, the NNT was found to be 25 Disclosure statement: Dr. Kroll has received honoraria you if the therapy is worth pursuing. Does patients over a 5-year period to prevent related to speaking from Abbott Laboratories, framing the data in RRR alter the perception one of these endpoints. The absolute risk GlaxoSmithKline and AstraZeneca. of therapeutic effectiveness in physicians? reduction over the two years of the study References listed on page 34. In the Helsinki Heart Study, after five years is 1.2%, reflecting a significantly lower of treatment with gemfibrozil, 2.73% of baseline risk in this population. From patients in the treatment arm experienced the relative risk reduction and from the a cardiac event comparing to 4.14% in the calculated NNT, statin therapy in patients

8 LipidSpin Specialty Corner: Coping with Statin Adverse Events—Focus on Pharmacokinetics and Pharmacodynamics

KENNETH A. KELLICK, PharmD, CLS, FNLA VA Western NY Health Care Center Buffalo, New York Diplomate, Accreditation Council for Clinical Lipidology

We all see patients in our practice who The following article reviews the either have complaints of muscle aches pharmacokinetic and pharmacodyamic after starting HMG-Co-A Redtucase parameters of the with a focus on inhibitors (statins) or have been referred the evidence and clinical aspects of the by other health care practitioners for management of the patient with statin Discuss this article at www.lipid.org management of dyslipidemia in the myopathy. Go to “Topics/Lipid Spin Fall 2012” presence of suggested diagnosis of statin and look for “Specialty Corner.” myopathy. A careful differential diagnosis Irrespective of statin use, other causes should take into account many factors: of myopathy have been noted. Many 1) The cause of the muscle pain. antibiotics along with cocaine or other illicit drugs have been associated with a TERMS 2) The timing of the muscle pain with focal myopathy. Colchicine, amiodarone, Myopathy: general term for every potential respect to statin initiation. cyclosporine, glucocorticoids, cimetidine muscle problem along with statins have been implicated in Asymptomatic myopathy: ↑ Creatinine 3) Confirming laboratory tests along diffuse myopathy. Extreme physical activity Kinase(CK) without myalgias or weakness with physical examination. has also been linked to severe muscle pain. A careful history, physical and laboratory Symptomatic myopathy: presence of myalgia, 4) The dose and specific statin used. data is essential to classification of a muscle weakness or cramps 5) The pharmacokinetics of the statin. problem.1-3 Rhabdomyolysis: evidence of muscle injury demonstrated by CK. 6) Other concomitant medications. Useful laboratory tests include a basic ↑ metabolic panel to determine renal 7) Pharmacodynamics with respect Mild ↑ CK: CK levels >normal but <10x ULN function and acid-base or electrolyte to statin which may abnormalities and a creatinine phospho- Moderate ↑ CK: CK levels >10x ULN but <50x be altered by genetic mutations in kinase (CPK) to categorize the degree certain enzyme systems. Marked CK increase: CK levels > 50x ULN of muscle damage. Serum and/or urine 8) Other clinical conditions or myoglobin may be helpful in the diagnosis 4-6 implicating factors. of rhabdomyolysis.

Official Publication of the National Lipid Association 9 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 Multi- diseases S/p post-operative period Table 1. Factors that increase the risk of statin-induced myopathy.7-11

Factors that pre-dispose the patient to been implicated in the pathogenesis of consensus that these patients should be muscle diseases (Table 1) should be taken statin myopathy.3,12 treated with statins due to cardiovascular into account. Common among these are risk associated with this condition. A recent family history of statin muscle pain, There are more than 30 different enzyme FDA ruling no longer recommends that recent vigorous exercise and gender. The systems and multiple families of enzymes liver done routinely before starting statin small frame, elderly female may respond associated with liver metabolism. therapy, certain patients such as those with more rigorously to small “pixie-dust” doses Commonly associated with statin active liver disease and NASH may require of statins than their male counterparts interactions are CYP 2C9 and CYP3A4. additional monitoring.11,13,18,21 and require appropriate dose adjustments. Additionally, aging is associated with a 20- Hypothyroidsim should be ruled out with 30% reduction in hepatic size and a 20-50% The issue surrounding the drug-drug thyroid function testing. Polypharmacy reduction in hepatic blood flow. Despite interactions appears to be related to the and multiple providers put patients at this, there is conflicting information serum and or intra-cellular levels of statins. risk for drug interactions. A complete regarding the impact of aging on hepatic When doses are increased higher levels of family history is must also be part of microsomal enzyme activity. Some patients the statin acid result and muscle toxicity any comprehensive evaluation. Single- with active liver disease or nonalcoholic can occur. This first became evident in the nucleotide polymorphisms (SNPs) impacting steatohepatitis (NASH) may have altered late 1990s when an attempt at approving a statin associated metabolic pathways have enzyme activity. There is, however, general 160mg dose of simvastatin was abandoned due to higher levels of myotoxicity. In Substrates Inhibitors Inducers August 2001, cerivastatin was recalled due acetaminophen, alfentanil, alprazolam, amiodarone, amiodarone, carbamazepine, to the gemfibrozil-cerivastatin interaction aminopyrine, amitriptyline, amlodipine, amprenavir, amprenavir, dexamethasone, antipyrine, astemizole, atorvastatin, benzphetamine, cannabinoids, ethosuximide, which produced very high serum budesonide, busulfan, cannabinoids, carbamazepine, cimetadine, glutethimide, concentrations of the parent drug and some celecoxib, cisapride, clarithromycin, clindamycin, clarithromycin, nevirapine, clomipramine, clozapine, codeine, cortisol, 19 cyclobenzaprine, cyclophosphamide, cyclosporin clotrimazole, phenobarbital, of its metabolites. A, dapsone, delavirdine, dexamethasone, cyclosporin, phenytoin, primidone, dextromethorphan, diazepam, digoxin,diltiazem, delavirdine, diltiazem, rifabutin, rifampin, disopyramide, docetaxel, donepezil, doxorubicin, ethinylestradiol, St. John’s Wort, Recently the FDA, following an analysis of dronabinol, erythromycin, ethinylestradiol, erythromycin, sulfadimidine, ethosuximide, etopside, felodipine, fentanyl, fluconazole, fluoxetine, sulfinpyrazone, the SEARCH trial, capped the maximal dose fexofenadine, flutamide, granisetron, haloperidol, fluvoxamine, indinavir, troglitazone, of simvastatin at 40mg daily due to the hydrocortisone, ifosfamide, imipramine, indinavir, intraconazole, troleandomycin isradipine, ketoconazole, lansoprazole, lidocaine, burden of myopathy and rhabdomyolysis loratadine, losartan, , methadone, mibefradil, ketoconazole, miconazole, midazolam, navelbine, nefazodone, metronidazole, at the higher dose of the drug. The latter nelfinavir, nicardipine, nifedipine, nimodipine, mibefradil, miconazole, nisoldipine, omeprazole, ondansetron, paclitaxel, nefazodone, problem was highest during the first year pravastatin, prednisone, propafenone, quinidine, nelfinavir, nicardipine, of treatment. Similarly, in February 2012 quinine, retinoic acid, rifampin, ritonavir, ropivacaine, norfloxacin, propafol, saquinavir, sertraline, sufentanil, tacrolimus, quinine, ritonavir, the FDA announced similar new labeling for tamoxifen, temazepam, teniposide, terfenadine, testosterone, THC, theophylline, triazolam, saquinavir, sertraline, lovastatin. Table 3 summarizes new FDA troleandomycin, verapamil, vinblastine, vincristine, troleandomycin, (R)-warfarin verapamil, zafirlukast labeling for lovastatin and simvastatin.20,21

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

10 LipidSpin Label Changes statins. These higher drug levels are thought to be directly related to increased Contraindicated with lovastatin: Contraindicated with simvastatin: • itraconazole • itraconazole incidence statin adverse reactions. Inducers • ketoconazole • ketoconazole the activity of these enzymes will increase • posaconazole • posaconazole the of the drug rendering it less erythromycin erythromycin • • 3,18,19,22 • clarithromycin • clarithromycin effective. • telithromycin • telithromycin • HIV protease inhibitors • HIV protease inhibitors Uridine diphosphate glucuronosyltrans- • boceprevir • nefazodone • telaprevir • gemfibrozil ferase (UGT) has been previously • nefazodone • cyclosporine implicated in the gemfibrozil–cerivastatin • danazol interaction. Ezetimibe undergoes rapid Avoid with lovastatin: Do not exceed 10mg simvastatin daily with: glucuronidation in intestinal mucosa cells • cyclosporine • verapamil by UGT1A1 and UGT1A3 and to a lesser • gemfibrozil • diltiazem • >1qt/day grapefruit juice degree, UGT2B15. Both fenofibrate and gemfibrozil can increase levels of ezetimibe Do not exceed 20mg lovastatin daily with: Do not exceed 20mg simvastatin daily with: • danazol • amlodipine due to their interaction with UGT enzyme • diltiazem • ranolazine family. The latter is not thought to be • verapamil • amiodarone (changed in Dec 2011) clinically significant.4,22 Do not exceed 40mg Lovastatin daily with: Avoid with simvastatin: • amiodarone • >1qt/day grapefruit juice In addition to liver enzymes, there are 20,21 Table 3. June/December 2011 and February 2012 FDA label changes. a number of transporters responsible through CYP3A4 and CYP2C8 and dose for hepatic uptake and clearance of The new hepatitis C drugs, boceprivir and adjustments with some statins are required statins. Table 3 lists enzymes that have telaprivir, may inhibit the metabolism of when with this agent. The FDA arbitrarily been implicated in statin myopathy and simvastatin through CYP 3A4. Grapefruit lowered the simvastatin dose cap to 10mg rhabdomyolysis. P-Glycoprotein (pGp) is juice in large quantities inhibits CYP3A4 when taken with amiodarone. This was an ATP dependent efflux pump member of and hence simvastatin, lovastatin and redacted in December 2011 to a maximum the ABCB1 transport protein. Its biologic atorvastatin. Once inhibited the ability simvastatin dose of 20mg due to lack of function is to prevent toxins from being of the enzyme takes up to 24 hours to clinical trial or pharmacokinetic data to absorbed through the GI tract and to rebound to pre-inhibitory concentrations support the lower dose.20,21 actively excrete toxins in the liver and after withdrawal of the grapefruit juice. kidney. Drugs that interact with pGp HAART regimen with newer or older The inhibition of statin metabolism is not can either inhibit or induce the activity protease inhibitors(PI) Amprenavir, limited to the CYP3A4 enzyme system. of this protein. This alters transport of saquinavir, lopinavir, duranavir and other Statins and non-statins, such as ezetimibe the substrate. Examples of common pGp protease inhibitors increase the risk for and gemfibrozil are affected by interacting interactions are noted on Table 5.22 atorvastatin, simvastatin and lovastatin agents. Inhibitors of CYP2C9 and CYP3A4 myopathy. Changing the statin or changing will likely increase the area under the PGp interactions are mostly associated with the PI to an alternative agent may be concentration-time curve (AUC) as well CYP3A4 metabolized drugs. Fluvastatin required. Amiodarone is metabolized as peak plasma concentrations of many and pravastatin do not significantly

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

Official Publication of the National Lipid Association 11 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) or 10x↑ 1.4x↑(10mg) 1.5fx↑(40mg) 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 Limited hepatic PgP, some CYP2C9 AND CYP2C8) (CYP 2C9 and hydroxylase CYP2C19) 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 inhibit pGp transport. Rosuvastatin has circulation to the hepatocyte. In the recent pharmacogenomics are all players in the not been shown to be a substrate or SEARCH trial it was noted that more than picture of statin induced muscle disorders. inhibitor of pGp or CYP3A4, yet when 60% of the myopathies were attributed to a In many patients statin metabolism is co-administered with itraconazole or noted gene variant in this enzyme system. altered producing higher serum drug cyclosporine serum concentrations This SLCO1B1 521T>C polymorphism levels resulting in symptoms of myalgia or increase. An alternative transporter, such may be associated with increased of myopathy. The science of statin metabolism as OATP2 may be responsible for the some statins such as simvastatin, but not continues to expand, with the hope that rosuvastatin-itraconazole interaction. Table pravastatin. someday a home monitoring test will be 5 shows the effect of commonly given available to assist the patient in profiling drugs (p-Glycoprotein substrates, inducers When approaching statin-drug interactions, which drug and or drug combination is and inhibitors) and their effect on statin the pharmacokinetics of statins need to be most safe and efficacious. n levels.23 considered (Table 6). Lipophilicity appears to have little role in predicting statin Disclosure statement: Dr. Kellick has no relevant disclosures. Polymorphisms in additional transport intolerance as does half-life. Synthetic References listed on page 34. systems may offer an alternative statins may be more tolerable than semi- explanation for statin induced myopathy. synthetic statins. OATP1B1 is an uptake transporter located on the hepatocyte and is responsible Drug-drug interactions, dosing, patient for transport of statins from the portal characteristics, pharmacodynamics and

12 LipidSpin Practical Pearls: Primary Hypertriglyceridemia—Treating Triglycerides When It’s Not the Usual Suspects

VANESSA L. MILNE, MS, NP, CLS Cardiac Vascular Nurse and Family Nurse Practitioner Bellevue Hospital Lipid Clinic New York, NY Diplomate, Accreditation Council for Clinical Lipidology

Hypertriglyceridemia (HTG) is defined as with cardiovascular disease is unclear; an excess of triglycerides in the blood. however, some types of primary HTG Primary HTG is caused by one or more convey higher risk for cardiovascular genetic defects leading to disease based on the specific lipoprotein elevation. Secondary HTG is acquired; the elevation. Understanding the types Discuss this article at www.lipid.org causes are plethoric and can be identified of primary HTG, as well as distinctive Go to “Topics/Lipid Spin Fall 2012” and look for “Practical Pearls.” by methodically assessing the factors responses to differences in treatment, listed in Table 1. Primary HTG should be allows the clinician to better assess and suspected if a secondary cause cannot be manage patient risk for pancreatitis and identified. In addition, an astute clinician cardiovascular disease. should consider primary HTG when the If a Patient Has Isolated HTG Consider: patient with a secondary cause has a Evaluation Familial hyperchylomicronemia fasting triglyceride measurement greater It can be challenging to definitively identify (Fredrickson Type 1)—Patients with than 300 mg/dL, since primary HTG may the genetic basis of a patient’s primary Familial hyperchylomicronemia have not reveal itself without a secondary HTG as genetic testing is not readily triglycerides > 1000 mg/dL, sometimes “insult” added to the clinical milieu. available and the diagnostic are exceeding 10,000 mg/dL, but often have muddied when a secondary component normal total cholesterol. The ratio of The National Cholesterol Education is involved. However, serum lipid levels, triglyceride to cholesterol is often cited Program (NCEP) Adult Treatment Panel personal and family history, and physical as being 10:1.2 The severe elevation III (ATP III) guidelines recommend first exam may guide the clinician to a likely in fasting results from a treating low density lipoprotein cholesterol genetic defect. First, consider the patient’s genetic causing an absence (LDL-C) to goal and then targeting non- serum levels. Does the patient have of (LPL), which high density lipoprotein cholesterol (non- an elevation in triglycerides and total metabolizes chylomicrons and very low HDL-C), unless triglycerides are ≥ 500 cholesterol or solely triglycerides? Second, density lipoprotein (VLDL), or a genetic mg/dL. At a level of ≥ 500 mg/dL, the does the patient or a family member have defect in a co factor, protein or enzyme patient is believed to be at risk for acute a history of pancreatitis or cardiovascular that obliterates LPL activity.3 Pancreatitis pancreatitis and lowering triglycerides disease? Third, are there any findings on is common. Patients with Familial is the initial goal.¹ Data on triglyceride physical exam suggestive of a specific type hyperchylomicronemia have low risk levels and their independent correlation of primary HTG? for coronary artery disease (CAD) since

Official Publication of the National Lipid Association 13 the elevated lipoproteins, chylomicrons, Secondary causes carry small amounts of cholesterol. Diseases/states Renal disease, thyroid disease, autoimmune disease, HIV, hepatic They can exhibit eruptive xanthomas, disease, pregnancy, diabetes, metabolic syndrome, obesity hepatosplenomegaly and lipemia retinalis. Diet and exercise Alcohol, high and/or high diet, physical inactivity This is a rare disorder and symptoms Medications Beta blockers, thiazide diuretics, bile acid sequestrants, usually manifest during childhood. , estrogen, androgens (rarely), SERMS, antiretrovirals, atypical antipsychotics, isotretinoin

Familial hypertriglyceridemia (Fredrickson Table 1. Secondary causes of HTG. Type 4)—Patients have normal to slightly elevated total cholesterol with triglycerides of Apo B, may have more clinical utility.2 Treatment ranging from 200-1000 mg/dL. VLDL is Orange palmar xanthomas, elbow and knee Secondary Causes elevated, which may result from a LPL tubero-eruptive xanthomas and peripheral Treating secondary causes of HTG will gene mutation that decreases LPL activity. vascular disease may be found on exam. improve triglyceride levels, thus requiring 2 Apo B is normal. A secondary component, less medication. Pregnant women with such as alcohol or high carbohydrate Primary mixed hyperlipidemia triglycerides > 350 mg/dL should be diet, is a common finding. Patients are (Fredrickson Type 5)—Like Familial referred to a high risk obstetrician and usually asymptomatic and have low risk for hyperchylomicronemia, patients with lipid specialist since pancreatitis can 4 atherogenicity. Primary mixed hyperlipidemia have increase fetal and maternal morbidity triglyceride levels >1000 mg/dL. Unlike and mortality.9 Examining the patient’s If a Patient Has HTG and Elevated Total Familial hyperchylomicronemia, the prescription list may reveal medicines Cholesterol Consider: patient’s total cholesterol levels are also that increase triglycerides, some of which Familial combined hypercholesterolemia elevated and the disorder usually manifests may be substituted for a lipid neutral (Fredrickson Type 2B)—Patients with in adulthood. Chylomicrons and VLDL medication. For example, the older beta Familial combined hypercholesterolemia elevations result from a partial deficiency blockers may be replaced by newer beta usually have triglycerides between 150-500 of LPL or Apo C- II. They are at risk for blockers, carvedilol or nebivolol. mg/dL and total cholesterol between 200 CAD and pancreatitis. They can exhibit and 400 mg/dL. A secondary component eruptive xanthomas, hepatosplenomegaly Diet and Exercise 6 such as insulin resistance or metabolic and lipemia retinalis. Alcohol abstinence is recommended syndrome is common. The disorder for the long-term prevention of is thought to be polygenic and large The appearance of a patient’s plasma pancreatitis.10 Fat restriction is extremely phenotypic variation can exist between can also aid in diagnosis. If a patient important for patients with Familial 5 family members. Apo B is usually elevated with severe HTG has not responded to hyperchylomicronemia, since they may (> 120mg/dL), which distinguishes it from medications, plasma should be visually not respond to medications. When 2 Familial hypertriglyceridemia. Patients assessed after phlebotomy. If plasma is hyperchylomicronemia is severe, fat should have low risk for pancreatitis, but are clear, as opposed to cloudy or lactescent, be restricted to < 15% of total calories at risk for CAD due to LDL and VLDL kinase deficiency should be per day.¹ Medium-chain triglycerides, 7 elevations. They do not have xanthomas. considered. Glycerol kinase deficiency, available as cooking , can provide an X linked genetic disorder, causes an fat that does not allow Dysbetalipoproteinemia (Fredrickson accumulation of free glycerol in plasma. formation since it bypasses the intestine.11 Type 3)—Triglycerides and total During triglyceride synthesis, three fatty Since Familial hypertriglyceridemia, cholesterol levels are elevated and equal acids attach to one glycerol . Dysbetalipoproteinemia and Familial in a one to one ratio, resulting from the Most labs count glycerol instead of combined hyperlipidemia can be Apolipoprotein (Apo) E isoform Apo E2/E2. triglycerides when calculating triglyceride exacerbated by metabolic disease or poor Since many people with isoform Apo E2/ levels, thus overestimating triglycerides if diet, it is important to counsel patients E2 do not demonstrate dyslipidemia, it is free glycerol is elevated. If one suspects about alcohol, fat and carbohydrate thought that a secondary cause contributes glycerol kinase deficiency, the clinician intake. 2,12,13 Replacing trans-fatty acids to this phenotype. An elevation in VLDL should seek a lab that controls for glycerol with monounsaturated or polyunsaturated 4 8 remnants increases CAD risk. It is concentrations. fat lowered triglyceride levels in a meta- thought that targeting non-HDL-C, instead

14 LipidSpin 14 analysis of controlled dietary trials. A low Medication Reduction in Mechanism of action Cautions and carbohydrate diet (<50% of calories from triglycerides contraindications 1,2 ) should be recommended. Fibric acids 20-60% Decreases serum VLDL and Renal disease, hepatic Dietary fiber and complex carbohydrates increases production of LPL disease, gallstones, should be emphasized and simple pregnancy, breastfeeding, caution with simultaneous 1,2 carbohydrates should be avoided. use of statins (avoid Weight loss, if needed, should be gemfibrozil), may increase encouraged as a weight loss of 5-10% LDL-C may result in a 20-30% reduction in Omega-3 35-50% Reduction in hepatic Fish allergy, may increase triglycerides.15 fatty acids triglyceride synthesis, an LDL-C increase in LPL activity and/or increased hepatic Exercise increases lipoprotein lipase and decreases activity, Niacin 20-50% Inhibits VLDL and LDL Pregnancy, peptic ulcer both which lower triglycerides. 16 synthesis disease, renal disease, liver disease, pre-diabetes, gout Unfortunately, patients with primary HTG may not experience the same decrease in Table 2. Medications used primarily for triglyceride lowering. triglycerides as someone with secondary or metabolic syndrome since it can worsen defect is significant when cardiovascular HTG. However, an exercise program glycemic status. disease and pancreatitis risk is considered. should still be recommended based on If the clinician believes that their patient patient age and abilities. Orlistat is a gastric and pancreatic lipase has an elevation in the atherogenic inhibitor which is FDA approved for lipoproteins, chylomicron remnants, Pharmacologic Treatment weight loss and maintenance. Dietary VLDL, VLDL remnants and LDL, then When a patient’s triglyceride level is fat cannot be hydrolyzed and undigested the clinician may focus on cardiovascular < 500 mg/dL, the clinician will first target triglycerides are not absorbed.17 disease prevention and screening.20 If LDL-C and non-HDL-C. The medications Orlistat has successfully lowered the clinician suspects an elevation in used to lower LDL-C and non-HDL-C also triglycerides in patients with Familial chylomicrons, then pancreatitis is a great lower triglycerides to varying degrees. hyperchylomicronemia when used as an concern. In addition, nuances in dietary Once the patient has met his or her LDL-C adjunct to dietary therapy.18 It has been and pharmacological treatment affect and non-HDL-C goals, or if a patient suggested that the triglyceride-lowering response between types of primary HTG. presents with triglycerides > 500 mg/dL, effect of omega-three fatty acids or Lastly, a discussion with patients about fibric acids, omega-3 fatty acids and niacin, medium chain triglycerides may be lost if the likelihood of a genetic basis for their used primarily for triglyceride lowering, administered simultaneously.18,19 disease may compel family members to be should be considered. Fibric acids are tested and treated. n often prescribed initially, although When managing a patient with elevated omega-3 fatty acids may be favored in cholesterol and HTG, it is important to Disclosure statement: Ms. Milne has received honoraria women of childbearing age. Doses at or related to speaking from Kowa Pharmaceuticals remember that bile acid sequestrants America. She has received consulting fees from Amarin above 4 grams daily of docosahexaenoic can increase triglycerides and are Corporation, Aegerion, and Genzyme. acid and eicosapentaenoic acid (DHA/ contraindicated at triglyceride level References listed on page 34. EPA) are usually necessary. If triglycerides > 500 mg/dL. Their effect on triglyceride are above 400 mg/dL, omega-3 fatty level should be monitored for those with acids and fibric acids can increase LDL- triglycerides > 300 mg/dL. C, although shifting the pattern to larger less dense low density lipoprotein (LDL) Does the Diagnosis Matter? particles and still lowering non-HDL-C. If patients with primary HTG are treated Niacin lowers LDL-C and increases high to goal, some would argue that the specific density lipoprotein cholesterol (HDL-C), genetic defect causing the HTG is not in addition to lowering triglycerides and significant. However, the lipoprotein non-HDL-C, but should be used with elevation that results from the genetic caution in patients who have pre-diabetes

Official Publication of the National Lipid Association 15 Case Study I: The Patient with Family History of Premature Coronary Heart Disease

Merle Myerson, MD, EdD, FACC Director, Center for Cardiovascular Disease Prevention Director, Cardiology Section, Center for Comprehensive Care (HIV) Clinic Attending Cadiologist St. Luke’s-Roosevelt Hospital New York, NY Assistant Professor of Clinical Medicine and Epidemiology Columbia University College of Physicians and Surgeons New York, New York

architect and is married with no children. The independent association of early CHD He took no medications. His blood in a first degree relative and associated pressure was 125/78. He was 175 cm tall risk has been demonstrated in many Discuss this article at www.lipid.org and he weighed 70 kg. A 12-lead EKG prospective cohort and case-control Go to “Topics/Lipid Spin Fall 2012” showed normal sinus rhythm at 66 beats studies. In the Atherosclerosis Risk and look for “Case Study I.” per minute and no other abnormalities. in Communities (ARIC) Study1 it was found that a family history of premature The month prior to his first visit the CHD was independent of other risk following levels were reported: factors. While many risk factors such as Patient LH, a 39-year-old white male came Total cholesterol 215 mg/dL hypertension and dyslipidemia are present to me for evaluation as he was concerned LDL-C 122 mg/dL in those with early CHD, these risk factors about his risk for coronary heart disease HDL-C 45 mg/dL account for only a portion of the aggregate (CHD). His father had coronary artery Triglycerides 242 mg/dL CHD seen in families.2,3 disease at age 46. He had 99% blockage of his right coronary artery and subsequent Based on NCEP ATP III, what are the The Framingham Risk Score does not stent placement. While not first degree lipid goals for this patient? He only has include family history. In a prospective relatives, he also has several aunts, uncles, one traditional risk factor, so this and study, Lloyd-Jones and colleagues used and cousins with early coronary heart Framingham Risk Score may not be helpful the Framingham cohort study data base to disease (defined as women prior to age 55 for this patient. Based on ATP III his LDL- investigate risk due to family history. Using and women prior to age 65). cholesterol (LDL-C) goal is < 160 mg/dL. validated events, they found that parental His triglycerides are elevated but may cardiovascular disease independently On his first visit he stated that he felt very well respond to dietary modification. predicted the future of offspring events very well overall and denied chest pain, Should I have stopped my evaluation here? in middle-aged adults. However, the pressure, or dyspnea. He is very active. What about the “family history?” investigators go on to say that the addition He runs 3 miles a day on weekdays and of validated parental data into multivariable 5-7 miles a day on weekends, He does Our patients often relate a family history functions predicting 10-year absolute risks not smoke, he has an occasional alcoholic of early CHD which should raise a “red may only increase the predictive accuracy beverage and had states he never used flag.” At present, it is difficult for clinicians to a small extent. “The overall C statistic illicit drugs. He admitted to a poor diet to assess and incorporate this information for our multivariable model increased from and often ate “take-out.” He worked as an into a management plan. 0.82 to 0.83.”4

16 LipidSpin In 2001, the NCEP ATP III Guidelines O’Donnell of the Framingham Heart Study A consensus panel of the European stated: “The presence and age of onset stated “…what has remained unclear are Atherosclerosis Society issued a statement of CHD in all first-degree relatives should the pathophysiological/genetic mechanisms stating that LP(a) should be measured once be assessed. The family history should of the familial risk, the extent to which in all patients at intermediate or high risk be considered positive for premature familial risk is independent of other risk of CVD/CHD who present with associated CHD if clinical CHD or sudden death factors, and the extent to which risk characteristics including family history can be documented in first degree male conferred by a positive family history of of premature CVD. The panel goes on to relatives younger than 55 years of age CHD is modifiable.”7 state “For reduction of plasma Lp(a) as a and in first degree female relatives secondary priority after LDL-cholesterol younger than 65 years of age. Because reduction, we recommend a desirable level a positive family history of premature The reason for for LP(a) < 80th percentile (less than about CHD provides information about the risk 50 mg/dL). Treatment should primarily be for CHD and the probability of having lack of complete niacin 1-3 g/day…”8 modifiable risk factors, it should serve important information helpful in making understanding The panel’s recommendation for testing treatment decisions relative to setting and and treating has been criticized by many reaching LDL-cholesterol goals in primary is that “family including Samuel Goldhaber who wrote prevention.” history” is a general that “problems with standardization and reporting of Lp(a) assays have persisted The Reynolds Risk Score was introduced term and does not without resolution.” More important, in 2007 to focus on risk for women. there has been no randomized prospective Thirty-five factors were assessed in healthy reflect a particular clinical trial of treatment of Lp(a).9 women who were 45 years of age or older. “Parental history of MI < age 60” is environmental or In 2011, an expert panel of the National included in the score.5 Lipid Association issued a statement on genetic abnormality. the clinical utility of advanced lipid testing. More recently, the European Guidelines Measurement of Lp(a) is reasonable when on Cardiovascular Disease Prevention state there is “a very strong family history of “The importance of familial prevalence While we cannot definitively assess vascular events…” The statement outlines of early-onset CVD is not yet sufficiently whether a positive family history has that the impact of treatment has yet to understood in clinical practice.” “Family conferred risk to our patients, many be determined by clinical trials, making history is a variable combination of providers use a positive family history use of niacin unclear, but other evidence and shared environment.” to weigh the balance towards aggressive suggests that an elevated Lp(a) should “Because of the polygenic and polyfactorial treatment of other risk factors including prompt aggressive reduction of LDL-C.10 determinants of the most common CVDs, lipids. Another approach is to perform the impact of any single polymorphism advanced lipid testing to help assess Residual Risk: Non-HDL Cholesterol, remains rather modest.” The guidelines do overall risk and to help determine need for , and LDL Particle go on to recommend “Familial prevalence pharmacologic treatment. Number of atherosclerotic disease or of major risk The concept of non-HDL cholesterol was factors…should be systematically sought Advanced Lipid and Biomarker Testing discussed in the NCEP ATP III guidelines. in the first-degree relatives of any patient It was recommended that in patients with Lipoprotein (a) [LP(a)] affected before 55 years in men and 65 TG > 200 mg/dL, non-HDL cholesterol LP(a) has a very strong genetic years in women.”6 (“atherogenic cholesterol”) should be a component—it is under the control of secondary target of therapy. the LP(a) gene. LP(a) is unaffected by diet The reason for lack of complete and most drugs; and has been associated understanding is that “family history” Non-HDL cholesterol has also been shown with premature CHD. Lp(a) has positive is a general term and does not reflect to improve on LDL-C in terms of risk predictive value that is additive to other a particular environmental or genetic prediction. Some recent investigations lipid and traditional risk factors. abnormality. In an editorial, Christopher J. have identified LDL-particle number and

Official Publication of the National Lipid Association 17 ApoB as even better able to predict risk specifically address their use in an the arterial wall by a gradient-driven and targets for therapy as non-HDL11,12,13 otherwise low-risk patient with family process. Once inside, the particles bind to however others have not.14,15 history, these tests can also be considered the arterial wall and the process of plaque to help determine risk and management in formation is initiated.17 The NLA Expert Panel recommends that such patients.16 measuring LDL-P is “reasonable for many I reviewed the lab testing with the patient. patients” with a family history of premature Follow-Up We discussed imaging studies (stress test, CHD” “When LDL-P is discordantly Given his high triglycerides and poor diet, CAC, CIMT), further lifestyle modification, elevated, consideration should be given I counseled the patient and gave him or pharmacologic treatment. to initiating LDL-lowering therapy.” The educational material on a heart-healthy panel also states that measurement of diet. I also ordered another fasting lipid We decided on CAC; his score was zero. ApoB is “reasonable for many patients” profile and advanced lipid testing. The With the absence of other risk factors and with a family history of premature CHD patient was compliant with the lifestyle zero calcium score, we decided to hold off based on the fact that “familial combined modifications and three months later had on pharmacologic treatment. He agreed hyperlipidemia is the most common another blood test. to go for medical counseling to atherogenic dyslipoproteinemia associated enforce the improvements in his diet. We with premature CHD.10 Total cholesterol 187 will recheck a basic lipid profile and LDL-P LDL-particle number 1723 in six months. n Lp-PLA2 LDL-C 125 This enzyme has shown to independently HDL-C 43 Editors’ Note: Question—How many of predict risk for CVD and to also be an Triglycerides 95 you would have tried to normalize his lipid active participant in development of Lp (a) 4 particles with medication given his family atherosclerosis. At present there is no Glucose 98 history and prior stent placement for the FDA-approved drug to treat Lp-PLA2 TSH 4.1 uIU/mL 90% occlusion? but existing lipid-lowering medications Lp-PLA2 155 have been shown to lower levels. The CRP 1 mg/L Disclosure statement: Dr. Myerson has received consulting fees from LipoScience Inc. and Kowa NLA Expert statement recommends Apolipoprotein B 120 mg/dL Pharmaceuticals America. Dr. Myerson has received measurement of Lp-PLA2 be “considered grants from Medtronic and LipoScience Inc. for selected patients” with a positive family The advanced testing results were all References listed on page 35. history.10 Lp-PLA2 is considered reasonable unremarkable with the exception of LDL- for patients in intermediate risk. particle number and Apolipoprotein B. His TG had improved most likely due to the CRP changes in his diet. His Lp(a), Lp-PLA2, and C-reactive protein is a non-specific CRP were low. inflammatory marker that has been extensively studied in terms of risk for Testing showed that there was discordance CHD. The NLA panel recommends “In between the LDL-C and LDL-P and ApoB. patients with a premature family history of While LDL-C and LDL-P are generally CHD…CRP measurement is a reasonable correlated, they may also be discordant— option to help determine if therapy should meaning one value is high and the other be started…”10 low, or vice versa. In this case, the LDL-C was low and at goal but the LDL-P number Testing for presence of subclinical was quite high. atherosclerosis In addition to advanced lipid and biomarker As discussed above, LDL-P has been shown testing, Coronary artery calcium and to potentially improve risk predication carotid intima-media thickness have been for CHD in groups of individual patients used to help risk-stratify patients with better than LDL-C. Mechanistically, the intermediate risk. While no guidelines particles, containing the cholesterol enter

18 LipidSpin Lipid Luminations: The Controversy Over Universal Cholesterol Screening for Children

Samuel S. Gidding, MD Cardiology Division Head A. I. DuPont Hospital for Children Nemours Cardiac Center Wilmington, DE

In 2011, the NLA and the National the whole child rather than managing Heart Lung and Blood Institute (NHLBI) individual risk factors independently. Each sponsored expert panel on Integrated set of recommendations has generated Cardiovascular Risk Reduction for Children controversy. Discuss this article at www.lipid.org and Adolescents each recommended Go to “Topics/Lipid Spin Fall 2012” universal lipid screening of United In the NLA consensus-based statement, and look for “Lipid Luminations.” States children at age 9-11 years.1,2 and for the first time in the United States, Prior reports recommended cholesterol FH is considered as a distinct disease measurement over age 2 years in the entity, separate from epidemiologically presence of a positive family history of based lipid assessment. Thus, increased In fact, if one looks deeply at current heart disease or elevated cholesterol or risk associated with lifelong exposure to cost analyses for FH care, one learns that the presence of a co-morbid condition severe and genetically elevated cholesterol treating an identified patient with FH is known to increase cardiovascular risk. levels is, finally, given appropriate highly cost effective (particularly with This latter recommendation was retained consideration. The controversy related to generic medications) and gene testing does by the NHLBI Integrated Risk Reduction the NLA recommendations is international, not substantially worsen these projections panel. The two guidelines, by design, where many Western countries and some (particularly as testing becomes much are essentially identical with regard to others have embraced cascade screening cheaper in the future). Adverse cost formal recommendations; however, the of identified index cases of FH, often in FH management is largely incurred purpose of each is somewhat different. with confirmation by genetic testing, as in case identification. The NLA panel The NLA recommendations are directed opposed to universal population screening recommended universal screening for FH towards identifying all children with as recommended in the NLA guideline. because of the historic failure of physicians familial hypercholesterolemia (FH). The For example, in the Netherlands where FH in this country to successfully implement Integrated Risk Reduction guideline takes genetic identification is most advanced, cascade screening, the recognition that a different approach to cardiovascular probably about 80% of FH carriers have family history is an inadequate criterion risk reduction in youth, integrating risk been identified. In the United Kingdom, for youth screening, and the high factor management developmentally across identification of those with FH between discrimination in childhood between true childhood and across all the risk factors the ages of 40-70 years and subsequent cases and unaffected individuals. Genetic to provide comprehensive primordial and cascade screening with genetic testing and testing was not recommended because risk primary prevention strategies that consider lipid treatment is highly cost effective.3 is determined more by LDL cholesterol

Official Publication of the National Lipid Association 19 level than genotype. In contrast, in the outweighed the evidence against. In the children at highest risk is identified. rest of the world, universal lipid screening minds of the panel, the knowledge that is prohibitively expensive, and index cases atherosclerosis begins in youth and is To summarize, it is probably worth are identified at older ages when genetic directly related to risk factors, that genetic considering if universal screening at age testing often helps risk stratification. In disorders of provide 9-11 years is that different from current my view, this discussion is not so much a overwhelming and consistent evidence recommendations. In ATP III, universal controversy as a very healthy scientific and for the benefit of lifelong LDL cholesterol screening is recommended at age 20 years, public health argument that in the short levels below 100 mg/dL, that clinical trials when very few people regularly go to the term will lead to increased recognition have been conducted that show medium doctor. Prior youth recommendations and awareness of FH in the medical and term safety and efficacy of statins with would test 60-65% of United States general community and, in the long term, improvement in subclincal atherosclerosis children, largely because of the high to cost effective treatment strategies outcomes, and that selective screening prevalence of obesity and positive family appropriate to the varied health care strategies fail to identify a significant history. What these new recommendations systems and resources around the world. percentage of those with severe elevations do is increase awareness of the importance of cholesterol outweighed gaps in evidence of healthy lifestyle habits for all, move The controversy over the evidence- related to long term safety and cost. the cholesterol test up about 10 years based NHLBI sponsored Integrated for about 35-40% of the population to Cardiovascular Risk Reduction Guideline Perhaps the most radical (and an age when genetic can exists mostly within the United States. underappreciated) change in the 2011 be recognized and at an optimal time Concerns are raised about the true benefit Integrated Guidelines compared to prior for intervention, and allow for dietary in cardiovascular disease risk reduction efforts is the fact that they are designed intervention at an age when preventive from early identification, the unknown to evaluate all cardiovascular risk factors health care is the norm. Is that so bad?. n harms of pharmacologic treatment, in every child both developmentally and and cost. These arguments are not that across all risk factors, as opposed to Editors’ Note: Dr. Gidding was a member different from those raised 20 years creating “risk silos” engendered by prior of the NLA and NHLBI expert panels that ago when the first selective screening guidelines for individual risk factors. drafted the lipid screening guidelines. recommendations were made and are The rationale for this approach comes legitimate concerns.4 However, to be from recognition of the importance of References listed on page 35. frank, I have a hard time accepting these preventing risk development in the first arguments as sufficient. In contrast to the place (primordial prevention), of the international debate on the best way to natural history of atherosclerosis and the recognize and treat FH, this argument has importance of multiple risk factors to rapid the potential to destroy efforts to prevent atherosclerosis progression, of the need to heart disease in this country. tailor recommendations to the age of the child and the needs of the entire family, The current NHLBI-sponsored and of the importance of obesity to the 2011 Integrated Guidelines are development of multiple cardiovascular unique compared to prior expert risk factors. Additionally, there is a small recommendations. Most important, they subset of children who need cardiovascular are evidence-based and were developed risk management: those with FH, diabetes, according to the highest recommended chronic kidney disease, and other high risk process as defined by the Institute of conditions. The focus on whether or not to Medicine. 5 The critiques described measure cholesterol in children undercuts above were considered in the weighting and deflects from the two more important of evidence (these critiques are actually goals of the 2011 guideline: to improve included in the text of the guideline) cardiovascular health across all risk factors and the panel’s conclusion was that before target organ injury is advanced the evidence for universal screening far and to make sure that small subgroup of

20 LipidSpin Case Study II Does Gender Matter in Cardiovascular Risk Assessment?

Danielle Duffy, MD, FACC Assistant Professor of Medicine, Jefferson Medical College Director, Cardiovascular Risk Reduction, Jefferson Heart Institute Philadelphia, PA

Edward Goldenberg, MD, FACC, FACP, FNLA Medical Director of Cardiovascular Prevention and Employee Wellness Christiana Care Health System Newark, DE

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

JR is a 69-year-old white female with long- ventricular hypertrophy. average of 10 years. In this study, there standing, well-controlled hypertension was no advantage to the use of aspirin treated with an ACE-inhibitor who comes Routine chemistries reveal normal renal 100 mg every other day in the reduction in for a cardiovascular risk evaluation. function, fasting blood glucose, and thyroid of a combined endpoint of stroke, She denies a personal history of diabetes, stimulating hormone. On fasting lipid non- fatal myocardial infarction (MI), or tobacco abuse, psoriasis, collagen vascular profile total cholesterol is 260 mg/dL, cardiovascular death. However, there was disease, or chronic kidney disease. There triglycerides 156 mg/dL, HDL-C 72 mg/dL, a significant 17% reduction in the risk is no family history of premature vascular LDL-C 157 mg/dL and non-HDL-C 188 mg/dL. of stroke. There was a 24% reduction in disease. She is moderately active and has ischemic stroke risk and a non-statistically no clinical symptoms referable to the Does she need an aspirin and what are her significant increase in hemorrhagic stroke cardiovascular system. Her medications lipid goals? risk. In a subgroup analysis of women over also include anti-depressants and the age of 65, aspirin significantly reduced supplemental thyroid. In the Women’s Health Study, 39,856 the risk of major cardiovascular events, women over the age of 45 without ischemic stroke, and MI.1 Her blood pressure is 135/85. Her physical baseline cardiovascular disease (CVD) examination and electrocardiogram are were randomized to low dose aspirin The 2011 American Heart Association normal. There are no findings of left versus placebo and followed for an (AHA) Effectiveness-Based Guidelines for

Official Publication of the National Lipid Association 21 the Prevention of Cardiovascular Disease JR’s risk of developing a stroke in the next Therefore, JR’s LDL-C of 156 mg/dL seems in Women recommends the use of aspirin ten years is 8%, which exceeds the average to be within her treatment goal as does her therapy in women 65 years of age or risk in the United States of 7.2%.6,7 Based non-HDL-C. Should we really stop here or older (81 mg daily or 100 mg every other on both the USPSTF recommendations are we missing something? day) if blood pressure is controlled and and the AHA Prevention Guidelines the benefit for ischemic stroke and MI for Women, low dose aspirin is a very It is now well-recognized that the prevention is likely to outweigh the risk of reasonable recommendation for JR. traditional Framingham risk assessment gastrointestinal bleeding and hemorrhagic has limitations and can underestimate risk stroke. These guidelines also note that How about a statin? in women, especially in young women. aspirin may be reasonable for women less Some of these limitations include: the than 65 years of age for ischemic stroke Statins have been proven to reduce focus on short-term (ie.10-year) risk of prevention.2 the risk of stroke in both primary and “hard” coronary outcomes only (MI or secondary prevention trials. In the Heart CHD death), the lack of inclusion of family It is important to note the gender Protection Study, 20,536 high-risk history in risk calculators, overestimation differences in the benefit of aspirin, patients were randomized to moderate- or underestimation of risk in nonwhite as the data from the Physicians Health dose statin versus placebo. In this trial, populations, and the fact that subclinical Study, although older, demonstrated a statin use was associated with a 25% CVD can have a relatively high prevalence 44% reduction in the risk of MI in men relative risk reduction in the occurrence among women who are scored as being who took 325 mg of aspirin every other of a first stroke event, regardless of at low risk.2 In order to address some day compared with those who received baseline LDL-C level.8 A recent meta- of these limitations, alternative risk placebo.3 This gender difference in the analysis by the Cholesterol Treatment stratification schemes have been adopted effectiveness of aspirin may be related to Trialists’ Collaborators also demonstrated in certain guidelines such as the AHA differences in vascular pathophysiology, a significant reduction in stroke risk Prevention Guidelines for Women.2 Indeed and is highlighted by demographic trends. with statin use and subsequent LDL-C the AHA guidelines propose three risk In 2008, there were 419,700 women and reduction, regardless of baseline risk level.9 categories: high risk, at risk, and ideal risk. 392,200 men who died of CVD.4 Death JR would fall into the “at risk” category from coronary heart disease (CHD) or MI Although stroke risk is lowered with based on her risk factors of hypertension was more common in men (73% of the statins, we generally consider the and elevated total cholesterol. Of note, men versus 59% of the women). However, recommendation for statin therapy based this “at risk” category also includes non- death from stroke, hypertension, or on a patient’s overall cardiovascular risk traditional risk factors, which JR doesn’t congestive heart failure was more common and the benefit of reducing all CVD events. have, such as poor exercise capacity, lupus in women (35% of the women versus 26% or rheumatoid arthritis, and evidence of of the men).4 Based on JR’s traditional Framingham risk subclinical CVD. For “at risk” women, the factors (age and hypertension, minus one AHA guidelines do recommend calculating The 2009 U.S. Preventive Services Task for having an HDL-C > 60 mg/dL), she a Framingham risk score using the newest Force (USPSTF) recommends the use would fall into the low risk category (0-1 Framingham risk calculator in order to of aspirin in women ages 55 to 79 for risk factor) with a LDL-C treatment target further refine treatment targets. stroke prevention when the potential of less than 160 mg/dL and a non-HDL-C benefit outweighs the potential risk of target of less than 190 mg/dL.10 Following As noted above, one of the limitations gastrointestinal bleeding. Specifically, the step-wise approach recommended of the traditional Framingham risk for women ages 60-69, aspirin is by the National Cholesterol Education calculation is that it only estimates the recommended when the 10 year risk of Program Adult Treatment Panel III (NCEP 10-year risk of CHD death or MI, and stroke is 8% or greater.5 For comparison, ATP III), we would not be expected to does not account for other vascular the USPSTF recommends the use of aspirin calculate a Framingham risk score. Even events. A newer risk assessment model, for prevention of MI in men ages 45 to 79 if we did, her 10-year risk of coronary also based on Framingham data, expands years when the potential benefit outweighs death or MI would also fall into the low the risk calculation to include all first the potential harm.5 risk category at 6%, notably lower than cardiovascular events such as coronary her estimated 10-year stroke risk of 8%. artery disease, stroke, manifestations

22 LipidSpin of peripheral vascular disease, or heart especially young patients, 10-year risk is For JR, a statin should be recommended in failure.11 If we calculate JR’s “general relatively short term, and the Framingham addition to aspirin to lower her overall risk cardiovascular risk score,” she actually risk score may be very low unless there are of CVD, including both coronary events falls into the moderate risk category with multiple uncontrolled risk factors. Lifetime and stroke. Her recommended LDL-C goal a 13.7% risk of developing a major vascular risk or 30-year risk has emerged as a tool should be less than 130 mg/dL with an event in the next 10 years.11,12 This general that better reflects the cumulative burden optional goal of less than 100 mg/dL, and a CVD risk profile also calculates a “vascular of risk factors over a much longer period moderate dose statin should be prescribed age,” which is a translation of the patient’s of time. A high lifetime risk can identify to achieve this goal. n general CVD risk points to the equivalent patients who may be at low short-term risk, age assuming all other risk factors are but would certainly benefit from additional Disclosure statement: Dr. Duffy has received grants from Roche/Genentech, Forest Laboratories, and Abbott optimal. JR’s vascular age is greater than lifestyle counseling or even preventive Laboratories. Dr. Goldenberg has received honoraria 80, over 10 years older than her biologic pharmacotherapies. Based on data from related to speaking from Takeda Pharmaceuticals, Boehinger-Ingelheim, Abbott Laboratories, and Merck age. Based on her general CVD risk score, the Cardiovascular Lifetime Risk Pooling & Co. Dr. Goldenberg has received consulting fees from JR’s LDL-C goal would be less than 130 Project, JR’s lifetime risk (to the age of 90) Amarin Corporation. mg/dL with an optional goal of less than of any event related to atherosclerotic CVD References listed on page 35. 100 mg/dL, and she would qualify for a is estimated at 38.7% based on her age statin as first line therapy in addition to and the presence of 2 major risk factors lifestyle counseling to achieve her LDL-C (treated hypertension and total cholesterol target.13 greater than 240 mg/dL). For comparison, One other important concept for assessing her risk would be 12.4% if all risk factors and communicating cardiovascular risk is were optimal.14 that of “lifetime risk.” For many patients,

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Official Publication of the National Lipid Association 23 Member Spotlight: Suneet Verma, MD

SUNEET VERMA, MD, FACP, FNLA Internal Medicine Physician Fox Chase Cancer Center Philadelphia, PA Diplomate, American Board of Clinical Lipidology

other issues led Dr. Verma to take an inter- east Lipid Association, he lives with his fam- est in complicated dyslipidemias and the ily in Cherry Hill, New Jersey. mechanics of atherosclerosis and vascular biology. He searched for resources and With the move to the Northeast came a new Discuss this article at www.lipid.org began attending NLA meetings to network opportunity: this September, Dr. Verma Go to “Topics/Lipid Spin Fall 2012” with others, as there were few lipidologists began a position at Fox Chase Cancer Cen- and look for “Member Spotlight.” in South Dakota. As his interest in lipids ter, a Temple University affiliate, where he When he moved to South Dakota to fulfill a grew, Dr. Verma became involved with re- works as an internal medicine physician and rural medicine requirement, Suneet Verma, search and successfully ran clinical trials at also will be developing a geriatric oncology MD, never guessed he would become fas- Avera Research Institute, where he served program. cinated with lipids. A native of Delhi, India, as principal investigator for the Stabiliza- Dr. Verma came to the United States to do tion of Atherosclerotic Plaque by Initiation “It’s a unique opportunity because cancer his post-graduate training in internal medi- of Darapladib Therapy Trial (STABILITY). patients have unique challenges, especially cine at the University of Pittsburgh Medical He participated in area television shows to in regard to their frailty, age, multiple co- Center. In South Dakota, he worked as an educate local residents about about genetics, morbidities and they often have very com- internist at Avera McKennan University dyslipidemia, cardiovascular risk factors and plicated dyslipidemias and polypharmacy,” Hospital and also as a Clinical Associate hypertension. Before long, Dr. Verma was he said. Professor of Medicine at the University of helping colleagues develop lipid clinics as a South Dakota School of Medicine, where he complimentary service at the hospital. While he is looking forward to the future, taught medical students, internal medicine Dr. Verma credits the NLA with much of his residents and mid-level providers. “I was the only lipidologist in Sioux Falls at early career success. Dr. Verma is a strong one time, the next closest one was the Mayo advocate to spread NLA’s mission among the Dr. Verma had significant interest in Clinic in Rochester, Minn., and some high general population and with his colleagues. preventive medicine and always enjoyed risk patients started to Google me and drive He has served on several NLA committees conducting patient education as part of in from the remote towns for office visits,” and the Midwest Lipid Association Board of his treatment strategy. He observed that he said. “I was impressed that patients were Directors. significant opportunity existed in South becoming aware of their risk factors, and I Dakota where rural farmers had poor un- started getting referrals from colleagues and “This organization offers a very collegial derstanding of cardiovascular risks and their building a little niche in this area.” setting and I really like the group of people eating habits were not necessarily healthy. who started the NLA,” he said. “It is easy to There was an epidemic of obesity, diabetes, After leaving South Dakota, Dr. Verma com- become involved and the NLA has become a metabolic syndromes and fatty liver issues. pleted a fellowship at Temple University in trusted source of clinical guidance.” n Studying fatty liver and how it relates to Philadelphia. Now a member of the North-

24 LipidSpin 2012 Scientific Sessions Poster Abstract Congratulations 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: Figure 1. does the evidence support the practice? 600 New ESRD Dx Ike Okwuosa, MD; Eric Tuday MD, PhD; Neil Stone, MD 500 New Statin Rx Abstract 400 300 Synopsis:

Patients with end stage renal disease (ESRD) are at high risk of # Patients 200 developing cardiovascular disease (CVD) related complications. 100 Statins have been proven to reduce cardiovascular complications in those at elevated CVD risk and per person meta-analyses of 0 2005 2006 2007 2008 2009 2010 randomized clinical trials have shown statins to be associated with increased survival. The Die Deutsche Diabetes Dialyse Studie 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 (the 4D study) and A Study to Evaluate the Use of Rosuvastatin patients. (p<.0001) 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 Figure 2. was begun in those on hemodialysis. In this study we attempt to assess physician practice patterns in response to the 4D and 300 AURORA study. New ESRD Dx in Diabetics New Statin Rx 250 Methods: This study was a single center retrospective review of patients with a diagnosis of ESRD on dialysis from 2006 to 2010 at 200

Northwestern Memorial Hospital. The primary end point of this # Patients study was to determine if there was a decline in incidence of 150 statin prescriptions following the 4D and AURORA studies. 100 Results: 2005 2006 2007 2008 2009 2010

From 2006 to 2010, 1725 patients were identified as having Figure 2 – New ESRD diagnoses with a concurrent diagnosis of diabetes by year compared with a diagnosis of ESRD. During this period 905 patients were a new statin therapy. Graphs show a significant increase in statin therapy among ESRD-diabetic patients. (p<.0001) 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 Figure 3. significant increase in the trend of prescribing statin therapy by year in all patients with ESRD. Amongst ESRD patient with 7575 diabetes, there was also a significant increase in the trend of AllAll Patients Patients prescribing statin therapy. DiabeticDiabetic Non-DiabeticNon-Diabetic 5050 Conclusions: Despite the results of the 4D and AURORA studies, two large multicenter randomized trials that demonstrated no survival 2525 benefit in initiating statins to patients with ESRD on hemodialysis, Percent on Statin the practice remains prevalent. Further studies are needed Percent on Statin to determine if there are subgroups that benefit from statin 00 initiation in those on hemodialysis. Moreover, physicians would 00 500500 10001000 15001500 20002000 benefit from guidance from clinical guidelines. TimeTime (days) (days)

Figure 3 – Kaplan-Meyer type analysis of time from dialysis initiation to initial or new-continued * The NLA Young Investigator Competion was sponsored by LipoScience Inc. 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)

Official Publication of the National Lipid Association 25 News and Notes

International Updates exceed “fair market value,” and often is New Impact Factor for Journal of NLA President Peter Toth, MD, PhD, only obtained by the physician when he Clinical Lipidology will represent the NLA at the Annual or she refers to that particular laboratory. In June, the 2011 impact factors were Conference of the Polish Lipid Association As the Advisory Opinion warns, “Where released by Thomson Reuters and the (PoLA) from September 7-8 in Warsaw, a laboratory pays a referring physician to Journal of Clinical Lipidology score went where he will present on the “Current perform blood draws, particularly where from 1.467 up to 1.583. The Journal’s Position of Fibrates in Lipid-lowering the amount paid is more than the laboratory Editor-in-Chief, W. Virgil Brown, MD, said Therapy.” receives in Medicare reimbursement, an that “The impact factor is an index of the inference arises that the compensation paid frequency of papers in our Journal being NLA member Kevin Maki, PhD, will is an inducement to the physician to refer quoted in the reviewed medical literature. present updates regarding cholesterol and patients to the laboratory.” The Journal is growing in quality and in triglycerides during the “Masters Class in volume of submissions. These are the Lipids and Cardiovascular Protection,” a This is not to say that all such contracts are factors that cause a rising impact factor. joint initiative of the NLA and the Australian inherently illegal; it does mean that they Authors are recognizing the Journal as a Atherosclerosis Society that will take place should be reviewed. source of key information that deserves in Sydney from October 5-6. referencing in their publications. We are FH Foundation Formed to Educate grateful to a very capable Editorial Board and Peter Toth, MD, PhD, will be a guest Patients and Family Members group of dedicated reviewers who provide speaker at the World Congress of Clinical The FH Foundation is a nonprofit critiques that result in accurate assessment Lipidology in Budapest, Hungary, from organization developed to raise awareness of the manuscripts submitted. Their December 6-9. He will be part of a plenary of FH through education, advocacy, and comments almost always help the authors session on lipid guidelines around the world research and also to establish a patient improve the presentation of their data.” and will lead a workshop on “Difficult to registry. The FH Foundation is led by Treat Hyperlipidemia.” patients with FH and by clinicians dedicated Actor John O’Hurley Joins Launch of to treating them. Their goal is to help FH USAGE Survey Important Legal Advice for Members of patients become better educated about On Tuesday, June 19, TV personality the NLA their health and that of their families and John O’Hurley joined the NLA, Kowa In recent weeks the NLA General Counsel to direct them to community resources Pharmaceuticals America and Eli Lilly and has reviewed several contracts in which and medical assistance. This organization’s Company in announcing the results of the physicians are to be paid by laboratories to development is seen as a great complement USAGE survey, “Understanding Statin collect and ship specimens and are even to the Foundation of the NLA and its goals use in America and Gaps in Education,” furnished the supplies to do so. of reaching Americans with information the largest known U.S. cholesterol survey about and solutions for managing FH. For involving more than 10,100 statin users. NLA members are cautioned to have such details about the FH Foundation, please visit NLA member Eliot Brinton, MD, is co- contracts reviewed carefully by a health care theFHfoundation.com. spokesperson for the survey with O’Hurley attorney. Under Counsel Advisory Opinion (Seinfeld and Dancing with the Stars), who is No 05-08, such arrangements may well Lipid Spin Support one of the 71 million Americans diagnosed run afoul of the Stark Law. A collection Special thanks go to Wayne Warren, MD, with high cholesterol. To visit the USAGE fee well in excess of what Medicare would for reviewing articles for this issue. website, please go to StatinUSAGE.com. pay for such services may be deemed to

26 LipidSpin Education and Meeting Update

Reducing CVD Risk in the Patient a complimentary benefit of membership in in conjunction with Pri-Med MidWest with High Triglycerides and Metabolic the NLA. Please visit lipid.realcme.com to 2012. There is no registration fee for the Syndrome or DM-2 access this activity. symposium or dinner. For more information Join Harold Bays, MD, Eliot Brinton, or to register, please visit aspconline.org. MD, W. Virgil Brown, MD, and Terry Learn from Leading Experts in a City Jacobson, MD, for a new online CME Near You: Join a Lipid Forum 4th Annual Orange County Symposium activity that includes faculty presentations This exciting, case-based, audience- on CVD Prevention: Case and Guideline- from a live symposium held on June 1 in driven, interactive CME meeting series Based Approaches to Clinical Lipidology, Scottsdale, Arizona. Please visit will feature world-renowned specialists Hypertension and Obesity lipid.org/education/online for more in lipidology discussing HDL functionality Saturday, October 27 information. and quantification, residual cardiovascular Newport Beach, CA  risk, and the latest clinical trials as well as Don’t miss your chance to attend this Highlights from the 2012 NLA Annual emerging therapies for HDL modulation, comprehensive one-day symposium that will Scientific Sessions CETP inhibition and reverse cholesterol explore practical solutions and strategies Check out multimedia highlights of what transport. This activity will be highlighted for managing challenging patients at risk you missed if you did not attend the NLA’s by “Meet the Experts” breakout sessions for cardiovascular disease including the Annual Scientific Sessions in Scottsdale, that will allow the learner to discuss management of lifestyle, Clinical Lipidology, Arizona. The highlights, featuring audio therapeutic dilemmas, complex topics, and pre-diabetes and hypertension. recordings and slides synched in real challenging cases in greater detail with all time, are based on the best-reviewed the faculty. For more information, please Symposium Topics Include: presentations from the meeting. Selected visit vindicomeded.com/lipidforum. • Approaches to the Patient with Low presentations also include written HDL-C summaries prepared by Linda Brookes, Preventive Cardiology: Update 2012 • Familial Hypercholesterolemia: MSc. Visit lipid.org/highlights for more Wednesday, September 19 Identification and Awareness with Live information. Donald E. Stephens Convention Center Patient Perspective 5555 North River Road Online Version of CLM-SAP Edition 14 Rosemont, IL • The Obesity Epidemic: New Strategies Available Sponsored by the ASPC • The Patient with Multiple CLM-SAP Edition #14: Evaluation Cardiometabolic Risk Factors and Severe and Management of Familial Make plans to attend Preventive Cardiology: Hypertriglyceridemia Hypercholesterolemia provides a Update 2012, a 4-hour dinner symposium, comprehensive, interactive self-assessment that will be held on September 19 at the For more information and to register, please that will strengthen your knowledge of the Donald E. Stephens Convention Center in visit leadingstar.com/ocsympo. most clinically relevant, evidence-based Rosemont, Illinois. This exciting program medicine related to FH. In addition, you will feature nationally renowned faculty will earn up to 3.0 CME/CE credits by members exploring cutting-edge topics participating in the program, which can be in preventive cardiology and will include applied toward meeting the requirements didactic lectures, interactive question-and- necessary to be eligible for certification in answer sessions and panel discussions. Clinical Lipidology. The CLM-SAP series is This dinner symposium will be held

Official Publication of the National Lipid Association 27 Events Calendar

2013 Scientific Meetings 2012 Meetings 2013 National Lipid Association Lipid Forum 2012 PCNA SIHD Lecture Series Clinical Lipid Update—Spring September 22, 2012 September 29, 2012 Hosted by the JW Marriott Renaissance Asheville Hotel Southwest Lipid Washington, D.C. Asheville, North Carolina Association and the Midwest Lipid 4th Annual European Workshop Lipid Forum 2012 Association on Lipid Mediators October 6, 2012 September 27, 2012 Atlanta, Georgia February 22–24, 2013 Pasteur Institute The Roosevelt Hotel Paris, France Lipid Forum 2012 New Orleans, Louisiana October 20, 2012 PCNA Fall Lecture Series Houston, Texas 2013 National Lipid Association September 29, 2012 Scientific Sessions Waterfront Plaza Hotel Oakland Lipid Forum 2012 Hosted by the Pacific Oakland, California November 17, 2012 Lipid Association Anaheim, California May 30–June 2, 2013 PCNA SIHD Lecture Series Red Rock Hotel September 29, 2012 World Congress of Clinical Las Vegas, Nevada HotelRED Lipidology Madison, Wisconsin December 6–8, 2012 Budapest Marriott Hotel PCNA SIHD Lecture Series Budapest, Hungary 2013 NLA Clinical Lipid Update—Fall September 29, 2012 Hosted by the Marriott New Orleans Southeast Lipid New Orleans, Louisiana Association and the Northeast Lipid Association

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

28 LipidSpin Foundation Update

ANNE C. GOLDBERG, MD, FNLA President, Foundation of the National Lipid Association Associate Professor of Medicine Washington University School of Medicine St. Louis, MO Diplomate, American Board of Clinical Lipidology

First, I would like to thank everyone who maintained membership in the NLA for five supported the NLA’s 10th Anniversary or more years, and then would be eligible to President’s Gala, which raised almost pay the $1,500 Lifetime Membership fee. $10,000 for the Foundation and was our Proceeds from the fee would be distributed largest fundraiser to-date. More than 200 between the Foundation and the NLA, with Discuss this article at www.lipid.org Go to “Topics/Lipid Spin Fall 2012” NLA members and guests attended the $1,000 of the fee going to the Foundation and look for “Foundation Update.” gala during the Annual Scientific Sessions to fund the fellowship/training program this past May in Scottsdale, Arizona, where fund. Lifetime Membership will become entertainment was provided by Alan available in 2013. by the NLA Communications Committee, Brown, MD, and his band This End Up. We chaired by James Underberg, MD, and had a great time supporting a tremendous In addition, The International Guidelines Robert Wild, MD, PhD. Please take a organization and I thank all of you for your Center published an FH Pocket Guide few minutes to visit the Sharecare website support. in May 2012 based on the NLA’s FH and refer it to your patients as a consumer- recommendations from 2011. This concise friendly . In addition, I would like to thank the guide is especially helpful to healthcare sustaining and individual donors who have providers working outside of the field of Finally, I would like to call your attention made almost $24,000 in contributions to Clinical Lipidology and who may need a to a new non-profit organization developed the Foundation since January. As the holiday quick reference for diagnosing and treating to raise awareness of FH through season draws near, please remember us in patients with FH. More than 1,900 copies education, advocacy, and research and your year-end contributions. To donate, visit of the FH Pocket Guide have been sold. also to establish a patient registry. The FH us online at lipidfoundation.org. Foundation is led by patients with FH and Sharecare.com, a consumer-friendly by clinicians dedicated to treating them. In May 2012, the NLA Board of Directors website that provides a “roundtable” of This organization’s development is seen as approved a recommendation by the NLA expert answers to patient questions, has a great complement to the Foundation of Membership Committee to establish and invited the Foundation and the NLA to join the NLA and its goals of reaching Americans fund a fellowship/training program by as partner organizations, and our first group with information about and solutions for offering a Lifetime Membership option of representatives will begin answering managing FH. For details about the FH to members. To qualify for Lifetime patient questions in late September. Our Foundation, please visit their website at Membership, one would need to have involvement with Sharecare is overseen theFHfoundation.com. n

Official Publication of the National Lipid Association 29 Guest Editorial: HDL-targeted Therapies—Where Do We Go From Here?

Daniel J. Rader, MD, FNLA Division of Translational Medicine and Human Genetics Cardiovascular Institute and Institute for Translational Medicine and Therapeutics Perelman School of Medicine at the University of Pennsylvania Philadelphia, PA Diplomate, American Board of Clinical Lipidology

EMIL M. deGOMA, MD Division of Cardiovascular Medicine Perelman School of Medicine at the University of Pennsylvania Philadelphia, PA Diplomate, American Board of Clinical Lipidology

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

A recent succession of negative studies— of cardiovascular events among patients acute coronary syndrome (ACS) on optimal including two randomized, placebo- with stable coronary artery disease (CAD) medical therapy.2 In phase II studies, controlled intervention trials1, 2 and a large treated to aggressive LDL-C targets (mean dalcetrapib 600 mg daily, the dose used genetic association analysis3—calls for a baseline 71 mg/dL, mean on-treatment 65 in the outcomes trial, increased HDL-C careful re-examination of the approach mg/dL).1 Peculiarities of study design as by an average of 25-31% and did not to HDL-directed therapies. In May 2011 recently reviewed limit the generalizability exhibit adverse off-target hemodynamic the Atherothrombosis Intervention in of the AIM-HIGH findings.5 More definitive or hormonal effects.6 Details regarding Metabolic Syndrome with Low HDL/High evidence regarding the effect of niacin on the prematurely terminated study remain Triglycerides: Impact on Global Health clinical outcomes awaits the conclusion of eagerly anticipated. As noted below, at (AIM-HIGH) trial was stopped early due to the Heart Protection Study 2: Treatment least two more potent CETP inhibitors are futility.4 In the setting of mildly reduced of HDL to Reduce the Incidence of still in clinical development. In addition HDL-C levels (mean baseline 35 mg/dL), Vascular Events (HPS2-THRIVE) trial. Dal- to these two disappointing clinical trials, the addition of extended-release niacin at a OUTCOMES succumbed to a similar fate a large Mendelian randomization analysis daily dose of 1500-2000 mg raised HDL-C as AIM-HIGH in May 2012 after interim published in May 2012 highlighted the by 10 mg/dL (28%), or 5 mg/dL (13%) analysis failed to demonstrate a benefit potential for inconsistency between compared to the control group.1 Despite of dalcetrapib, an inhibitor of cholesteryl higher HDL-C levels and a lower risk of the observed increase in HDL-C, niacin use ester transfer protein (CETP), on hard myocardial infarction (MI).3 Carriers of was not associated with a lower incidence cardiovascular endpoints in patients with a single nucleotide polymorphism in the

30 LipidSpin endothelial lipase gene (LIPG Asn396Ser) cholesterol transport, arguably the most routine clinical practice. With regard to exhibited HDL-C levels 5.5 mg/dL higher critical anti-atherogenic function of HDL, optimal management of dyslipidemia, than non-carriers with no significant as well as anti-inflammatory activity. One a recent international study of 9,518 difference in LDL-C or other lipids. study utilized a validated ex vivo system ambulatory patients on lipid-lowering Observational cohort studies suggest to quantify cholesterol efflux capacity therapy revealed that 34% of high-risk that this modest increment in HDL-C using incubation of macrophages with apo patients and 71% of very high-risk patients would confer a 13% reduction in MI risk. B-depleted serum.9 Healthy participants do not meet their recommended LDL-C However, analysis of 20,913 MI cases exhibited an inverse relationship goals.11 Moreover, data from tertiary and 95,407 controls demonstrated no between efflux capacity and carotid lipid clinics suggest that the majority of association between LIPG Asn396Ser and intima-media thickness before and after patients referred for complex dyslipidemia MI (odds ratio 0.99, 95% CI 0.88-1.11, adjustment for HDL-C. Among subjects fail to achieve target LDL-C levels.12, 13 p=0.85). Several other variants associated who underwent coronary angiography for Broadening the scope of comparative with HDL-C were also found to have no clinically suspected CAD, efflux capacity effectiveness research to include clear association with MI, unless they were remained a strong inverse predictor of populations such as those unable to also associated with triglyceride or LDL- C coronary disease status after adjustment take high-dose statin therapy addresses levels. for traditional risk factors as well as considerable unmet need and may also HDL-C (adjusted OR for CAD per 1-SD facilitate the development of useful HDL- The principal lesson from these recent increase in efflux capacity, 0.75; 95% CI directed therapies. findings lies in the complexity of the 0.63-0.90) and apo A-I (OR 0.74; 95% CI relationship between HDL cholesterol and 0.61-0.89). A second study demonstrated Fortunately, now more than ever, a cardiovascular disease. A wealth of data an association between CAD status myriad of HDL-targeted drug candidates is from traditional epidemiologic studies and HDL inflammatory index (HII), the available to test new approaches.14 Lipid- as well as statin trials support an inverse latter quantified as the ratio of in vitro poor apo A-I—phospholipid complexes relationship between HDL-C and coronary LDL oxidation of a fluorescein substrate have been studied extensively in animals events, a powerful association incorporated incubated with and without participant and in preliminary studies in humans. into most global risk equations including HDL.10 Among 193 symptomatic Preclinical studies have demonstrated that the Framingham risk score.7 However, patients undergoing angiography, HII the administration of apo A-I is associated despite the popularly ingrained concept of was significantly higher (less antioxidant with the inhibition or regression of HDL-C as the “good” cholesterol, evidence capacity) among those with acute coronary atherosclerosis, enhanced macrophage- indicates that higher levels of HDL-C are syndrome (ACS) than those without CAD specific reverse cholesterol transport, and not synonymous with improved outcomes. (1.57 vs 1.17, p 0.005) or with stable CAD the inhibition of vascular inflammatory HDL-C suffers from limitations intrinsic (1.57 vs 1.11, p 0.006). Association with pathways, endothelial adhesion to its static, mass-based measurement.8 ACS remained significant after adjusting molecule expression and phospholipid First, as a snapshot of the steady-state for traditional risk factors (OR 3.8 p oxidation.15-17 Moreover, short exploratory cholesterol pool, HDL-C does not 0.003). clinical studies of apoA-I infusion using directly assess the rate of centripetal recombinant apoA-I Milano/phospholipid cholesterol flux from peripheral foam AIM-HIGH and dal-OUTCOMES (MDCO-216),18 purified native apoA-I/ cells to the liver, which is influenced by additionally suggest that demonstrating phospholipid (CSL-111),19 and autologous many factors beyond the mass of HDL-C incremental clinical benefit above and delipidated HDL (PDS-2)20 have yielded alone. Second, circulating HDL-C values beyond current optimal medical therapy, decreases in coronary atherosclerosis as fail to convey information regarding the inclusive of aggressive LDL-lowering, may assessed by coronary imaging. anti-inflammatory, antioxidant, anti- be challenging for new therapies. Such a thrombotic, and endothelial function high hurdle may inadvertently weed out Two novel compounds enable further promoting benefits of HDL, despite effective treatments for individuals unable testing of the CETP-inhibition strategy. evidence supporting the potential clinical to achieve ideal targets, including those Unlike dalcetrapib, which exerts modest significance of these pleiotropic functions. suffering from medication intolerance effects on HDL-C alone, anacetrapib and (e.g., statin myopathy) or extreme evacetrapib yield significant reductions Recent publications shed light on phenotypes (e.g., familial dyslipidemias). in atherogenic lipoproteins as well as promising measures that assess reverse This population is not insignificant in more potent increases in HDL-C, at least

Official Publication of the National Lipid Association 31 suggesting a greater potential for clinical Activation of liver X receptors (LXRs) of messenger RNAs (mRNAs) and benefit. The phase III Determining the has been demonstrated to promote causing translational repression and/or Efficacy and Tolerability of CETP Inhibition mobilization of intracellular cholesterol, mRNA destabilization.31 Genome-wide with Anacetrapib (DEFINE) randomized, increase macrophage cholesterol efflux screening identified miR-33, encoded placebo-controlled trial examined via macrophage ABCA1 and ABCG1, and within intron 16 of sterol regulatory the effect of 100 mg of anacetrapib augment intestinal HDL generation.24-26 element binding transcription factor 2 administered daily for 18 months to 1623 Two LXR isoforms have been identified— (SREBF2), from a subset of differentially patients with CAD or at high-risk for CAD LXRα and LXRβ. Therapeutic development expressed miRNAs modulated by cellular events who had achieved LDL-C treatment of LXR agonists has been hindered by cholesterol content.32 In vitro and in goals with statin therapy.21, 22 Treatment hepatic steatosis and increased plasma vivo murine studies demonstrated, in with anacetrapib was associated with a triglyceride concentrations reported the setting of miR-33 overexpression, 40% reduction in LDL-C from 81 mg/dl to in preclinical studies of these drugs.27 suppressed macrophage and hepatocyte 45 mg/dl (P <0.001) and a 138% increase Fortunately, dissociating LXR efficacy and expression of ABCA1, reduced circulating in HDL-C from 41 mg/dl to 101 mg/dl (P toxicity might be possible owing to the HDL-C levels, and attenuated efflux to <0.001) compared with placebo.22 Lp(a) differential effects of LXR agonism by apoA-I. Conversely, silencing of miR-33 decreased 36% compared with placebo receptor isoform and by -specific was associated with greater macrophage from 27 nmol/l to 15 nmol/l. No increases effects. Administration of a nonselective and hepatocyte expression of ABCA1 and in clinic-based blood pressure, serum LXR agonist to LXRα-deficient mice increased HDL-C levels. In a mouse model aldosterone levels, or cardiovascular events stimulated macrophage ABCA1 expression of atherosclerosis, administration of an were observed following anacetrapib and cholesterol efflux without inducing antisense oligonucleotide (ASO) to miR-33 treatment at 76 weeks. Supported by fatty liver and with minimal upregulation significantly increased HDL-C by 35% and these improvements in LDL, HDL, and of hepatic triglyceride synthesis.28 A promoted macrophage-specific reverse Lp(a), as well as an apparently benign second approach to safer LXR development cholesterol transport, augmenting hepatic safety profile, the Randomized Evaluation might be to selectively activate intestinal and fecal delivery of radiolabeled tracer by of the Effects of Anacetrapib through Lipid- LXR. Fatty liver arises from activation of 42% and 82%, respectively.33 Importantly, Modification (REVEAL) is underway. This hepatic LXR, which, through upregulation these favorable changes in HDL parameters study will examine major coronary events, of SREBP1c, stimulates .29 were accompanied by atheroma regression defined as coronary death, myocardial Elevation of triglyceride levels occurs via (35% reduction in aortic sinus lesion area infarction and coronary revascularization SREBP1c and the subsequent suppression compared to baseline and controls) as procedures, in 30,000 patients with CAD, of apo A-V, which inhibits VLDL synthesis well as histologic evidence of remodeling cerebrovascular atherosclerotic disease, or and stimulates VLDL hydrolysis. On the toward a more stable plaque phenotype peripheral artery disease. The estimated other hand, LXR expression on both (28% decrease in lipid accumulation, 35% study completion date is January 2017. macrophages and the small intestine reduction in macrophage content, and Evacetrapib administration in daily doses contributes to the regulation of reverse 2-fold increase in collagen content).33 In a of 30-500 mg decreased LDL-C from 20-51 cholesterol transport. An intestine-specific non-human primate model of dyslipidemia, mg/dL (14-36%) and increased HDL-C LXRα/β agonist, GW6340, promoted subcutaneous delivery of anti-miR-33 from 30-66 mg/dL (54-129%) in a 12-week macrophage-specific reverse cholesterol ASO over a 12-week period increased randomized trial of 398 dyslipidemic transport, augmenting the fecal excretion HDL-C up to 50%.34 Greater macrophage patients.23 Addition of evacetrapib of radiolabeled sterol by 52% via increased cholesterol efflux was observed following 100 mg daily to statin therapy yielded intestinal HDL production and intestinal incubation of foam cells with serum further reductions in LDL-C of 16-21 mg/ excretion of HDL-derived cholesterol.30 obtained from treated monkeys compared dL (11-14%) and increments in HDL-C to equivalent volumes of serum isolated of 41-48 mg/dL (79-89%).23 Effects on Elucidation of posttranscriptional pathways from control monkeys, correlating with lipoprotein(a) were not reported, and no of HDL metabolism has identified the HDL-C levels in the two groups. adverse events were observed in the small additional targets for pharmacotherapeutic Monkeys administered the anti-miR-33 study. Apparently, a large phase III clinical intervention. Short non-coding sequences also exhibited attenuated expression of outcomes trial is planned to elucidate the of RNA, termed microRNAs (miRNAs), genes involved in synthesis, efficacy and safety of evacetrapib. inhibit gene expression by binding to enhanced expression of genes involved in complementary 3’ untranslated regions fatty acid oxidation, and a decrement in

32 LipidSpin VLDL triglycerides of up to 50%, suggesting inhibitors, LXR agonists, and miR-33 therapeutic potential for additional antagonists comprise several HDL-targeted metabolic derangements associated with candidate drug classes under current insulin resistance.33 It will be interesting investigation. n to see if anti-miR-33 approaches are taken into clinical development. Disclosure statement: Dr. deGoma has no disclosures to report. Dr. Rader has received consulting fees from In conclusion, recent negative studies AstraZeneca, Bristol-Myers Squibb, Daiichi Sankyo Inc., suggest the need for a revised approach Eli Lilly & Co., GlaxoSmithKline, Johnson and Johnson, Merck & Co., Novartis Pharmaceuticals, Pfizer Inc., to the evaluation of novel HDL-directed Regeneron, Roche, Sanofi, Alnylam, Catabasis, and therapies. Therapeutic elevation of Omthera. HDL-C does not necessarily mitigate References listed on page 35. 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

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Official Publication of the National Lipid Association 33 References

Clinical Feature References high-density lipoprotein size and is a novel marker of cardiovascular effects of gender, age, ethnicity, and liver cirrhosis on cytochrome 1. Di Angelantonio E, Gao P, Pennells L, et al. Lipid-related markers disease susceptibility. Circulation. 2010;122:470-7. P450 enzyme activity in human liver microsomes and inducibility and cardiovascular disease prediction. JAMA. 2012;307:2499-506. 22. Kathiresan S, Willer CJ, Peloso GM, et. al. Common variants at 30 in cultured human hepatocytes. Toxicol Appl Pharmacol. 2004 Sep 2. Cholesterol Treatment Trialists’ (CTT) Collaboration, Baigent C, loci contribute to polygenic dyslipidemia. Nat Genet. 2009;41:56- 15;199(3):193-209. Review. Blackwell L, Emberson J, Holland LE, Reith C, Bhala N, Peto R, 65. 12. George J, Byth K, Farrell GC. Age but not gender selectively affects Barnes EH, Keech A, Simes J, Collins R. Efficacy and safety of more 23. Teslovich TM, Musunuru K, Smith AV, et. al. Biological, clini- expression of individual cytochrome P450 in human liver. intensive lowering of LDL cholesterol: a meta-analysis of data from cal and population relevance of 95 loci for blood lipids. Nature. Biochem Pharmacol 50: 727–730. 170,000 participants in 26 randomized trials. Lancet. 2010 Nov 2010;466:707-13. 13. Cohen DE, Anania FA, Chalasani N. An assessment of statin safety 13;376:1670-81. 24. Rashedi N, Brennan D, Kastelein JJ, et. al. Impact of cholesteryl by hepatologists. Am J Cardiol. 2006;97(suppl 8A):77C–81C. 3. Barter P, Gotto AM, LaRosa JC, Maroni J, Szarek M, Grundy SM, ester transfer protein inhibition on nuclear magnetic resonance 14. McLean AJ, Le Couteur DG. Aging biology and geriatric clinical Kastelein JJ, Bittner V, Fruchart JC; Treating to New Targets Inves- derived lipoprotein particle parameters (abstr). Atherosclerosis . Pharmacol Rev. 2004 Jun;56(2):163-84. Review. tigators. HDL cholesterol, very low levels of LDL cholesterol, and Supplements. 2011. 15. Nair KS. Aging muscle. Am J Clin Nutr 81: 953–963, 2005. cardiovascular events. N Engl J Med. 2007;357:1301-10. 25. Airan-Javia SL, Wolf RL, Wolfe ML, et. al. Atheroprotective lipopro- 16. Tandra S, Vuppalanchi R. Use of statins in patients with liver dis- 4. Barter PJ, Caulfield M, Eriksson M, Grundy SM, Kastelein JJ, Koma- tein effects of a niacin-simvastatin combination compared to low- ease. Curr Treat Options Cardiovasc Med. 2009;11:272–278. jda M, Lopez-Sendon J, Mosca L, Tardif JC, Waters DD, Shear CL, and high-dose simvastatin monotherapy. Am Heart J. 2009;157:687. 17. Tolman KG. The liver and lovastatin. Am J Cardiol 2002; 89: 1374- Revkin JH, Buhr KA, Fisher MR, Tall AR, Brewer B; ILLUMINATE e1-8. 1380. Investigators. Effects of torcetrapib in patients at high risk for coro- 26. Robins SJ, Collins D, Wittes JT, et. al. VA-HIT Study Group. Veter- 18. Weltman MD, Farrell GC, Hall P. Hepatic cytochrome P450 2E1 is nary events. N Engl J Med. 2007;357:2109-22. ans Affairs High-Density Lipoprotein Intervention Trial. Relation of increased in patients with nonalcoholic steatohepatitis. Hepatology. 5. AIM-HIGH Investigators, Boden WE, Probstfield JL, Anderson T, gemfibrozil treatment and lipid levels with major coronary events: 1998;27:128–133. Chaitman BR, Desvignes-Nickens P, Koprowicz K, McBride R, Teo VA-HIT: a randomized controlled trial. JAMA. 2001;285:1585-91. 19. Corsini A, Bellosta S, Baetta R, et. al. New insights into the phar- K, Weintraub W. Niacin in patients with low HDL cholesterol levels macodynamic and pharmacokinetic properties of statins. Pharmacol receiving intensive statin therapy. N Engl J Med. 2011;365:2255- EBM Tools for Practice References Ther. 1999; 84: 413–428. 67. 1. Bucher HC, Weinbacher M, Gyr K. Influence of method of reporting 20. Food and Drug Administration (2011) FDA Drug Safety Communica- 6. Roche. (2012). Roche provides update on Phase III study of dal- study results on decision of physicians to prescribe drugs to lower tion: New restrictions, contraindications, and dose limitations for cetrapib. Retrieved from http://www.roche.com/media/media_re- cholesterol concentration. Br. Med. J., 1994 309:761-764. Zocor (simvastatin) to reduce the risk of muscle injury. Available at: leases/med-cor-2012-05-07.htm. 2. Bobbio M, Demichelis B, Giustetto G. Completeness of reporting http://www.fda.gov/Drugs/DrugSafety/ucm256581.htm. 7. Harrison SC, Holmes MV, Humphries SE. Mendelian randomiza- trial results: Effect on physicians willingness to prescribe. Lancet, Available at: http://www.fda.gov/Drugs/DrugSafety/ucm283137.htm. tion, lipids, and cardiovascular disease. Lancet 2012 [Epub ahead 1994 343:1209-1211. 21. Food and Drug Administration (2012) FDA Drug Safety Com- of print]. 3. Haynes RB, Sacket DL, Gray JM, et. al. Transferring evidence from munication: FDA announces safety changes in labeling for some 8. Voight BF, Peloso GM, Orho-Melander M, et. al. Plasma HDL cho- research into practice. A series of editorials. 1996-1997 ACP cholesterol-lowering drugs , February 28, 2012. Available at: lesterol and risk of myocardial infarction: a mendelian randomisa- Journal Club. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ tion study. Lancet. 2012. [Epub ahead of print]. 4. Sever PS, Dahlof B, Poulter NR, et. al. Prevention of coronary and ucm293623.htm. 9. Otvos J. Jeyarajah EJ, Cromwell WC. Measurement issues related stroke events with atorvastatin in hypertensive patients who have 22. Eckel R. Approach to the patient who is intolerant of statin therapy. to lipoprotein heterogeneity. Am J Cardiol. 2002;90:22i-29i. average or lower-than-average cholesterol concentrations, in the J Clin Endocrinol Metab 2010; 95(5):2015-2022. 10. Gotto AM, Whitney E, Stein EA, et. al. Relation between baseline Anglo-Scandinavian Cardiac Outcomes Trial--Lipid Lowering Arm 23. Holtzman C, Wiggins B, Spinler, S.Role of P-glycoprotein in Statin and on-treatment lipid parameters and first acute major coronary (ASCOT-LLA): a multicentre randomised controlled trial. Lan- Drug Interactions. Pharmacotherapy. 2006;26 (11), 1601-1607. events in the Air Force/Texas Coronary Atherosclerosis Prevention cet 2003 361:1149-1158. Study (AFCAPS/TexCAPS). Circulation. 2000;101:477-84. 5. Ridker PM, Danielson E, Fonseca FA, et. al. Rosuvastatin to Prevent Practical Pearls References 11. Glomset JA, Wright JL. Some properties of a cholesterol esterifying Vascular Events in Men and Women with Elevated C-Reactive Pro- 1. National Cholesterol Education Program, Third Report of the enzyme in human plasma. Biochim Biophys Acta. 1964;89:266-76. tein N Engl J Med 2008; 359:2195-2207. National Cholesterol Education Program (NCEP) Expert Panel on 12. Glomset JA. The plasma lecithins: cholesterol acyltransferase reac- 6. Sattar N, Preiss D, Murray HM, et. al. Statins and risk of incident Detection, Evaluation and Treatment of High Blood Cholesterol in tion. J Lipid Res. 1968;9:155-67. diabetes: a collaborative meta-analysis of randomised statin tri- Adults (Adult Treatment Panel III) Final Report. National Institutes 13. Rosenson RS, Brewer HB, Davidson WS, et. al. Cholesterol efflux als, Lancet, 2010 375:735-742. of Health; 2002. and atheroprotection: advancing the concept of reverse cholesterol 7. Naylor CD, Chen E, Strauss B. Measured enthusiasm: Does the 2. Miller M, Stone N, Ballantyne C, et. al. Triglycerides and Cardio- transport. Circulation. 2012;125:1905-19. method of reporting trial results alter perceptions of therapeutic ef- vascular Disease; A scientific statement from the American Heart 14. Rosenson RS, Brewer HB, Chapman MJ, et. al. HDL measures, par- fectiveness? Ann. Internal Med., 1992 117: 916-921. Association. Circulation. 2011; 123:2292-2333. ticle heterogeneity, proposed nomenclature, and relation to athero- 3. Gaudet D, Methot J, Kastelein J. Gene therapy for lipoprotein sclerotic cardiovascular events. Clin Chem. 2011;57:392-410. Specialty Matters References lipase deficiency. Curr Opin Lipidol. 2012;23:00-000. doi:10.1097/ 15. Camont L, Chapman MJ, Kontush A. Biological activities of HDL 1. Golomb BA, Evans MA. Statin adverse effects: a review of the litera- MOL.0b013e3283555a7e. subpopulations and their relevance to cardiovascular disease. ture and evidence for a mitochondrial mechanism. Am J Cardiovasc 4. Blumenthal RS, Foody JM, Wong ND. Preventive Cardiology: A Trends Mol Med. 2011;17:594-603. Drugs 2008; 8: 373-4182. Companion to Braunwald’s Heart Disease. Philadelphia, PA: Saun- 16. Kuller LH, Grandits G, Cohen JD, et. al. Multiple Risk Factor Inter- 2. Jacobson TA. Overcoming “ageism” bias in the treatment of hy- ders;2011. vention Trial Research Group. Lipoprotein particles, insulin, adipo- percholesterolaemia: a review of safety issues with statins in the 5. Gaddi A, Cicero AFG, Odoo FO, et al. Practical guidelines for famil- nectin, C-reactive protein and risk of coronary heart disease among elderly. Drug Saf. 2006; 29: 421–448. ial combined hyperlipidemia diagnosis: An up-date. Vasc Health Risk men with metabolic syndrome. Atherosclerosis. 2007;195:122-8. 3. Thompson PD, Clarkson P, Karas RH. Statin-associated myopathy. Manag. 2007;3(6):877–886. 17. van der Steeg WA, Holme I, Boekholdt SM, et. al. High-density JAMA. 2003;289:1681–1690. 6. Yuan G, Al-Shali K, Hegele R. Hypertriglyceridemia: its etiology, ef- lipoprotein cholesterol, high-density lipoprotein particle size, and 4. Joy TR, RA Hegele. Narrative Review: Statin-Related Myopathy. Ann fects and treatment. CMAJ. 2007;176(8):1113-1120. apolipoprotein A-I: significance for cardiovascular risk: the IDEAL Intern Med. 16 June 2009;150(12):858-868. 7. Tremblay K, Methot J, Brisson D, et. al. Etiology and risk of lactes- and EPIC-Norfolk studies. J Am Coll Cardiol. 2008;51:634-42. 5. Rosenson RS. Am J Med. 2004; 116:408-416; Ann Intern Med. cent plasma and severe hypertriglyceridemia. JCL. 2011;5(1):37-44. 18. Mackey RH, Greenland P, Goff DC Jr, Lloyd-Jones D, Sibley CT, 2009; 150:858-868. 8. Backes J, Dayspring T, Mieras T. Pseudohypertriglyceridemia: Two Mora S. High-Density Lipoprotein Cholesterol and Particle Con- 6. Sathasivam S, Lecky B. Statin induced myopathy. BMJ. 2008; cases of probable glycerol kinase deficiency. JCL. doi:10.1016/j. centrations, Carotid Atherosclerosis, and Coronary Events: MESA 337:1159-62. jacl.2012.02.001. (Multi-Ethnic Study of Atherosclerosis). J Am Coll Cardiol. 2012 7. Bays HE, McKenney J, Maki KC, Doyle RT, Carter RN, Stein E. Ef- 9. Goldberg A, Hegele R. Severe hypertriglyceridemia in pregnancy. June 27 [Epub ahead of print]. fects of prescription omega-3-acid ethyl esters on non–high-density J Clin Endocrin Metab. 2012; 97(8):0000-0000. doi:10.1210/ 19. Parish S, Offer A, Clarke R, Hopewell JC, Hill MR, Otvos JD, Armit- lipoprotein cholesterol when coadministered with escalating doses jc.2012-1250. age J, Collins R; Heart Protection Study Collaborative Group. Lipids of atorvastatin. Mayo Clin Proc. 2010;85:122-128. 10. Ewald N, Hardt PD, Kloer HU. Severe hypertriglyceridemia and and lipoproteins and risk of different vascular events in the MRC/ 8. Bellosta S, Paoletti R, Corsini A . Safety of statins: focus on pancreatitis: presentation and management. Curr Opin Lipidol. BHF Heart Protection Study. Circulation. 2012;125:2469-78. clinical pharmacokinetics and drug interactions. Circulation. 2009;20:497–504. 20. Otvos JD, Collins D, Freedman DS, et. al. Low-density lipoprotein 2004;109(suppl 1):III50-III57. 11. Davignon J, Dufour R. Primary Hyperlipidemias. Oxford, UK: Clinical and high-density lipoprotein particle subclasses predict coronary 9. Chasman DI, et. al. Pharmacogenomics study of statin therapy and Publishing; 2007. events and are favorably changed by gemfibrozil therapy in the cholesterol reduction. JAMA 2004; 291(23) 2821-2827. 12. Davidson MH , Toth PP, Maki KC, eds. Therapeutic Lipidology. Veterans Affairs High-Density Lipoprotein Intervention Trial. Circu- 10. Ho, CK. Statins and their interactions with other lipid-modifying Totowa, NJ: Humana Press; 2007. lation. 2006;113:1556-63. medications: safety issues in the elderly. Ther Adv Drug Saf. 2012; 13. Pejic R, Lee D. Hypertriglyceridemia. JABFM. 2006;19(3):310-316. 21. Vergeer M, Boekholdt SM, Sandhu MS, et. al. Genetic variation 3(1) 35 –46. 14. Mozaffarian D, Clarke R. Quantitative effects on cardiovascular at the phospholipid transfer protein locus affects its activity and 11. Parkinson A, Mudra DR, Johnson C, Dwyer A, Carroll KM. The risk factors and coronary heart disease risk of replacing partially

34 LipidSpin hydrogenated vegetable with other fats and oils. Eur J Clin Nutr. strategies. Heart. Jul 2011;97(14):1175-1181. syndrome but not in stable coronary artery disease. Journal of the 2009;63(suppl 2):S22–S33. 4. Newman TB, Garber AM. Cholesterol screening in children and American College of Cardiology. 2011;58:2068-2075. 15. Van Gaal LF, Mertens IL, Ballaux D. What is the relationship be- adolescents. Pediatrics. Mar 2000;105(3 Pt 1):637-638. 11. Chiang CW, Santos RD, Waters DD, Messig M, Tarasenko L, Jukema tween risk factor reduction and degree of weight loss? Eur Heart J 5. Gidding SS, Daniels SR, Kavey RE. Developing the 2011 Integrated JW, Ferrieres J, Foody J, Seung KB. Reaching c-reactive protein and Suppl. 2005;7(suppl L):L21–L26. Pediatric Guidelines for Cardiovascular Risk Reduction. Pediatrics. low-density lipoprotein cholesterol goals in dyslipidemic patients 16. Ballantyne C. Clinical Lipidology; A Companion to Braunwald’s May 2012;129(5):e1311-1319. (from the lipid treatment assessment project [l-tap] 2). The Ameri- Heart Disease. Philadelphia, PA: Saunders; 2009. can Journal of Cardiology. 2011;107:1639-1643. 17. Xenical [package insert]. South San Francisco, CA: Genentech USA Case Study II References 12. Klinke JA, Malek F, Gao M, Holmes D, Frohlich JJ. Reaching target Inc; 2012. 1. Ridker PM, Cook NR, Lee, IM, et al. A randomized trial of low- lipid levels in patients at high risk of cardiovascular event: The 18. Tzotzas T, Krassas GE, Bruckert E. Administration of orlistat in dose aspirin in the primary prevention of cardiovascular disease in experience of a canadian tertiary care lipid clinic. Central European a patient with familial hyperchylomicronemia. Atherosclerosis. women. N Engl J Med 2005; 352:1293-1304. Journal of Public Health. 2007;15:106-109. 2002;165(1):185-6. 2. Mosca L, Benjamin EJ, Berra K, et. al. Effectiveness-based guidelines 13. Pirro M, Del Giorno R, Lupattelli G, Mannarino MR, Roscini AR, 19. Goldberg I. Hypertriglyceridemia: Impact and treatment. Endocrinol for the prevention of cardiovascular disease in women—2011 Covelli D, Schillaci G, Pasqualini L, Bagaglia F, Siepi D, Mannarino Metab Clin N Am. 2009; 38:137-149. Update: A Guideline From the American Heart Association. Circula- E. Cardiovascular risk factors and recommended lipid goals attain- 20. Citowitz E. Hypertriglyceridemia. Medscape reference. http:// tion. 2011; 123, 1243-1262. ment among patients referred in a tertiary care lipid clinic. Euro- emedicine.medscape.com/article/126568-overview, Accessed July 3. Steering Committee of the Physicians’ Health Study Research pean Journal of Internal Medicine. 2011;22:412-417. 20, 2012. Group. Final report on the aspirin component of the ongoing physi- 14. Degoma EM, Rader DJ. Novel hdl-directed pharmacotherapeutic cians’ health study. N Engl J Med. 1989;321:129–135. strategies. Nature reviews. Cardiology. 2011;8:266-277. Case Study I References 4. Heart disease and stroke statistics—2012 update: a report from the 15. Badimon JJ, Badimon L, Fuster V. Regression of atheroscle- 1. Bensen JT, Li R, Hutchinson RG, Province MA, Tyroler HA. American Heart Association. Circulation. 2012;125:e2-e220. rotic lesions by high density lipoprotein plasma fraction in the Family history of coronary heart disease and pre-clinical carotid 5. Aspirin for the prevention of heart disease. U.S. Preventive Services cholesterol-fed rabbit. The Journal of Clinical Investigation. artery atherosclerosis in African-Americans and whites: the ARIC Task Force. Ann Intern Med 2009;150:396-404. 1990;85:1234-1241. Study: Atherosclerosis Risk in Communities. Genet Epidemiol. 6. D’Agostino RB, Wolf PA, Belanger AJ, Kannel WB. Stroke risk profile: 16. Chiesa G, Monteggia E, Marchesi M, et. al. Recombinant 1999;16:165-178. adjustment for antihypertensive medication. The Framingham apolipoprotein a-i(milano) infusion into rabbit carotid artery 2. Snowden CB, McNamara PM, Garrison RJ, Feinleib M, Kannel Study. Stroke. 1994;25:40–43. rapidly removes lipid from fatty streaks. Circulation Research. WB, Epstein FH. Predicting coronary heart disease in siblings—a 7. Stroke. Framingham Heart Study website. Accessed online at http:// 2002;90:974-980. multivariate assessment. The Framingham Study. Am J Epide- www.framinghamheartstudy.org/risk/stroke.html on August 27, 17. Zhang Y, Zanotti I, Reilly MP, et. al. Overexpression of apolipopro- miol.1982;115:217-222. 2012. tein a-i promotes reverse transport of cholesterol from macrophages 3. Khaw KT, Barrett-Connor E. Family history of heart attack: a modifi- 8. Collins R, Armitage J, Parish S, et. al. Heart Protection Study Col- to feces in vivo. Circulation. 2003;108:661-663. able risk factor: Circulation. 1986;74:239-244. laborative Group. Effects of cholesterol-lowering with simvastatin 18. Nissen SE, Tsunoda T, Tuzcu EM, et. al. Effect of recombinant apoa- 4. Lloyd-Jones DM, Nam B-H, D’Agostin RB, Levy, D, Murabito JM, on stroke and other major vascular events in 20536 people with i milano on coronary atherosclerosis in patients with acute coronary Wang TJ, Wilson PWF, O’donnell CJ. Parental cardiovascular disease cerebrovascular disease or other high-risk conditions. Lancet syndromes: A randomized controlled trial. JAMA : the Journal of the as a risk factor for cardiovascular disease in middle-aged adults. 2004;363:757-67 American Medical Association. 2003;290:2292-2300. JAMA. 2004;291:2204-2211. 9. Cholesterol Treatment Trialists’ (CTT) Collaborators. Mihaylova B, 19. Tardif JC, Gregoire J, L’Allier PL, et. al. Effects of reconstituted high- 5. Ridker, PM, Buring JE, Rifai N, Cook NR. Development and valida- Emberson J, Blackwell L, et. al. The effects of lowering LDL choles- density lipoprotein infusions on coronary atherosclerosis: A random- tion of improved algorithms for the assessment of global cardiovas- terol with statin therapy in people at low risk of vascular disease: ized controlled trial. JAMA : the Journal of the American Medical cular risk in women. JAMA. 2007;297:611-619. meta-analysis of individual data from 27 randomised trials. Lancet. Association. 2007;297:1675-1682. 6. European guidelines on cardiovascular disease prevention in clinical 2012 Aug 11;380(9841):581-90. 20. Waksman R, Torguson R, Kent KM, et. al. A first-in-man, random- practice (version 2012). European Heart Journal. 2012;33:1635- 10. Expert Panel on Detection, Evaluation, and Treatment of High Blood ized, placebo-controlled study to evaluate the safety and feasibility 1701. Cholesterol in Adults. JAMA. 2001;285:2486-2497. of autologous delipidated high-density lipoprotein plasma infusions 7. O’Donnell CJ. Family History, subclinical atherosclerosis, and coro- 11. D’Agostino RB, Vasan RS, Pencina MJ, Wolf PA, Cobain M, Massaro in patients with acute coronary syndrome. Journal of the American nary heart disease risk. Circulation. 2004;110:2074-2076. JM, Kannel WB. General cardiovascular risk profile for use in College of Cardiology. 2010;55:2727-2735. 8. Nordestgaard BG, et al. Lipoprotein (a) as a cardiovascular risk fac- primary care. Circulation 2008; 117:743--753. 21. Cannon CP, Dansky HM, Davidson M, et. al. Design of the define tor: current status. European Heart Journal. 2010;31:2844-2853. 12. General Cardiovascular Risk. Framingham Heart Study website. trial: Determining the efficacy and tolerability of cetp inhibition 9. Goldhaber SZ. European atherosclerosis society screening recom- Accessed online at http://www.framinghamheartstudy.org/risk/gen- with anacetrapib. American heart journal. 2009;158:513-519 e513. mendations for lipoprotein(a) and high-sensitivity C-reactive protein: cardio.html on August 27, 2012. 22. Cannon CP, Shah S, Dansky HM, et. al. Safety of anacetrapib in double standard or failure of evidence-based medicine? Clinical 13. Grundy SM, Cleeman JI, Bairey Merz CN, et. al. Implications of patients with or at high risk for coronary heart disease. The New Chemistry. 2010;56:1544-1546. recent clinical trials for the National Cholesterol Education Program England Journal of Medicine. 2010;363:2406-2415 10. Davidson MH, et al. Clinical utility of inflammatory markers and ad- Adult Treatment Panel III guidelines. Circulation. 2004;110:227- 23. Nicholls SJ. Evacetrapib. Current Cardiology Reports. 2012;14:245- vanced lipid testing: advice from an expert panel of lipid specialists. 239. 250. Journal of Clinical Lipidology. 2011;5:338-367. 14. Berry JD, Dyer A, Cai X, et.al. Lifetime risks of cardiovascular dis- 24. Rigamonti E, Helin L, Lestavel S, et. al. Liver x receptor activation 11. Cromwell WC, Otvos JD, Keyes MJ, Pencina MJ, Sullivan L, Vasan ease. NEJM. 2012; 366(4):321-9. controls intracellular cholesterol trafficking and esterification in RS, Wilson PWF, D’Agostino RB. LDL particle number and risk of human macrophages. Circulation Research. 2005;97:682-689. future cardiovascular disease in the Framingham offspring study— Guest Editorial References 25. Costet P, Luo Y, Wang N, Tall AR. Sterol-dependent transactivation implications for LDL management. J Clin Lipidol. 2007;1:583-592. 1. Boden WE, Probstfield JL, Anderson T, Chaitman BR, Desvignes- of the abc1 promoter by the liver x receptor/retinoid x receptor. 12. Otvos JD, Mora S, Shalurova I, Greenland P, Mackey RH, Goff DC Nickens P, Koprowicz K, McBride R, Teo K, Weintraub W. Niacin in The Journal of Biological Chemistry. 2000;275:28240-28245. Jr. Clinical implications of discordance between low-density lipopro- patients with low HDL cholesterol levels receiving intensive statin 26. Brunham LR, Kruit JK, Iqbal J, et. al. Intestinal directly con- tein cholesterol and particle number. J Clin Lipidol. 2011;5:105- therapy. The New England Journal of Medicine. 2011;365:2255- tributes to hdl biogenesis in vivo. The Journal of Clinical Investiga- 113. 2267. tion. 2006;116:1052-1062. 13. St-Pierre AC, Cantin B, Dagenais GR, Despres JP, Lamarche B. 2. Roche. (2012). Roche provides update on Phase III study of dalcetra- 27. Grefhorst A, Elzinga BM, Voshol PJ, et. al. Stimulation of lipogenesis Apolipoprotein-B, low-density lipoprotein cholesterol, and the pib. Retrieved from http://www.roche.com/media/media_releases/ by pharmacological activation of the liver x receptor leads to produc- long-term risk of coronary heart disease in men. Am J Cardiol. med-cor-2012-05-07.htm. tion of large, triglyceride-rich very low density lipoprotein particles. 2006;97:997-1001. 3. Voight BF, Peloso GM, Orho-Melander M, et. al. Plasma HDL cho- The Journal of Biological Chemistry. 2002;277:34182-34190. 14. Boekholdt SM, Arsenault BJ, Mora S, et. al. Association of LDL lesterol and risk of myocardial infarction: A mendelian randomisa- 28. Lund EG, Peterson LB, Adams AD, et. al. Different roles of liver x cholesterol, non-HDL cholesterol, and apolipoprotein B levels with tion study. Lancet. 2012. receptor alpha and beta in lipid metabolism: Effects of an alpha- risk of cardiovascular events among patients treated with statins: a 4. NHLBI. Nih stops clinical trial on combination cholesterol treat- selective and a dual agonist in mice deficient in each subtype. meta-analysis. JAMA. 2012;307:1302-1309. ment. 2011;2012. Biochemical Pharmacology. 2006;71:453-463. 15. Parish S, Offer A, Clarke R, et al. Lipids and lipoproteins and risk fo 5. Brinton EA. Search and rescue for hypotheses surviving aim-high, 29. Yoshikawa T, Shimano H, Amemiya-Kudo M, et. al. Identification different cardiovascular events in the MRC/BHF Heart Protection the niacin therapy earthquake: Still problematic after the primary of liver x receptor-retinoid x receptor as an activator of the sterol Study. Circulation. 2012;125:2469-2478. publication. Journal of Clinical Lipidology. 2012;6:312-317. regulatory element-binding protein 1c gene promoter. Molecular 16. ACCF/AHA 2007 Clinical expert consensus document on coronary 6. Stein EA, Stroes ES, Steiner G, Buckley BM, Capponi AM, Burgess and Cellular Biology. 2001;21:2991-3000 artery calcium scoring by computed tomography in global cardiovas- T, Niesor EJ, Kallend D, Kastelein JJ. Safety and tolerability of dalce- 30. Yasuda T, Grillot D, Billheimer JT, et. al. Tissue-specific liver x cular risk assessment and in evaluation of patients with chest pain. J trapib. The American Journal of Cardiology. 2009;104:82-91. receptor activation promotes macrophage reverse cholesterol trans- Am Coll Cardiol. 2007;49:378-402. 7. Cooney MT, Dudina AL, Graham IM. Value and limitations of port in vivo. Arteriosclerosis, Thrombosis, and Vascular Biology. 17. Tabas I, Williams KJ, Boren J. Subendothelial lipoprotein retention existing scores for the assessment of cardiovascular risk: A review 2010;30:781-786. as the initiating process in atherosclerosis: update and therapeutic for clinicians. Journal of the American College of Cardiology. 31. Bartel DP. Micrornas: Target recognition and regulatory functions. implications. Circulation. 2007;116:1832-1844. 2009;54:1209-1227. Cell. 2009;136:215-233. 8. deGoma EM, deGoma RL, Rader DJ. Beyond high-density lipoprotein 32. Rayner KJ, Suarez Y, Davalos A, et. al. Mir-33 contributes to the reg- Lipid Luminations References cholesterol levels evaluating high-density lipoprotein function as in- ulation of cholesterol . Science. 2010;328:1570-1573. 1. Daniels SR, Gidding SS, de Ferranti SD. Pediatric aspects of familial fluenced by novel therapeutic approaches. Journal of the American 33. Rayner KJ, Sheedy FJ, Esau CC, et. al. Antagonism of mir-33 in mice hypercholesterolemias: recommendations from the National Lipid College of Cardiology. 2008;51:2199-2211. promotes reverse cholesterol transport and regression of atheroscle- Association Expert Panel on Familial Hypercholesterolemia. Journal 9. Khera AV, Cuchel M, de la Llera-Moya M, Rodrigues A, Burke rosis. The Journal of Clinical Investigation. 2011;121:2921-2931. of clinical lipidology. Jun 2011;5(3 Suppl):S30-37. MF, Jafri K, French BC, Phillips JA, Mucksavage ML, Wilensky RL, 34. Rayner KJ, Esau CC, Hussain FN, et. al. Inhibition of mir-33a/b in 2. Gidding SS. Familial Hypercholesterolemia: A Decade of Progress, Mohler ER, Rothblat GH, Rader DJ. Cholesterol efflux capacity, non-human primates raises plasma hdl and lowers vldl triglycerides. Part 2. J Pediatr. Feb 23 2012. high-density lipoprotein function, and atherosclerosis. The New Nature. 2011;478:404-407. 3. Nherera L, Marks D, Minhas R, Thorogood M, Humphries SE. Prob- England Journal of Mmedicine. 2011;364:127-135. abilistic cost-effectiveness analysis of cascade screening for familial 10. Patel PJ, Khera AV, Jafri K, Wilensky RL, Rader DJ. The anti-oxidative hypercholesterolaemia using alternative diagnostic and identification capacity of high-density lipoprotein is reduced in acute coronary

Official Publication of the National Lipid Association 35 ™ 2011 Update Now Available

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Sponsored by the National Lipid Association. This activity has been approved for AMA PRA Category 1 Credit™. CE credit provided by AKH Inc, Advancing Knowledge in Heathcare. This activity is eligible for ACPE, ANCC and CDR credit; see final CE activity announcement for specific details. CDR provider #AN008. Full accreditation information and details regarding order fulfillment available at www.lipid.org/SAP Questions: Call the NLA office at 904.998-0854 FOR YOUR PATIENTS The Facts About Fats

Dietary Fats and Heart Disease-Understanding the Di erence Between the Good and the Bad Fat Composition of Oils/Fats Dietary 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 butter wrong type of fat. Dietary fat is composed of several di erent fatty lard acids which can have a considerable e ect on cholesterol levels. margarine Unsaturated or “heart healthy” fats are derived mainly from plant and soybean sh sources and can help to improve lipid levels, whereas saturated Monounsaturated fat comes from animal products and can worsen lipid levels and corn Polyunsaturated Saturated increase the risk for heart disease. Oil, used in cooking or as an peanut

ingredient in salad dressings, margarines, and mayonnaise, is a sesame signicant source of dietary fat. Unfortunately, selecting the best oil can be confusing. canola olive

Limit the Bad Fats 0% 20% 40% 60% 80% 100% Percent Fat Foods 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 at least twice a week to reduce cardiovascular risk. In patients with fatty meats, such as sausage, bacon, and hot dogs, poultry with skin, evidence of heart disease a daily supplement containing 1000 mg of lunch meats such as bologna and salami, and regular fat dairy EPA plus DHA may be recommended by your provider.1 products, including whole milk, cheese, butter, and ice cream. It is recommended that we limit saturated fat in our diet to less than 7 Monounsaturated Fats percent of total calories, which is approximately 15 grams based on Monounsaturated fatty acids (MUFA) contain one double bond; oleic an 1800 calorie diet. acid is the most common dietary form. Oils high in oleic acid include canola and olive oil. Other dietary sources of MUFA include Trans-Fatty Acids avocados and nuts. Epidemiologic evidence from the Mediterranean Hydrogenation, the addition of hydrogen to an unsaturated region, where diets are rich in MUFA, has demonstrated a lower fat, can create unnatural trans-fats. The major sources of trans-fatty incidence of CHD. Short term clinical trials of a Mediterranean-style acids in the U.S. are partially hydrogenated vegetable oils, such as diet have shown improvement in a number of risk factors, including those found in stick margarines and deep fried fast foods. Food lowering serum triglycerides and reduction of inammatory markers, manufacturers have used this process to prolong the shelf-life of such as C-reactive protein. Provision of some calories from MUFA foods such as crackers, cookies, potato chips, and puddings. Several that might otherwise be provided from carbohydrates or saturated large studies have shown that trans-fatty acids increase the risk of fatty acids can lower LDL-C without lowering HDL-C or raising coronary heart disease (CHD) by raising low density lipoprotein triglyceride levels. cholesterol (LDL-C) levels and decreasing high density lipoprotein cholesterol (HDL-C) levels. You should look for soft tub margarines Cooking with Fats and Oils and food products that contain zero grams of trans-fats. It is impossible to completely eliminate all saturated and trans-fats from your diet, but you should try to eat as little as possible. When Choose the Good Fats cooking choose the oil with the lowest amount of saturated fat that Polyunsaturated Fats will provide the particular avor that you desire. Heating oil changes Two major categories of polyunsaturated fatty acids (PUFA) are its characteristics, so it is equally important to select cooking oil omega-6 and omega-3 fatty acids. Substitution of PUFA for saturated based on its intended use. Corn, sunower or saower oil, because fat in the diet lowers LDL-C and reduces risk for CHD. Vegetable oils of their high smoke points, are best used for deep frying, a cooking such as corn, sunower, saower, soybean, cottonseed, and peanut method that should be used very infrequently. Canola, extra virgin are high in omega-6 fatty acids. These oils provide linoleic acid (LA). olive, sesame, and peanut oil are best used for baking, oven cooking Omega-3 fatty acids include eicosapentaenoic acid (EPA) and or stir frying. Since all fats are equally caloric, however, limited use in docosahexaenoic acid (DHA), as well as alpha-linolenic acid (ALA). food preparation is advised to maintain a reasonable body weight. EPA and DHA are marine-based fatty acids found in cold sh, including tuna, swordsh, salmon, mackerel, sardines, and herring —Fran Burke, MS, RD and may provide cardiac benets. Alpha-linolenic acid is plant-based and found in canola, axseed and to some extent in soybean oil and Reference 1. Kris-Etherton PM, Harris WS, Apper LJ. Fish consumption, fish oil, omega-3 fatty acids, and walnuts. The American Heart Association advises consumption of sh cardiovascular disease. Circulation. 2002;106:2747-2757.

Name:______Date:______Healthcare Provider:______LDL Goals:______Weight Loss Goals:______Activity/Exercise Goals:______Medications Recommended:______Provided by the National Lipid Association 6816 Southpoint Pkwy., Ste. 1000 • Jacksonville, FL 32216 • www.learnyourlipids.com Official Publication of the National Lipid Association 23 Healthcare Providers—access this tear sheet at www.learnyourlipids.com 6816 Southpoint Pkwy Suite 1000 Jacksonville, Florida 32216