Official Publication of the National Lipid Association LipidSpin pot·pour·ri noun /,pou pu’ri:/

1. a mixture of dried flower petals, leaves, and spices that is used to make a room smell pleasant

2. a collection of different things1

Special Freelance Edition Featuring: Dyslipidemia in the Patient Living with HIV

Also in this issue: The Impact of Gilbert’s Syndrome on Atherosclerosis Dyslipidemia, Cardiovascular Disease, and Youth with Diabetes This issue sponsored by the National Lipid Association

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Pharmacists, Nurses, Physicians, Physician Assistants, Dietitians, Exercise Specialists, Industry and Research Professionals

Physicians The Accreditation Council for Clinical Lipidology The only advanced certi cation program of its kind oers two levels to recognition: available to physicians who wish to validate their Basic Competency in Clinical Lipidology Exam: rigorous training and expertise in lipidology. For individuals with general involvement in lipidology who want to sharpen their skills and The American Board of Clinical Lipidology was knowledge in lipid management. established to assess the level of knowledge required to be certi ed as a Clinical Lipidologist, to Clinical Lipid Specialist Certi cation Program: encourage professional growth in the practice Provides an opportunity for health care of lipidology, and to enhance physician practice professionals who provide specialized care to behavior to improve the quality of patient care. patients with dyslipidemia and related cardiometabolic conditions to become certi ed as clinical lipid specialists. www.lipidboard.org www.lipidspecialist.org In This Issue:

Editors 2 From the NLA President JAMES A. UNDERBERG, MD, MS, FACPM, FACP, FNLA* Passing the Torch Clinical Assistant Professor of Medicine —Terry A. Jacobson, MD, FACP, FAHA, FNLA NYU School of Medicine & NYU Center for Prevention of Cardiovascular Disease Director Bellevue Hospital Lipid Clinic 4 Letter from the LipidSpin Editor Look for the NLA Community logo to discuss New York, NY Moving Forward With articles online at www.lipid.org ROBERT A. WILD, MD, PhD, MPH, FNLA* Recommendations Clinical Epidemiology and Biostatistics and — Robert A. Wild, MD, MPH, PhD, FNLA Clinical Lipidology Professor Oklahoma University Health Sciences Center 22 Dyslipidemia in the Patient Oklahoma City, OK 5 Letter from the LipidSpin Editor Living with HIV Cholesterol Limbo — How Low Can —Merle Myerson, MD, EdD, FACC, FNLA Managing Editor MELISSA HEYBOER You Go? National Lipid Association — James A. Underberg, MD, MS, FACPM, FACP, 25 Niacin: The Third or Fourth FNLA Executive Director Option CHRISTOPHER R. SEYMOUR, MBA —Terrance J. Moran, MD, FACC, FAHA National Lipid Association 6 Apo A1 Remnant Ratio Contributing Editor —Heidi T. May, PhD, MSPH Reflections: An Aggressively —John R. Nelson, MD, FACC, FASNC, FNLA 27 KEVIN C. MAKI, PhD, CLS, FNLA Managed Lipidologist Can Have an Associate Editor for Patient Education Acute Coronary Syndrome VANESSA L. MILNE, MS, NP, CLS 8 Statins in Chronic Kidney —Edwin Ferguson, MD, FNLA Cardiac Vascular Nurse and Family Nurse Practitioner Disease and Dialysis: Clinical Trials, —Thomas D. Dayspring, MD, FACP, NCMP, FNLA Bellevue Hospital Lipid Clinic New York, NY Mechanisms, Dosing and Treatment Recommendations 30 Foundation Update LipidSpin is published quarterly by the —Lakshmi Kannan, MD, MSc National Lipid Association —Janani Rangaswami, MD, FACP Education, News and Notes 6816 Southpoint Parkway, Suite 1000 —Edgar V. Lerma, MD, FNLA 33 Jacksonville, FL 32216 Phone: 904-998-0854 | Fax: 904-998-0855 35 Events Calendar Copyright ©2015 by the NLA. 11 Disorders of High-Density All rights reserved. Lipoprotein (HDL) References —Rajasree Pai Ramachandra Pai, MD 36 Visit us on the web at www.lipid.org. Provider Tear Sheet The National Lipid Association makes every effort to 13 Recent Trials Regarding Exercise 40 provide accurate information in the LipidSpin at the time of publication; however, circumstances may alter and Cardiovascular Outcomes certain details, such as dates or locations of events. —Kavita S. Sharma, MD 41 Patient Tear Sheet Any changes will be denoted as soon as possible. —Martha Gulati, MD, MS, FACC, FAHA The NLA invites members and guest authors to provide scientific and medical opinion, which do not necessarily reflect the policy of the Association. 17 The Impact of Gilbert’s Syndrome on Atherosclerosis Memorial Wall —James A. Trippi, MD The National Lipid Association (NLA) is proud to present the first annual 19 Dyslipidemia, Cardiovascular Memorial Wall. Please see special insert Disease, and Youth with Diabetes in this LipidSpin. *indicates ABCL Diplomate status —Don P. Wilson, MD, FNLA —Piers R. Blackett, MD, FNLA —Catherine McNeal, MD, PhD, FNLA

Official Publication of the National Lipid Association 1 From the NLA President: Passing the Torch

TERRY A. JACOBSON, MD, FACP, FAHA, FNLA President, National Lipid Association Professor of Medicine, Emory University Atlanta, GA Director, Lipid Clinic and Cardiovascular Risk Reduction Program Diplomate, American Board of Clinical Lipidology

the torch glowing bright with energy and comment period. Once all the comments passion to the next set of capable NLA and suggestions have been fully vetted, leaders. the NLA will release Part II of the NLA Discuss this article at Recommendations for Patient-Centered www.lipid.org/lipidspin We fulfilled many of our important Management of Dyslipidemia in the Fall of missions this year including publishing the 2015. full report of the “NLA Recommendations “Skate to where the puck is going to be, not for Patient-Centered Management of Although there were many NLA milestones to where it has been.” Wayne Gretzky Dyslipidemia,” which appeared in the during the year that I am very proud of, a April 2015 issue of the Journal of Clinical few stand out in my mind. First, the NLA As I write this last president’s letter for the Lipidology (JCL). The NLA has also been was able to come together and put forth annual Potpourri edition of the LipidSpin, very diligent in the development of our core beliefs and recommendations in I’m reminded of how fortunate I’ve been Part II of our NLA Recommendations, one document. This has been something to serve as the President of the National which will focus on special populations that the NLA has wanted to do for Lipid Association (NLA) during the past including children, elderly, women, many years, but whose time course year. The year has been a very exciting African Americans, Hispanic and Latinos, was accelerated by the release of the one, and I’m so privileged to have served and those of Asian/South Asian descent. 2013 ACC/AHA Cholesterol Guidelines. with such distinguished company. The Our Recommendations will be announced Although the NLA could have taken a eternal flame of our organization has during our annual meeting in Chicago, different direction and solely concentrated always been the combined passion of our and a public comment period will be made on a critique of the strengths and members. It consists of individuals with available to all members and interested weaknesses of the current guidelines, we tremendous energy, drive, determination, stakeholders. What we have learned from decided that it was more important that and conviction; to make a difference in our comment period with the NLA Part we put forth our own recommendations. the lives of others. Whether we make a I Recommendations is the importance I believe that this is one of the defining difference one on one in a clinical setting of receiving feedback and being open to moments in the history of the NLA. or in the broader community where stakeholder concerns, interpretations, Despite tremendous external and internal we live, our efforts through education, suggestions, and values. We welcome pressure, we were able to stand strong, research, and advocacy have been quite and encourage all NLA members to articulate our beliefs based on the totality impactful. It is indeed exciting now to pass give their feedback during our public of the science, and formulate evidence-

2 LipidSpin based recommendations that will help (2) Recommend that the NLA expand its managing those at highest cardiovascular move the field forward. Finally, one other advocacy efforts by the creation of a risk, but also in preventing the disease of accomplishment that I think will help the new Science and Policy Council. atherosclerosis as we know it today. The NLA and other allied health providers far future is indeed great and I look forward into the future, was the release of the (3) Recommend that the NLA address to working with other members of the first NLA Annual Summary of Clinical the fast changing national needs NLA in eliminating the number one cause Lipidology. This initial effort spearheaded of the organization, by expanding of death and disability in this country — under the leadership of Harold Bays, MD, the number of regional participants Atherosclerotic Cardiovascular Disease. involved the participation of 27 NLA on each National committee, and clinical lipidology experts, and will become creating a newly independent council While my time as the President of the NLA a yearly update that will help to codify the of Regional Affairs. In doing so it has come to an end, I am thankful for the latest developments in clinical lipidology. will be an opportunity to get more opportunity to serve such a wonderful Thus, over time, this “living document” regional members involved early membership. I am particularly thankful with future clinical updates will become in leadership positions on various to our hardworking Executive Committee a source of “one-stop shopping” for all national level committees, thus giving (Carl Orringer, MD; Robert Wild, MD; of the latest advances in the science of more voice to the needs of members Joyce Ross, MSN; and Matt Ito, PharmD), lipidology. This will surely be of value to at the regional and grassroots level of our Chief Scientific Officer (Peter Jones, our members, and to the broader primary our organization. MD), the awesome administrative staff and care and subspecialty community for many leadership (Chris Seymour, Brian Hart) of years ahead. During our annual meeting in Chicago, the NLA, and to the many members that NLA members will have the opportunity to have shared their wisdom, friendship, After spending the year hearing from vote on these recommendations that will vision, and passion. our members on ways to improve the change the bylaws of the organization. NLA, the NLA leadership convened a Thanks again for all you do for the NLA and Strategic Planning Retreat in February The future of clinical lipidology is indeed for patients everywhere. I look forward to 2015 in Orlando, Fla., to embark on very bright. We will continue to work on a bright future for the continued growth of future strategies that will help both our improving the standing of the lipidologist the NLA and for the emerging science and members now and serve the NLA well through the recognition of lipidology art of clinical lipidology. n into the future. With representatives from within the respective disciplines of each region across the country, members healthcare organizations. We will continue of the executive committee, chairs of our to offer high quality educational programs key committees, select representatives through multiple venues. We will try from the NLA Board of Directors, the to engage more members to become NLA Foundation, the American Board of active at the national level so that we Clinical Lipidology, and the Accreditation accomplish even more with individuals Congratulations Council for Clinical Lipidology, we plotted with a diverse set of skills. Finally, we will a strategic path forward for the NLA. We continue to pursue and endorse advances to our 2014–2015 are very excited to share here a few key in the science base, that allows us to Award Winners, features of our strategic recommendations differentiate ourselves from other member Fellows, going forward. We propose the following organizations, in order to translate the and Diplomates. changes to the organization: very best evidenced based medicine into practice. In other words, according to the (1) Recommend that the NLA focus on great hockey player Wayne Gretzky, we Please see page 32 for a the enhancement of member and will skate to “where the puck is going complete listing of recipients. membership services by creating an to be, not to where it has been.” With independent Membership Services the advent of new therapies such as the Council. PCSK9 inhibitors, we will not only have the opportunity to make a serious dent in

Official Publication of the National Lipid Association 3 Letter From the LipidSpin Editor: Moving Forward with Recommendations

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

women’s health issues, race differences, These Recommendations are being put elderly populations, HIV patient questions, together by teams of experts in each of inflammatory disorders, the importance these areas and then they are vetted for Discuss this article at and methods to encourage adherence, as best clinical interpretation in keeping with www.lipid.org/lipidspin well as recommendations for team based the theme of the NLA. Our mission is to collaborative care. enhance the practice of lipid management The National Lipid Association (NLA) in clinical practice and we hope that these is proud to move forward with its While every clinical question is different, Recommendations offer assistance to that Recommendations for Patient-Centered the purpose in their development is to end. Management of Dyslipidemia for those review the current evidence, then to practicing clinical lipidology in an develop the most important principles We trust that you will find these useful environment where many clinical queries in each of these areas, and then to make and practical. We also hope that you remain unanswered for clinicians. To that recommendations based on the best give us feedback as to how useful these end, the NLA has developed Part II of these evidence available. Recommendations really are to you. We Recommendations. ask that you also pass on other favorite Our hope is that these Recommendations topics where you think that clinical The ACC/AHA Guidelines and many will be highlighted in future issues of recommendations might be helpful. other guidelines throughout the world the LipidSpin and will be available to all are very broad and generic in the sense practitioners through its publication in As always, we appreciate your feedback as that they do not address many unique the Journal of Clinical Lipidology (JCL) and we partner to reduce atherosclerosis and specific challenges that come up for through lipid.org. its consequences. n all of us in every day practice. Part II is designed to offer assistance to clinicians to Draft slides from Part II of these address some of these conundrums. More Recommendations are scheduled to publish To view and comment on the recommendations are planned in the future on the NLA website. A public comment NLA Recommendations for to offer even more clarity. period will follow in June. We want to hear Patient-Centered Management of your thoughts on these Recommendations, Dyslipidemia – Part II, visit Recommendations are being prepared for so please visit lipid.org to view and lipid.org. The public comment period CVD risk reduction related to exercise, comment. The final document is scheduled will take place in June. children, gender differences, unique to publish in the JCL later this year.

4 LipidSpin Letter From the LipidSpin Editor: Cholesterol Limbo — How Low Can You Go?

JAMES A. UNDERBERG, MD, MS, FACPM, FACP, FNLA Clinical Assistant Professor of Medicine NYU School of Medicine & NYU Center for Prevention of Cardiovascular Disease Director, Bellevue Hospital Lipid Clinic New York, NY Diplomate, American Board of Clinical Lipidology

The greater danger for most of us lies not in studies however seem to minimize these setting our aim too high and falling short; but risks. At the American College of Cardiology in setting our aim too low, and achieving our meeting this past March in San Diego, data mark.” Michelangelo Buonarroti was presented examining the safety data of Discuss this article at patients treated with the PCSK9i Alirocumab www.lipid.org/lipidspin Along with the NLA Scientific Sessions, the obtaining LDL-C levels either <25 mg/dL summer also brings the anticipation of the or < 15 mg/dL.3 Fourteen different trials safety concerns. While the ACC/AHA Prescription Drug User Fee Act (PDUFA) were analyzed evaluating 796 patients <25 Guidelines on the Treatment of Blood dates for two new monoclonal antibody mg/dL and 288 patients <15 mg/dL. No Cholesterol suggest that for those patients inhibitors for proprotein convertase subtilisin/ safety signals were observed. Concern for who achieve LDL-C levels <40 mg/dL lipid kexin type 9 (PCSK9). Data to date with this low achieved LDL-C on treatment has been lowering therapy should be removed, there is new class of medication for LDL lowering a concern since the data from the Stroke no scientific basis for this recommendation.6 has shown dramatic reductions with minimal Prevention by Aggressive Reduction in In a recent article in the Lancet, Paul Ridker, safety signals. Early data published in the New Cholesterol Levels (SPARCL) trial published in MD, reviews the data regarding LDL and England Journal of Medicine (NEJM) shows 2006 showed a small increase in hemorrhagic genetics. These data consistently support low statistically significant reductions in short- stroke in those patients recent stroke or LDL syndromes as having cardio-protective term safety trials for both of these products in TIA treated with high dose atorvastatin.4 benefits.7 More recent data showing that cardiovascular events.1,2 The remaining safety Data published online in April in Circulation mutations associated with the NPC1L1 analysis of these agents has been similar to evaluates the risk of intracranial hemorrhage receptor translate to a lifetime reduction in placebo. (ICH) from statin use in Asian patients.5 This 12 mg/dL in LDL-C and translate to a >50 nationwide cohort study showed no observed percent reduction in cardiovascular events.8 Patients treated with PCSK9 inhibitors association between cumulative statin use Low levels of LDL from birth seem to be (PCSK9i) in clinical trials encompass and risk of ICH among subjects without a desirable and safe. many different patient groups. Some have prior history of stroke. There was a signal extremely high entry LDL-C levels in the toward increased risk in those with no history In summary, we are entering a new era of low setting of familial hypercholesterolemia, while of hypertension, however, which remains to LDL levels in our effort to prevent and treat others remain at high risk despite optimal be explained. cardiovascular risk. While the landscape is lipid management, and obtain very low new and challenging, the roadmap seems to LDL-C levels. The lingering concern for these Ultimately, naturally occurring or obtained be one well worth following. n patients is the potential harm of achieving low LDL levels with lipid lowering therapy very low LDL cholesterol levels. Two recent do not seem to be associated with increased References are listed on page 36.

Official Publication of the National Lipid Association 5 Apo A1 Remnant Ratio

HEIDI T. MAY, PhD, MSPH Intermountain Heart Institute Intermountain Medical Center Murray, UT

JOHN R. NELSON, MD, FACC, FASNC, FNLA Director, California Cardiovascular Institute Assistant Clinical Professor, University of California San Francisco School of Medicine, Fresno Medicine Residency Program, Volunteer Fresno, CA Diplomate, American Board of Clinical Lipidology

that more completely reflect residual Apo A1, VAP Apo A1 has a correlation cardiovascular risk. One promising new coefficient of 0.92 and a standard error of marker is the recently described novel estimate of 10.3mg/dl.4 biomarker ratio: Apolipoprotein A1 (Apo Discuss this article at www.lipid.org/lipidspin A1) divided by the sum of the cholesterol The percent coefficient of variations components of very low-density lipoprotein for VLDL3-C and IDL-C as measured by 3 (VLDL3-C) and intermediate-density density-gradient ultracentrifugation are, 5 Although low-density lipoprotein lipoprotein (IDL-C)-Apo A1/VLDL3-C respectively, 4.9 percent, 8.2 percent. cholesterol (LDL-C) lowering with +IDL-C. This is referred to as the Apo A1 The lower limit of normal for Apo A1 is statin therapy has been part of the Remnant Ratio (AARR). 118mg/dl and the upper limit of normal National Cholesterol Education Program for VLDL3-C and IDL-C are, respectively, guidelines for 26 years, significant residual The utility of the AARR was first evaluated 10mg/d1 and 20mg/d1. cardiovascular risk remains in both primary- in 711 women > 50 years of age, referred and secondary-prevention patients. This for cardiac catheterization.3 The AARR was In this study, the AARR was more residual risk is particularly prominent obtained utilizing Atherotech’s Vertical predictive of death/MI at 3 years than any in patients following an acute coronary Auto Profile (VAP) method. Apo A1 was individual lipid, sublipid, or other well- syndrome (ACS). Post ACS patients have estimated by a derivative of high-density known ratis (Tg/HDL-C, Apo B/Apo A1, two-year cardiovascular event rates of up lipoprotein cholesterol (HDL-C) species TC/HDL-C). to 22.4 percent despite high-dose statin and VLDL-C was measured by density- therapy.1 In addition, nearly 50 percent of gradient ultracentrifugation. The clinical importance of the AARR is patients hospitalized with coronary artery potentially driven by both the numerator disease(CAD) have LDL-C <100 mg/dl.2 The percent coefficient of variation is 2.9 and denominator. Apo A1 is the protein Thus, there has been a search for markers percent; compared to directly measured component of HDL, which is a principle

6 LipidSpin participant in reverse cholesterol transport. associated with incident ischemic stroke lipids and standard lipid ratios such as TC/ In review, it accepts cholesterol from in postmenopausal women.14 Is it possible HDL-C, Tg/HDL-C, and LDL-C/HDL-C. the macrophage Adenosine triphosphate- that AARR is more predictive for future binding membrane cassette transport CHD events than LDL-C, non-HDL-C, or In a recent preliminary report, the AARR protein A1 (ABCA1). Unlike HDL-C, Apo Apo B? All Apo B-containing lipoproteins in a primary prevention cohort of African A1 has a consistent inverse relationship are not equally atherogenic. It is not just Americans — 4,722 participants in the with coronary heart disease (CHD) events.6 the cholesterol content of the lipoproteins Jackson Heart Study — was found to In our study, low levels of Apo A1, not but also their triglyceride content better stratify risk for CHD incidence than HDL-C, were associated with an 80 that contributes to inflammation and standard lipids, non-HDL-C, Apo B or Apo percent increase in one- and three-year atherosclerosis. The triglyceride content A1.22 death/MI rates. in VLDL and IDL is estimated to be 55 and 23 percent, respectively; however, In summary, the novel biomarker AARR The denominator of the AARR is VLDL3-C the triglyceride content in LDL is only 6 has been demonstrated in one study and in and IDL-C, these measures reflect remnant percent.15 a preliminary report with a larger, second lipoprotein cholesterol (RLP-C) when clinical cohort to be more predictive of elevated. RLPs in the non-fasting state In a study involving human aortic CHD than standard lipids, non HDL-C, Apo include chylomicron remnants, VLDL endothelial cells exposed to the hydrolysis B, and common lipid/lipoprotein ratios. remnants, and IDL remnants, and are the of human postprandial TRGL it was shown This exciting, novel, new biomarker ratio result of hydrolysis of triglyceride-rich that it was the free fatty acids derived from is readily available. However, it needs to lipoproteins (TGRL). Dr. John Gofman the hydrolysis not the free cholesterol that be evaluated in further populations. Of first showed that RLPs are associated with was associated with endothelial production interest is whether targeting the AARR will CHD more than 60 years ago.7 RLPs have of tumor necrosis factor alpha (TNFa), be a better target than LDL-C for lowering been shown to predict future coronary intracellular adhesion molecule(ICAM), the cardiovascular risk burden. n events in patients with or without CAD or and reactive oxygen species.16 TGRL diabetes mellitus independent of elevated hydrolysis products also increase Disclosure statement: Dr. May has no disclosures to report. Dr. Nelson has received speaker honoraria triglycerides, low HDL-C or elevated LDL- endothelial permeability. Exposure of from Amarin, AstraZeneca, Atherotech Diagnostic C.8,9 Multiple, serial angiographic studies cultured endothelial cells to fatty acids has Lab, and Kowa Pharmaceuticals America Inc. He’s been on the advisory board from Amarin, Atherotech have demonstrated that CAD progression been shown to result in increased transfer Diagnostic Lab, and Kowa Pharmaceuticals American has a greater association with IDL mass of LDL across the endothelium.17,18 Thus, Inc. He’s received consulting fees and been a stockholder for Amarin. than LDL mass as measured by analytical the adverse effects of TGRL hydrolysis ultracentrifugation.10,11 Recently, using a products allows increased subendothelial References are listed on page 36. Mendelian randomization approach in a access, not just for LDL particles but also large study of 73,513 subjects, RLP-C was for RLP. Once becoming subendothelial, shown to be a causal factor for ischemic unlike LDL, RLPs do not require oxidation heart disease, independent of reduced or modification for the development of HDL-C.12 It was found that, for every 39 foam cells. This is apparent in patients mg/dL increase in RLP-C, there was a 2.8- with Type III or Type IV hyperlipidemia fold greater risk for ischemic heart disease. whose oxidized beta-VLDL (B-VLDL) or VLDL remnants were found to cause Our study showed that the AARR was greater macrophage cholesteryl ester more predictive for death/MI than formation than oxidized LDL.19,20 In non HDL-C or Apo B. RLP-C has been addition, because of their increased reported to predict stroke in patients diameter, RLPs carry more cholesteryl ester with mild carotid atherosclerosis and molecules than LDL. It has been estimated metabolic syndrome independent of non- that chylomicron remnants — TGRL of HDL-C.13 In the Women’s Health Initiative 100 nanometers in diameter — contain Observational study, unlike HDL-C, LDL- 40 times more cholesteryl ester than LDL C, baseline triglycerides, VLDL size, and particles.21 Therefore, the AARR provides IDL particle numbers were significantly unique information compared to standard

Official Publication of the National Lipid Association 7 Statins in Chronic Kidney Disease and Dialysis: Clinical Trials, Mechanisms, Dosing, and Treatment Recommendations

LAKSHMI KANNAN, MD, MSc Department of Medicine Einstein Medical Center Philadelphia, PA

JANANI RANGASWAMI, MD, FACP Department of Medicine Einstein Medical Center Philadelphia, PA Delaware Valley Nephrology Associates Philadelphia, PA

EDGAR V. LERMA, MD, FNLA Section of Nephrology UIC/Advocate Christ Medical Center Oak Lawn, IL

events and mortality in several at-risk Outcomes (KDIGO)7 Lipid Work Group, patient populations.3 The efficacy of and collateral guidelines by the American statins in reducing the risk of CVD and College of Cardiology (ACC) and the mortality in people with CKD (not on American Heart Association (AHA) on Discuss this article at dialysis) is robust.4 However, the impact lipid management in those at high risk www.lipid.org/lipidspin of statins on cardiovascular outcomes in for atherosclerotic cardiovascular diseases patients on dialysis is less impressive. (ASCVD) were published in 2013. This Patients with chronic kidney disease (CKD) Major trials such as the German Diabetes review summarizes salient aspects of the including those undergoing dialysis have an and Dialysis (4D) study5 and the Study 2013 KDIGO guidelines on dyslipidemia increased risk of premature cardiovascular to Evaluate the Use of Rosuvastatin in management in CKD, dosing strategies, disease (CVD).1 CKD patients also have a Subjects on Regular Hemodialysis: An and landmark trials that form the backbone high rate of coronary death and myocardial Assessment of Survival and Cardiovascular for these recommendations. infarction — rates equivalent to those Events (AURORA),6 concluded no benefit of diabetics. CKD, per se, has thus been in initiation of statin therapy in this CKD, Hyperlipidemia, and the Dialysis classified as a coronary heart disease risk population. The release of new guidelines Paradox equivalent.2 Statin therapy has been proven on dyslipidemia management in CKD by Hyperlipidemia is a well-known to reduce the incidence of cardiovascular the Kidney Disease: Improving Global cardiovascular risk factor, and lipid-

8 LipidSpin lowering therapy has been consistently in the relative hazard of the primary primary end point (a composite of cardiac shown to improve cardiovascular outcomes outcome of major atherosclerotic events death, non-fatal MI, and fatal and non-fatal in the general population without kidney in 9,270 participants with CKD, of which stroke) in a four-year follow-up of 1,255 disease. Dialysis patients with the 6,247 were not on dialysis. hemodialysis patients.5 This was followed highest and lowest levels of low-density by a large-scale multicenter trial called the lipoprotein cholesterol (LDL-C) and total AURORA trial, which evaluated benefits of cholesterol (TC) are at the highest risk of rosuvastatin in dialysis patients between adverse outcomes such as all-cause and “Lipid assessment 50 and 80 years of age. This was a placebo- cardiovascular mortality. This paradoxical controlled double-blinded randomized trial association between cholesterol and and treatment is a that studied the effect of rosuvastatin on outcomes appears to be to the result of multiple primary endpoints, namely non- effect modification by protein energy key step in reducing fatal myocardial infarction, non-fatal stroke, wasting, inflammation, and malnutrition.7 cardiovascular and cardiovascular-specific mortality, in statin naïve patients on hemodialysis. KDIGO recommendations for initial morbidity and Some 2,776 hemodialysis patients were assessment of lipid status in adults with assigned to either rosuvastatin or placebo CKD mortality in the CKD and followed for a median of 3.8 years. – In adults with newly identified CKD Rosuvastatin did not reduce the risk of (including kidney transplant recipients and population inherently individual components of the primary end those on chronic dialysis), an initial lipid point or all-cause mortality, despite a 43 profile is recommended (total cholesterol, at high risk.” percent reduction in the LDL cholesterol LDL, HDL, triglycerides) (1C). level.6

– In adults with CKD (including those – In adults ages 18 to 49 years with CKD The largest trial to date was the SHARP treated with chronic dialysis or kidney but not treated with chronic dialysis or trial, which studied the effects of transplantation), follow-up measurements kidney transplantation, statin therapy is simvastatin plus ezetimibe on primary of lipid levels are not required (Not recommended in people with one or more cardiovascular end points in CKD patients. Graded). Since higher cardiovascular risk of the following (2A): SHARP assigned 9,270 participants > 40 and not-elevated LDL are now the primary • known coronary disease years old with CKD to receive simvastatin indications for initiation and adjustment • diabetes mellitus 20 mg plus ezetimibe, 10 mg or placebo of lipid-lowering therapy in CKD,7 KDIGO • prior ischemic stroke and followed them for 4.9 years. Of them, recommends a “fire and forget” strategy • estimated 10-year incidence of 33 percent of patients were receiving when initiating lipid therapy in adults with coronary death or non-fatal myocardial maintenance dialysis. While this study CKD, wherein statins are initiated but not infarction > 10 percent. showed a 17 percent risk reduction in the titrated to any target lipid goals. primary outcome of major atherosclerotic KDIGO recommendations for events, combination therapy did not show KDIGO recommendations for pharmacotherapy of lipids in adults a significant risk reduction in the subgroup pharmacotherapy and dosing of statins with dialysis dependent CKD of more than 3,000 patients treated with in adults with CKD – In adults with dialysis-dependent CKD, dialysis at baseline.4 When findings from – In adults age > 50 years and with statins or statin/ezetimibe combinations SHARP, 4D, and AURORA are considered eGFR< 60 cc/min /1.73 m2 but not should not be initiated (2A). together, the clinical benefits of statins — treated with chronic dialysis or kidney alone or in combination with ezetimibe transplantation, treatment with a statin This recommendation was based on clinical – are unclear in prevalent dialysis patients. or statin/ezetimibe combination is studies that showed statins do not improve Even if statins do prevent cardiovascular recommended (1A). cardiovascular outcomes in hemodialysis events in dialysis patients, the magnitude patients despite lowering LDL cholesterol. of relative risk reduction is substantially In the Study of Heart and Renal Protection The first of these studies was the 4D lesser than in the earlier stages of CKD. (SHARP),4 simvastatin plus ezetimibe study. In the 4D study, atorvastatin had therapy resulted in a 17 percent reduction no effect on the single components of the This recommendation also was supported

Official Publication of the National Lipid Association 9 10 Recommended doses (mg/d) of statins in adults with CKD those on dialysis, including C-reactive protein (CRP), serum amyloid A, inflammatory cytokines — including interleukins 1, 2, 4, 5, 6, 12, and 13 — and tumor necrosis factor alpha (TNF- alpha). Numerous studies have shown that some of the above inflammatory markers, such as CRP, are independent predictors of CVD-related mortality in dialysis patients.11,12 Inflammation impacts cardiovascular mortality through a complex mechanism involving plaque progression, vascular, and valvular calcification and progression of malnutrition. Statins have pleotropic effects in the general population, anti-inflammatory effects being the most important of them. Statins have dose-dependent effects. Future prospective studies are needed to study these dose- Table 2. Reproduced with permission from the KDIGO Clinical Practice Guideline on Lipid Management dependent effects in the end-stage renal in CKD disease (ESRD)/dialysis population, because it is quite evident that mere lipid-lowering 8 by a Cochrane review in 2013 that the recommended doses. (Table 1) effects do not impact CVD risk in dialysis concluded there was no cardiovascular patients. benefit to statin therapy in terms of Regardless of CKD severity, the KDIGO primary prevention in dialysis-dependent Work Group recommends baseline levels In summary, lipid assessment and CKD. of transaminases to be measured before treatment is a key step in reducing initiating statin therapy. Routine follow-up cardiovascular morbidity and mortality in KDIGO recommends adult kidney of liver function tests or CK levels is not the CKD population inherently at high risk transplant recipients be treated with a recommended, unless clinical evidence of for such events. However, the benefits of statin (2B) hepatotoxicity or myopathy ensues. The statin therapy in prevalent dialysis patients The Assessment of Lescol in Renal Work Group also recommends that statins remain uncertain at this time. Data from 9 Transplant (ALERT) trial examined the and fibrates not be used concomitantly in major trials including dialysis patients effects of statin therapy on cardiovascular patients with CKD. Given that evidence for should be pooled to undertake individual risk reduction in 2,102 patients ages 30 clinical benefit is higher with statins than patient data meta-analyses to assess to 75 years with a functioning kidney fibrates, the Work Group recommends in greater detail the potential benefits transplant. Fluvastatin led to a significant that statins be chosen in preference to of lipid-lowering agents in the dialysis 35 percent relative risk reduction of fibrates when clinicians are considering population. n cardiac death or definite non-fatal MI. pharmacotherapy.

Dosing of Pharmacological Lipid- CKD, ESRD, and Atherosclerosis — A Disclosure statement: Dr. Kannan has no disclosures to report. Dr. Rangaswami has no disclosures to report. Lowering Therapy in CKD Missing Link Dr. Lerma has received speaker honoraria from Otsuka CKD patients are at high risk of adverse Atherosclerosis is an inflammatory Pharmaceuticals and Questcor/Mallinckrodt. He was on the advisory board for Otsuka Pharmaceuticals. events from lipid pharmacotherapy because disorder. Inflammation in the CKD patient of reduced renal excretion, polypharmacy, sets the stage for a perfect plaque. A References are listed on page 36. and multiple co-morbidities.9 Given the generalized increase in inflammatory potential for toxicity with high-dose statins markers and acute-phase responses has in CKD, the KDIGO Work Group suggests been noted in CKD patients, especially

10 LipidSpin Disorders of High-Density Lipoprotein (HDL)

RAJASREE PAI RAMACHANDRA PAI, MD Endocrinologist Eureka, CA

A 35-year-old healthy woman is seen at HDL-cholesterol (HDL-C) refers to free the endocrine clinic for above-normal cholesterol and cholesterol ester carried high-density lipoprotein (HDL). Her by HDL in the circulation. In practice, triglyceride level is 200mg/dl, and low- the terms HDL and HDL-C often are density lipoprotein (LDL) is 90mg/dl, with used interchangeably. Lipoproteins Discuss this article at HDL of 129mg/dl. She has no risk factors Apo A-I and Apo A-II are the major www.lipid.org/lipidspin for coronary artery disease (CAD), except structural components of HDL.2 In that her father died of premature coronary healthy individuals, around 30 percent of artery disease at the age of 42. cholesterol is carried by HDL.1 HDL-C has hyperalphalipoproteinemia and endothelial an inherited basis in 40 to 80 percent of lipase deficiency may not protect against How does one approach a patient with cases.3 Extreme levels of HDL-C can have a cardiovascular disease.8,9,10 Patients with abnormal HDL? When is HDL protective polygenic origin.3 promoter variants of hepatic lipase(LIPC) and when is it not? How do we treat have elevated HDL-C and, paradoxically, low HDL? This editorial discusses those U.S. National Cholesterol Education increased cardiovascular risk.11 questions as well as when to consider Program Adult Treatment Panel III (ATP genetic testing in patients with HDL III) guidelines define an HDL-C of 60 mg/ Secondary causes of high HDL-C include disorders. dL or greater as a negative risk factor.4 Low primary biliary cirrhosis and thyroid HDL-C level is below 40 mg/dL in men and disorders, possibly because of increased HDL mobilizes cellular cholesterol and less than 50mg/dL in women.4 phospholipid to protein ratio and effect transport of cholesterol for hepatic on hepatic lipase, respectively.12,13 High uptake.1 Cholesterol carried by HDL is Factors that increase HDL-C include female HDL-C in patients not taking lipid- sometimes referred to as “atheroprotective gender5 and moderate alcohol intake.6 Age lowering drugs should prompt a diagnostic cholesterol,” because it transports is positively correlated with HDL-C.7 evaluation, including hepatic function and cholesterol away from lipid-laden cells Elevated HDL-C usually correlates thyroid-stimulating hormone levels. (macrophages) known as foam cells with decreased cardiovascular risk in in arteries and tissues to the liver for observational analyses.1 However, high Primary causes of high HDL-C are genetic excretion and reutilization.1 Therefore, HDL-C levels caused by genetic disorders mutations causing overproduction or HDL may help prevent atherosclerosis and such as cholesteryl ester transfer protein decreased HDL clearance. CETP deficiency reduce macrophage accumulation. (CETP) deficiency, primary familial is an autosomal recessive disorder caused

Official Publication of the National Lipid Association 11 by CETP gene mutation.14 CETP facilitates and triglyceride levels are not affected.23 and thrombocytopenia and intracellular transfer of cholesterol esters from HDL to Symptoms include xanthomas and corneal accumulation of cholesterol ester other lipoproteins. Affected patients have opacities. Heterozygotes of the Apo A-I deposition in lymphoid organs.25,26 Plasma asymptomatic elevation of HDL cholesterol Milano variant exhibit low HDL-C levels levels of Apo A-I are reduced to about 3 above 150 mg/dL.14 but reduced CAD,22 whereas carriers of the percent of normal, and triglyceride levels Apo A-I Paris variant are protected against are increased along with reduced LDL-C Primary familial hyperalphalipoproteinemia CAD.22 (50 percent of normal).26 is an autosomal-dominant condition caused by genetic mutations of Apo protein Treatments for LDL cholesterol and A-I overproduction or Apo protein C-III triglycerides often increase HDL variants. It is diagnosed incidentally with “A patient with cholesterol, and the three objectives can plasma HDL-C levels above 80 mg/dL9. sometimes be achieved simultaneously. high or low HDL The Heart Protection Study 2-Treatment Even though high HDL does not need of HDL to Reduce the Incidence of to be treated, per se, the patient needs and a family history Vascular Events (HPS2-THRIVE) study27 counseling to avoid risk factors such as of cardiovascular and the Atherothrombosis Intervention smoking in light of her family’s CAD in Metabolic Syndrome with Low HDL/ history. It has to be considered that the disorders makes High Triglycerides: Impact on Global high HDL, in her case, is not likely to Health Outcomes (AIM-HIGH)28 trial protect against CAD. a case for genetic failed to demonstrate that an increase in HDL-C with niacin in statin-treated Low HDL, in general, is associated with testing.” patients resulted in a reduced CAD risk. increased CAD risk.15 Obesity, a high- Fibrates and CETP inhibitors (dalcetrapib) fat diet, a lack of physical activity, and have failed to demonstrate cardiovascular smoking are among the modifiable risk LCAT converts free cholesterol into outcome benefits, in spite of increasing factors low HDL-C levels.16,17 Type 2 cholesteryl ester. LCAT deficiency causes HDL-C levels.14,29 diabetes mellitus is also associated with accelerated catabolism of Apo A-I and reduced HDL-C levels.16 ApoA-II and low HDL. Heterozygotes Recombinant HDL (Apo protein A-1 have 40 percent reductions in HDL- Milano) is a possible future treatment Multiple epidemiological studies and C. Symptoms include corneal opacity option for atherosclerosis. the landmark Framingham Heart Study in partial LCAT deficiency (fish eye), have shown that low HDL-C represents a proteinuria, and anemia. Both partial LCAT A patient with high or low HDL and a significant and independent predictor of deficiency and familial LCAT deficiency family history of cardiovascular disorders cardiovascular disease (CVD).15,18,19,20 increase the risk of premature CAD.23,24 makes a case for genetic testing. A family history of longevity is reassuring in a Genetic disorders causing low HDL are Patients with ABCA1 gene mutations patient with extremes of HDL levels with Apo lipoprotein A-1 (Apo A-I) deficiency, (Tangier disease), are not at increased no other risk factors. n lecithin: cholesterol acyltransferase (LCAT) cardiovascular risk as these patients Disclosure statement: Dr. Ramachandra Pai has no deficiency, and ATP-Binding Cassette can have cholesterol delivered onto disclosures to report. Transporter A1 (ABCA1) deficiency, all of more mature HDL via the ABCG1 (ATP- References are listed on page 36. which are rare and autosomal-recessive.21 Binding Cassette G1) Transporter.25,26 Apo A-I mutations cause the most elevation In Tangier disease, ABCA1 function is in cardiovascular risk compared with other impaired. Apo A-I cannot be lipidated, gene mutations in HDL metabolism. Not leading to rapid clearance that results in all genetic forms of very low HDL-C are significantly reduced levels of Apo A-I and associated with increased risk of CVD.22 the presence of small pre–β-HDL particles. Apo A-I deficiency is characterized by Symptoms include peripheral neuropathy, the absence of apoA-I, whereas LDL-C hepatosplenomegaly, corneal opacities,

12 LipidSpin Recent Trials Regarding Exercise and Cardiovascular Outcomes

KAVITA S. SHARMA, MD The Ohio State University Wexner Medical Center Department of Medicine, Division of Cardiovascular Medicine Columbus, Ohio Diplomate, American Board of Clinical Lipidology

MARTHA GULATI, MD, MS, FACC, FAHA The Ohio State University Wexner Medical Center Department of Medicine, Division of Cardiovascular Medicine Columbus, Ohio

Lifestyle-related risk factors can prevent benefits were similar between lower and or promote atherosclerotic cardiovascular higher doses of running. There were no disease (ASCVD). Thus, management of significant differences in the hazard ratios lifestyle factors is crucial in addressing of all-cause and CVD mortality across Discuss this article at the burden of ASCVD. Nonetheless, quintiles of weekly running time. Even www.lipid.org/lipidspin addressing these factors has often been running at slower speeds and at lower overshadowed by the administration of “doses” (defined as < 51 minutes, < 6 medications. Over the past few years, miles, 1-2 times/week, < 6 miles/hour) there has been increasing interest in a key was associated with significant and similar cause mortality (0.22: 95 percent CI: 0.10 lifestyle component — exercise — and its benefit. to 0.47); the HR for moderate joggers was influence on cardiovascular disease (CVD) 0.66 (95 percent CI: 0.32 to 1.38) and for risk. Several recent studies illustrate the The Copenhagen City Heart Study strenuous joggers was 1.97 (95 percent cardioprotective impact of exercise. examined the relationship between CI: 0.48 to 8.14). The group of strenuous all-cause mortality and dose of jogging joggers had almost the same mortality risk The association of leisure-time running as calibrated by pace, quantity, and as the sedentary non-joggers. This U-shaped with all-cause and CVD mortality in adults frequency.2 Physical activity was graded, association suggests the existence of an was recently examined.1 Participants were with joggers divided into light, moderate, optimal upper limit for exercise dosing. The grouped into six groups: non-runners and strenuous categories. Jogging from dose of running that is most favorable for and five quintiles of varying amounts one to 2.4 hours/week was associated reducing mortality was jogging from 1 to of running. When compared with non- with the lowest mortality. Each group of 2.4 hours/week with no more than three runners, runners at every quintile had joggers were compared to the sedentary running days/week, at a pace suggested lower all-cause and CVD mortality (30 non-joggers group. Light joggers had the to be from 6 to 7 miles/hour. It is notable and 45 percent lower risk). The mortality most favorable hazard ratio (HR) for all- that two deaths occurred in the 40-person

Official Publication of the National Lipid Association 13 “strenuous” group, which was not moderate-intensity exercise five days/ have elevated triglycerides,33 and visceral statistically significant. week or 20 to 60 minutes of vigorous- adipose tissue is strongly associated with intensity exercise three days/week).14,15 elevated triglycerides.34 Physical activity An overall healthy lifestyle has been shown Walking, in forms such as parking farther can improve body weight and body fat; in recent studies to be beneficial. A healthy away, taking stairs, and using a pedometer therefore physical activity’s effect to lifestyle was associated with decreased risk (approximately 2,000 steps equal one mile), reduce body weight and fat may explain for coronary heart disease (CHD) in the is the most common type of moderate- why triglycerides lower with exercise. Nurse’s Health Study.3 In a study of men intensity exercise and has significant health Furthermore, those with increased body fat in Sweden, low-risk behavior (included benefits. are more likely to show a reduction in body five factors: a healthy diet, moderate fat and the concomitant lipid panel changes alcohol consumption, no smoking, being with exercise. In addition, the triglyceride physically active, and having no abdominal reduction tends to be larger when an obesity) was found to be protective “Exercise and individual has higher baseline triglycerides, against myocardial infarction(MI).4 In post- higher body fat, or both. menopausal women from the Women’s fitness can improve Health Initiative, increasingly healthy Residual Risk lifestyles were associated with decreasing cardiovascular Residual cardiovascular risk is a term heart failure risk.5 coined for the persistence of CVD outcomes and may risk after aggressive LDL-C reduction, The concept of improved overall healthy result in beneficial typically with high-intensity statins. In lifestyle habits contributing to improved statin trials, although statins reduced cardiovascular outcomes is not a new effects on the lipid CVD events compared to placebo, one. In the Study of Risk Factors for First there remained a significant CVD event Myocardial Infarction in 52 countries and profile and other risk rate in the statin-treated arms. In the more than 27,000 subjects (INTERHEART), Scandinavian Simvastatin Survival Study lifestyle-related risk factors accounted for factors.” (4S), a significant reduction in CVD events most of the risk of MI internationally.6 occurred with statin treatment compared Furthermore, Gulati et al. showed to placebo, but a 20 percent CVD event that exercise capacity was a strong, rate was noted in statin patients.35 Similar independent predictor of all-cause mortality How does exercise affect cholesterol findings were seen in the Pravastatin or in asymptomatic women.7 Numerous levels? Atorvastatin Evaluation and Infection additional prior studies have shown the Aerobic physical activity in adults has been Therapy-Thrombolysis in Myocardial association with exercise or fitness, healthy shown to reduce low-density lipoprotein Infarction 22 (PROVE IT-TIMI)36 and lifestyle, and improved cardiovascular cholesterol (LDL-C) by 3-6 mg/dL,16-21 Treating to New Targets (TNT) studies.37 outcomes.8-12 (Table 1) non-high-density lipoprotein cholesterol In the recent past, there has been (non-HDL-C) by 6 mg/dL,19,22,23 and low increased attention placed on the What do the guidelines recommend in density lipoprotein particle number (LDL- relationship of cardiovascular risk and other terms of exercise? P) by 75 nmol/liter.22,24,25 Although the lipid parameters, particularly triglyceride- The American Heart Association, American results have not been consistent, aerobic rich particles, which are contained within College of Cardiology, and the Centers exercise has been shown to increase non-HDL-C. High triglycerides have been for Disease Control recommend at least HDL-C in some studies.16-19,23,26-29 Similarly, associated with CVD.38,39 In a large meta- 150 minutes/week of moderate-intensity aerobic exercise has not been consistently analysis, triglycerides were shown to be physical activity, or 75 minutes/week of shown to decrease triglycerides, a strong and independent predictor of vigorous-intensity aerobic physical activity although some studies suggest a benefit cardiovascular disease risk.40 However, our or a combination of both, performed in of as much as a 24-percent reduction knowledge of the impact of triglyceride- episodes of at least 10 minutes, preferably in triglycerides.16-20,28,30-32 Triglyceride lowering therapies on cardiovascular events spread throughout the week.13 The levels have been shown to be affected by is limited by the fact that no major outcome American College of Sports Medicine body weight and body fat distribution. trials have focused on patients with recommends 30 to 60 minutes of Individuals who are overweight are likely to moderate to severe hypertriglyceridemia.

14 LipidSpin Author/Year Published Population Intervention Results Notes Lee, et al./20141 55,137 adults followed by the Running: Participants were grouped When compared with non- – Running at slower speeds, defined Cooper Clinic in Dallas, Texas, for into 6 groups: non-runners and 5 runners, runners had lower all- as < 51 minutes, < 6 miles, 1 to 2 a mean of 15 years quintiles of varying amounts of cause and CVD mortality (30% times/week, < 6 miles/hour, was running. and 45% lower risk) with a 3-year associated with significant and life expectancy benefit. similar benefit. – Persistent runners over an average of 6 years had the most significant mortality benefit with 29% and 50% lower risk of all-cause and CVD mortality. Schnohr, et al./20152 5,048 participants in fourth Jogging: – Jogging from 1 to 2.4 hours per – U-shaped association suggests an examination of the Copenhagen Physical activity was graded with week was associated with the upper limit for exercise dosing that City Heart Study (from 2001 to joggers divided into light, moderate lowest mortality (multivariable HR is optimal for health benefits. 2003) followed until 2013, divided and strenuous categories. There 0.29; 95% CI 0.11 to 0.80). – The dose of running that was most into 1,098 joggers and 3,950 were almost 3x as many sedentary – Lower mortality rates were favorable was jogging from 1 to 2.4 non-joggers non-joggers as joggers. associated with slow jogging pace hours per week, with no more than 3 (HR 0.51; 95% CI 0.24 to 1.10) and running days per week, at a slow or moderate jogging pace (HR 0.38; average pace, which was suggested 95% CI 0.22 to 0.66). to be 6 to 7 miles per hour. - The group of fast paced joggers – Only two deaths occurred in the had almost the same risk for 40-person “strenuous” group and mortality as the sedentary non- was not statistically significant. joggers (HR 0.94; 95% CI 0.4 to 2.18). Chomistek, et al./20153 88,940 women ages 27 to 44 Engagement in 6 healthy lifestyle Those with all 6 factors had a – Nonsmoking, a healthy body mass years at baseline in the Nurse’s choices (defined as not smoking, a 92% lower risk for CHD. index, exercise, and a healthy diet Health Study, followed from 1991 normal body mass index, physical were independently and significantly to 2011 activity > 2.5 h/week, television associated with lower CHD risk. viewing < 7 h/week, diet in the top – Approximately 73% (95% CI: 40% of the Alternative Healthy 39% to 89%) of CHD cases were Eating Index-2010, and 0.1 to 14.9 g/ attributable to poor adherence to a day of alcohol) healthy lifestyle. – 46% (95% Cl: 43% to 49%) of clinical CVD risk factor cases were attributable to a poor lifestyle. Akesson, et al./20144 20,721 men from Sweden Engagement in 5 low risk factors Men having all 5 low risk factors These researchers suggested that (healthy diet, moderate alcohol compared with those with 0 low- approximately 80% of MIs in men consumption, no smoking, being risk factors had a relative risk of may be preventable. physically active, no abdominal 0.14 (95% CI: 0.04 to 0.43). obesity) Agha, et al./20145 84,537 post-menopausal women Healthy lifestyles: A healthy lifestyle Decreased heart failure risk, even from the Women’s Health score (HL score) was created in the absence of antecedent CVD, Initiative wherein women received 1 point hypertension and diabetes for each healthy criterion met: high- scoring Alternative Healthy Eating Index, physically active, healthy body mass index, and currently not smoking. Armstrong/201550 1.1 million women in the United Physical activity: details obtained by Compared to inactive women, – Women reporting strenuous Kingdom questionnaire those reporting moderate activity physical activity daily had had significantly lower risks of higher risks of CHD (p=0.002), first coronary heart disease event, cerebrovascular disease (p<0.001) a first cerebrovascular event, or a and VTE (p<0.001) than those first venous thromboembolic event reporting doing such activity 2-3 (VTE) (p<0.001 for each). times per week. – Among active women it was not seen that progressive reductions in risk of vascular diseases occurred with increasing frequency of activity. Fitzgerald, et al./201551 1,635 older adults in the Lifetime Physical activity: s edentary Daily time spent being sedentary Duration, but not intensity (i.e., Interventions and Independence behavior and physical activity were was positively associated with mean counts/min), of daily physical for Elders (LIFE) study objectively measured by predicted 10-year hard coronary activity was inversely associated using a hip-worn, solid-state triaxial heart disease (HCHD) risk among with HCHD risk score in women accelerometer mobility-limited in this population among people older adults. without CVD.

Official Publication of the National Lipid Association 15 Yusuf, et al./20046 INTERHEART: case-control study Risk factors assessed: Smoking, – All risk factors were Abnormal lipids, smoking, of acute MI in 52 countries, raised Apo B/Apo A1 ratio, history of significantly related to acute MI hypertension, diabetes, abdominal representing every inhabited hypertension, diabetes, abdominal (p<0.0001 for all risk factors and obesity, psychosocial factors, continent; 15,152 cases and obesity, psychosocial factors, p=0.03 for alcohol) consumption of fruits, vegetables 14,820 controls were enrolled. lack daily consumption of fruits – Collectively, these nine risk and alcohol and regular physical and vegetables, regular alcohol factors accounted for 90% of the activity account for most of the risk consumption, lack of regular physical population attributable risk in men of MI in both sexes and in all ages. activity assessed. and 94% in women. Gulati, et al./20037 5,721 women who underwent Exercise capacity: Assessed in Exercise capacity was shown – For each unit (1 MET) increase in baseline exercise stress tests metabolic equivalents (MET). to be a strong, independent exercise capacity, there was a 17% in 1992 predictor of all-cause mortality in reduction in mortality rate. asymptomatic women, even after – Framingham Risk Score-adjusted controlling for traditional cardiac hazard ratios (with 95% CI) of death risk factors. associated with MET levels of <5, 5 to 8, and >8 were 3.1 (2.0 to 4.7), 1.9 (1.3 to 2.9) and 1.00, respectively.

Table 1. Recent Trials Relating Exercise and Cardiovascular Outcomes

Non-HDL-C has been shown to be strongly remains present, despite optimal medical related to CVD risk41-43 and it has been therapy.49 All too often the patient who shown to be a stronger predictor of continues to have CVD events despite CVD risk than LDL-C. This finding was optimal LDL-C levels and appropriate statin independent of whether the triglyceride intensity fits this metabolic picture to a T. level was < 200 mg/dL or > 200 mg/dl.44 The cluster of factors may be explained by A cluster of factors tends to be present a lifetime of poor diet and exercise habits. in patients with high triglycerides, Perhaps a trial that specifically targets including low HDL-C; high non-HDL-C; the this group with a focus on exercise and presence of small, dense LDL particles; nutrition could answer this question. the presence of increased very low-density lipoprotein cholesterol (VLDL-C); insulin Conclusion resistance; and increases in coagulability In recent months, important studies have and viscosity.45-48 Importantly, regular been published that explored the impact physical activity can improve this cluster of exercise and diet in CVD prevention. of metabolic abnormalities, including the Patients should be counseled on the reduction of non-HDL-C.13 appropriate dose of exercise to reduce CVD events. The interplay of exercise, diet New Directions and lipid levels often explains a substantial Can lack of exercise and healthy lifestyle portion of residual risk. Reducing that risk habits explain the residual risk of CVD in may require a greater emphasis on lifestyle patients on optimal medical therapy for change than is currently the rule. n ASCVD? Exercise and fitness can improve cardiovascular outcomes and may result in Disclosure statement: Dr. Sharma has no disclosures to report. Dr. Gulati’s spouse has received salary for beneficial effects on the lipid profile and employment at Bayer. other risk factors. References are listed on page 37.

It may be that a lifetime of inactivity and poor diet leads to a cluster of metabolic factors. These are the hallmarks of the metabolic syndrome and include high triglycerides, low HDL-C, high non-HDL-C, hypertension, and hyperglycemia. This can explain much of the residual risk that

16 LipidSpin The Impact of Gilbert’s Syndrome on Atherosclerosis

JAMES A. TRIPPI, MD Lipidologist, Complex Cholesterol Center St. Vincent Health Indianapolis, IN Diplomate, American Board of Clinical Lipidology

A 51-year-old female with a history of symptoms or complications have arisen eight premature coronary heart disease and months after restarting medications. coronary artery bypass grafting at age 36 was referred for hyperlipidemia. She Discussion Discuss this article at www.lipid.org/lipidspin had untreated low-density lipoprotein Augustin Gilbert described in 1901 a cholesterol (LDL-C) >600 mg/dL, a previous syndrome of asymptomatic mild jaundice. cholecystectomy, and non-alcoholic fatty This syndrome is characterized by the levels. Glucuronyl transferase conjugates liver. On maximal medical therapy with absence of disease or complications, bilirubin with one or two glucuronic acid rosuvastatin 40 mg per day, ezetimibe 10 mg with only an excess level of indirect molecules, rendering it soluble. Conjugated per day, and extended-release niacin 1,000 (unconjugated) bilirubin, which is regarded (direct) bilirubin then enters the bile mg per day, lipid levels remained elevated; as merely a benign laboratory abnormality. and is excreted. GS is most commonly LDL apheresis was added. Diagnostic genetic The hyperbilirubinemia of GS is noted to attributed to a homozygous mutation of tests showed compound heterozygous increase with fasting, stress, and some glucuronyl transferase at the UGT1A1*28 familial hypercholesterolemia. On apheresis, medications that are metabolized by the allele with genotype 7/7. This genotype her LDL-C on maximal standard therapy liver, including many antibiotics, some causes decreased conjugation of bilirubin. exceeded 300 mg/dL, so lomitapide was oral contraceptives, benzodiazepines, Prevalence of this genotype varies widely started at 5 mg per day. Liver-function tests indomethacin, and phenytoin. Smoking across populations, with a maximum of 10 were normal at baseline but bilirubin rose to decreases serum bilirubin. percent of Europeans and a minimum of 3 3.4 mg/dL after the addition of lomitapide. percent of South Asian Islanders manifesting No symptoms were reported but, out Hemoglobin is metabolized by heme- the syndrome. of caution, medications were withheld, oxygenase to biliverdin, which is converted bilirubin sub-fractions were obtained and a by biliverdin reductase to bilirubin. Solute There are some clinical associations with GS. hepatology consult was obtained. Gilbert’s carrier anion transporter 1B (SLCO1B1) Gallstones are increased in frequency with syndrome (GS) was confirmed. It was transports unconjugated bilirubin from the GS. Neutropenia and diarrhea can occur in noted that indirect bilirubin immediately blood into the liver. Mutations of this organic patients with GS on irinotecan chemotherapy returned to normal when the patient was anion transporter increase simvastatin and for colon cancer. Some investigators have off medications. When medications were other statin medication levels, contributing to also reported increased fatigue, decreased restarted, total bilirubin returned to 3.0-3.4 myalgia. Loss-of-function mutations or drug mental concentration, and nonspecific mg/dL with indirect bilirubin at 2.2-2.8 mg/ competition at SLCO1B1 with statins also symptoms affecting the body as a whole in dL and direct bilirubin at 0.6-0.8 mg/dL. No may increase total and unconjugated bilirubin patients with GS.

Official Publication of the National Lipid Association 17 Laboratory Results Date rosuvastatin ezetimibe niacin apheresis lomitipide AST ALT total bili direct bili cholesterol LDL-C pre-apheresis 2012 x x x 31 38 1.1 553 466 2013 x x x x 14 19 0.9 320 228 2014 x x x x x 11 16 3.1 0.6 299 224 2014 x x x x x 23 15 3.8 0.7 287 198 2014 x 18 21 1.6 457 356 2014 x 19 11 1.2 0.3 397 325 2014 x x x x x 14 19 2.7 282 218 2015 x x x x x 13 19 3.1 0.7 305 231

Numerous studies note an inverse between UGT1A1*28 allele genotype 7/7 in GS. Even with homozygous familial association between bilirubin levels and demonstrating a higher bilirubin level and hypercholesterolemia, she has had no further atherosclerosis. In patients with familial 1/3 the risk of cardiovascular disease and clinical progression of cardiovascular disease hypercholesterolemia, elevated serum coronary heart disease versus carriers of the after coronary bypass surgery 15 years ago. bilirubin was associated with a decreased 6 allele. There also was a non-significant This may be due, in part, to the protective risk for early coronary atherosclerosis. The trend toward fewer myocardial infarctions. effect of GS on atherosclerosis. protective effect of bilirubin was comparable Furthermore, Cox hazard regression analysis to that conferred by high-density lipoprotein with serum bilirubin and UGT1A1*28 Future clinical considerations may include (HDL) cholesterol.1 Results from a meta- revealed that the association with the recommending a full liver function test with analysis of 11 published studies showed an UGT1A1 polymorphism was not significant bilirubin level before initiating statin therapy. inverse relationship between bilirubin levels when bilirubin was added — raising the Full liver function tests are recommended and the severity of atherosclerosis.2 Similarly, possibility that other aspects of hemoglobin before and during lomitipide therapy. The studies have recognized a direct linear metabolism may contribute more significantly NLA statin safety liver taskforce noted the association between low bilirubin levels, to bilirubin levels, even in those with the value of albumin, prothrombin time and atherosclerosis,3 and stroke.4 UGT1A1*28 genotype 7/7.7 An inverse possibly direct bilirubin measurements relationship between the UGT1A1*28 prior to statin therapy.10 Presently, the FDA Various mechanisms have been proposed allele, bilirubin levels, and cardiovascular recommends “liver enzyme measurements” to explain the beneficial effects of disease was discovered in Chinese males.8 only before initiating statin therapy and no bilirubin on atherosclerosis. Bilirubin Using Mendelian randomization to address longer advocates routine monitoring during acts as an antioxidant in vitro and in vivo. confounding variables such as obesity, therapy.11 Given the high prevalence of GS This antioxidant effect has been shown cholesterol, and blood pressure, UGT1A1*28 in patients of European heritage and its to suppress the oxidation of lipids and homozygotes were associated with higher association with reduced atherosclerosis, lipoproteins, especially LDL. Bilirubin also serum bilirubin, smaller brachial artery measuring the total bilirubin level may has some anti-inflammatory properties that diameter, and cold pressor reactivity. This contribute to a more thorough cardiovascular can inhibit tumor necrosis factor-a (TNF-a), suggests that the benefits of higher bilirubin risk assessment. At this time, however, vascular cell adhesion molecule 1 (VCAM- may affect cardiovascular disease through routine genetic testing for the UGT1A1*28 1), and intercellular adhesion molecule pathways associated with arterial size such genotype is not recommended and does not 1 (ICAM-1).5 The anti-inflammatory and as vasomotor tone, reactivity, and possibly appear to significantly contribute to patient antioxidant properties of bilirubin may arterial wall structure. 9 care. Developing therapies to increase serum mediate other risk factors that promote bilirubin levels in those with low levels may atherosclerosis. Bilirubin may also function In the above case study, our patient was reduce cardiovascular risk in the future. n as an anti-thrombotic agent by reducing noted to progress from a normal baseline oxidative platelet hyper-reactivity, thereby total bilirubin to hyperbilirubinemia with Disclosure statement: Dr. Trippi has received speaker honoraria from Aegerion Pharmaceuticals Inc., Amarin, reducing athero-thrombosis.6 the addition of lomitapide. However, there LipoScience, Merck & Co. Inc., and Sanofi. were no untoward effects secondary to the References are listed on page 37. More recently, studies have been hyperbilirubinemia with more than one year performed to further characterize the of therapy. It is noted that our patient had genetic basis for GS. The Framingham a previous cholecystectomy in accordance Offspring Study showed a strong association with the known higher risk of gallstones

18 LipidSpin Dyslipidemia, Cardiovascular Disease, and Youth with Diabetes

DON P. WILSON, MD, FNLA Department of Pediatrics Pediatric Endocrinology and Diabetes Cook Children’s Medical Center Fort Worth, TX Diplomate, American Board of Clinical Lipidology

PIERS R. BLACKETT, MD, FNLA Department of Pediatrics University of Oklahoma Health Sciences Center Oklahoma City, OK Diplomate, American Board of Clinical Lipidology

CATHERINE McNEAL, MD, PhD, FNLA Department of Pediatrics Department of Internal Medicine Division of Cardiology Scott & White Healthcare Temple, TX Diplomate, American Board of Clinical Lipidology

Introduction The Role of Glucose Individuals with diabetes have an increased CVD mortality increases with increases risk of morbidity and mortality related in plasma glucose and HbA1c,5,6 and the to cardiovascular disease,1 accounting association maintains significance after Discuss this article at for 44 percent of deaths in patients with adjustment for potential confounders in www.lipid.org/lipidspin type 1 diabetes mellitus and 57 percent both T1D and T2D.7,8 The risk of CVD of deaths in patients with type 2 diabetes occurs long before the onset of overt mellitus.2 Although youth with diabetes are hyperglycemia,9,10 suggesting that glucose rarely symptomatic, there is unequivocal is a continuous risk factor for CVD evidence that atherosclerosis is well mortality.11 The underlying mechanisms in those with diabetes increases in the established in some by adolescence.3,4 are undergoing extensive research to presence of other CVD risk factors The increasing prevalence of diabetes, determine the role of specific pathways/ (Table 1).13 Risk factors that contribute prolonged exposure to hyperglycemia, and metabolites and potential for reversal.12 to atherosclerosis in youth are highly other traditional CVD risk factors present prevalent and strongly predictive of future from such a young age make youth with CVD Risk Factors in Diabetes CVD event risk. Some 21 percent have T1D and T2D uniquely vulnerable to CVD. In addition to hyperglycemia, mortality more than two CVD risk factors, the

Official Publication of the National Lipid Association 19 Cardiovascular Risk Factors Lipid Screening and Management of Youth with Diabetes Risk Factors Type 1 diabetes Type 2 diabetes I. Lipid Screening • Obesity Prerequisite: Lipid screening should be Lipid screening should be • Sedentary lifestyle done after glucose control done after glucose control • Dyslipidemia has been established has been established Elevated LDL/non HDL-cholesterol If family history for CVD is: Low HDL-cholesterol Known and Negative Lipid screening should begin Lipid screening should begin • Insulin resistance/hyperglycemia at >10 years of age or onset at diagnosis. • Hypertension of puberty. • Microalbuminuria Unknown or Positive Lipid screening should begin at diagnosis in children >2 • Cigarette smoking years of age. Table modified from reference24 Screening method: A fasting or non-fasting A fasting or non-fasting Table 1. blood sample drawn by blood sample drawn by venipuncture or finger stick. venipuncture or finger stick. Either allows calculation of Either allows calculation of prevalence increasing with age, being the non-HDL cholesterol, an the non-HDL cholesterol, an higher among girls and varying by race/ estimate of all atherogenic estimate of all atherogenic ethnicity.14 Compared to T1D, youth with lipoprotein particles. If the lipoprotein particles. If the T2D are much more likely to have at least non-HDL-C is >145 mg/dL non-HDL-C is >145 mg/ (95thpercentile), two fasting dL (95th percentile), two 2 CVD risk factors (14 percent versus 92 lipid profiles should be fasting lipid profiles should percent), contributing to T2D’s more lethal obtained and the results be obtained and the results phenotype and higher mortality. averaged before determining averaged before determining the most appropriate the most appropriate The Critical Role of LDL-C intervention. intervention. Elevated LDL-C is a major predictor of If screening results are: CVD, including in those with diabetes.15,16 Normal Screen every 5 years Screen every 5 years Mean LDL-C levels are similar in those Abnormal Monitor annually Monitor annually with and without diabetes, but levels II. Lipid-lowering Therapy vary widely among individuals because Medical Nutritional Step 2 AHA diet* Step 2 AHA diet* of a variety of genetic and environmental Therapy causes.17 In the Search for Diabetes in Youth cohort,18 1 in 5 T1D and 1 in 3 T2D Lipid-lowering After >10 years of age if After >10 years of age if MNT medication MNT and lifestyle changes and lifestyle changes are youth >10 years of age had TC >200 mg/ are unsuccessful in reaching unsuccessful in reaching dL; ~50 percent of youth with either T1D lipid goal. lipid goal. or T2D had LDL-C >100 mg/dL. If LDL-C is:

Risk Reduction >160 mg/dL (4.1 mmol/L) Start a statin** Start a statin** Intensive diabetes therapy has long-term >130 mg/dL (3.4 mmol/L) With >1 CVD risk factor, start With >1 CVD risk factor, start beneficial effects on the risk of CVD in a statin** a statin** both T1D and T2D. Although optimal III. Lipid Goal LDL-C <100 mg/dL (2.6 LDL-C <100 mg/dL (2.6 glycemic control prolongs survival, mmol/L) mmol/L) individuals with T1D continue to have a shorten life expectancy by more than a *The ADA Standards of Medical Care in Diabetes-2014 recommends the Step 2 American decade.19,20 Even in those who achieved Heart Association diet which consists of saturated fat 7% of total calories; cholesterol 200 mg/ day.29 **All statins, except pitavastatin, have been approved by the FDA for use in children with good glycemic control, the risk for death familial hypercholesterolemia; pravastatin at >8 years of age, all others (simvastatin, fluvastatin, over an eight-year period was more than lovastatin, atorvastatin and rosuvastatin) >10 years of age. Table modified from references24-27 doubled.21 With a HbA1c of <6.9 percent, Table 2.

20 LipidSpin the risk was found to be more than (Table 2).24-27 Despite potential benefits, Disclosure statement: Dr. Wilson is a speaker for the Osler Institute, participated in an advisory board of twofold for all-cause mortality and nearly few children with diabetes currently Aegerion Pharmaceuticals, participated in an advisory threefold for CVD mortality. Although receive lipid-lowering therapy.18,28 board of and as an educational speaker for Synageva renal disease is strongly associated with Biopharma Corp., and received research funding from Merck Sharp & Dohme and Novo Nordisk Inc. Dr. CVD in diabetes, surprisingly the all-cause Conclusion Blackett is a consultant for Roche Pharmaceuticals. Dr. and CVD mortality risks were also noted In addition to poor glycemic control, other McNeal has no disclosures to report. to be three times higher among those CVD risk factors, such as elevated levels References are listed on page 38. with T1D who did not have renal disease. of LDL-C, are common in youth with This finding contradicts those of prior diabetes. observational studies. Improved glycemic control, early In adults with diabetes, statins are identification, and effective management effective in the primary and secondary of all CVD risk factors may help decrease prevention of major CVD events.22,23 the high rate of morbidity and mortality An LDL-C reduction of 38.7 mg/dL was prevalent in this disease. associated with a 21 percent decrease in major vascular events.22 Although long- Acknowledgements The authors would like to acknowledge Karen term safety and efficiency has not been Keller, Dena Hanson, and Lynn Harmon for studied in youth with diabetes, selective their assistance in preparing and editing this use of statins is currently recommended manuscript. n

Official Publication of the National Lipid Association 21 Dyslipidemia in the Patient Living with HIV

MERLE MYERSON, MD, EdD, FACC, FNLA Director, Mount Sinai Roosevelt and St. Luke’s Hospitals Cardiovascular Disease Prevention Program & Lipid Clinic Pre-Exercise Heart Screening Program Cardiology Section, Institute for Advanced Medicine/HIV Diplomate, American Board of Clinical Lipidology

leading cause of morbidity and mortality in that becomes integrated into the cell this patient population, making diagnosis nucleus and rapidly replicates. The virus and management of CVD risk factors — in has a high mutation rate, making treatment Discuss this article at particular, dyslipidemia — essential to – and finding a vaccine – challenging.7,8 www.lipid.org/lipidspin patient care.4,5 HIV and Risk for Cardiovascular Introduction There have been no specific and Disease The development and use of antiretroviral comprehensive guidelines or risk Infection with HIV produces a medications to treat patients infected with stratification schemes for management cardiometabolic syndrome consisting HIV have dramatically changed the course of dyslipidemia in patients infected with of insulin resistance, lipodistrophy (fat of this disease from one that was fatal to a HIV. The National Lipid Association maldistribution, including increase in chronic and more manageable condition. Recommendations for Patient-Centered abdominal visceral fat), and abnormal However, with antiretroviral therapy (ART) Management of Dyslipidemia: Part 2 will lipids (elevated triglycerides [TG] and low came a new spectrum of diseases brought include management recommendations for high-density lipoprotein cholesterol [HDL- about by metabolic changes related to the this patient population. C]). Therapy with ART can exacerbate virus, side effects of ART, and the fact these abnormalities.6,9,10 The mechanisms that people with HIV were living to ages This review presents background of these metabolic abnormalities are at which cardiovascular disease (CVD) was information to understand the interactions complex and interdependent with more prevalent. of HIV, antiretroviral therapy, and the impaired glucose metabolism and dyslipidemia in patients living with HIV. dyslipidemia, due in part to abnormal fat Recent epidemiologic studies have shown distribution (especially abdominal fat) and that people infected with HIV have an Background: Human Immunodeficiency inflammation.11,12 increased risk of CVD at all ages compared Virus to the general population, and that it The virus infects cells in the immune More research is needed to better define remains even after control of traditional system, specifically CD4+ T cells, which the role of inflammation in HIV and how risk factors.1 This population also has are white blood cells. After entering the this influences CVD risk. The National higher rates of smoking, behavioral, and CD4+ T cell, the viral RNA genome is Institutes of Health (NIH) has initiated social factors that increase risk.2,3 It is converted (a process known as “reverse the Randomized Trial to Prevent Vascular anticipated that CVD will become the transcription”) into double-stranded DNA Events in HIV (REPRIEVE) study, a multi-

22 LipidSpin center, prospective, randomized clinical transcriptase inhibitors (NNRTI), integrase infected with HIV, although two groups trial of HIV-infected individuals who are at inhibitors, and protease inhibitors (PI). have proposed scoring systems. The Data low risk according to the 2013 American Combination regimens are standard. Collection on Adverse Effects of Anti-HIV College of Cardiology American Heart Drugs (D:A:D) Study group has developed a Association (ACC/AHA) Guideline on the As noted above, infection with HIV confers risk calculator that includes both traditional Treatment of Blood Cholesterol to Reduce metabolic changes that may be exacerbated risk factors and exposure to individual Atherosclerotic Cardiovascular Risk in by ART. Protease inhibitors are the agents antiretroviral drugs.26 The Veterans Aging Adults.13 Participants will be randomized that produce the most adverse effects, Cohort Study (VACS) was used to develop to either statin therapy (pitavastatin) but non-nucleoside/nucleotide reverse the “VACS Index” to predict overall or placebo and followed to investigate transcriptase inhibitors also influence mortality. The index includes age, CD4 how statins may reduce the risk for CVD lipids.9,16-18 count, viral load, hemoglobin, aspartate, through non-low-density lipoprotein and alanine transaminase, platelets, (LDL)-lowering benefits, including anti- creatinine, and hepatitis C status. The inflammatory properties. The study is Patients infected VACS Index has been used in studies sponsored by the National Heart, Lung and predicting coronary heart disease (CHD) Blood Institute (NHLBI) in collaboration with HIV may have a risk but has not been validated for this with the National Institute of Allergy and use.27 Infectious Diseases (NIAID).14 discordance between Use of the Framingham Risk Score, Antiretroviral Therapy measures, with LDL-C although not validated in patients with There currently is no cure for HIV. lower than LDL-P HIV, is endorsed by the HIV Medical ART provides viral suppression, but not Association (HIVMA) of the Infectious elimination of the virus, and allows the and apo B, therefore Diseases Society of America (IDSA)28 body to maintain higher CD4 counts and and the European AIDS Clinical Society better immune function. There is less underestimating risk (EACS).29 However, it is unclear if likelihood of the virus being transmitted Framingham and other risk scores are while a patient is on ART with viral and treatment targets. appropriate for this patient population. suppression. The classes of ART prevent At this time, it is reasonable to use the viral replication in different ways and are National Cholesterol Education Program’s used in combination. Newer drugs with Lipid Changes with HIV Infection and Adult Treatment Panel III- (NCEP ATP higher potency, lower toxicity, better ART III-) and Framingham-based algorithms dosing, and fewer side effects now exist, Acute infection lowers LDL-C19 but levels with consideration for increasing one risk facilitating early and long-term treatment. may return to baseline after virologic category for patients infected with HIV. Treatment progress is monitored by suppression with ART.20,21 Chronically, measuring CD4 count and viral load. CD4 there often is a pattern of low HDL and Lipid Targets for Patients Living With counts of ≥300 cells/µL were found to be elevated TG that results from the metabolic HIV LDL-Cholesterol associated with good immune function.15 changes clustered in these patients22,23 and Treatment of and targets for dyslipidemia Healthy people who are not infected often worsened by specific antiretrovirals, for the general population traditionally with HIV generally have CD4 counts in many of which are now less commonly have been focused on low-density the range of 800 to 1,200 cells/µL. Viral prescribed.17,24 The magnitude of these lipoprotein cholesterol (LDL-C) and based suppression is achieved when plasma RNA changes also is reflective of ethnicity, race, on risk stratification, with lower targets for levels are below detectable limits.16 gender, lifestyle factors, and genomic those with greater risk. traits.25 As noted above, PI and NNRTI are The different classes of ART each interfere the ART that most significantly influence More recent guidelines for management with a different step in the replication lipid levels. of dyslipidemia in the general population of the virus. These classes include entry have introduced the concept of “residual inhibitors, fusion inhibitors, nucleoside/ Risk Stratification and Scores risk.”30 LDL-C is highly associated with nucleotide reverse transcriptase No validated risk score or stratification CVD but does not reflect the total amount inhibitors (NRTI), non-nucleoside reverse scheme currently exists for patients of atherosclerotic particles,31-33 meaning all

Official Publication of the National Lipid Association 23 particles that have an apolipoprotein B (apo in patients with HIV is characterized B). Measures of residual risk, including by elevated TG (greater than 150 mg/ non-HDL-C (total cholesterol minus HDL- dL) and reduced HDL-C because of HIV C), apo B or LDL particle number (LDL-P) infection itself and ART-induced metabolic better predict risk for CVD than LDL-C disturbances, such as impaired glucose with apo B and LDL-P, performing better tolerance with insulin resistance, visceral than non-HDL-C.31,32 Certain populations adiposity, and peripheral lipoatrophy.38,39 of patients, such as those with diabetes, are felt to have discordance between HDL-Cholesterol LDL-C and these other measures, which ATP III identifies HDL < 40 as being may result in under- or over-treatment.31,34 low.30 Viral suppression, treatment of Patients infected with HIV also may co-morbid conditions (central adiposity, have a discordance between measures, diabetes) and lowering TG with medication with LDL-C lower than LDL-P and apo and lifestyle changes can help raise B, therefore underestimating risk and HDL-C. Medications to specifically raise treatment targets.35,36 Although measures HDL-C consist of the niacin preparations, of residual risk are being increasingly but these medications often are poorly incorporated into diagnosis and tolerated and may exacerbate the cluster of management plans, LDL-C continues to metabolic abnormalities, including insulin be used in the general population and for resistance in patients with HIV. Treatment patients infected with HIV. aimed specifically for low HDL-C is not recommended at this time for patients Existing recommendations for patients infected with HIV. infected with HIV include the European AIDS Clinical Society (EACS), where a Conclusion target of < 155 mg/dL for total cholesterol It is important to understand that and < 80 mg/dL for LDL-C is identified.29 attainment of targets for LDL-C and TG Recently issued guidelines by HIVMA of may not be reached, although there is the IDSA for primary care of patients with incremental benefit to optimizing lipids HIV state that lipid testing and targets and lipoproteins. Care for patients living should be based on the NCEP’s ATP III with HIV is complex, with side effects of guidelines with consideration for more medications, problems with adherence to stringent targets.28 Metabolic syndrome is a multi-drug regimen, and co-morbidities considered in ATP III to be a risk factor. that impact on lipids. Review of all Because this is prevalent in patients medical conditions and medications with infected with HIV, clinicians should assess the patient’s other providers can help for metabolic syndrome and, if present, to identify priorities for the patient. incorporate it in the risk stratification and Viral suppression generally is considered identification of target for LDL-C.24 foremost, although treatment of other conditions also may merit priority. Part II Triglycerides of the NLA Recommendations will provide Because of the lack of evidence for treating more information on the diagnosis and in this patient population, the EACS does management of dyslipidemia for patients not recommend treatment of moderately living with HIV. n elevated TG in patients infected with HIV.29 Guidelines for the general Disclosure statement: Dr. Myerson has received consulting fees from Gilead and Kowa; an educational population consider values ≥ 150 mg/ grant from Gilead, Kowa, and LipoScience; and dL as high and ≥ 500 mg/dL as very high research funds from LipoScience. 37 and a risk for pancreatitis. Dyslipidemia References are listed on page 38.

24 LipidSpin Niacin: The Third or Fourth Option

TERRANCE J. MORAN, MD, FACC, FAHA Director, Advance Lipid Management Program Tyler Heart Institute, Community Hospital of the Monterey Peninsula Monterey, CA Associate Clinical Professor of Family Practice University of California at San Francisco Diplomate, American Board of Clinical Lipidology

After the clinical studies, Atherothrombosis Niacin is an LDL-lowering drug, specifically Intervention in Metabolic Syndrome with lowering LDL particle number (LDL-P) Low HDL/High Triglyceride and Impact and apolipoprotein (apoB).3 One proposed on Global Health Outcomes (AIM-HIGH) mechanism is the inhibition of diacylglycerol and Heart Protection Study 2-Treatment of O-acyltransferase 2 (DGAT2), which lowers Discuss this article at HDL to Reduce the Incidence of Vascular hepatic triglyceride production, leading www.lipid.org/lipidspin Events (HPS2-THRIVE), the National Lipid to decreased apoB and very low-density Association released a statement on the use lipoprotein (VLDL)/LDL secretion.6 Niacin of niacin: “We believe that niacin remains also reduces proprotein convertase subtilisin/ Based on IMPROVE-IT, ezetimibe can be a valuable adjunct to statin treatment kexin type 9 (PCSK9).8 Niacin increases a second option as an add-on, but what for LDL-C lowering, and a valuable statin LDL particle size, so LDL-C and LDL-P other options exist? Bile acid sequestrants alternative in statin intolerant patients.”1 may not change concordantly.3 In general, are reasonable, but have gastrointestinal niacin drops LDL-C. However, while there’s problems and the newest one (colesevelam) Niacin has been promoted for decades as a no published evidence to support it, I’ve is expensive. Niacin also has side effects, but high-density lipoprotein (HDL)-raising drug. personally observed rare occasions where it is now inexpensive with numerous generic It does increase HDL cholesterol (HDL-C) by LDL-C may change only minimally despite an formulations. Yet is there any benefit in reducing the number of small, cholesterol- effective drop in LDL-P. As such, following using niacin? poor HDL particles and increasing the apoB or LDL-P may be a more accurate numbers of large, cholesterol-rich particles, reflection of niacin’s effect than LDL-C. Imaging studies using carotid intima-media but it does not increase the total number of thickness (CIMT) testing, carotid wall HDL particles (HDL-P).2,3 Studies suggest that The IMProved Reduction of Outcomes: volumes by magnetic resonance imaging changes in HDL subclass distribution are not Vytorin Efficacy International Trial (MRI), and coronary angiography have shown independently associated with cardiovascular (IMPROVE-IT) and the meta-analysis by regression or reduction in progression with disease (CVD) risk after accounting for Robinson, et al., make the point that it is not niacin added to a statin — ARBITER 2, HDL-P levels.4 An NLA expert panel in 2011 how LDL is reduced that reduces risk, but Oxford Niaspan Study, HATS — or niacin claimed there was no evidence that a shift in rather how much it is reduced.9,10 added to a bile acid sequestrant — FATS, HDL subfractions translated into changes in AFREGS, CLAS.12-17 In FATS, the niacin- disease progression or improved outcome.5 Studies with maximum-dose atorvastatin colestipol group did as well at preventing So, although niacin increases HDL-C, it has or rosuvastatin show that 62 to 80 percent progression and obtaining regression as the minimal to no effect on increasing HDL-P. of patients did not get below 70mg/dl.11 lovastatin-colestipol group.

Official Publication of the National Lipid Association 25

MAJOR VASCULAR EVENTS by baseline lipids A recent systemic review and meta- Randomized alloca=on Het or trend Χ² regression evaluated 11 clinical trials of ERN/LRPT Placebo Risk ra=o & 95% CI (uncorrected p value) niacin, either alone or combined with mg/dL (mmol/L) (12838) (12835) other lipid-altering therapy, and showed HDL cholesterol a significant reduction in the composite <35 (0.9) 388 (15.8%) 399 (16.3%) 0.20 ≥35 <43 560 (13.7%) 546 (13.5%) (p=0.66) endpoints of any cardiovascular event (P = ≥43 (1.1) 748 (11.9%) 813 (12.8%) 0.007) and any major coronary heart disease LDL cholesterol event (P = 0.02). There was no association <58 (1.5) 724 (14.7%) 679 (13.8%) 5.91 ≥58 <77 685 (12.4%) 761 (13.7%) (p=0.02) between event reduction and changes in ≥77 (2.0) 287 (12.0%) 318 (13.5%) HDL-C.18 Triglycerides <89 (1.0) 541 (13.2%) 563 (13.4%) 0.66 ≥89 <151 694 (12.8%) 712 (13.2%) (p=0.42) Two recent trials, AIM-HIGH and HPS2- ≥151 (1.7) 461 (13.9%) 483 (14.8%) THRIVE, were designed to see if adding All 1696 (13.2%) 1758 (13.7%) 3.5% SE 3.3 niacin to an aggressive lipid-lowering regimen reduc>on (statin and, frequently, ezetimibe) could fur- 0.8 1.0 1.2 ther reduce residual atherosclerotic risk. ERN/LRPT be[er Placebo be[er

The first, AIM-HIGH, with 3,414 coronary Figure 1. As baseline LDL-C increased, niacin treatment showed a trend toward risk reduction (P=0.02). From artery disease patients, failed to show any HPS2-THRIVE slide set at www.thrivestudy.org with permission by Dr. Jane Armitage. incremental benefit in adding niacin.19 Several limitations of this study have been HPS2-THRIVE noted the following side four years. Other effects: aggravation of gout. raised: (1) It was designed to detect a ≥ 25 effects: Skin — mainly rash or flushing. percent reduction in events and, as such, Gastrointestinal — primarily dyspepsia and In summary: Niacin is not an HDL-P-raising had too few participants. (2) 90 percent diarrhea. Also, an increase in liver function drug but does lower LDL-C, apoB, and LDL- of patients had been on aggressive lipid- tests (LFTs) >3x ULN (1.4 percent over 3.5 P. Weigh the risks and benefits of niacin lowering efforts for more than a year, which years) but drug-related hepatitis or elevated before using. Periodically monitor LFTs (ALT, may have led to plaque regression and transaminases plus elevated bilirubin AST), glucose, HgAIC, and uric acid. Avoid stabilization prior to entry. (3) The placebo no different than placebo. Myopathy — use in patients with inadequately controlled arm had 7 percent more on simvastatin 80mg primarily in the Chinese patients studied diabetes. Niacin is reasonable as a third- and 12 percent more on ezetimibe. Niacin is and with no significant difference amongst or fourth-option drug for use in high-risk an LDL-lowering drug, so the more aggressive European patients in the trial. Increased patients who cannot get LDL to goal or in LDL-lowering therapy in the placebo arm may bleeding — primarily in the GI tract with patients who are statin intolerant.1,22,26,27 n have significantly altered the results.20,21 no significant difference in intracranial bleeding. Increased infection rate — mainly Disclosure statement: Dr. Moran has received speaker The second trial, HPS2-THRIVE, skin or lower respiratory tract (1.4 percent honoraria from AstraZeneca, Merck, Health Diagnostic demonstrated in 25,673 vascular patients no over four years). Increased glucose levels Lab, and LipoScience. He has received consultant fees from Health Diagnostic Lab. significant benefit to adding extended-release — disturbances in glucose control, much of niacin (combined with laropiprant) to attain which required hospitalization (3.6 percent References are listed on page 39. further event reduction.22 A major concern over four years), were noted. In comparison, about the study was the baseline lipid profile: the Arterial Disease Multiple Intervention direct LDL-C 63 mg/dl (calculated LDL-C Trial (ADMIT) study of 468 patients on 59mg/dl), HDL-C 44mg/dl, triglyceride 2,500mg/day niacin showed a glucose rise 125mg/dl, and non-HDL 84mg/dl. Despite of 6.3mg/dl in non-diabetics and 8.7mg/dl this, patients with a higher baseline LDL-C in diabetics at 60 weeks.24 Another study had a “nominally significant trend (P = 0.02) of 2,000mg/day niacin showed a glucose toward a greater reduction in risk” consistent increase of 7 percent at three months but with niacin’s action as an LDL-lowering only 3 percent at six months.25 Increased agent.22 (Figure 1) diagnosis of diabetes — 1.4 percent over

26 LipidSpin Reflections: An Aggressively Managed Lipidologist Can Have an Acute Coronary Syndrome

EDWIN FERGUSON, MD, FNLA Emeritus Professor of Medicine University of Wisconsin School of Medicine Madison, WI Diplomate, American Board of Clinical Lipidology

THOMAS D. DAYSPRING, MD, FACP, NCMP, FNLA Foundation for Health Improvement and Technology Richmond, VA Diplomate, American Board of Clinical Lipidology

Author Edwin Ferguson, MD, is a 70-year- revealed coronary artery disease (CAD) old practicing preventive cardiologist and with reduced coronary perfusion in the left certified clinical lipidologist who, despite anterior descending (LAD) and circumflex 20 years of treatment for dyslipidemia, arteries. His lipid concentrations remained Discuss this article at recently had an ST elevation myocardial abnormal and an elevated lipoprotein (a) www.lipid.org/lipidspin infarction (STEMI). His cardiovascular [Lp(a)] mass was discovered. Ferguson journey began in medical school when, reduced dietary saturated fat and despite his normotension and normal carbohydrates and started a vigorous weight, testing revealed a triglyceride exercise program. His medication regimen (TG)/high-density lipoprotein (HDL) axis consisted of diltiazem SR (slow-release) Subsequently, on-treatment lipid abnormality.1(Table 1) A decade later, 180 mg twice a day, aspirin 81 mg daily, concentrations and lipoprotein his lipid panel remained abnormal and simvastatin 20 mg, and immediate-release concentrations dramatically improved, untreated. At that time no guidelines niacin titrated to 2,000 mg/daily with meeting guideline-advised goals.4 Blood were cognizant of the importance of minimal flushing. Niacin subsequently pressure remained excellent, averaging non-high-density lipoprotein cholesterol raised the homocysteine level and elevated 110-130/60 mmHg. He switched from (non-HDL-C) or that an elevated TG/HDL-C his glucose levels into the 90s (mg/dL), simvastatin to atorvastatin and then, ratio was a clue to the presence of insulin but also induced acanthosis nigricans. in 2004, to rosuvastatin 20 mg daily. resistance (IR). Metformin was started and titrated to A follow-up PET scan in 1997 showed 2,250 mg daily. Exercise-related transient substantial perfusion improvements. In 1994, exertional tightness in his back episodes of atrial fibrillation, another In 2005, a low omega-3 index led to prompted Ferguson to undergo a positron potential niacin side effect,2,3 ceased after omega-3 supplementation and, in 2012, a emission tomography (PET) scan, which starting metoprolol and ramapril. cholesterol synthesis/absorption biomarker

Official Publication of the National Lipid Association 27 Date TC HDL-C LDL-C TG Non-HDL-C TG/HDL-C Lp(a) LDL-P

1972 35 208 5.9 1980s ~225 ~32 ~159 ~170 ~193 ~5.3 1994 215 23 160 160 192 76 2000 100 60 60 50 40 0.83 27 600 2005 39 300 Table 1. Author Dr. Ferguson’s lipid/lipoprotein concentrations over time (all in mg/dL except LDL-P which is nmol/L). panel revealed significantly elevated (3 to Two months after stopping niacin, Dr. D3 4,000 units (capsules) one a day, 4 X ULN) absorption markers (sitosterol, Ferguson had a STEMI. Angiography metformin 2,250 mg a day, aspirin 81 mg campesterol, and cholestanol).5 Ezetimibe revealed the older, moderate LAD calcified daily and prasugrel. After being stabilized, therapy was started at 10 mg daily, leading stenosis and a 75 to 85 percent more Dr. Ferguson was stunned that he had had to further lipid/lipoprotein improvements. proximal calcified nondominant left an ACS, in spite of aggressive therapy with In 2013, sleep apnea was diagnosed and circumflex lesion, both with a normal “good if not excellent” lipid/lipoprotein treated with nasal CPAP. In 2014, despite thrombolysis in myocardial infarction 3 concentrations. So what might explain his normoglycemia, novel biomarkers of (TIMI 3) flow score. A drug-eluting stent residual risk? insulin resistance and beta-cell function was placed in the mid-right coronary demonstrated significant abnormalities, artery and successfully reduced a 99 Analysis of Framingham Offspring Study including elevated leptin and reduced percent suspected plaque rupture lesion data9 and several genetic disorders10 adiponectin.6 His body mass index was to zero percent occlusion. After the acute suggests that far more important than high normal, and his exercise was limited coronary syndrome (ACS), his medication any given absolute lipid/lipoprotein to walking two miles a day. regimen comprised: rosuvastatin 20 mg concentrations is the exposure of the a day, ezetimibe 10 mg a day, metoprolol vasculature to such concentrations Many lipidologists were stunned with XL 50 mg once a day, ramipril 5 mg three over years and decades. For most of the results of the Atherothrombosis times daily, ethyl ester fish oil (EPA and Dr. Ferguson’s life, lipid-associated risk Intervention in Metabolic Syndrome with DHA) 4 grams a day, methylfolate 3 mg was untreated and his arteries were

Low HDL/High Triglycerides: Impact on with vitamin B12 and B6 one a day, vitamin continuously subjected to that exposure. Global Health Outcomes (AIM-HIGH) trial and the “Heart Protection Study 2 - Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE)” trial.7,8 In both studies, adding niacin or niacin/ laropiprant to patients on statins or statins plus ezetimibe brought no additional outcome benefit and revealed an incidence of niacin-related side effects not previously appreciated. Dr. Ferguson decided to stop the niacin but remained on a rosuvastatin plus ezetimibe regimen. Off niacin, his lipid/lipoprotein concentrations worsened. On statin/ezetimibe, his absorption markers were normal and the cholesterol synthesis biomarker, desmosterol Figure 1. Percentage of major cardiovascular events in the subgroups of the HPS2-THRIVE study treated with concentration, was low — as often is seen simvastatin (40 mg) or simvastatin + ezetimibe. Data are distributed according niacin/laropiprant (ERN/LRPT) on statin therapy. or placebo arms and total (from reference 15, with permission).

28 LipidSpin Despite the fact that niacin did not ACS patients.16 (Figure 1) At the same rosuvastatin 20 mg daily, which meet the primary endpoint in its only time came data showing that loss of had no effect on Lp(a) mass in the randomized prospective outcome trial, the function of the Niemann-Pick C1- Justification for the Use of Statins Coronary Drug Project,11 it was promoted Like 1 protein, ezetimibe’s target, is in Prevention: an Intervention Trial by too many, in large part because of its associated with reductions in both lifelong Evaluating Rosuvastatin (JUPITER) ability to increase HDL-C and reduce Lp(a) LDL-C concentrations and incidence of study, lowered cardiovascular (CV) mass.3 The AIM-HIGH and HPS2-THRIVE atherosclerotic endpoints.17 In view of Dr. events significantly in those with high trials suggest that such niacin-induced Ferguson’s hyperabsorptive state, likely Lp(a).27 lipid changes bring no outcome benefits. aggravated by statin18 or statin + niacin Lipidologists are now recognizing that therapy,19 ezetimibe should have been Dr. Ferguson’s case reminds us that used far sooner than it was. as clinical lipidologistis we need to: 1) optimize statin therapy by using additional “The AIM-HIGH and Other potential contributors to his residual therapies to maximally reduce apo B risk include: or its many surrogates, 2) aggressively HPS2-THRIVE trials (1) Increased concentrations of attack insulin resistance, and to control phytosterols, the atherogenicity of homocysteinemia. Importantly, all of these suggest that such which is under debate.20,21 Data from preventive approaches need to be started niacin-induced lipid the Scandinavian Simvastatin Survival much earlier in life. Beyond lifestyle, Study (4S) showed that statin therapy ezetimibe and bile acid-binding agents changes bring no did not reduce events in patients such as colesevelam are excellent and safer with hyperabsorption of cholesterol, than niacin add-on-to-statins therapies to outcome benefits.” leading the study’s author to help achieve physiologic cholesterol and conclude in 1998 that cholesterol- apo B levels goals, which we now know are a major risk related to low HDL-C is absorption blockers might improve far lower than we previously thought. hyperbetalipoproteinemia.12 Many still statin efficacy.22 advocate niacin as an apo B-lowering Acknowledgements We thank Dawn L. Thiselton, PhD, for editorial drug,13 ignoring the fact that adding niacin (2) Belated lowering of assistance. n to statin or to statin plus ezetimibe in AIM- hyperhomocysteinemia related to MTHFR C677T and A1298C HIGH further lowered apo B by 13 percent Disclosure statement: Dr. Ferguson has received yet produced no additional outcome mutations with methylated folic acid speaker honorarium for Health Diagnostic Lab Inc. Dr. 23,24 Dayspring has received consulting fees from Health 14 and vitamin B . benefit. Analysis of the HPS2-THRIVE 12 Diagnostic Lab Inc., AstraZeneca, and Merck. He’s received speaking honorarium from AstraZeneca and data revealed that, among the randomized 6 (3) Belated recognition and treatment was a minor stakeholder for GSK and Amarin. patients, 13,542 were on simvastatin of insulin resistance and beta-cell monotherapy and 12,131 needed strain, despite normoglycemia. In References are listed on page 39. ezetimibe co-administration to achieve retrospect, Dr. Ferguson admits LDL-C goals. The number of major events his lifestyle had slipped for three reported, regardless of niacin or placebo to four years prior to the ACS, as group assignment, was 1,894 (14 percent) he felt somewhat protected by the in the simvastatin group and 1,560 (12.8 medications.25 percent) in the simvastatin-plus-ezetimibe group.15 (4) Increased concentrations of Lp(a) mass and the genomic variation Amazingly, this later finding forecasted in Lp(a) are major risk factors the “IMProved Reduction of Outcomes: for atherothrombotic events,26 Vytorin Efficacy International Trial but despite the fact that niacin (IMPROVE-IT) results, a randomized dramatically reduced his Lp(a) trial showing simvastatin plus ezetimibe mass and Lp(a)-P ­— similar to the was superior to simvastatin alone in AIM-HIGH results — there was reducing events and cholesterol in no clinical benefit.14 Interestingly,

Official Publication of the National Lipid Association 29 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

Visit CholesterolCounts.com to see the Treatments to Prevent Atherosclerosis.” poll and learn more about the program. This award is to honor the scientific There, you can view the initial poll results achievements of Dr. Akira Endo of of more than 12,000 Americans via Tokyo, Japan, the discoverer of statins. Discuss this article at The winner of the 2015 Endo Award is www.lipid.org/lipidspin interactive maps to compare national and state-by-state data, and find information Harry R. “Chip” Davis, Jr., PhD, for his about this serious condition and why it’s tremendous involvement in advancing important to manage and track cholesterol the therapy of lipid disorders. W. Virgil The Foundation of the National Lipid levels. Brown, MD, FNLA, will present Dr. Davis Association continues to make strides with the award at the 2015 International to help educate and promote clinical The first poll-data analysis from the Symposium on Atherosclerosis (ISA). The lipidology — both to clinicians and to the Cholesterol Counts campaign was released award will continue to be presented at public. Feb. 18, 2015, during American Heart future ISA meetings, which occur every Month. CholesterolCounts.com is three years, to a scientist who has made In the last Foundation Update, we being updated bi-monthly with new data. major contributions in the development discussed the launch of “Cholesterol Physician’s Weekly interviewed Dr. Vicari of treatments to prevent atherosclerosis, Counts,” an unbranded cholesterol on April 1 to discuss the campaign. An the leading cause of death of developed awareness campaign geared toward article based on their discussion is set to countries throughout the world. consumers to assess their knowledge of be released in Physician’s Weekly’s new cholesterol and how their knowledge Lipid Clinic Edition in the summer of If you are attending the NLA Scientific stacks up against other Americans. The 2015. Sessions in Chicago, make sure you check Foundation of the NLA and representatives out a couple of the Foundations latest from Mended Hearts and Preventive At the end of 2015, a one-year progress projects and events. Cardiovascular Nurses Association (PCNA) report that utilizes all data gathered from are working with Sanofi US, Regeneron the poll responses depicting the awareness Memorial Wall Pharmaceuticals, Cohn & Wolfe, and of cholesterol in the U.S will be developed. Starting this year at the NLA Scientific The Harris Poll to support this initiative. Sessions, the Foundation of the NLA President-Elect of the Foundation of the Another initiative the Foundation has will be sponsoring a memorial wall NLA, Ralph Vicari, MD, FNLA, is leading been working on is the “Akira Endo Award posthumously honoring past leaders and this initiative for the Foundation. for Achievements in the Development of pioneers in the field of lipidology. These

30 LipidSpin banner “walls” will be placed in the Ancel Keys, PhD; Robert Knopp, MD; Peter complimentary photo booth to capture Poster Hall and are meant to recognize Kwiterovich Jr., MD; Robert Levy, MD; the unforgettable occasion and take home the tremendous contributions that Gustav Schonfeld, MD; Daniel Steinberg, memories. have been made in areas relating to the MD; Roger Williams, MD; and Donald Tickets are $195/person. Please see an causes, prevention, and treatment of Zilversmit, PhD. Please see special insert in NLA staff member to purchase your ticket cardiovascular disease and lipids. Please this LipidSpin. if you have not already done so. If you stop by the Poster Hall not only to take a cannot make it to Chicago, we understand! look at the great abstracts that have been Fun[d]Raising at the House of Blues But we hope to see you at future submitted, but also to view the Memorial Join us at the House of Blues in downtown Foundation events. These events are Wall. Chicago for an evening packed with music, intended not only to raise money but also food, and fun. Bring your family and to raise awareness about the Foundation Honorees for 2015 include: E.H. “Pete” support the Foundation, while enjoying as a whole within the membership of the Ahrens, Jr., MD; Edwin Bierman, MD; today’s most popular songs, delicious NLA, and to encourage fellowship amongst John Brunzell, MD; William Connor, MD; food, and tasty drinks with colleagues and our members. Donald Fredrickson, MD; John Gofman, friends. Foundation board member and MD; Dewitt Goodman, MD; Jeffrey Hoeg, Chicago native Dr. Alan Brown and his As always, we appreciate your support MD; Donald Hunninghake, MD; Roger band, This End Up, will provide the tunes of the Foundation and look forward to Illingworth, MD; William Kannel, MD; for the evening! Take advantage of the continued success. n

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Official Publication of the National Lipid Association 31 2015 Award Recipients & Fellows

2015 Distinguished Achievement Award

Patrick McBride, MD Associate Dean of Student Services University of Wisconsin School of Medicine and Public Health Madison, WI Diplomate, American Board of Clinical Lipidology

2015 Honorary Lifetime Membership Award Akira Endo, PhD Distinguished Professor Emeritus Tokyo University of Agriculture and Technology Tokyo, Japan

2015 President’s Service Award

Harold E. Bays, MD, FNLA Medical Director/President Louisville Metabolic and Atherosclerosis Research Center Inc. Louisville, KY Diplomate, American Board of Clinical Lipidology

James A. Underberg, MD, FNLA Clinical Assistant Professor of Medicine NYU Medical School New York, NY Diplomate, American Board of Clinical Lipidology

2015 Fellows of the NLA The National Lipid Association would like to extend its congratulations to the new Fellows of the NLA

Karen Aspry, MD, FNLA* Douglas Jacoby, MD, FNLA* Zuhier Awan, MD, FNLA* Carol Kirkpatrick, PhD, FNLA Alexis Baass, MD, FNLA* Vasudevan Raghavan, MD, FNLA* P. Barton Duell, MD, FNLA Khalid Sheikh, MD, FNLA*

*Denotes Diplomate, American Board of Clinical Lipidology

32 LipidSpin Education and Meeting News and Notes

Register Now for the NLA’s Fall Clinical the NLA’s Trainee Travel Grant Program! associated with high LDL-C. President-Elect Lipid Update in Pittsburgh Fifteen grants are available for the NLA of the FNLA, Ralph Vicari, MD, FNLA, is Register now for the NLA’s Fall Clinical Lipid Academy Courses, each including leading this initiative for the Foundation. Lipid Update (CLU) in Pittsburgh. The a $500 travel grant and complimentary Visit CholesterolCounts.com to see the 2015 Fall CLU will take place September attendance for the Lipid Academy — plus poll and learn more about the program. 18–20, 2015, at the Omni William Penn NLA membership for lipid focused fellows- There, you can view the initial poll results of Hotel. Check lipid.org/fallclu for more in-training is always complimentary. more than 12,000 Americans via interactive information and regular updates as they Travel grants are still available for the Fall maps to compare national and state-by-state become available. Clinical Lipid Update in Pittsburgh. Due data, and find information about this serious to the popularity of this program, please condition and why it’s important to manage Are you Receiving your NLA Emails? act quickly. For more information, contact and track cholesterol levels. The NLA communicates with members Sandra Goode at [email protected]. For by mail, fax, our website and Facebook. additional trainee opportunities, visit At the end of 2015, a one-year progress However, for getting important information lipid.org/education/fellows. report that utilizes all data gathered from in front of you quickly, nothing beats email. the poll responses depicting the awareness In today’s noisy Internet environment Masters in Lipidology Online Course of cholesterol in the U.S will be developed. filled with SPAM and other unwanted The Masters in Lipidology Online Course conversations, we might be getting lost is now available! Adapted from the live SELA Endorses 19th Annual Conference in your Inbox, or you may even have course, the Masters in Lipidology Online on Hypertension, Diabetes, and Lipids accidentally unsubscribed yourself, in your Course is designed to bring participants the The Southeast Lipid Association (SELA) has hurry to get rid of the clutter. Please take a experience of an intensive two-day training endorsed the 19th Annual Conference on moment to check your email settings. Make course while providing the flexibility to Hypertension, Diabetes, and Lipids. This sure @lipid.org is added to your email learn at their own pace from anywhere in three-day intensive conference will be whitelist or allowed senders lists. Check the world! This user-friendly program offers held June 26–28, 2015, at the Charleston your SPAM folders regularly to ensure you an in-depth review of the core curriculum Marriott in downtown Charleston, S.C. For are not missing anything and if you find us in clinical lipidology for healthcare more information on this conference, visit there, be sure to click the “Not SPAM” or professionals who desire to practice at an cmemeeting.org/charleston-summer- “Allow Sender” options. And if you don’t advanced level within the field. The course 2015-cme. see us in any of those places, either because features slide-audio presentations recorded you’ve previously unsubscribed or we don’t by expert faculty, along with evidence- Harry R. “Chip” Davis Jr., PhD, Wins have your email address, head on over to based references, and a robust collection 2015 Endo Award lipid.org/subscribe and get signed up. of resource materials for further study. For The NLA and FNLA are proud to announce more information, visit lipideducation. Harry R. “Chip” Davis Jr., PhD, as the NLA members can now update their email com/masters.php. In the future, check winner of the first Endo Award, given in subscription preferences. You now have lipideducation.com for a comprehensive honor of the scientific achievements of Dr. the option to receive select NLA emails. listing of all the NLA’s online training Akira Endo, the discoverer of statins. The For example, you can now select to receive courses. award will be given every third year to a only our breaking news or information on scientist who has made major contributions upcoming NLA meetings. To update your FNLA Participates in Cholesterol in the development of treatments to subscription preferences, visit Awareness Campaign prevent atherosclerosis, the leading cause lipid.org/subscribe. Regeneron Pharmaceuticals and Sanofi US of death of developed countries throughout in collaboration with the FNLA, Mended the world. This year’s winner was presented Get Involved in NLA’s Trainee Travel Hearts, and PCNA, launched Cholesterol with their award at 17th International Grant Program Counts, an awareness program that Symposium on Atherosclerosis May 23–16, Are you a fellow-in-training who has a measures how much Americans know about in Amsterdam, Netherlands. focus in lipid management? Learn about cholesterol, their numbers, and the risks

Official Publication of the National Lipid Association 33 asters M in ipidology LOnline Course

This comprehensive program for physicians, nurse practitioners, pharmacists, nurses, and other healthcare professionals with an interest in lipid management, provides participants with complete lectures synchronized with slides from the live course.

Expand your knowledge of Clinical Lipidology Advance your personal standard of practice Improve clinical decision making skills

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Complete from anywhere on computer, laptop, or iPad/tablet Earn CME/CE credits Prepare for certification Bonus online resources and tools to enhance your learning and practice

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Full accreditation information available at www.lipid.org/mastersonline. For questions about this educational activity contact the NLA at 904-998-0854.

34 LipidSpin NLA Events Calendar

2015 National Lipid Association Clinical Lipid Update—Fall Hosted by the Northeast and Southeast Chapters September 18–20, 2015 Omni William Penn Hotel Pittsburgh, PA Lipid Academy lipid.org/fallclu September 17–18, 2015 Pittsburgh, PA

March 17–18, 2016 2016 National Lipid Association San Diego, CA Clinical Lipid Update—Spring Hosted by the Pacific and Midwest Chapters March 18–20, 2016 Omni San Diego Hotel San Diego, CA lipid.org/springclu

Masters in Lipidology September 17–18, 2015 Pittsburgh, PA

March 17–18, 2016 San Diego, CA

SWLA WINS! Congratulations to the SWLA Chapter for winning the Membership Recruitment Competition.

Enjoy your all-day access to a private lounge at the 2015 NLA Scientific Sessions in Chicago with free wi-fi, drinks and snacks. Not to mention bragging rights!

Official Publication of the National Lipid Association 35 References

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Laing SP, Swerdlow AJ, Slater SD, et al. Mortality from heart dis- Results from the D:A:D study(*). HIV Medicine. 2011;12(7):412- infected with HIV: 2013 update by the HIV Medicine Association ease in a cohort of 23,000 patients with insulin-treated diabetes. 421. of the Infectious Diseases Society of America. Clinical Infectious Diabetologia. 2003;46:760-765. 4. Smith CJ, Ryom L, Weber R, et al. Trends in underlying causes of Diseases. 2014;58(1):e1-34. 2. Morrish NJ, Wang SL, Stevens LK, Fuller JH, Keen H. Mortality and death in people with HIV from 1999 to 2011 (D:A:D): A multico- 29. Lundgren JD, Battegay M, Behrens G, et al. European AIDS Clinical causes of death in the WHO multinational study of vascular disease hort collaboration. Lancet. 2014;384(9939):241-248. Society (EACS) guidelines on the prevention and management of in diabetes. Diabetologia. 2001;44:S14-S21. 5. Esser S, Gelbrich G, Brockmeyer N, et al. Prevalence of cardiovascu- metabolic diseases in HIV. 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Otvos JD, Mora S, Shalaurova I, Greenland P, Mackey RH, Goff DC media thickness in children with type 1 diabetes. Diabetes. quality of care for patients living with HIV/AIDS: Executive sum- Jr. Clinical implications of discordance between low-density lipopro- 2002;51:493-498. mary. Circulation. 2008;118(2):198-210. tein cholesterol and particle number. Journal of Clinical Lipidology.

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Official Publication of the National Lipid Association 39 Provider Tear Sheet

The National Lipid Association Recommendations for Patient-Centered Management of Dyslipidemia—Part I

Carl E. Orringer, MD, FNLA The leadership of the National Lipid Association convened an Expert Panel to develop Recommendations for Patient-Centered Management of Dyslipidemia in Clinical Medicine, the Executive Summary of which was published in the Journal of Clinical Lipidology in September 2014. The full paper was published in the April 2015 issue. The major conclusions of the Panel are enumerated below:

1. An elevated level of cholesterol carried by circulating apolipoprotein (apo) B-containing lipoproteins (non-HDL-C and LDL-C, termed atherogenic cholesterol) is a root cause of atherosclerosis, the key underlying process contributing to most clinical ASCVD events.

2. Reducing elevated levels of atherogenic cholesterol will lower ASCVD risk in proportion to the extent that atherogenic cholesterol is reduced. This benefit is presumed to result from atherogenic cholesterol lowering through multiple modalities, including lifestyle and drug therapies.

3. The intensity of risk-reduction therapy should generally be adjusted to the patient’s absolute risk for an ASCVD event.

4. Atherosclerosis is a process that often begins early in life and progresses for decades before resulting in a clinical ASCVD event. Therefore, both intermediate-term and long-term/lifetime risk should be considered when assessing the potential benefits and hazards of risk-reduction therapies.

5. For patients in whom lipid-lowering drug therapy is indicated, statin treatment is the primary modality for reducing ASCVD.

6. Non-lipid ASCVD risk factors should also be managed appropriately, particularly high blood pressure, cigarette smoking, and diabetes mellitus.

7. The measurement and monitoring of atherogenic cholesterol levels remain an important part of a comprehensive ASCVD prevention strategy.

The NLA Recommendations advocate risk categorization, beginning with very-high and moving to progressively lower risk groups. Specific criteria are used for each risk category. Once the clinician defines the highest risk category applicable to a patient, the next step is discussion with the patient about risk-appropriate atherogenic cholesterol lowering therapy. Recognizing that lifestyle therapy is always advocated as the basis for ASCVD prevention, this table provides the NLA perspective on non-HDL-C and LDL-C thresholds for considering drug therapy and treatment goals. The non-HDL-C and LDL-C levels at which drug therapy should be considered vary in accordance with the absolute risk of the patient. However, the treatment goals are all <130 for non-HDL-C and <100 mg/dL for LDL-C, except in the very high-risk patient in whom the non-HDL-C goal is <100 and LDL-C goal <70 mg/dL. Patient Tear Sheet

The National Lipid Association Recommendations for Patient Centered Management of Dyslipidemia-Part I

Joyce L. Ross, MSN, CRNP, FNLA

In 2014 the American College of Cardiology and the American Heart Association (ACC/AHA) released new guidelines for reducing heart disease risk. You may feel confused by the news reports surrounding these guidelines. For a long time, you have been familiar with having certain goals for your cholesterol levels, such as an LDL (known as “bad cholesterol”) below 100. The new ACC/AHA guidelines no longer recommend LDL goals, and instead, recommend a 30 to 50 percent reduction in LDL (or greater in some), no matter where the LDL was at the start. The leadership of the National Lipid Association (NLA) set up an Expert Panel of cholesterol specialists to develop Recommendations for Patient-Centered Management of Dyslipidemia, which are not meant to conflict with the ACC/ “Heart disease is a AHA Guidelines, but rather to be used in a complementary fashion. The NLA feels strongly that we need to treat more than just the LDL, but also another problem that often type of bad cholesterol called non-HDL cholesterol, which has been shown to begins when you are increase heart attack and stroke risk. In addition, the NLA also feels strongly that we still need cholesterol goals. young, and increases Heart disease is a problem that often begins when you are young, and increases for many years for many years before a heart attack happens. Therefore, your provider will consider both intermediate and long-term/lifetime risk when evaluating the before a heart attack pros and cons of risk-lowering treatments for you. When your provider finds happens.” high levels of blood fats called triglycerides, or low levels of HDL, known as the “protective cholesterol,” stronger heart disease prevention strategies may be recommended.

Your treatment plan will be based on your individual needs after a conversation with your healthcare provider. The plan will include exercise and diet, and may often include medications called statins. In some cases, another type of cholesterol lowering medication may be recommended. Your provider will also want to have occasional blood tests done to see how effective your treatment plan is. Other risk factors, such as high blood pressure, diabetes, and smoking, will also be addressed. It is still important to “know your numbers” and discuss your prescription plans and cholesterol goals with your provider!

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