Official Publication of the National Lipid Association

pot·pour·ri LipidSpin 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

STATINS STATINS

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Editors 2 From the NLA President 24 Statin Therapy in the Very DANIEL SOFFER, MD, FNLA* Newly Published Guidance for Non- Elderly (>80) With CAD: Balancing Clinical Associate Professor of Medicine Statin Therapies from the American the Benefits and Risks University of Pennsylvania — Judith A. Collins, MSN, APRN-BC, FPCNA, FNLA Internal Medicine and Preventive Cardiology College of Cardiology University of Pennsylvania Health System — Joyce L. Ross, MSN, FNLA Philadelphia, PA 27 The Potential Role of Universal JOSEPH J. SASEEN, PharmD, BCPS, BCACP, CLS, FNLA 4 From the LipidSpin Editor Genetic Screening for Familial Professor, Clinical Pharmacy and Family Medicine HOPE Springs Eternal for Defective Apolipoprotein B-100 in University of Colorado Denver Intermediate-Risk Primary Prevention Southern Pennsylvania Anschutz Medical Campus — Rolf L. Andersen, MD, FACC, FNLA Aurora, CO Patients — Joseph J. Saseen, PharmD, FNLA — Lars Andersen, BA Managing Editor MELISSA HEYBOER National Lipid Association 6 From the LipidSpin Editor 29 Omega-3 Fatty Acid Fish Oil Dietary Supplements for Disease Executive Director Looking Back, Moving Forward BRIAN HART, JD — Daniel Soffer, MD, FNLA Management: Are They Appropriate National Lipid Association for Patients? 7 The Advent of PCSK9 Inhibitors in — R. Preston Mason, PhD LipidSpin is published five times a year by the — Daniel E. Hilleman, PharmD National Lipid Association Real Life 6816 Southpoint Parkway, Suite 1000 — Cezary Wójcik, MD, FNLA Jacksonville, FL 32216 32 Pseudohypertriglyceridemia in a Phone: 904-998-0854 | Fax: 904-998-0855 9 Search for the Secondary Cause: Teenager: Evaluation, Management, Copyright ©2016 by the NLA. Implications, and Literature Review All rights reserved. Worth the Pause — Allison Ducharme-Smith, MD — James J. Maciejko, MS, PhD, FACC — Premchand Anne, MD, MPH, FACC Visit us on the web at www.lipid.org. — Balint Laczay, MD — Viraj Prakash Raygor, MD — Manisha Ravi The National Lipid Association makes every effort to — Neil J. Stone, MD, FNLA provide accurate information in the LipidSpin at the 34 Sanofi Regeneron Young time of publication; however, circumstances may alter Investigator Award Winner certain details, such as dates or locations of events. Any 12 Clinical Conundrum: The changes will be denoted as soon as possible. The NLA — Imran Baig, MD invites members and guest authors to provide scientific Estimated LDL-C Below 40 mg/dL and medical opinion, which do not necessarily reflect — Donald G. Lamprecht Jr., PharmD, BCPS, FNLA the policy of the Association. — Sheila L. Stadler, PharmD, BCPS-AQ Cardiology 36 Red Yeast Rice as an Alternative Therapy for Hyperlipidemia CETP Inhibitors Remaining in — Ram Y. Gordon, MD 15 — David J. Becker, MD Clinical Development: A History and Update for Clinicians — Sean D. Stewart, PharmD, BCACP, FNLA 38 Foundation Update 40 Member Acknowledgement 18 Coronary Artery Calcium Scoring in Decision Making: the MESA Score 43 Education, News and Notes — Edward Goldenberg, MD, FNLA — Steven Meng, MD 44 Events Calendar 21 Omega-3 Fish Oil: 45 References *indicates ABCL Diplomate status Cardioprotective or Not? — Terrance J. Moran, MD, FACC, FAHA 49 Patient Tear Sheet

Official Publication of the National Lipid Association 1 From the NLA President: Newly Published Guidance for Non-Statin Therapies from the American College of Cardiology

JOYCE L. ROSS, MSN, CRNP, FPCNA, FNLA President, National Lipid Association Consultative Education Specialist Cardiovascular Risk Intervention University of Pennsylvania Health System – Retired Philadelphia, PA Diplomate, Accreditation Council for Clinical Lipidology

approved a new class of medications Algorithms found within the current termed proprotein convertase subtillisin/ document provide a suggested clinical kexin 9 or, most often referred to as, workflow for consideration of additional Discuss this article at PCSK9 inhibitors for high-risk patients who non-statin therapies. Ten points were www.lipid.org/lipidspin may require additional therapies to bring specifically highlighted to assist the the LDL-C to a more acceptable threshold. provider to fully understand and implement The recent results of the HPS2-THRIVE its recommendations. In April 2016, an expert consensus and IMPROVE-IT trials have also provided decision pathway on the role of non- new data that provided new evidence 1. The decision pathway was created to statin therapies for lowering LDL-C with regard to the addition of second non- address GAPS in recommendations in the management of atherosclerotic statin agents when additional lowering is for LDL-C lowering to reduce ASCVD cardiovascular disease (ASCVD) risk was warranted. in high-risk subsets based on recent published in the Journal of the American clinical trial evidence and the College of Cardiology. This document, The publication of these new guidelines introduction of a new class of lipid- which was endorsed by the National Lipid are in concert with the standards and lowering medication Association (NLA), and with the diligent recommendations made by the NLA, and 2. The 2013 ACC/AHA cholesterol and consistent work of our Immediate we are excited to endorse the work of guidelines identified four major statin Past President Carl Orringer, MD, as the initial “think tank,” which resulted in benefit groups, which remain intact one of its authors, provides practical this publication. We are further pleased to and include: guidance for clinicians and patients in report that Dr. Orringer has accepted the situations that were not covered by the invitation of the ACC committee when it a. Patients > 21 with clinical joint 2013 American College of Cardiology/ convenes this Fall in Washington, DC, as ASCVD American Heart Association (ACC/AHA) it moves its work forward assessing and guidelines. The need for such a document making recommendations for barriers b. Adults > 21 years of age with was emphasized by recent additions to around implementation of evidence-based LDL-C > 190 mg/dL (after ruling the body of knowledge for risk factor LDL-C lowering therapies for ASCVD out secondary causes) reduction in cardiovascular disease. Since reduction. We are grateful for the ongoing the publication of the last guidelines, energy that he brings to this work and look c. Adults 40–75 years old without the Food and Drug Administration has forward to outcomes from this meeting. known ASCVD but with diabetes, with LDL-C 70-189 mg/dL

2 LipidSpin • Volume 14, Issue 4 • August 2016 d. Adults 40–75 years without 8. In cases of suspected statin for most patients. ASCVD or diabetes, with an intolerance, the provider should LDL-C 70–189 mg/dL, and an include temporary discontinuation 3. Bile acid sequestrants (BAS) may be estimated 10-year risk for ASCVD of statin therapy, lower dosing, considered as second-line therapy who of > 7.5 percent, as determined re-challenge preferably with 2–3 are not able to tolerate ezetimibe, but by the pooled cohort equations. different statins that utilize different they should be avoided in patients metabolic pathways, and intermittent with triglycerides > 300 mg/dL. 3. The 2013 guidelines recommended (1–3 Xs weekly) dosing of long half- 4. PCSK9 inhibitors may be considered using either high- or moderate- life statins. intensity statin therapy for primary if LDL goals are not achieved on and secondary prevention, with 9. In selected high-risk patients (those maximally tolerated statin and dose adjustments as identified for with existing ASCVD or those with ezetimibe therapy in higher-risk adverse effects, elderly population, an LDL-C > 190 mg/dL), use of non- patients with ASCVD or FH. These comorbidities, or drug-drug statin therapies may be considered agents are not recommended in interaction. if maximally tolerated statin therapy primary prevention patients who do has not achieved > 50 percent not have FH. 4. The evidence-based recommendations reduction in LDL-C from baseline. from the 2013 guidelines provided the 5. In patients with homozygous framework for the newest guideline 10. Guidance on other factors are also hypercholesterolemia (HoFH), and incorporated the most recent provided including the absolute referral to a lipid specialist is clinical trial data and the newly LDL-C level achieved, the extent strongly recommended, for potential approved PCSK9 inhibitors. of available scientific evidence for considerations for use of lomitapide, safety and tolerability, potential for mipomerson, and LDL apheresis as 5. Three questions were utilized drug-drug interactions, efficacy of necessary. n to provide more detailed additional LDL-C lowering in ASCVD recommendations for specific patient event reduction, cost, convenience scenarios. and medication storage, pill burden, route of administration, potential to a. In what patient populations jeopardize adherence to evidence should non-statin therapies be based therapies, and, importantly, considered? patient preferences. The National Lipid b. In what situations should non- Association would like to statin therapies be considered? The panel emphasized that LDL-C levels acknowledge and thank our c. If non-statin therapies are to be are not firm triggers for adding medication, longtime members for their however, there are factors that may be added, which agents or therapies commitment to the NLA and should be considered and in what considered within the broader context of the field of lipidology. The order? an individual’s clinical situation. Specific recommendations for add-on mediations strength and longevity of our 6. All pathway recommendations include: organization is only possible include assurance that the patient because of the dedication is consistent with ongoing healthy 1. A referral to a lipid specialist or lifestyle recommendations. registered dietitian may be considered and contributions of our for higher-risk patients with members. See page 40 for 7. Fasting LDL-C levels should be statin intolerance, and is strongly assessed regularly after the initiation complete list. encouraged for patients with familial of lipid-lowering medications, and hypercholesterolemia (FH). every three to 12 months thereafter as appropriate. 2. Ezetimibe (Zetia) is the first non-statin medication that should be considered

Official Publication of the National Lipid Association 3 From the LipidSpin Editor: HOPE Springs Eternal for Intermediate-Risk Primary Prevention Patients

JOSEPH J. SASEEN, PharmD, BCPS, BCACP, FNLA Professor, Clinical Pharmacy and Family Medicine University of Colorado Denver Anschutz Medical Campus Aurora, CO Diplomate, Accreditation Council for Clinical Lipidology

medications. The original HOPE trial was Skeptics also cite that women and a randomized placebo-controlled trial that diverse patients (i.e., not white patients) demonstrated reduced risk of CV events have not been adequately represented Discuss this article at in patients with ramipril-based therapy, in primary prevention outcome trials www.lipid.org/lipidspin even in the absence of hypertension.3 evaluating statin therapy. The JUPITER This had high impact with ACE inhibitor trial in 2008 had a reasonable number The annual Potpourri edition of the therapy broadly being adapted as an of women and non-white patients and LipidSpin is one of my favorites. What is evidence-based recommendation in many demonstrated a significant reduction published typically reflects what is in the high-risk patients. The most recently in CV events with rosuvastatin 20 mg forefront of the minds of several clinical published HOPE-3 trial used a prospective daily versus placebo.4 However, JUPITER lipidologists and clinical lipid specialists. randomized placebo controlled trial design included only patients with elevated I have spent the past several months to evaluate the effect of rosuvastatin 10 hs-CRP, which is a risk marker for CV debating how the 2016 American College mg daily among 12,705 intermediate- events. The HOPE-3 included 28 percent of Cardiology Expert Consensus Decision risk primary prevention patients. After a Hispanic patients and 45 percent Asian Pathway, endorsed by the National median of 5.6 years, there was a significant patients. Patients were enrolled based Lipid Association (NLA), will change my 24 percent relative risk reduction in the on the “uncertainty principle,” meaning practice.1 I have also anticipated (fretted primary CV endpoint (3.7 and 4.8 percent patients who were excluded had clear might be a better word) how approval of for rosuvastatin and placebo, respectively; indications or contraindications for statin generic rosuvastatin will or will not be p=0.002). therapy. This means there was reasonable embraced by most insurers. I’m puzzled doubt of the benefits of statin therapy in about the Food and Drug Administration’s I am not certain why the HOPE-3 results the study population because they were decision to allow omega-3 fatty acid have not received more attention. This intermediate-risk primary prevention products to be promoted off-label. is a landmark study and the results without elevated hs-CRP or diabetes. However, the Heart Outcomes Prevention are impactful. Guidelines and expert Considering the results and the diversity Evaluation-3 (HOPE-3) trial results were recommendations have endorsement of the population, the HOPE-3 expands the what I found most appeasing.2 treating certain primary prevention patient population with proven evidence patients. However, skeptics have that statin therapy reduces CV events. The HOPE trials are a series of questioned the benefits of statin therapy clinical trials evaluating the long-term in intermediate-risk primary prevention The safety results of HOPE-3 were also cardiovascular (CV) benefits of different patients who do not have diabetes. important. Rosuvastatin was associated

4 LipidSpin • Volume 14, Issue 4 • August 2016 with small, but significant increase in clinical trials with a comparable amount patients who are intermediate-risk. Expect muscle symptoms and need for cataract of LDL-C lowering. This supports the LDL to hear more about HOPE-3 in the near surgery compared to placebo. However, hypothesis. future. there was no increased risk of new onset diabetes with rosuvastatin, which is in The HOPE-3 trial adds to the already rich It is a privilege to be the co-editor of contrast to other clinical trials. This should evidence base supporting statin therapy in LipidSpin. I hope you enjoy this Potpourri garner further interest. The HOPE-3 is primary prevention patients. Considering edition as much as I have! n not without limitations. There was only a that the rate of ASCVD events seen in the 26.5 percent difference in LDL-C between placebo rate is similar to a 10-year ASCVD References are listed on page 45. rosuvastatin 10 mg daily and placebo. The event rate of approximately 10 percent, study dose of rosuvastatin is moderate- these primary patients are candidates for intensity so this difference should have moderate-to-high intensity statin therapy been much greater, even with some according to the 2013 American College nonadherence. Nonetheless, CV events of Cardiology/American Heart Association were reduced and the reduction is similar cholesterol guidelines.5 Most importantly, to what has been demonstrated in other it provides additional data in diverse

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OOfficial Publication of the National Lipid Association 5 From the LipidSpin Editor: Looking Back, Moving Forward

DANIEL SOFFER, MD, FACP, FNLA Clinical Associate Professor of Medicine University of Pennsylvania Internal Medicine and Preventive Cardiology University of Pennsylvania Health System Philadelphia, PA Diplomate, American Board of Clinical Lipidology

We reminded our colleagues that clinical LipidSpin. This is a great time to recognize lipidologists offer an important expertise, what our colleagues are thinking about. and thus, we were updated on PCSK9 We included articles on PCSK9 inhibitors, inhibitors, CETP inhibitors, myopathy, causes of secondary hyperlipidemia, Discuss this article at and the unusual presentation of tuberous measuring low LDL-C levels, coronary www.lipid.org/lipidspin xanthomae. artery calcium scoring, fish oil, red yeast rice, CETP inhibitors, treating the elderly, It is a great time to be a clinical lipidologist We devoted an entire issue to the pseudyhypertriglyceridemia, and the finding and I want to thank all of the readers for a importance of guidelines and learned how of a very specific FH founder effect in wonderful year as co-editor of LipidSpin! It to meld public health standards with a Pennsylvania Amish. has been the year of the PCSK9 inhibitor personalized medicine approach to care. introduction and that has captured In fact, every issue is a bit of a potpourri everyone’s attention. But that is not all that More focused attention to very special meant to reflect the thoughts and character is going on in clinical lipidology; our field is circumstances followed in the unusual of the NLA membership. We have had rolling and we have tried to cover as much of dyslipidemia issue. We saw articles on an contributions from seasoned veterans, it as possible in the LipidSpin this past year. unusual response to a very low carbohydrate young trainees, nutritionists, pharmacists, diet, reviews on sitosterolemia and LAL- physicians, nurses, young, and old. I feel Since our last Potpourri issue, we have deficiency, and then a case of red yeast rice thankful to have the opportunity to co-edit covered primary prevention, lipid specialty associated myopathy. the issues with Joseph Saseen, PharmD, the care, guidelines, unusual dyslipidemias, and Publications Committee members who act lipid myths. Our last completed issue on lipid myths as peer reviewers, and of course the chapter was particularly well received. We got the presidents who carry the reigns for each Our LipidSpin predecessors, Robert big picture on HDL and insulin, reviews of issue. Wild, MD, and Jamie Underberg, MD, chelation therapy, coconut oil, butter vs. congratulated the NLA last year for devoting margarine, and summaries on major nutrition Melissa Heyboer, the NLA Communications their efforts to special populations, and then topics and dietary supplements. I have never Manager, keeps us all in line, on time, and called for authors to address this further. felt as well prepared for the cocktail party well organized. Her attention and care has Right on cue, our next edition on primary conversations as I did after reading that made this job truly a joy. I look forward to prevention was devoted to gender specific issue. every submission and every issue; and I management, metabolic syndrome in youth, look forward to our second year with this and elderly care. I hope you enjoy this Potpourri issue of the LipidSpin team. n

6 LipidSpin • Volume 14, Issue 4 • August 2016 The Advent of PCSK9 Inhibitors in Real Life

CEZARY WÓJCIK, MD, PhD, FNLA Assistant Professor of Family Medicine Oregon Health and Science University Portland, OR Diplomate, American Board of Clinical Lipidology

Patients of all ages and with all kinds of I was preparing several of my high-risk problems seek help in our busy family patients for the advent of new drugs. medicine clinic (10 providers, 33,000 Many of them were eagerly following the visits a year), which is part of a four-clinic news, while others were hesitant, afraid network of the Oregon Health & Science of the “new statins.” The day after the Discuss this article at University (OHSU) Family Medicine FDA approved alirocumab, the first patient www.lipid.org/lipidspin Department. I work independently willing to embrace the new treatment (although we do collaborate) from the was already in my office. In total, I OHSU Preventive Cardiology Division as started 13 patients on PCSK9 inhibitors. patients on evolocumab used the biweekly the only lipidologist within our department, Unfortunately, three of them were denied dosing of 140 mg. Not a single patient taking referrals from my colleagues. by their insurance and thus discontinued wanted the monthly administration of three therapy. consecutive injections.2 After initiation When the U.S. Food and Drug of either alirocumab or evolocumab, low- Administration (FDA) approval dates I always offered both PCSK9 inhibitors to density lipoprotein cholesterol (LDL-C) and were approaching for PCSK9 inhibitors, I my patients without recommending one low-density lipoprotein particle (LDL-P) contacted field medical teams of Sanofi/ over the other. So far, insurers did not decreased 50 to 70 percent. I have observed Regeneron (alirocumab) and Amgen have a preference, but this is likely going to no major effects on high-density lipoprotein (evolocumab). I wanted both scientific change in the immediate future. My first six cholesterol (HDL-C) or triglyceride levels, information and access to pamphlets, patients were started on alirocumab because except in one case, when the latter coupons, and other resources. OHSU does it was the first drug available in July 2015. increased. not allow the dispensing of samples to All were started on the lowest dose, 75 mg, patients in office. However, both companies every two weeks.1 Because of their excellent Dummy autoinjectors were used to offered assistance programs allowing response, their dose was not increased. demonstrate drug administration during the patients to get started on free samples sent Once evolocumab entered the market, initial office visit. I worked together with my to their homes within one to two weeks most patients chose it over alirocumab patients to fill out the paperwork, including from an office visit. They also offered help because of the advertised 30-day storage the prescription for the specialty pharmacy. with reimbursement/insurance specialists, at room temperature without need for Forms were changing initially almost every who were crucial to getting the patients refrigeration (vs. 24 hours for alirocumab). week. Patients could also fill out requests approved by insurance. Most of my patients have an active lifestyle, for free samples and financial assistance and therefore it was a clear advantage. All provided by the companies.

Official Publication of the National Lipid Association 7 One patient came for an office visit to myalgias. One patient complained of demonstrating asymptomatic atherosclerotic perform the first self-administration in my constipation with statins, ezetimibe, and cardiovascular disease (ASCVD). Moreover, presence. Another patient was initially basically any drug that was not injectable. his genetic testing was negative, which in afraid to inject himself but, after four visits, Another patient reported rashes with the insurers view, closed the case. This he was comfortable enough to continue statins, niacin, and ezetimibe. The rest patient reacted to statins with time- and them at home. None of the other patients reported “clouded minds” or some degree dose-dependent cognitive impairment; had any issue initiating injections at home. of cognitive impairment. All of them therefore he cannot use them as they Patients occasionally reported minor pain/ have tolerated PCSK9 inhibitors without impair his work. In contrast, a different irritation at injection sites. One patient problems. insurer provides the same drug to a patient reported cold symptoms with each injection. with truly psychogenic statin intolerance Even the most skeptical patients did not Real-life prescribing of PCSK9 inhibitors with mixed dyslipidemia and a baseline report any other side effects. One potential means a tough fight with insurance LDL-C of 150 mg/dL. These two examples candidate for this therapy had refused the companies. Initially, many insurers rejected demonstrate striking differences in access use of injectable drugs. the drugs because they did not fit algorithms to PCSK9 inhibitors depending on the based on the 2013 American Heart insurance company. To get PCSK9 inhibitors The FDA approval for the PCSK9 inhibitors Association/American College of Cardiology approved, insurers often request fulfillment is to use them as an “adjunct to diet and (AHA/ACC) guidelines.3 Some insurers of the NLA criteria for statin intolerance.5 maximally tolerated statin therapy for the even argued that they were “experimental Frequently, insurers also request proof of treatment of adults with heterozygous drugs.” With time, insurers created a more failing ezetimibe therapy before approving familial hypercholesterolemia or clinical uniform application process demanding PCSK9 inhibitors. atherosclerotic cardiovascular disease, details of previously attempted therapy with who require additional lowering of LDL- statins and other agents. Application forms It is frustrating that insurance clerks cholesterol.”1,2 In addition, evolocumab often request the prescription to be written without lipid knowledge make decisions is indicated to treat homozygous familial by or in consultation with cardiologists, jeopardizing patient care. They do not hypercholesterolemia (FH).2 endocrinologists, or “lipid specialists.” understand arguments about elevated Such designation did not appear initially Lp(a) or elevated LDL-P/apoB/non-HDL-C, My patients started PCSK9 inhibitors for on some forms. Insurance companies were following pre-set insurance algorithms. a range of indications. Two of them were often unaware of our existence. The ability Fortunately, recently published guidance prescribed PCSK9 inhibitors for secondary of clinical lipidologists to prescribe PCSK9 from the ACC about non-statin therapy prevention. One patient had heterozygous inhibitors has been now added to the is of help in the discussion.6 The return familial hypercholesterolemia (HeFH) with forms I have seen so far, being a welcomed of LDL-C goals in the document clarifies coronary artery bypass grafting (CABG) recognition of our specialty. what constitutes the need for “additional at age 36 and subsequent angina while lowering of LDL-C.” The completion of on rosuvastatin 40mg and ezetimibe For some patients, the path to get insurance cardiovascular outcome studies will surely 10 mg. After starting a PCSK9 inhibitor approval was easy; for others, it was not. provide even more arguments for a wider her LDL-C is now at 84 mg/dL. Another Some became angry and frustrated. They use of PCSK9 inhibitors. Hopefully, once patient had recurrent coronary events after saw excellent lipid profiles after using bocozicumab (Pfizer) receives FDA approval, CABG followed by stenting, despite taking free samples, which turned again into bad increased competition will drive their price atorvastatin 80 mg plus ezetimibe 10 mg. numbers, when insurance refused the further down. His LDL-C hovered above 70 mg/dL. Now, it approval. Some insurers approved PCSK9 has been successfully lowered to 35 mg/dL. inhibitors only if the patient fulfilled This has been a challenging introduction of Dutch Lipid Clinic Criteria for definite this new class of drugs. It has come with a The remaining 11 patients were prescribed HeFH with a score greater than eight, fight. It truly challenges my resolve given PCSK9 inhibitors for primary prevention refusing to accept the National Lipid the time consuming, faulty, and sometimes in the context of HeFH (eight) or mixed Associatoin (NLA) and AHA criteria.4 One random criteria for approval. n dyslipidemia (three), the latter being an of my patients had a score of eight with off-label indication. All of them have at an untreated LDL-C of 204 mg/dL. His Dr. Wójcik has no disclosures to report. least some degree of statin intolerance, but insurance refused him PCSK9 inhibitors References are listed on page 45. only five patients reported statin-associated despite him having an Agatson score of 390

8 LipidSpin • Volume 14, Issue 4 • August 2016 Search for the Secondary Cause: Worth the Pause

ALLISON DUCHARME-SMITH, MD VIRAJ PRAKASH RAYGOR, MD Feinberg School of Medicine Feinberg School of Medicine Division of Cardiology Division of Cardiology Northwestern University Northwestern University Chicago, IL Chicago, IL

BALINT LACZAY, MD NEIL J. STONE, MD, MACP, FNLA Feinberg School of Medicine Bonow Professor of Medicine Division of Cardiology Feinberg School of Medicine Northwestern University Division of Cardiology Chicago, IL Northwestern University Chicago, IL Diplomate, American Board of Clinical Lipidology

The approach to understanding hyper- therapy for almost one year. Because of his cholesterolemia, hypertriglyceridemia, diabetes, he was given atorvastatin 10 mg or both, starts with consideration of the daily. He developed chronic clostridium underlying lipoprotein abnormalities difficile (CD) infection and required a fecal 1,2 present. This is followed by asking to microbial transplant. This led to acute Discuss this article at what degree genetic or acquired causes worsening of his nephrotic syndrome and www.lipid.org/lipidspin explain the observed abnormalities. Since high-dose prednisone therapy (60 mg/ those with lipoprotein abnormalities and day). Cautioned to avoid weight gain, he increased risk for either atherosclerotic presented to a lipid clinic with minimal intake, uncontrolled diabetes, and overt cardiovascular disease (ASCVD) or weight change but elevated cholesterol and albuminuria.3 Recent guidelines list pancreatitis are candidates for drug triglyceride, raised high-density lipoprotein secondary causes of hyperlipidemia often therapy, finding acquired causes and cholesterol (HDL-C), and elevated low- encountered in clinical practice (Table 2).1 instituting lifestyle changes could spare density lipoprotein cholesterol (LDL-C), The patient was advised to adhere to a drug treatment or, at a minimum, reduce and non-HDL-C (Table 1). Concerned, he healthy lifestyle by increasing his activity the intensity of such treatment. We asked to discuss his treatment options. level and decreasing his caloric intake. His present an informative case to illustrate statin dosage was not changed. Over the issues related to secondary hyperlipidemia Yet the recent onset of his hyperlipidemia next month, his prednisone was tapered where a search for the cause and not and his complicated medical history from 60 mg to 14 mg daily. Two months pharmacotherapy is the primary approach. made consideration of secondary causes later, his repeat lipid panel had significantly crucial. A report from a lipid specialty improved. His lipid improvements were Case 1. A 43-year-old man with a history clinic noted that the most frequently attributed to the resolution of his acute of minimal-change kidney disease and encountered secondary causes of episode of nephrotic syndrome, decreased type 2 diabetes had been off steroid hyperlipidemia included excessive alcohol steroids, and improved lifestyle and weight

Official Publication of the National Lipid Association 9 Patient’s Labs VISIT 1 VISIT 2 VISIT 3 VISIT 4 underlying causes of nephrotic syndrome. 3/12/2015 5/25/2015 7/24/2015 9/12/2015 This is reflected in recommendations Prednisone60 mg/day Prednisone 12 mg/day by the Kidney Disease International Global Outcomes (KDIGO) guidelines for Total Cholesterol 153 167 336 215 treatment of nephrotic syndrome. KDIGO Triglycerides 180 202 299 268 supported our management with a weak HDL-C 33 53 105 59 recommendation for not initiating statin LDL-C 84 74 171 102 therapy for minimal-change disease when clinical resolution with normalization of Non-HDL-C 120 114 231 156 the lipid profile is likely.8 Table 1. Clinical Case Data control. He did not wish further lipid levels includes increased hepatic synthesis Although space limitations preclude medications and indicated he wished to of apoproteins B, C-II and E, but without another case, clinicians also should be work further on lifestyle changes with the increased production of apoproteins A-I aware of liver-related causes of elevated hope of improving his lipid measurements. and A-II.5,6 These metabolic derangements lipids. For example, non-alcoholic lead to markedly elevated cholesterol fatty liver disease (NAFLD) may be As part of the clinical discussion before levels. In a cohort of 207 nondiabetic accompanied by the atherogenic lipid lipid medication is given, it is essential to patients with nephrotic syndrome, the triad of high triglycerides, elevated small review secondary causes of hyperlipidemia. LDL-C was noted to average 208 mg/dl.7 dense LDL,9 and a low HDL-C.10 These Although thyroid may be more common, Such a marked elevation in the LDL-C lipid derangements are associated with both renal- and liver-associated lipid could prompt an initiation of a high- increased ASCVD risk.11 This requires abnormalities illustrate the importance intensity statin per the current 2013 an initial focus on lifestyle change with of pausing to find a secondary cause. American College of Cardiology/American subsequent consideration of statin use. One renal cause is nephrotic syndrome. Heart Association (ACC/AHA) guidelines.1 In the setting of stable liver disease, This often is accompanied by elevated But high-intensity statin therapy may not NAFLD itself is not a contraindication LDL-C, triglycerides, and lipoprotein(a), be immediately required if the mechanism to statin therapy.12 Primary biliary and normal or decreased HDL-C.4 The of increase in LDL-C is reversible5 and cholangitis, on the other hand, alters mechanism underlying abnormal lipid can resolve with specific treatment of the cholesterol metabolism by causing reflux

Secondary Cause Elevated LDL-C Elevated Triglycerides Diet Saturated or trans fat, weight gain, anorexia Weight gain, very-low-fat diets, high intake of refined nervosa carbohydrates, excess alcohol intake Drugs Diuretics, cyclosporine, glucocorticoids, Oral estrogens, glucocorticoids, bile acid sequestrants, A-alcohol, amiodarone protease inhibitors, retinoic acid, anabolic steroids, siroli- acne medications mus, raloxifene, tamoxifen, beta blockers (not alpha beta atypical antipsychotics blockers such as carvedilol), thiazide diuretics B-beta-blockers C-chemotherapy D-diuretics diabetes medications E-epilepsy F- fibrillation meds G-glucocorticoids H-HIV medications (protease inhibitors) I-immunosuppressants Diseases Nephrotic syndrome, biliary obstruction Nephrotic syndrome, chronic renal failure, lipodystrophies Disorders and altered states of metabolism Hypothyroidism, obesity, pregnancy Diabetes (poorly controlled); hypothyroidism, obesity, pregnancy *Modified from Reference 1 with permission. Table 2. Secondary Causes of Hyperlipidemia Commonly Encountered in Clinical Practice*

10 LipidSpin • Volume 14, Issue 4 • August 2016 of biliary lipids into the circulation and supported by strong evidence, and downregulation of lethicin-cholesterol recommending clinician-patient risk acetyltransferase (LCAT) activity,13 resulting discussions in lower-risk primary in an increase in triglycerides, LDL-C, prevention before statin assignment and HDL-C (although HDL-C decreases despite the risk score. They advised the with disease progression). However, need to consider secondary causes of the elevation in LDL-C is driven by the lipid abnormalities before assuming that accumulation of lipoprotein-X, a lipoprotein lipid changes were primary. Identification that is resistant to in-vitro oxidation and of secondary causes whether they be which some believe may protect against medication, dietary, or related to diseases atherogenesis.14 Thus, lipid derangements or disorders of metabolism is crucial secondary to cholestasis may not increase before pharmacotherapy for lipids is given. ACSVD risk.15,16 Importantly, patients also may benefit from intensive lifestyle counseling to mitigate many changes in lipid parameters that can accompany secondary causes. Thus, when “Identification of you see abnormal lipids, remember to secondary causes search for a secondary cause(s); it’s worth the pause. n whether they be *Written permission was obtained from the patient.

medication, dietary, Disclosure statement: Dr. Ducharme-Smith has no disclosures to report. Dr. Laczay has no disclosures or related to diseases to report. Dr. Raygor has no disclosures to report. Dr. Stone was the lead author of the 2013 ACC/AHA or disorders of Cholesterol Guidelines. metabolism is References are listed on page 45. crucial...”

Finally, medications may cause secondary elevations of lipids. We offer the following list of medications that can affect lipids. Most drug effects are mild but the drugs that greatly raise triglycerides can lead to pancreatitis.2 Often, it may be especially useful to focus on lifestyle interventions to minimize the effects on lipids. We suggest a mnemonic (ABCDEFGHI) for remembering frequently encountered classes of medications that affect lipids (Table 2).

Conclusion: The new cholesterol guidelines were notable for providing guidelines that focus on defining at-­risk clinical groups, prioritizing interventions

Official Publication of the National Lipid Association 11 Clinical Conundrum: The Estimated LDL-C Below 40 mg/dL

DONALD G. LAMPRECHT Jr., PharmD, BCPS, FNLA Clinical Pharmacy Specialist, Clinical Pharmacy Cardiac Risk Service Kaiser Permanente of Colorado Clinical Assistant Professor University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, CO Diplomate, Accreditation Council for Clinical Lipidology

SHEILA L. STADLER, PharmD, BCPS-AQ Cardiology Clinical Pharmacy Specialist, Clinical Pharmacy Cardiac Risk Service Kaiser Permanente of Colorado Clinical Assistant Professor University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, CO

LDL-C is persistently <40 mg/dL.2 This the range of 30–70 mg/dL and individuals recommendation may be misconstrued with familial hypobetalipoproteinemia as meaning LDL-C levels <40 mg/dL are have LDL-C levels in the range of 0–20 harmful and may carry the unintended mg/dL for homozygotes and 30–50 mg/dL Discuss this article at consequence of patients at high risk for for heterozygotes.4,5 In the past decade, www.lipid.org/lipidspin ASCVD receiving a statin that is less than contemporary clinical trials have reported the recommended intensity. Furthermore, increased numbers of patients with LDL-C Recent clinical trial data has strengthened LDL-C levels below 40 mg/dL, as estimated levels <40 mg/dL (Table 1).1,6–10 the argument that lowering low-density by the Friedewald equation [LDL-C = lipoprotein cholesterol (LDL-C) to levels (total cholesterol) – (HDL-C) – (TG/5)], The basis for the ACC/AHA recommen- well below those previously targeted often are inaccurate in the setting of dation stems from the treatment approach provides incremental benefit in terms elevated triglyceride (TG) levels.3 What employed in certain clinical trials in which of lowering the risk of atherosclerotic follows is a discussion focused on how an LDL-C <40 mg/dL was an arbitrary cardiovascular disease (ASCVD).1 The clinicians caring for patients at risk for threshold set for investigators to consider increased use of high-intensity statins, ASCVD may interpret very low levels of a down titration of statin therapy.11,12 In irrespective of baseline LDL-C, has resulted LDL-C, including practical suggestions for fact, the ACC/AHA detailed supplemental in clinicians more frequently encountering how to approach this clinical conundrum. full panel report states that there is no LDL-C levels below 40 mg/dL. The evidence of harm when LDL-C remains 2013 American College of Cardiology/ Historically speaking, there has been <40 mg/dL on statin therapy, a point American Heart Association (ACC/AHA) limited experience with extremely low which is echoed in the 2014 National blood cholesterol guidelines suggest levels of LDL-C. Gestational and neonatal Lipid Association (NLA) Recommendations considering a statin dose reduction when LDL-C levels have been reported to be in for Patient-Centered Management of

12 LipidSpin • Volume 14, Issue 4 • August 2016 Number of Patients Achieving Very Low LDL-C Clinical Trial (publication year) < 50 mg/dL < 44 mg/dL < 40 mg/dL < 25 mg/dL OSLER6 (2015) 1,532 773 ODYSSEY LONG-TERM7 (2015) 575 IMPROVE-IT1 (2015) 5,926 JUPITER8 (2008) 4,154 2,225 PROVE-IT9 (2004) 193 TNT10 (2005) 98 Table 1. Clinical trials reporting the number of subjects achieving very low LDL-C

Dyslipidemia.2,13 LDL-C (OSLER) and the Long-Term LDL-C.3,15 The reason for the discrepancy Safety and Tolerability of Alirocumab in between estimated and directly measured In the Incremental Decrease in Clinical High Cardiovascular Risk Patients with LDL-C stems from the fact that the Endpoints Through Aggressive Lipid Hypercholesterolemia not Adequately equation assumes a fixed ratio (5:1) of Lowering (IDEAL) trial, which compared Controlled with Their Lipid Modifying TG to VLDL-C. Employing a fixed factor atorvastatin 80 mg a day to simvastatin Therapy (ODYSSEY LONG TERM) PCSK9 of 5 to estimate VLDL-C from TG creates 20–40 mg a day in patients with a history inhibitor trials, wherein safety analyses of a problem in that TG:VLDL-C ratio is not of myocardial infarction (MI) (baseline patients obtaining LDL-C <40 mg/dL, and constant across a range of TG and total LDL-C 121 mg/dL), investigators were even those <25 mg/dL, showed adverse cholesterol (TC) values. To get around given the option to decrease statin event rates similar to those with LDL-C this problem, one should assess non- doses if LDL-C fell below 39 mg/dL.11 >40 mg/dL.6,7 high-density lipoprotein cholesterol (non- Similarly, in the HDL Atherosclerosis HDL-C) levels, which is the primary goal of Treatment Study (HATS) trial, which therapy in the NLA Recommendations, or compared various doses of simvastatin “A growing body of consider using an adjustable factor for the in combination with niacin in patients TG:VLDL-C ratio based off TG.13,15 with angiographic evidence of coronary evidence suggests artery disease (baseline LDL-C 125 mg/ A recent scenario encountered in our dL), investigators were given the option to that LDL-C levels practice involved a 68-year-old patient reduce the statin dose if LDL-C was <40 with established ASCVD (MI w/stent mg/dL.12 Conversely, in the Collaborative can be safely driven in 2014) and diabetes mellitus taking Atorvastatin Diabetes Study (CARDS) atorvastatin 40 mg once daily. A fasting trial, which compared atorvastatin 10 mg to very low levels in lipid panel revealed: TC 136, TG 385, a day to placebo in patients with diabetes individuals at high HDL-C 42, LDL-C 17, and non-HDL-C 94 (baseline LDL-C 117 mg/dL) the study mg/dL. Since triglycerides were <400 drug was continued regardless of LDL-C risk for ASCVD.“ mg/dL, the reported LDL-C represented level and the data and safety monitoring a Friedewald estimation. Her primary board did not identify any safety concerns care physician expressed concern about in patients with LDL-C <39 mg/dL.14 the patient’s LDL-C being too low and In patients at very high risk for ASCVD Most laboratories report Friedewald suggested a reduction in atorvastatin events, the NLA guidance recommends estimated LDL-C unless TG are >400 dose. In this scenario, one could start by against statin dose reduction when LDL-C mg/dL, in which case a direct LDL-C is pointing out that non-HDL-C is near 100 measures <40 mg/dL, presuming there are reported. However, research by Martin mg/dL, which would provide rationale for no tolerability- or safety-related concerns.13 and colleagues has demonstrated that even not decreasing the statin dose to maintain Support for this recommendation can be at mildly elevated TG levels (i.e. >150 the recommended intensity of statin and found in data from both the Open-Label mg/dL), the Friedewald equation becomes ensure optimal ASCVD risk reduction. Study of Long-Term Evaluation Against increasingly inaccurate at lower levels of Next, using a method proposed by Martin,

Official Publication of the National Lipid Association 13 et al., 15 the TG:VLDL-C ratio would be 9.5, the near future and may address some of impractical, it is important to remember which would yield an estimated LDL-C of the safety concerns that have been raised that non-HDL-C serves as an inexpensive 53 mg/dL. Finally, one could request that with treating to very low LDL-C levels means by which to estimate circulating the laboratory parse out a direct LDL-C (eg. hemorrhagic stroke and cognitive levels of atherogenic particles. Taking from the blood sample. In fact, this was effects). When an LDL-C <40 mg/dL is these steps may help to minimize performed in this case and the directly encountered, a statin dose reduction may inappropriate statin dose reductions in measured LDL-C was 52 mg/dL. Each of not be necessary, particularly in patients patients with LDL-C below 40 mg/dL. n these strategies should lead to the same at high risk for ASCVD. Exceptions Disclosure statement: Dr. Lamprecht has no conclusion for this patient: It is reasonable might include the presence of advanced disclosures to report. Dr. Stadler has no disclosures to to continue atorvastatin at the current age, statin drug interactions, or patient- report. dose. reported side effects. Further complicating References are listed on page 45. matters is the fact that when TG are A growing body of evidence suggests elevated and LDL-C is driven to very low that LDL-C levels can be safely driven to levels, the accuracy of the Friedewald very low levels in individuals at high risk equation is severely compromised. When for ASCVD. Clinical outcomes data from concerns arise over a seemingly “too PCSK9 inhibitor trials are anticipated in low” LDL-C and direct measurement is

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14 LipidSpin • Volume 14, Issue 4 • August 2016 CETP Inhibitors Remaining in Clinical Development: A History and Update for Clinicians

SEAN D. STEWART, PharmD, BCACP, FNLA Clinical Pharmacist, Medication Management Park Nicollet Health System St. Louis Park, MN Diplomate, Accreditation Council for Clinical Lipidology

Statins currently stand as the cornerstone concentration with cardiovascular of therapeutic strategies for the reduction disease incidence7 of atherosclerotic cardiovascular events.1–4 However, despite their chronicled • A link between genetic variants of successes over the past 30 years since CETP activity and the risk for coronary Discuss this article at 8,9 the U.S. Food and Drug Administration artery disease www.lipid.org/lipidspin (FDA) approved lovastatin, multiple Pfizer developed and tested the first analyses of clinical trial data reveal residual CETP inhibitor, torcetrapib. In the and Roche discontinued development of cardiovascular risk in patients treated Phase 3 Investigation of Lipid Level dalcetrapib in May 2012. In other studies, with statins, even those achieving optimal Management to Understand Its Impact it was shown that dalcetrapib did not have reduction of low-density lipoprotein in Atherosclerotic Events (ILLUMINATE) any off-target adverse effects; however cholesterol (LDL-C).5 Therefore, the trial, patients treated with torcetrapib it did not have any appreciable effect on pharmaceutical industry has turned to new had significantly higher rates of major LDL-C, which was the major reason cited therapeutic modalities to modulate this cardiovascular and cerebrovascular events, for the negative results. Eli Lilly recently residual risk in statin-treated patients. and higher mortality resulting from halted development of evacetrapib in cancer and infection.10 The trial, and all October 2015, after a planned interim A major area of focus over the past 10 further development of torcetrapib, was analysis of its Phase 3 Aliskiren and the years has been modulation of cholesteryl terminated in December 2006. It is largely Calcium Channel Blocker Amlodipine ester transfer protein (CETP). Interest accepted that off-target effects on cortisol, Combination as an Initial Treatment in this target was based on several endothelin-1, and aldosterone led to the Strategy for Hypertension (ACCELERATE) observations, including: observed adverse outcomes.11 Dalcetrapib, trial also demonstrated insufficient efficacy. • The physiologic actions of CETP in developed by Hoffman-La Roche, followed Results of the study were presented at increasing high-density lipoprotein- torcetrapib. In the Phase 3, Dalcetrapib the 2016 American College of Cardiology cholesterol (HDL-C)6 in Stable Coronary Heart Disease Patients Scientific Sessions and publication of the full results are expected this year. • The involvement of high-density with Recent Acute Coronary Syndrome Evacetrapib had no off-target effects, lipoproteins (HDLs) in the reverse (dal-OUTCOMES) trial, treatment with decreased LDL-C by 37 percent, and cholesterol transport pathway and the dalcetrapib did not alter the risk of major 12 increased HDL-C by 130 percent, yet did inverse association of high-density cardiovascular events. The study was not decrease atherosclerotic cardiovascular lipoprotein cholesterol (HDL-C) stopped early based on a futility analysis

Official Publication of the National Lipid Association 15 CETP Inhibitor Pharmaceutical Company Stage of Development Status Torcetrapib Pfizer Phase 3 ILLUMINATE (NCT00134264) terminated December 2, 2006, for lack of efficacy and adverse effects10 Dalcetrapib Roche/DalCor Phase 3 dal-OUTCOMES (NCT00658515) terminated in September 2012 for lack of efficacy. dal-GenE (NCT02525939) ongoing12 Evacetrapib Eli Lilly Phase 3 ACCELERATE (NCT01687998) terminated for lack of efficacy13 Anacetrapib Merck Phase 3 REVEAL (NCT01252953) ongoing. After futility analysis, trial will continue until January 201714 TA-8995 Amgen/Dezima Phase 2 No Phase 3 trial announced

Table 1. Developmental Stages of CETP Inhibitors events in more than 12,000 high-risk original planned completion date.14 In the Determining the Efficacy and Tolerability patients.13 No reasons for the negative months since this announcement, many of CETP Inhibition with Anacetrapib results of evacetrapib have yet been have questioned the reasons underlying (DEFINE) trial, low concentrations of hypothesized. this decision given three past CETP anacetrapib were detectable in plasma as inhibitor failures and Merck’s huge capital late as four years after the last dose was After three straight negative outcomes investment in anacetrapib. There are some taken.17 Using population pharmacokinetic trials, significant questions exist about the reasons speculated as to why this decision modeling, the estimated half-life was 550 validity of CETP as a therapeutic target was made. First, although anacetrapib days. Although no accumulation of drug for reducing residual risk. However, there has similar effects on LDL-C and HDL-C is expected, it remains what impact this are two CETP inhibitors that remain in as evacetrapib, the REVEAL trial is more would have in patients who suffer adverse different phases of development and than twice as large as ACCELERATE, which drug reactions or who become or expect to one that has been resurrected based on increases the statistical power to detect a become pregnant during treatment.18 pharmacogenomics data. difference in associated outcomes. Second, anacetrapib reduces lipoprotein (a) (Lp On Sept. 16, 2015, prior to Eli Lilly’s Following the announcement of the [a]) by about 32 percent.15 This effect announcement about evacetrapib, Amgen termination of evacetrapib, Merck added is thought to be shared by evacetrapib. acquired the oral CETP inhibitor TA-8995 a futility analysis to its planned interim However, at the time of this writing, in a deal to purchase Dezima Pharma, review of the Phase 3 Rapid Evaluation of no data for evacetrapib was available which had developed TA-8995 to that Vessel Healing After Angioplasty (REVEAL) for comparison.16 Nevertheless, should point. Data from its Phase 2 Cholesterol trial of its CETP inhibitor, anacetrapib. REVEAL prove positive and anacetrapib ester transfer protein inhibition by TA- On Nov. 13, 2015, Merck announced make it to market, one area of concern 8995 in Patients with Mild Dyslipidaemia that, based on this analysis, REVEAL is its unusually long terminal half-life. In (TULIP) trial identified several potentially would continue with no changes to its a subset of 30 patients from its Phase 2 advantageous properties. First, it

Other Lipid-Lowering % Change from baseline to end of follow-up CETP Inhibitor Treatment LDL-C HDL-C ApoB Lp (a) ApoA-I Efflux Capacity Torcetrapib10 Atorvastatin -24% +61% -13% ND +23% Increased with 120 mg dose Dalcetrapib12 Statin NS +31% +2% ND +13% ND Evacetrapib13,21 Statin -37% +130% -16% -32% +36% +21-28% Anacetrapib22 Statin -36% +139% -18% -32% +42% ND TA-899519 ND -28-69% +74-177% -21-51% -23-35% +29-61% 17-37%

NS = not significant, ND = no data Table 2. Efficacy of CETP Inhibitor on Various Lipid Parameters

16 LipidSpin • Volume 14, Issue 4 • August 2016 decreased LDL-C up to 69 percent, 3 trial, the Effect of Dalcetrapib vs. Placebo been resurrected based on observed increased HDL-C up to 177 percent, on CV Risk in a Genetically Defined benefit in a genetic subgroup of patients. decreased apolipoprotein B (apo B) up to Population with Recent ACS (dal-GenE). While this shows promise for dalcetrapib 51 percent, and decreased Lp (a) up to 35 The trial plans to enroll 5,000 patients and possibly the other CETP inhibitors percent, making it the most potent CETP who recently have been hospitalized as well, there are unknowns about the inhibitor. Second, it decreased increased with acute coronary syndrome and have plausibility of the genetic link. n apolipoprotein A-I (apo AI) up to 63 a previously identified AA genotype of percent and increased cholesterol efflux the ADCY9 gene. It started recruiting Disclosure statement: Dr. Stewart has no disclosures to report. up to 37 percent, suggesting functional patients in March. There have been HDL particles. Third, it has a much shorter several criticisms of this trial including a References are listed on page 45. half-life — about two weeks compared lack of foundational knowledge about the to anacetrapib.19 There has been no functions of the ADCY9 gene and its link announcement by Amgen as to whether the mechanism of CETP. TA-8995 will enter a Phase 3 clinical trial.

Following Roche’s termination of the “Of the four CETP development of dalcetrapib, investigators at the Montreal Heart Institute conducted inhibitors that a retrospective analysis of a cohort of patients from the dal-OUTCOMES and have been brought Safety and Efficacy of Dalcetrapib on Atherosclerotic Disease Using Novel to clinical trials, Non-invasive Multimodality Imaging (dal- PLAQUE-2) studies. A single nucleotide three have been polymorphism (SNP) identified at a abandoned due specific location in the adenylate cyclase type 9 (ADCY9) gene on chromosome to lack of clinical 16 was found to be associated with cardiovascular events in dalcetrapib- benefit or off-target treated patients. In patients homozygous for the minor allele (AA), there was a 39 effects.” percent decrease in the trial’s composite endpoint, which was coronary heart disease death, resuscitated cardiac arrest, In summary, of the four CETP inhibitors nonfatal myocardial infarction, nonfatal that have been brought to clinical trials, stroke, unstable angina, or urgent coronary three have been abandoned due to lack revascularization. In patients homozygous of clinical benefit or off-target effects. for the wild-type allele (GG), there was a Anacetrapib and TA-8995 remain in 27 percent increase in the same endpoint. development. The REVEAL trial with No such genetic differences were observed anacetrapib is large enough that it may in patients receiving placebo.20 This ultimately show cardiovascular benefit, yet analysis was sponsored by Roche, which it remains to be seen whether the benefit subsequently filed for patents covering this will be appreciable enough for clinical genetic marker for use with dalcetrapib utility. TA-8995 showed some promising and the other CETP inhibitors. A different results in its phase II study; however, pharmaceutical company, DalCor, acquired similar results were demonstrated with exclusive licensing rights from Roche for other CETP inhibitors that ultimately did the use of dalcetrapib and the genetic not translate to improvements in outcomes marker. DalCor is sponsoring its own Phase of their phase III trials. Dalcetrapib has

Official Publication of the National Lipid Association 17 Coronary Artery Calcium Scoring in Decision Making: the MESA Score

EDWARD GOLDENBERG, MD, FNLA Clinical Professor of Medicine Thomas Jefferson University Medical Director of Cardiovascular Prevention Christiana Care Health System Newark, DE Diplomate, American Board of Clinical Lipidology

STEPHEN MENG, MD Cardiovascular Fellow Christiana Health Care System Newark, DE

approach that estimates risk for a specific hypertension or cholesterol medications. patient population but not necessarily The following cases will illustrate the for an individual. This approach can added clinical utility of the CAC and MESA identify those patients at high risk based scores. Discuss this article at on traditional risk factors, but frequently www.lipid.org/lipidspin does not address those with low or LS is a 57-year-old white female whose intermediate risk who contribute most of father had a myocardial infarction (MI) Evaluation of a patient’s risk for the population-attributable risk. in his 40s. She stopped smoking in her cardiovascular disease (CVD) is the basis 30s and has no history of hypertension of deciding whether to institute statin Coronary artery calcium (CAC) is a disease or diabetes. Her calculated 10-year risk therapy. The 2013 ACC/AHA Guidelines score that integrates the effect of genetics, of ASCVD using the ACC/AHA Pooled on the Assessment of Cardiovascular Risk environment, traditional risk factors, Cohort Equations is 1.5 percent and her recommend using the Pooled Cohort biomarkers, and the unknown. It correlates lifetime risk is 27 percent. She had a Equation to predict the10-year risk of with the degree of atherosclerosis and chest computed tomographic angiography having an atherosclerotic cardiovascular the risk of developing symptomatic in 2009 because of chest pain, which disease (ASCVD) event in non-Hispanic cardiovascular disease.2 The Multi-Ethnic showed no evidence of “any significant Whites and African Americans, 40 to 79 Study of Atherosclerosis (MESA) score obstruction,” but did demonstrate years of age. This calculation includes all is a new coronary heart disease (CHD) calcification in the proximal left anterior forms of cardiovascular disease, including risk calculator (https://www.mesa-nhlbi. descending artery. A follow-up CAC stroke and coronary heart disease (CHD). org/calcium/input.aspx) that incorporates score was 247 Agatston units, placing her Several other risk calculators have been CAC score in addition to the traditional in the 97th percentile for her age. Her developed to assess an individual’s risk factors of demographics, cholesterol, MESA 10-year CHD risk score was 2.5 CVD risk, however, all have limitations. systolic blood pressure, diabetes, smoking, percent without her CAC score and 6.7 Risk calculators provide a bio-statistical family history of CHD, and the use of percent with the score. A standard lipid

18 LipidSpin • Volume 14, Issue 4 • August 2016 profile showed cholesterol 158 mg/dL, there is uncertainty regarding statin related to traditional risk factors, while triglycerides 128 mg/dL, HDL-C 58 mg/ therapy. The 2013 guidelines state that two-thirds are related to endothelial dL, and LDL-C 74 mg/dL. She had a normal CAC score may be considered (Class IIb function, inflammation, and smooth muscle NMR LipoProfile, lipoprotein-associated recommendation) to inform treatment cells.4 CAC score provides insight into phospholipase A2 (Lp-PLA2), lipoprotein(a) decision-making in patients when such a the effect that these pathophysiological [Lp(a)], and flow-mediated dilatation. decision is unclear after conventional risk processes have on an individual’s risk of Because of her absolute CAC score, she assessment.3 The authors of the guidelines CVD. was placed on a high-intensity statin and should be commended for supporting the aspirin. Of note, her older sister also had use of “non-traditional” risk factors to aid The CAC score is most likely to affect a similar lipid profile and a significantly in clinical decision-making. the management of patients deemed at elevated CAC score. intermediate or low risk for CVD based INTERHEART: A Global Case-Control on traditional risk factors.5 A zero CAC LE is a 68-year-old white female referred Study of Risk Factors for Acute Myocardial score in the MESA trial was the strongest by her primary care physician after the Infarction evaluated 15,152 cases negative predictor with a diagnostic patient developed myalgias on numerous of acute myocardial infarction in 52 likelihood ratio (DLR) of 0.41 for CHD and statins. Her cholesterol was 249 mg/dL, countries. There were nine risk factors 0.54 for CVD. DLR quantifies the change triglycerides 119 mg/dL, HDL-C 57 mg/ that accounted for 93 percent of the in risk obtained with knowledge of a test dL, and LDL-C was 168mg/dL. She had population-attributable risk. The individual result and a value less than one indicates no history of hypertension, smoking, or risk factors that had the largest impact that the test result is less likely to be seen diabetes mellitus. Her father had a MI in were apolipoprotein B/apolipoprotein in those with disease and may be used to his 50s. Her calculated 10-year ASCVD A-1 (58.9 percent), psychosocial factors downgrade risk. However, a zero calcium risk was 8.5 percent using the ACC/AHA (43.5 percent), and smoking (40.7 score does not mean there is no CAD. calculator. Her MESA risk score was 6.4 percent). Abdominal obesity had a greater Gottlieb, et al. reported that a zero CAC percent without her CAC score and 2.6 impact than hypertension and diabetes. score had a negative predictive value of percent with her CAC score of zero. After In 6 percent of the study population, no 68 percent in finding a greater than 50 reviewing the information with the patient, conventional risk factor was identified. percent stenosis in patients referred to it was decided not to pursue statin therapy It has been reported that only 60 to 70 cardiac catheterization for symptoms.6 or start aspirin. She was instead referred percent of patients who present with Defining the 10-year risk category by for weight management. early atherosclerosis will have traditional using an absolute calcium score — such risk factors.4 There are 64 genomic loci as <100 being low risk and >400 being These cases help to demonstrate that associated with CAD. Only one-third are high risk — is more predictive than incorporating the CAC score into risk calculations can alter patient management. 100 The ACC/AHA 2013 Guidelines on the 90 Treatment of Blood Cholesterol to Reduce 80 Atherosclerotic Cardiovascular Risk in 70 p for dierence across strata for both CAC thresholds: < 0.01 60 Adults recognize the effectiveness of CAC > 0 50 statins in reducing cardiovascular risk CAC ≥ 100 in four clinical scenarios: patients ≤75 40 30 years of age with clinical ASCVD, patients 20 ≥21 years of age with LDL-C ≥190mg/ (%) Prevalence CAC 10 dL, patients 40–75 years of age with 0 diabetes mellitus, and patients 40–75 0 – 2.5% 2.5 – 5% 5.1 – 10% >10% Estimated 10-year FRS Categories years of age with an estimated 10-year ASCVD risk ≥7.5 percent, based on the Figure 1. CAC Score Compared With FRS Prevalence of coronary artery calcium (CAC) scores >0 and ≥100 compared across 10-year ACC/AHA Pooled Cohort Equations. CAC Framingham Risk Score (FRS) strata in the CARDIA study. There was signicant concordance score can be used for cardiovascular risk between CAC prevalence/amount and FRS such that prevalance of CAC scores >0 and ≥100 stratification in patients who do not fall were low in the lower FRS strata and increased with FRSs. into one of these four categories when Figure 1. CAC score compared to FRS

Official Publication of the National Lipid Association 19 100 CHD risk compared to using traditional 90 risk factors alone. The AUC increased 80 from 0.75 to 0.8. External validation in 70 both the Dallas Heart Study and Heinz 60 Nixdorf Recall studies showed very good Percentage of 50 11 Patients discrimination and calibration. 40 30 In assessing a patient’s cardiovascular risk, 20 CAC score provides additional information 10 0 when added to traditional risk factors. 45 50 55 60 65 70 75 80 The MESA score is a new clinical tool Age/Years that incorporates CAC score into CHD CAC=0 CAC 1-100 CAC>100 risk assessment. Ultimately, there is no Proportion of Patients in Each CAC Group with Increasing Age CAC: coronary artery calcium perfect risk calculator that can substitute Figure 2. Portions of Patients in Each CAC Group with Increasing Age for clinical decision-making. A healthcare provider must integrate all of the available information to arrive at a joint decision indexing the score for age.7 Based on Framingham Risk Score (FRS).8 This figure with the patient regarding management. n the results of the Heinz Nixdorf Recall, demonstrates the presence of CAC, even in MESA, and Rotterdam studies, the ACC/ those individuals deemed low risk. Disclosure statement: Dr. Goldenberg has no AHA supported revising an individual’s disclosures to report. Dr. Meng has no disclosures to report. risk assessment upward if a patient has a In the MESA study, CAC varied by age CAC score of greater than 300 Agatston (Figure 2). Even at the extremes of age References are listed on page 46. units or 75th percentile for their age. 45–50 versus 75–80, CAC was predictive Interestingly, statins may actually increase of risk (Figure 3).9 CAC score through “de-lipidation” of soft, cholesterol-laden plaques leading to a rise Area under the curve (AUC)/c-statistic in calcium density. Therefore, serial CAC evaluates the ability to discriminate scores should not be used to determine the between patients who will and will not

A: All CHD Events B: Hard CHD Events Only 25 20 20 15 15 10 10 5 5 0 0 45-54 55-64 65-74 75-84 45-54 55-64 65-74 ≥ 75 CAC=0 CAC 1-100 CAC>100

Incident CHD Rate/1000 Person-Years- Distribution Among Age Groups and CAC P<.001 for trends in both 3A and 3B. CAC: coronary artery calcium; CHD: coronary heart

Figure 3. Incident CHD Rate/1,000 Person Years – Distribution Among Age Groups and CAC Groups efficacy of statin therapy. develop the defined event. A review of various calculators shows that most In the Cardia Study, there were 2,831 generally have an AUC of 0.7510 (1 is people between the ages of 33 and 45 who perfect and 0.5 is random). Inclusion of had coronary calcium imaging. In Figure CAC in the MESA risk score significantly 1, the CAC prevalence is compared to the improves the prediction for 10-year

20 LipidSpin • Volume 14, Issue 4 • August 2016 Omega-3 Fish Oil: Cardioprotective or Not?

TERRANCE J. MORAN, MD, FACC, FAHA Director, Advance Lipid Management Program Tyler Heart Institute, Community Hospital of the Monterey Peninsula Monterey, CA Diplomate, American Board of Clinical Lipidology

Often there is a dichotomy regarding When looking at OM3 trials, there are six information published in the lay press things to be aware of: versus what is presented in the medical literature. So it’s nice when both agree, 1. Was the study trying to show short-term except on those rare occasions, when both or long-term benefits? Short-term benefit: Discuss this article at get it wrong. (One to two years on OM3) a reduction www.lipid.org/lipidspin in fatal cardiovascular events, generally Despite numerous epidemiologic and because of a reduction in ischemic, observational studies to the contrary, Men’s Health had a recent article titled membrane with OM3 “Is Fish Oil the New Snake Oil?”1–4 They • Electrophysiologic effects on various based that on several recent “high-profile “A meta-analysis is ion channels reviews” in “trusted medical journals” • Autonomic effects, such as reduction that no longer supported the original only as good as the in heart-rate variability and increased health claims regarding fish oil. They were studies it includes, vagal tone referring to two review articles recently • Reduction in perfusion arrhythmias published in the medical literature.5,6 The which gives an idea • An anti-inflammatory effect result is an uncertainty for both physicians and the public regarding the use of of the validity of Long-term benefit: (>3 years on OM3) omega-3 fish oil. a reduction in non-fatal or fatal cardiac these two recent events, such as acute coronary syndrome. The problem, though, is not a lack of Potential mechanisms include an anti- benefit from using omega-3 fatty acids meta-analyses.” inflammatory and/or an antithrombotic (OM3), specifically eicosapentaenoic acid effect. Do not look for a reduction in long- (EPA) and docosahexaenoic acid (DHA). term benefits when examining studies with The problem is that there was a lack of induced ventricular tachyarrhythmias.7 a short time span. quality fish oil studies included in these Potential anti-arrhythmic actions of OM3: two review articles.5,6 • A membrane-stability effect by 2. Was the patient receiving an appropriate enrichment of the myocardial dose? Short-term benefit trials need at

Official Publication of the National Lipid Association 21 of OM3 vs. the control. Sudden cardiac death (SCD) was reduced by 47 percent at four months (p=0.048).12 Note: There was minimal invasive treatment post-MI and only moderate medication use.

JELIS involved 18,645 high-risk or vascular-disease patients put on placebo vs. 1.8 gm of EPA.13 A five-year follow-up showed a 19 percent reduction (p=0.011) in major coronary events, primarily unstable angina and nonfatal MIs. Most risk reduction occurred after 2.5 years. Post-hoc analysis: 53 percent reduction in cardiovascular (CV) events in patients with Table 1. elevated triglycerides and low HDL-C.14

GISSI-HF involved 6,988 patients with least 0.5–1.0 gm/day of OM3, while the Men’s Health seems to have keyed on New York Heart Association (NYHA) class long-term trials generally require ≥1.5–2.0 the two recent review articles that II-IV and an average ejection fraction of gm/day. claimed there was insufficient evidence of 33 percent, randomized to placebo vs. secondary prevention with OM3 use. Kwak 1 gm OM3. Follow-up was 3.9 years.15 3. Were OM3 blood levels obtained evaluated 14 studies, while Rizos looked at There was a significant 9 percent reduction to show that the treated group had an the same 14 plus six additional studies.5,6 in mortality (p=0.041) and 8 percent adequate OM3 blood level vs. the control Both meta-analyses had numerous reduction in mortality and admissions for group? People have different OM3 shortcomings: 11 studies had follow-up chronic heart failure (CHF) (p=0.009). absorption abilities, different genetic ≤2.5 years, 11 had samples sizes of only Survival curves started to diverge after two handling of OM3, and the fish they eat 50–550, nine had no fish restriction, 14 years. may contain significantly different levels of had no measured omega-3 level, and most OM3. OM3 levels cannot be assumed to were not designed to detect cardiovascular Those showing no benefit: be adequate.8,9 endpoints.10 OMEGA randomized 3,804 immediate post-MI patients to OM3 1 gm vs. olive 4. Was the population large enough for the Of the eight studies in the review articles oil.16 There was no difference in SCD study? Primary prevention trials need to that had more than 550 patients: at one year. Problems: The study was have a much larger study population than underpowered. Aggressive post-MI secondary prevention trials. Those showing benefit: therapy, including percutaneous coronary DART randomized 2,033 men with recent intervention in 78 percent, dropped the 5. Was there a limitation on fish intake by myocardial infarction (MI) to OM3 — expected SCD rate of 3.5 percent down to the control group? Too much intake by the either oily fish or fish capsules — vs. 1.5 percent. Also, 44 percent of placebo control group could mask any benefit seen the control.11 There was a 29 percent patients were ingesting fish several times in the treated group. reduction in all-cause mortality (primarily a week. cardiac) over two years. The best reduction 6. What was the concurrent therapy used? in events was seen in those taking fish Alpha Omega Trial had 4,837 Aggressive revascularization and multiple capsules vs. simply increasing fish intake, participants with prior MI.17 Participants drug therapies may lessen the incidence of which may indicate a threshold effect for were randomized to placebo or 400 mg fatal cardiac events to such an extent that OM3. OM3 and followed for 3.5 years. Overall, it is hard to demonstrate benefit in short- there was no reduction in CV event rates, term studies. Long-term trials are not as GISSI Prevenzione had 11,323 patients but diabetics had a 50 percent reduction affected by concurrent therapy. <3 months post-MI randomized to 1 gm in coronary heart disease (CHD) events

22 LipidSpin • Volume 14, Issue 4 • August 2016 No. Favors Favors Omega-3 Control Studies Events Participants RR (95% CI) PUFAs Outcome All-cause mortality 17 6295 63279 0.96 (0.91-1.02) Cardiac death 13 3480 56407 0.91 (0.85-0.98) Sudden death 7 1030 41751 0.87 (0.75-1.01) Myocardial infarction 13 1755 53875 0.89 (0.76-1.04) Stroke 9 1490 52589 1.05 (0.93-1.18)

0.6 0.8 1.0 1.2 1.4 Relative Risk (95% CI) Figure 1. Association Between Omega-3 Fatty Acid Supplementation and Risk of Major Cardiovascular Disease Events: A Systematic Review and Meta-analysis and rate of arrhythmic events similar to p-value for significance at 0.006 and GISSI. Problems: Participants were given claimed, therefore, that the finding was an inadequate dose of OM3 and follow-up not significant (Figure 1).6 was too short. The JELIS curve didn’t start to diverge until 2.5 years. Summary: A meta-analysis is only as good as the studies it includes, which gives an ORIGIN randomized 12,536 high-risk idea of the validity of these two recent patients with impaired fasting glucose to meta-analyses. Yet, for some reason, they placebo vs. 900 mg of OM3 with a 6.2- have been accepted by the public and year follow up.18 There was no difference various physicians as evidence that there is in event rates. Problems: Patients received no cardiovascular benefit from OM3 use. an inadequate dose for long-term benefits. We need to keep sight of the numerous The placebo group was ingesting 40–568 other reviews and studies that have mg of OM3 a day. There was no measured described the advantages of using OM3 for OM3 level. cardiovascular benefits and continue to use OM3 for cardiovascular risk reduction (see SU.FOL.OM3 had 2,501 patients table with citations). n with a history of cardiovascular disease Disclosure statement: Dr. Moran is a speaker for randomized to OM3 600 mg vs. placebo.19 Amgen, Repatha, Sanofi, and Regeneron. They were followed for 4.7 years. There was no difference in cardiovascular events. References are listed on page 46. Problems: Patients received an inadequate dose. There was no fish restriction in the placebo group. It was underpowered.

So despite the inclusion of these suboptimal “no benefit” studies, omega-3 use in the larger of the two meta-analyses still favored a reduction in all-cause mortality, sudden death, and MI, although these reductions were not statistically significant. What was significant was the reduction in cardiac death (p=0.01) seen in the meta-analysis. The usual p-value for significance is≤ 0.05 so this result was impressive. Rizos, et al., for arguable reasons, decided to set the

Official Publication of the National Lipid Association 23 Statin Therapy for the Very Elderly >80 with ASCVD: Balancing the Benefits and Risks

JUDITH A. COLLINS, MSN, APRN-BC, FPCNA, FNLA Cardiovascular Nurse Practitioner Montrose Memorial Hospital Montrose, CO Diplomate, Accreditation Council for Clinical Lipidology

trial,8 randomized 5,804 United Kingdom significant all-cause mortality reduction patients age 70 to 82 with a history of, favoring atorvastatin. Overall treatment- or risk factors for, vascular disease to 40 related adverse events were 17.3 Discuss this article at mg pravastatin or placebo with an average percent on atorvastatin, 13.9 percent on www.lipid.org/lipidspin follow-up of 3.2 years. Mean low-density pravastatin, but not statistically different. lipoprotein cholesterol (LDL-C) reduction There is a large population >80 in the was 34 percent with pravastatin, which was LDS Hospital/University of Utah2 U.S., some who have either been advised well tolerated with 24 percent coronary conducted a prospective observational to or chose to discontinue statin therapy. heart disease (CHD) mortality reduction cohort study of 7,220 CAD patients for an Randomized clinical trials have typically and no significant adverse effects on liver average of 3.3 years. Statin therapy was excluded very elderly subjects or group function, muscle enzymes, cognition, or associated with mortality reductions in all all elderly into age >65. There are vast disability. Pravastatin treatment was not age groups, with greatest mortality benefit differences in this population in terms associated with a decrease in mortality. found in the >80 group (29.5 percent vs. of frailty vs. vigorousness, comorbidities, 8.5 percent, p=0.03). motivation, and financial resources. In The Study Assessing Goals in the Elderly the rapidly growing 80+ age group, the (SAGE) trial,9 a prospective multicenter A prospective observation study by NY prevalence of ASCVD exceeds that of randomized double-blind international trial, Medical College and University of Texas younger age groups, affecting 84.7 percent compared treatment with atorvastatin 80 Medical School3 followed 1,410 post-MI of men and 85.9 percent of women.1 mg to pravastatin 40 mg in 893 coronary patients with a mean age of 81 and LDL-C Prescribing patterns for the elderly have artery disease (CAD) patients age 65–85. >125 mg/dl in a long-term healthcare been reportedly low,2–5 and patient The primary endpoint was change in facility with a mean follow-up of three adherence rates tend to significantly ischemia duration on comparison of 48- years. New coronary event incidence was decrease over time.6–7 The evidence base hour holter monitor studies at baseline, 46 percent on statin vs. 72 percent on no regarding the use of statin specifically in three months, and 12 months. Both arms statin. the over 80 age group follows. had significant reduction in ischemia duration. There was no significant A retrospective chart abstraction of 5,500 Relevant Clinical Research Studies difference between the groups, although acute MI patients, found patients <80 The Pravastatin in Elderly Individuals there was a favorable trend in major who were prescribed a statin at discharge at Risk of Vascular Disease (PROSPER) coronary events and a post-hoc finding of had a significant 16 percent lower

24 LipidSpin • Volume 14, Issue 4 • August 2016 three-year all-cause mortality compared MRI.14 The FDA found rare post-marketing simvastatin dose for new patients because to patients not discharged on a statin reports of cognitive impairment have not of the increased risk of muscle damage, (p=.002). Patients >80 were not found to generally been serious and are reversible and the avoidance or dose modification have a significant statin-related mortality on discontinuation.15 In a 2013 systematic of specific medications to reduce benefit.4 review of 57 statin studies, University rhabdomyolysis risk.20 of Pennsylvania researchers concluded An observational Swedish study of 14,907 that the evidence does not support New cancer diagnosis in PROSPER acute MI patients >age 80 with median an association between statin use and increased on pravastatin,8 however, follow-up of 296 days and a maximum memory loss or dementia.16 extended follow-up of subjects to an of five years, compared outcomes for average of 8.6 years found no increased patients who had been prescribed statin The FDA reviewed post-marketing data of cancer risk.21 A Swedish study of MI therapy compared to no statin treatment clinically serious hepatotoxicity with statin patients age >80 found no statin-related at discharge. Following exclusion of use and noted extremely low incidence of increase in cancer mortality.7 Setoguchi patients who died within the first year, <2 per 1 million patient-years.15 A 2008 et al found rates of colorectal, lung, and the remaining patients were found to have meta-analysis of seven randomized clinical breast cancers in patients >65 similar to a 37 percent reduction in cardiovascular trials found more intense statin regimens the general population.22 mortality and acute MI mortality (RR 0.64, associated with a 1 percent increased CI 0.57-0.73).10 drug discontinuation rate due to elevated In conclusion, the decision to implement transaminases.17 statin therapy for the high risk very The meta-analysis of more vs. less intensive elderly with ASCVD should incorporate a statin therapy by the Cholesterol Treatment These data prompted the FDA to remove shared decision-making approach with an Trialists Collaboration11 included five trials routine LFT monitoring for asymptomatic upfront discussion of benefits and risks, of acute coronary syndrome or stable CAD patients from the statin package insert and consideration of patient perceptions, patients. Subjects >75 on more intense in 2012. PROSPER8 reported a very comorbidities, concurrent medications, statin had a statistically significant reduced low 0.03 percent incidence of >3 fold frailty, and cost concerns. The majority risk of major vascular events of 4.8 percent transaminases increase. In contrast, the of studies show overall a very favorable compared to 5.4 percent on less intense SAGE investigators,9 reported elevated cardiovascular benefit with low associated statin (p<0.0001). transaminases on atorvastatin 80 mg were risk that may help preserve quality of life. 4.3 percent compared to 0.2 percent The decision, however, to prescribe high Statin-prescribing practices are also on pravastatin 40 mg, however, they intensity statin therapy needs to take into strongly influenced by the provider’s and normalized on repeat testing or statin account factors that may predispose them patient’s perception of safety concerns. discontinuation. Considering these data, to increased risk, with regular monitoring The evidence base specifically regarding clinicians may want to monitor LFTs for the incorporated. Randomized clinical trials the over 80 age group is summarized very elderly on high intensity statin. with this population are needed. n below. The risk of myopathy has been associated Disclosure statement: Judith Collins has no disclosures to report. Potential Statin Safety Concerns with advancing age, female gender, Li et al13 found no significant association and renal or hepatic abnormalities,18 References are listed on page 46. between statin use and dementia or with underrepresentation of these Alzheimer disease in their prospective populations in clinical trials. Myalgia study of 2,356 cognitively intact randomly incidence was 1 percent in PROSPER, selected patients >65. Brain autopsies of with no rhabdomyolysis cases.8 Terry A. 110 subjects aged 65–79 years with prior Jacobson, MD, discussed factors associated statin use found a reduced risk for typical with muscle injury risk for the elderly, Alzheimer’s pathology. The Cardiovascular including hypothyroidism, concomitant Health Study, a longitudinal study of 3,334 cytochrome P450 inhibitor, fibrate, or patients >65, found statin use associated immunosuppressant use, reduced lean with slight reduction in cognitive decline body mass, and polypharmacy.19 In 2011, and lower risk of silent infarcts detected by the FDA advised avoidance of the 80 mg

Official Publication of the National Lipid Association 25 INDUSTRY COUNCIL The National Lipid Association would like to acknowledge the following companies for their support of the NLA’s overall mission and goals for 2016. They are honored as Industry Council members:

Akcea Therapeutics, A Subsidiary of Ionis Pharmaceuticals, Inc.

Alexion Pharmaceuticals, Inc.

Amarin Pharma Inc.

Amgen Inc.

AstraZeneca LP

Kastle Therapeutics

Kowa Pharmaceuticals America, Inc.

LabCorp®

Merck & Co., Inc.

Novartis Pharmaceuticals Corporation

Pfizer Inc.

Quest Diagnostics

Sanofi-Regeneron

26 LipidSpin • Volume 14, Issue 4 • August 2016 The Potential Role of Universal Genetic Screening for Familial Defective Apolipoprotein B-100 in Southern Pennsylvania

ROLF L. ANDERSEN, MD, FACC, FNLA Director Preventive Cardiology and Apheresis Clinic Lancaster General Health/Penn Medicine Lancaster, PA Diplomate, American Board of Clinical Lipidology

LARS ANDERSEN, BA Research Assistant Lancaster General Health/Penn Medicine Lancaster, PA

Familial defective apolipoprotein by FDB suffer myocardial infarction B-100 (FDB) is an autosomal dominant nine years earlier than non-carriers, and disorder of lipid metabolism considered R3500Q carriers have been reported by international guidelines to be a to display increased coronary artery genetically defined cause of familial calcification (CAC) even when compared Discuss this article at hypercholesterolemia (FH).1–3 FDB arises with non-carriers presenting with www.lipid.org/lipidspin from mutations in apolipoprotein B (apoB) equivalent levels of LDL-C.9,10 affecting the affinity of apoB-containing low-density lipoprotein particles for the Compared with LDL-R, relatively few low-density lipoprotein receptor (LDL-R) pathogenic mutations have been identified Chinese background.14–18 Furthermore, and, subsequently, their rate of endocytosis in apoB, and, unlike LDL-R, most fall an association study of genetic variants and catabolism in hepatocytes.4 FDB within a mutation “hotspot” affecting affecting lipid levels in over 50,000 is associated with both hyperlipidemia the conformation of the protein.11,12 subjects reported R3500Q to be the single and increased risk of atherosclerotic Interestingly, of mutations associated with variant most strongly associated with cardiovascular disease (ASCVD), although FDB, the two most common, known as elevated LDL-C in Americans of European the hypercholesterolemia caused by R3500Q and R3500W, affect the same site background, leading to an average increase FDB is often milder than that because within apoB.1,13 The R3500Q mutation is in LDL-C of 71 mg/dL.19 of mutation in LDL-R, the most frequent frequently reported in European cases of cause of autosomal dominant FH, and clinical heterozygous FH, and is thought In 2010, the Amish Research Clinic in is therefore frequently underdiagnosed to have arisen in a common central Lancaster, Pa., found that approximately by standard diagnostic criteria such as European ancestor due to the elevated 12 percent of members of the Old Order the Dutch Lipid Clinic Network and US prevalence reported in the region; its twin Amish, an Anabaptist group of Swiss- MEDPED criteria.5–9 Recent results from mutation, R3500W, was recently reported German origin, carried the R3500Q the Copenhagen General Population Study to comprise a plurality of mutations mutation, roughly 60 times the rate found report that on average, individuals affected affecting subjects with clinical FH of Han in the general Caucasian population.10

Official Publication of the National Lipid Association 27 The investigators who discovered the Number 251, established provision for Pennsylvania and support for addressing high prevalence of FDB among the “screening tests of newborn children” FDB as an issue of public health. n Amish described the phenomenon as a for several inherited diseases, including “founder effect,” wherein a population those more common among the Old Order Disclosure statement: Dr. Andersen has no disclosures to report. Lars Andersen has no disclosures to report. bottleneck and subsequent endogamy over Amish and other Anabaptist groups such generations led to a dramatic increase in as phenylketonuria (PKU) and glutaric References are listed on page 46. the prevalence of the R3500Q mutation. acuduria (GA).23 As a disorder of lipid Founder effects for mutations causing metabolism conferring elevated lifelong FH have been reported in several other risk for atherosclerosis and myocardial infarction, FH due to the R3500Q mutation poses a significant burden on the “ Low rates of correct population health of special groups and the general population in Pennsylvania, diagnosis according however, screening and early treatment for FDB in this region presents a unique to standard clinical opportunity in lipid-focused preventive medicine. In addition to the benefits of FH diagnostic criteria lifelong treatment and management of the further underscore disorder, identification of newborns with FDB could serve as a starting point for the importance of “reverse” cascade screening of parents and molecular diagnosis other affected relatives. As a single nucleotide polymorphism for FDB.” (SNP), diagnostic testing for the R3500Q mutation can be completed inexpensively and quickly en masse, and with currently populations, such as French Canadians and available lipid-lowering treatment, the Afrikaners (South African ethnic group disease burden of FH due to mutations descended from predominantly Dutch in apoB can be significantly reduced. As settlers); however, the reported population an internationally accepted, frequently prevalence rates of FH mutations within reported cause of FH, FDB diagnosed these groups are significantly lower as part of universal screening would than that of FDB among the Amish, a also qualify those affected for specialty rapidly growing demographic group.20,21 care, including therapy with monoclonal Furthermore, approximately 10 to 20 antibody inhibitors of proprotein percent of the Amish enter the general convertase subtilisin/kexin type 9 population each generation, leaving not (PCSK9).24,25 Low rates of correct diagnosis only present members of the Amish according to standard clinical FH diagnostic community but also the many individuals criteria further underscore the importance of extended Amish background at risk.22 of molecular diagnosis for FDB. The unique population of southern Pennsylvania thus To provide early preventive care and presents an opportunity to implement reduce lifelong disease burden in the individualized therapy based on mutational public, the Pennsylvania Department status on a population scale, a generational of Health has undertaken since 1965 a goal not only for lipid specialists, but for newborn child genetic screening protocol. the entire medical field. We therefore call Last updated in 2014, the Newborn Child for the addition of the R3500Q mutation Testing Act, also known as P.L. 497, to universal genetic screening protocols in

28 LipidSpin • Volume 14, Issue 4 • August 2016 Omega-3 Fatty Acid Fish Oil Dietary Supplements for Disease Management: Are They Appropriate for Patients?

R. PRESTON MASON, PhD Department of Medicine, Cardiovascular Division Brigham and Women’s Hospital Harvard Medicine School Boston, MA Elucida Research LLC Beverly, MA

DANIEL E. HILLEMAN, PharmD Creighton University School of Pharmacy and Health Professions Omaha, NE

Perceptions of Fish Oil Dietary taking either a FODS or a prescription Supplements (FODS) omega-3 fatty acid (OM3FA) product. According to 2008 national health Of these patients, 40 percent indicated statistics, fish oil dietary supplements that they were taking the product for Discuss this article at (FODS) are the most commonly used general health, while 60 percent reported www.lipid.org/lipidspin supplements among U.S. adults.1 There taking FODS for a specific health benefit.4 is a general public perception that These specific health benefits typically consumption of fish is a healthy dietary corresponded to the medical conditions habit.2 This perception may be responsible of the individual survey respondents. mixture of eicosapentaenoic acid [EPA] for a greater than threefold increase in Myocardial infarction and coronary disease and docosahexaenoic acid [DHA]), yet the use of FODS among older adults in were most commonly mentioned.5 Only only nine of those patients were actually the U.S. over the past decade.3 Individual 10 percent of cardiology patients indicated filling the prescription.4 Fewer than one perceptions of the benefits of fish and they were using the product for lipid in four of the 496 patients could identify FODS cover a wide spectrum. These disorders.4 that OM3FAs were the active ingredients perceptions include the idea that FODS in their FODS or prescription OM3FA may improve general health, reduce The same survey also showed that, among product, and less than 5 percent knew the atherogenic lipids, and improve brain and the patients known to be using either actual amount of active ingredient in the heart function, and that fish serves as a FODS or a prescription OM3FA product, product they were using.4 The number of good source of protein.2,4 only 9 percent (45 of 496 patients) pills (capsules or dosage units) taken each indicated that their physician told them to day ranged from 1 to 8. Daniel E. Hilleman, PharmD, one of the use the product.4 About half (n = 22) of authors of this article, conducted a survey those patients said their physician wrote a The majority of patients (73 percent) in of 496 patients with known cardiovascular prescription for omega-3-acid ethyl esters Hilleman’s survey said they bought the disease who indicated that they were (an OM3FA drug product containing a same FODS at each purchase.4 However,

Official Publication of the National Lipid Association 29 only 17 percent of patients indicated that they bought their FODS in a pharmacy.4 Given that the vast majority of patients are buying their FODS outside of pharmacies, pharmacists and other healthcare providers need to be proactive when taking patient histories and document the use of these products at times other than when they are purchased. A complete history of patient use of prescription and non-prescription products, including dietary supplements, should be taken each time a patient visits his or her pharmacy and/or treating provider. An additional concern is that research shows that some pharmacists have a knowledge gap about the safety and efficacy of common dietary supplements.6 Pharmacists need additional education and training about commonly used dietary supplements, including FODS, since they are not approved by the Food and Drug Administration (FDA) to treat disease.

Fish Oil Dietary Supplements (FODS) versus Prescription Omega-3 Fatty Acids (OM3FAs) for Patient Care For patients with elevated triglyceride (TG) levels, the American Heart Association has recommended 2–4 g/day of EPA+DHA.7 To achieve this goal, patients may choose Figure 1. Fatty acid (FA) content of three leading (by U.S. sales) fish oil dietary supplements (FODS 1, FODS to take FODS on their own instead of 2, and FODS 3). FA content was determined by GC-FAME analysis. Each FODS contained more than 30 fatty acids, including 10-14 saturated fat species comprising up to 36% of the total fatty acid content. Levels taking prescription products indicated of OM3FA also varied widely among the DS (33%-79%). Data are presented as % of total FA (for a given as an adjunct to diet to reduce TG levels DS sample) by weight. The structure of each FA is denoted by the number of carbon atoms followed by a in adults with severe (≥500 mg/dL) colon and then the location of the first double bond counted from the –COOH end of the chain. Locations of additional double bonds are indicated in parentheses. The term “cis” indicates that the two hydrogen atoms hypertriglyceridemia. Some managed-care adjacent to a double bond are located on the same side of the chain while “trans” indicates they are on plans require patients to fail on FODS opposites sides of the chain. before covering prescription products. Although FODS are widely available, dose of EPA or EPA+DHA equivalent to are cooked at about 100°C.10 OM3FAs are dietary supplements are not subject to prescription OM3FA 4 g/day,9 potentially susceptible to free radical damage during the strict regulations governing over- negating any cost advantage. such manufacturing processes, and the the-counter drug approval by the FDA, damage is accelerated in the presence of so their content and chemical integrity Oil extracted from marine animals is a light and contaminants.10 Free radicals are not regulated in a rigorous manner.8 common source of FODS but it also is an contribute to oxidative modification of Additionally, their efficacy and safety are extremely unstable product. Fish oil is OM3FAs, which may interfere with the not regulated prior to marketing and are obtained primarily from processing plants intended biological or potential clinical not well documented.8 Additionally, the during the manufacturing of fishmeal from benefit of FODS.12,13 low EPA and DHA content of FODS may whole or filleted fish bodies.10,11 To aid require patients to take ≥10 capsules/ in the coagulation of tissue protein and Independent studies from various day in an attempt to reach a therapeutic expression of the oils, the harvested fish laboratories have verified concerns about

30 LipidSpin • Volume 14, Issue 4 • August 2016 the OM3FA content and integrity of FODS. such as OM3FAs.18 All of the supplements Conclusion A study funded by the U.S. Department exceeded recommended maxima for most Despite the widespread use of FODS in of Agriculture found that 74 percent of of these oxidation products.18 By contrast, the U.S., there is substantial confusion 47 FODS tested contained less than the the prescription product did not produce about their benefits and appropriate use amounts of EPA and/or DHA indicated on significant levels of oxidation products among both healthcare providers and their labels.14 A scientific study in New under identical test conditions.18 patients. There is the perception that Zealand of 36 FODS demonstrated that FODS produce various health benefits, more than 80 percent had unacceptably including a reduction in atherogenic lipids high levels of lipid peroxides, an indication “Despite the and improvements in brain and heart of lipid decomposition.15 Of those tested, function, but these have not been clinically only three (8 percent) met international widespread use of proven. FODS are not approved by the standards for acceptable peroxide and FDA to treat or cure disease and are not total oxidation levels. Additionally, FODS FODS in the U.S., categorized as over-the-counter drugs, sold in North America have been shown there is substantial but as dietary supplements, equating to to have unacceptably high levels of lipid less rigorous regulation regarding efficacy, peroxides.16 An elevated peroxide value confusion about safety, content, and chemical integrity. indicates high levels of primary oxidation While containing varying amounts of and hydroperoxides, which can interfere their benefits desirable OM3FAs, leading FODS also with any intended biological antioxidant contain more than 30 fatty acids, including activity. and appropriate significant levels of saturated fat. FODS also contain elevated levels of primary and Recently presented data highlighted use among secondary lipid oxidation products that the fatty acid content issues of leading both healthcare interfere with their biological activity and FODS (by sales) in the U.S. with respect may have adverse clinical implications. to saturated fat, EPA, and DHA.17 Also providers and These data indicate that there is a need measured were the extent of oxidative for more education about the quality and damage in the oil compared to a patients.” appropriate use of FODS. As a product prescription form with respect to purity without rigorous FDA regulation and with and the ability to prevent human low- varying levels of fatty acids and oxidation density lipoprotein (LDL) oxidation in Finally, the biological activity of the products, FODS are not an appropriate vitro.17 This research was presented by OM3FAs isolated from a leading FODS substitute for prescription products in R. Preston Mason, PhD, co-author of was compared to non-oxidized and patients diagnosed with certain medical this article, at the 2015 meeting of the oxidized preparations of EPA/DHA conditions, such as very high TG levels. n Academy of Managed Care & Specialty mixtures to determine their effects on Pharmacy (AMCP).17 The fatty acid small, dense LDL (sdLDL) oxidation.18 Disclosure statement: Dr. Mason has no disclosures to report. Dr. Hilleman has no disclosures to report. content of six FODS was determined and Oxidation of sdLDL was inhibited by more than 30 fatty acids were identified >95 percent (P<0.001) with the non- References are listed on page 47. in the FODS samples, including 10 to oxidized OM3FAs but was not inhibited 14 saturated fatty acids in each sample, by the oxidized OM3FAs or the FODS comprising as much as 36 percent of total isolate, which contained both oxidized fatty acid content (Figure 1).17 Additionally, and non-oxidized OM3FAs.17 The clinical OM3FA levels varied widely among the translation of the lack of biological effect FODS (33 to 79 percent), including levels from oxidized FODS has been reported of EPA (21 to 52 percent) and DHA (9 to to include negative therapeutic effects on 31 percent). This study also measured blood lipid levels12 and a lack of intended primary and secondary products of effectiveness on lipid or inflammatory oxidation that are associated with fatty parameter levels.19 acids containing multiple double bonds,

Official Publication of the National Lipid Association 31 Pseudohypertriglyceridemia in a Teenager: Evaluation, Management, Implications, and Literature Review

JAMES J. MACIEJKO, MS, PhD, FACC MANISHA RAVI Director, Adult and Pediatric Lipid Clinics University of Michigan St. John Hospital and Medical Center Ann Arbor, MI Professor, Department of Internal Medicine Wayne State University School of Medicine Detroit, MI

PREMCHAND ANNE, MD, MPH, FACC Pediatric and Adult Congenital Cardiology St. John Providence Children’s Hospital Clinical Assistant Professor, Department of Pediatrics Wayne State University School of Medicine Detroit, MI

academically. He denies tobacco, alcohol, oriented, and appeared well-nourished. and illicit drug use. His medical history The physical exam was unremarkable. is unremarkable and he does not take medications. He was born at full term, Pertinent chemistry results: Thyroid Discuss this article at without complications. stimulating hormone: 1.58 mcU/mL; www.lipid.org/lipidspin free thyroxine: 1.3 ng/dL; fasting blood Family history: The patient has a 12-year- glucose: 96 mg/dL; hemoglobin A1c: 5.4 old sister, whose lipid profile is not known. percent; creatinine: 0.9 mg/dL; aspartate Pediatric hypertriglyceridemia (fasting His mother (age 45 years) is being treated aminotransferase: 7 IUnits/L; alanine triglycerides ≥ 130 mg/dL) was identified for hypothyroidism, and is otherwise aminotransferase: 30 units/L. by routine screening in a healthy healthy. His maternal grandparents (ages 14-year-old male. He was subsequently 72 and 75 years) are healthy, as is his Impressions and recommendations: referred to our pediatric lipid clinic for maternal great-grandmother at age 90 The elevated fasting triglyceride level, evaluation. A fasting lipid profile confirmed years. His father (age 48 years) has a the absence of secondary causes, and hypertriglyceridemia: total cholesterol normal lipid profile. The patient’s paternal the lack of a significant family history of (TC): 136 mg/dL, triglyceride (TG): 357 grandparents are in their mid-80s and hyperlipidemia suggested the diagnosis of mg/dL, low-density lipoprotein cholesterol healthy. No significant family history of sporadic hypertriglyceridemia.1 (LDL-C): 18 mg/dL, high-density early atherosclerotic cardiovascular disease lipoprotein cholesterol (HDL-C): 47 mg/dL, (ASCVD), hyperlipidemia, or diabetes was Sporadic hypertriglyceridemia is a and non-HDL-C: 89 mg/dL. reported. primary dyslipidemia that is distinguished from familial hypertriglyceridemia by The patient is an active ninth grader who Physical examination: His body mass the lack of a family history of isolated participates in track and cross country, index (BMI) was 16.2 Kg/m2 (6th percentile hypertriglyceridemia in 50 percent follows a prudent diet, and does well for age and gender). The patient was alert, or more of first- and second-degree

32 LipidSpin • Volume 14, Issue 4 • August 2016 maternal or paternal family relatives.1 The blanked TG: 68 mg/dL, glycerol: 3763 of triglycerides to glycerol and fatty acids. triglyceride concentration is generally mmol/L. With confirmation of glycerolemia The second step utilizes glycerol kinase to modestly elevated (250–400 mg/dL), and normal triglycerides, a letter phosphorylate glycerol. The final step is although it can be very high (≥ 500 documenting pseudohypertriglyceridemia the formation of a colored phosphorylated mg/dL) if associated with secondary was provided to the family to accompany glycerol that can be measured causes of hypertriglyceridemia (e.g., subsequent lipid profile analyses. spectrophotometrically to provide an unhealthy body weight, hyperglycemia, estimate of the triglyceride concentration. hydrochlorothiazide, steroids, beta-blocker Pseudohypertriglyceridemia: The Since these enzymatic assays measure use, and/or excess alcohol consumption).2 American Academy of Pediatrics (AAP) triglycerides as the quantity of glycerol in defines fasting triglyceride levels into a specimen, the elevated plasma glycerol An over-the-counter (OTC) marine three categories: acceptable (<90 mg/ concentration in hyperglycerolemia causes omega-3 fatty acid supplement containing dL), borderline-high (90–129 mg/dL) and an overestimation of the true triglyceride 300 mg of eicosapentaenoic acid (EPA)/ high (≥130 mg/dL).4 It is recommended concentration. Glycerol-blanking docosahexaenoic acid (DHA) per one gram that elevated triglycerides initially be triglyceride assays “blank” or subtract the (1 gram capsule, twice daily), along with treated with lifestyle changes, including free plasma glycerol from the specimen dietary reduction of refined carbohydrates dietary modification (i.e. reduced intake of and assay only the glycerol produced was recommended. A repeat fasting lipid refined carbohydrate), weight reduction, from the enzymatic hydrolysis of the profile assessment after three months decreased consumption of alcohol, and triglycerides.3 of following these recommendations control of underlying disorders such as indicated no significant change in the diabetes mellitus and hypothyroidism. Summary: The evaluation of fasting triglycerides level; TC: 134 mg/ Pharmacologic therapies including hypertriglyceridemia should always include dL, TG: 353 mg/dL, LDL-C: 17 mg/dL, omega-3 fatty acids, niacin, and fibrates a detailed medical and family history. A apolipoprotein B (apoB): 75 mg/dL, HDL-C: can be considered for fasting triglyceride 12-hour fast is recommended to optimally 46 mg/dL. The OTC marine omega-3 fatty levels greater than 500 mg/dL.3,4 Should assess triglyceride levels. Should lifestyle acid supplement was discontinued and an elevated fasting triglyceride remain changes (dietary improvement, physical replaced with the prescription omega-3- unchanged following lifestyle modification activity, weight reduction), control of fatty acid ethyl ester (465 mg EPA and 375 with or without pharmacological therapy, secondary metabolic or pharmacologic mg DHA per 1 gram capsule), at one gram pseudohypertriglyceridemia should be causes, and/or triglyceride-lowering therapy capsule taken twice daily. This change considered.3 fail to reduce the triglyceride level, the to the prescription omega-3 fatty acid presence of pseudohypertriglyceridemia ethyl ester was instituted to eliminate the An elevated plasma concentration stemming from hyperglycerolemia should potential variability in EPA/DHA content of glycerol can cause pseudohyper- be included in the differential diagnosis. A in OTC omega-3 fatty acid supplements. triglyceridemia. Glycerolemia can be glycerol-blanked triglyceride assay should The prescription omega-3 fatty acid ethyl secondary to stress, glycerol-containing be performed to confirm this diagnosis. n ester has a standard composition of EPA intravenous medications, parental and DHA content. Dietary and adherence nutrition and metabolic disorders such as Disclosure statement: Dr. Maciejko has no disclosures to report. Dr. Anne has no disclosures to report. recommendations were reinforced. glycerol kinase deficiency (GKD). This is Manisha Ravi has no disclosures to report. an X-linked recessive disorder occurring Follow-up: A clinical chemistry assessment in isolation or in complex form involving References are listed on page 47. after six weeks of taking the prescription adrenal malfunction.5 The frequency of omega-3-fatty acid ethyl ester indicated asymptomatic isolated GKD is unclear, no reduction in the fasting triglyceride although rare, with only 25 cases level; TC: 153 mg/dL, TG: 385 mg/dL, reported.3 LDL-C: 30 mg/dL, HDL-C: 45 mg/dL. This suggested “pseudohypertriglyceridemia.”3 Almost all clinical laboratories analyze A subsequent glycerol-blanked triglyceride concentrations using enzymatic triglyceride assessment confirmed methods that involve three basic steps. The pseudohypertriglyceridemia: glycerol- first step uses lipases for the hydrolysis

Official Publication of the National Lipid Association 33 AtheroscleroticImran Baig, MD, placed first Arteriesin the Sanofi Regeneron with YoungCholesterol Investigator Award Crystals Competition at the Enhance Bacterial Growth: Risk for Plaque Destabilization 2016 NLA Scientific Sessions in New Orleans. You can view a downloadable version of this abstract online at lipid.org/util/eposters/PDF/177.pdf. The Young InvestigatorImran Baig, Competition Apoorv was sponsored Kalra, by Amy an Scharmen, Manjunath Raju, Joseph Gardiner, educational grant from Sanofi U.S. and Regeneron Pharmaceuticals.Heather De Feijter-Rupp, Abed Janoudi, George S. Abela Atherosclerotic Arteries with CholesterolDepartment of Crystals Medicine, EnhanceDivisions ofBacterial Cardiology, Growth: Infectious Risk Diseases for Plaque and Department Destabilization Atherosclerotic Arteries with Cholesterol Crystals Enhance Bacterial Growth: Risk offorImran Epidemiology, Plaque Baig, ApoorvDestabilization Michigan Kalra, Amy State Scharmen, University Manjunath and Sparrow Raju, Joseph Hospital, Gardiner, East Lansing, Michigan Imran Baig, Apoorv Kalra, Amy Scharmen, Manjunath Raju, Joseph Gardiner, Heather De Feijter-Rupp, Abed Janoudi, George S. Abela Heather De Feijter-Rupp, Abed Janoudi,Background George S. AbelaDepartment of Medicine,Methods Divisions of Cardiology, Infectious DiseasesResults and Department Department of Medicine, Divisions of Cardiology,In previous reports Infectious we demonstrated Diseases that ofand Epidemiology, Department• Ten NZW rabbits Michigan were made State atherosclerotic University byand •SparrowArterial samples Hospital, with Eastatherosclerosis Lansing, had Michigan significantly higher bacterial count compared of Epidemiology, Michigan State Universitycholesterol and Sparrow occupies greater Hospital, space East when Lansing, balloon Michigan de-endothelialization and feeding a crystallizing from a liquid to a solid state cholesterol enriched diet for six months. with the normal controls (Fig. 3). forming sharpBackground tipped crystals that can tear Methods • UsingResults analysis with Box-Cox transformation • Arterial tissue was sampled from the aortas fibrous membranes (1,2). Similar findings have of bacterial count there was a significantly In previous reports we demonstrated that • Ten NZWafter rabbits euthanasia were made and atherosclerotic placed in a washer by • ringArterial to samples with atherosclerosis had Background Methods been noted in humanResults coronary arteries of higher bacterial count present in 1µm cholesterol occupies greater space when balloonexpose de-endothelialization only the intimal and surface feeding ato a broth significantly higher bacterial count compared patients dying with acute myocardial infarction atherosclerotic arteries compared with In previous reports we demonstrated that • Ten NZW rabbits were made atherosclerotic by crystallizing• Arterial samples from a liquid with atherosclerosis to a solid state had cholesterol enriched diet for six months. with the normal controls (Fig. 3). solution with Staphylococcus aureus (Fig. 2). normal controls (p<0.0001), (Fig. 4). Figure 5: (left) Control cholesterol occupies greater space when balloon de-endothelialization and feeding a forming(Fig.significantly 1). sharp tipped higher crystals bacterial that count can tearcompared • Using analysis with Box-Cox transformation • Arterial tissue was sampled from the aortas crystals (right) crystallizing from a liquid to a solid state cholesterol enriched diet for six months. fibrouswith membranesthe normal controls(1,2). Similar (Fig. findings3). have • The same was repeated for normal controlof bacterial• countBy SEM there Staphylococcus was a significantly aureus bacteria after euthanasia and placed in a washer ring to Bacteria attaching to forming sharp tipped crystals that can tear been• Using noted analysis in human with coronary Box-Cox arteries transformation of rabbits fed normal rabbit chow without intimalhigher bacterialwere count found present attached in to cholesterol crystals 1µm • Arterial tissue was sampled from the aortas expose only the intimal surface to a broth cholesterol crystals fibrous membranes (1,2). Similar findings have patientsof bacterial dying withcount acute there myocardial was a significantly infarction injury. atheroscleroticin thearteries atherosclerotic compared with arteries and appeared after euthanasia and placed in a washer ring to solution with Staphylococcus aureus (Fig. 2). Figure 5: (left) Controlon atherosclerotic been noted in human coronary arteries of (Fig.higher 1). bacterial count present in 1µm normal controlsto be (p<0.0001), dissolving (Fig. them 4). (Fig. 5). expose only the intimal surface to a broth crystals (right) arterial wall patients dying with acute myocardial infarction atherosclerotic arteries compared with • The •sameTen was samples repeated were for obtainednormal control from 5 • By SEM Staphylococcus aureus bacteria solution with Staphylococcus aureus (Fig. 2). Figure 5: (left) Control Bacteria attaching dissolvingto and pitting (Fig. 1). normal controls (p<0.0001), (Fig. 4). atherosclerotic rabbits and 5 normal controls.were found attached to cholesterol crystals rabbitscrystals fed normal(right) rabbit chow without intimal cholesterol crystalsthe crystals. • • By SEM Staphylococcus aureus bacteria in the atherosclerotic arteries and appeared The same was repeated for normal control injury.Bacteria• For each attaching group, to five samples were incubated in on atherosclerotic rabbits fed normal rabbit chow without intimal were found attached to cholesterol crystals to be dissolving them (Fig. 5). • Ten cholesterolsamplesbroth werefor crystals 1 obtained h and another from 5 five samples were arterial wall injury. in the atherosclerotic arteries and appeared on atherosclerotic dissolving and pitting to be dissolving them (Fig. 5). atheroscleroticincubated rabbits for 3 and h. Bacterial5 normal controls.colony counts were • Ten samples were obtained from 5 arterial wall the crystals. Conclusion • For eachmeasured group, five at sampleseach time were interval. incubated in atherosclerotic rabbits and 5 normal controls. dissolving and pitting broththe• for Bacterialcrystals. 1 h and anotherpresence five on samples the intimal were surface was • This study demonstrates that bacteria have a • For each group, five samples were incubated in Figure 3. (left) Bacterial growth from normal artery incubatedexamined for 3 h. Bacterialby scanning colony electron counts microscopywere high affinity to cholesterol crystals in arterial broth for 1 h and another five samples were measured at each time interval. as control inoculum. (right) Bacterial growth from Conclusion (SEM) from additional arterial samples exposed atherosclerotic artery inoculum. tissues rich in cholesterol crystals. incubated for 3 h. Bacterial colony counts were . Scanning electron micrograph (SEM) of Figure 1 • Bacterialto presencebacteria. on the intimal surface was • This study demonstrates• The presence that bacteria and growthhave a of bacteria in measured at each time interval. left anterior descending artery in a patient who Conclusion Figure 3. (left) Bacterial growth from normal artery examined by scanning electron microscopy as control inoculum. (right) Bacterial growth from high affinity to cholesterol crystals in arterial 20000 atherosclerotic plaques have the potential of • Bacterial presence on the intimal surface was died with acute cardiovascular event. Cholesterol (SEM)• This from study additional demonstrates arterial samplesthat bacteria exposed have a atherosclerotic artery inoculum. tissues rich in cholesterol crystals. Figure. Scanning 3. (left) Bacterial electron growth micrograph from normal (SEM) artery of destabilizing the plaque leading it to rupture. examined by scanning electron microscopy Figurecrystals 1 are noted perforating the intimal surface to bacteria.high affinity to cholesterol crystals in arterial 18000 • The presence and growth of bacteria in left anterioras control descending inoculum. (right)artery Bacterial in a patient growth who from Normal • Further studies on the mechanism of (SEM) from additional arterial samples exposed justatherosclerotic below the plaque artery inoculum. rupture site (1). tissues rich in cholesterol crystals. 16000 atherosclerotic plaques have the potential of Figure 1. Scanning electron micrograph (SEM) of died with acute cardiovascular event. Cholesterol 20000 interaction between bacteria and cholesterol to bacteria. • The presence and growth of bacteria in 14000 Atherosclerotic destabilizing the plaque leading it to rupture. left anterior descending artery in a patient who crystals• Bacteria are noted have perforating been reported the intimal present surface in human 18000 crystals need to be performed. However, a just below the plaque rupture site (1). atherosclerotic plaques have the potential of Normal12000 • Further studies on the mechanism of died with acute cardiovascular event. Cholesterol atherosclerotic20000 plaques (3). Both gram positive 16000 plausible explanation for our findings may be destabilizing the plaque leading it to rupture. Atherosclerotic10000 interaction between bacteria and cholesterol crystals are noted perforating the intimal surface • Bacteria(Staphylococcus18000 have been aureusreported) andpresent gram in humannegative 14000 just below the plaque rupture site (1). Normal • Further studies on the mechanism of crystals need to berelated performed. to bacteria However, utilizing a cholesterol as a atherosclerotic(Pseudomonas16000 plaques aeruginosa (3). Both) bacteria gram positive have been 12000 8000 Atherosclerotic interaction between bacteria and cholesterol plausible explanationsource for our of nutrition.findings may be • 14000 10000 6000 Bacteria have been reported present in human (Staphylococcusshown to interact aureus with) and cholesterol gram negative crystals. crystals need to be performed. However, a related to bacteria utilizing cholesterol as a 12000 8000 4000 atherosclerotic plaques (3). Both gram positive (Pseudomonas aeruginosa) bacteria have been plausible explanation for our findings may be source of nutrition. 10000 6000 count colony Bacterial (Staphylococcus aureus) and gram negative shown to interact withObjective cholesterol crystals. related to bacteria utilizing1µ cholesterol as a 2000 References (Pseudomonas aeruginosa) bacteria have been 8000 4000 source of nutrition. 0 1µ 1. Abela GS, Aziz K. Cholesterol Crystals Rupture Biological Membranes and Human 6000 count colony Bacterial 2000 References shown to interact with cholesterol crystals. In this study weObjective investigate if arteries with 1µ 1 3 Plaques During Acute Cardiovascular Events: A Novel Insight into Plaque Rupture 4000 0 by Scanning Electron Microscopy. Scanning 2006; 28:1-10. Incubation1µ time (hours)1. Abela GS, Aziz K. Cholesterol Crystals Rupture Biological Membranes and Human

atheroscleroticcount colony Bacterial plaque rich in cholesterol 1µ In this study2000 we investigate if arteries with References 1 3 Plaques During Acute Cardiovascular2. Abela GSEvents: et al. A EffectNovel Insightof cholesterol into Plaque crystals Rupture on plaques and intima in arteries of Objective by Scanning Electron Microscopy.patients Scanning with2006; acute 28:1 coronary-10. and cerebrovascular syndromes. Am J Card 2009;103: crystals0 will enhance bacterial growth1µ FigureIncubation 4: Bacterial time colony (hours) counts following incubation of atherosclerotic plaque rich in cholesterol 1. Abela GS, Aziz K. Cholesterol Crystals Rupture Biological Membranes and Human 2. Abela GS et al. Effect of cholesterol959– 968.crystals on plaques and intima in arteries of compared to normal non-atherosclerotic Plaques During Acute Cardiovascular Events: A Novel Insight into Plaque Rupture normal (gray) and atherosclerotic (black) aorta segments In this study we investigate if arteries with crystals will enhance1 bacterial growth 3 Figure 4: Bacterial colony counts following incubation of patients with acute coronary3. and Izadi cerebrovascular M et al. Helicobacter syndromes. speciesAm J Cardin atherosclerotic2009;103: plaques of patients with by ScanningFigure Electron 2 Microscopy.. Washer Scanning with 2006;exposed 28:1-10. arterial intima. with Staphylococcus aureus for 1 or 3 hours. Bars959– 968.= 㼼 SD. arteries in a rabbitIncubation model. time (hours) normal (gray) and atherosclerotic (black) aorta segments coronary artery disease. Cardiovasc Pathol 21:307-311. atherosclerotic plaque rich in cholesterol compared to normal non-atherosclerotic 2. Abela GS et al. Effect of cholesterol crystals on plaques and intima in arteries of Figure 2. Washer with exposed arterial intima. with Staphylococcus aureus for 1 or 3 hours. Bars = 㼼 SD. 3. Izadi M et al. Helicobacter species in atherosclerotic plaques of patients with crystals will enhance bacterial growth arteriesFigure in 4: a Bacterial rabbit model.colony counts following incubation of patients with acute coronary and cerebrovascular syndromes. Am J Card 2009;103: coronary artery disease. Cardiovasc Pathol 21:307-311. 959–968. compared to normal non-atherosclerotic normal (gray) and atherosclerotic (black) aorta segments Figure 2. Washer with exposed arterial intima. with Staphylococcus aureus for 1 or 3 hours. Bars = 㼼 SD. 3. Izadi M et al. Helicobacter species in atherosclerotic plaques of patients with arteries in a rabbit model. coronary artery disease. Cardiovasc Pathol 21:307-311.

34 LipidSpin • Volume 14, Issue 4 • August 2016 Atherosclerotic Arteries with Cholesterol Crystals Enhance Bacterial Growth: Risk for Plaque DestabilizationAtherosclerotic Arteries with Cholesterol Crystals Enhance Bacterial Growth: Risk for Plaque Destabilization Atherosclerotic Arteries with Cholesterol Crystals Enhance Bacterial Growth: Risk for Plaque Destabilization Imran Baig, Apoorv Kalra, Amy Scharmen, Manjunath Raju, Joseph Gardiner, Imran Baig, Apoorv Kalra, Amy Scharmen, Manjunath Raju, Joseph Gardiner, Heather De Feijter-Rupp, Abed Janoudi, George S. Abela Imran Baig, Apoorv Kalra, Amy Scharmen, Manjunath Raju, Joseph Gardiner, Department of Medicine, Divisions of Cardiology, Infectious Diseases and Department Heather De Feijter-Rupp,Atherosclerotic Abed Janoudi, HeatherArteries Dewith George Feijter Cholesterol-Rupp, S. AbedCrystals Abela Janoudi, Enhance George Bacterial S. Abela Growth: Risk for Plaque Destabilization of Epidemiology, Michigan State University and Sparrow Hospital, East Lansing, Michigan Imran Baig, Apoorv Kalra, Amy Scharmen, Manjunath Raju, Joseph Gardiner, Department of Medicine, Divisions of Cardiology, Infectious Diseases and Department Heather De Feijter-Rupp, Abed Janoudi, George S. Abela Background Methods Results of Epidemiology, Michigan State University and Sparrow Hospital, East Lansing, Michigan Department of Medicine, Divisions of Cardiology, InfectiousDepartment ofDiseases Medicine, Divisions and of Cardiology, Department Infectious Diseases and Department In previous reports we demonstrated that • Ten NZW rabbits were made atherosclerotic by • Arterial samples with atherosclerosis had of Epidemiology, Michigan State University and Sparrow Hospital, East Lansing, Michigan cholesterol occupies greater space when balloon de-endothelialization and feeding a significantly higher bacterial count compared crystallizing from a liquid to a solid state cholesterol enriched diet for six months. with the normal controls (Fig. 3). forming sharp tipped crystals that can tear • Using analysis with Box-Cox transformation of Epidemiology, Michigan State University and Sparrow Hospital, East Lansing, Michigan • Arterial tissue was sampled from the aortas Background Methods Results fibrous membranes (1,2). Similar findings have of bacterial count there was a significantly after euthanasia and placed in a washer ring to Background Methods Results been noted in human coronary arteries of higher bacterial count present in 1µm expose only the intimal surface to a broth patients dying with acute myocardial infarction atherosclerotic arteries compared with In previous reports we demonstrated that • Ten NZW rabbits were made atherosclerotic by • Arterial samples with atherosclerosis had solution with Staphylococcus aureus (Fig. 2). Figure 5: (left) Control In previous reports we demonstrated that • Ten NZW rabbits were made atherosclerotic by • Arterial samples with atherosclerosis had (Fig. 1). normal controls (p<0.0001), (Fig. 4). crystals (right) cholesterol occupies greater space when cholesterolballoon occupies de- endothelializationgreater space when and feedingballoon de a-endothelialization significantly and feeding higher a bacterialsignificantly count higher compared bacterial count compared • By SEM Staphylococcus aureus bacteria • The same was repeated for normal control Bacteria attaching to crystallizing from a liquid to a solid state cholesterol enriched dietwith for six the months. normal controlswith (Fig.the normal 3). controls (Fig. 3). were found attached to cholesterol crystals crystallizing from a liquid to a solid state cholesterol enriched diet for six months. rabbits fed normal rabbit chow without intimal cholesterol crystals forming sharp tipped crystals that can tear • Using analysis with Box-Cox transformation in the atherosclerotic arteries and appeared forming sharp tipped crystals that can tear • Arterial tissue was sampled• Using from analysis the aortas with Box-Cox transformation injury. on atherosclerotic Background Methods fibrous membranes (1,2). Similar findingsResults have of bacterial count there was a significantly to be dissolving them (Fig. 5). • Arterial tissue was sampled from theafter aortas euthanasia and placed in a washer ring to arterial wall fibrous membranes (1,2). Similar findings have been noted in human coronary arteries of of bacterial count therehigher was bacterial a significantly count present in 1µm • Ten samples were obtained from 5 after euthanasia and placed in a washerexpose ringonly the to intimal surface to a broth dissolving and pitting patients dying with acute myocardial infarction higher bacterial countatherosclerotic present in arteries compared with 1µm atherosclerotic rabbits and 5 normal controls. been noted in human coronary arteries of solution with Staphylococcus aureus (Fig. 2). Figure 5: (left) Control the crystals. (Fig. 1).expose only the intimal surface to a broth normal controls (p<0.0001), (Fig. 4). patients dying with acute myocardial infarction atherosclerotic arteries compared with crystals (right) • For each group, five samples were incubated in • • Arterial samples with atherosclerosis had • By SEM Staphylococcus aureus bacteria In previous reports we demonstrated that Ten NZW rabbits were made atherosclerotic by solution with Staphylococcus aureus• The same(Fig. was 2). repeated for normal control Figure 5: (left)Bacteria Control attaching to broth for 1 h and another five samples were (Fig. 1). normal controls (p<0.0001),were found (Fig. attached 4). to cholesterol crystals rabbits fed normal rabbit chow without intimal crystals (right)cholesterol crystals incubated for 3 h. Bacterial colony counts were significantly higher bacterial count• By compared SEM Staphylococcus in the aureus atherosclerotic bacteria arteries and appeared Conclusion cholesterol occupies greater space when balloon de-endothelialization and feeding a • The same was repeated for normalinjury. control Bacteria attachingon atherosclerotic to measured at each time interval. were found attached toto cholesterolbe dissolving them crystals (Fig. 5). arterial wall rabbits fed normal rabbit chow without• Ten samples intimal were obtained from 5 • Bacterial presence on the intimal surface was • This study demonstrates that bacteria have a with the normal controls (Fig. 3). cholesteroldissolving crystals and pitting Figure 3. (left) Bacterial growth from normal artery crystallizing from a liquid to a solid state cholesterol enriched diet for six months. atherosclerotic rabbits andin the5 normal atherosclerotic controls. arteries and appeared examined by scanning electron microscopy high affinity to cholesterol crystals in arterial injury. on atheroscleroticthe crystals. as control inoculum. (right) Bacterial growth from (SEM) from additional arterial samples exposed atherosclerotic artery inoculum. tissues rich in cholesterol crystals. • Using analysis with Box• For- eachCox group, transformation five samplesto be were dissolving incubated inthem (Fig. 5). Figure 1. Scanning electron micrograph (SEM) of forming sharp tipped crystals that can tear • arterial wall to bacteria. • The presence and growth of bacteria in Ten samples were obtained from 5 broth for 1 h and another five samples were left anterior descending artery in a patient who • Arterial tissue was sampled from the aortas dissolving and pitting atherosclerotic plaques have the potential of atherosclerotic rabbits and 5 normalincubated controls. for 3 h. Bacterial colony counts were died with acute cardiovascular event. Cholesterol 20000 of bacterial count there was a significantly destabilizing the plaque leading it to rupture. fibrous membranes (1,2). Similar findings have measured at each time interval. the crystals. Conclusioncrystals are noted perforating the intimal surface 18000 Normal • Further studies on the mechanism of after euthanasia and placed in a washer ring to • For each group, five samples were incubated in just below the plaque rupture site (1). 16000 • 1µm• been noted in human coronary arteries of higher bacterial count presentBacterial presence in on the intimal surface was This study demonstrates that bacteria have a Atherosclerotic interaction between bacteria and cholesterol broth for 1 h and another five samples were Figure 3. (left) Bacterial growth from normal artery • Bacteria have been reported present in human 14000 examined by scanning electron microscopy as control inoculum. (right) Bacterial growth from high affinity to cholesterol crystals in arterial crystals need to be performed. However, a expose only the intimal surface to a broth 12000 incubated for 3 h. Bacterial colony (SEM)counts from were additional arterial samples exposed atherosclerotic artery inoculum. tissues rich in cholesterolatherosclerotic crystals. plaques (3). Both gram positive plausible explanation for our findings may be patients dying with acute myocardial infarction Figureatherosclerotic 1. Scanning electron micrograph arteries(SEM) of compared with 10000 to bacteria. • The presence and (growthStaphylococcus of bacteria aureus in ) and gram negative related to bacteria utilizing cholesterol as a left anteriormeasured descending at artery each in a timepatient interval.who Figure 5: (left) Control Conclusion 8000 solution with Staphylococcus aureus (Fig. 2). atherosclerotic plaques(Pseudomonas have the potential aeruginosa of ) bacteria have been diednormal with acute cardiovascular controls event. Cholesterol (p<0.0001), (Fig. 4). 20000 source of nutrition. (Fig. 1). destabilizing the plaqueshown leading to interact it to withrupture. cholesterol crystals. 6000 crystals• Bacterial are noted perforating presence the intimal on thesurface intimal surface was 18000 crystals (right)• This study demonstrates that bacteria have a 4000 Figure 3. (left) Bacterial growth from normalNormal artery • Further studies on the mechanism of just below the plaque rupture site (1). 16000 count colony Bacterial • Byexamined SEM byStaphylococcus scanning electron microscopy aureus bacteria high affinity to cholesterol crystals in arterial 1µ 2000 References • The same was repeated for normal control as control inoculum. (right) Bacterial growthAtherosclerotic from interaction between bacteria and cholesterolObjective • 14000 0 1µ Bacteria(SEM) have frombeen reported additional present arterial in human samples exposed atherosclerotic artery inoculum. Bacteria attachingtissues to richcrystals in cholesterol need to be performed. crystals. However, a 1. Abela GS, Aziz K. Cholesterol Crystals Rupture Biological Membranes and Human . Scanning electron micrograph (SEM) of atherosclerotic plaques (3). Both gram positive 12000 In this study we investigate if arteries with 1 3 Plaques During Acute Cardiovascular Events: A Novel Insight into Plaque Rupture rabbits fed normal rabbitFigure chow 1 without intimal were found attached to cholesterol crystals plausible explanation for our findings may be by Scanning Electron Microscopy. Scanning 2006; 28:1-10. (Staphylococcusto bacteria. aureus) and gram negative 10000 • The presence and growthatherosclerotic of bacteria plaque in rich in cholesterol Incubation time (hours) left anterior descending artery in a patient who cholesterol crystals related to bacteria utilizing cholesterol as a 2. Abela GS et al. Effect of cholesterol crystals on plaques and intima in arteries of 8000 (Pseudomonas aeruginosa) bacteria have been atherosclerotic plaquescrystals have willthe enhance potential bacterial of growth Figure 4: Bacterial colony counts following incubation of patients with acute coronary and cerebrovascular syndromes. Am J Card 2009;103: injury. died with acute cardiovascular event. Cholesterol in the atherosclerotic arteries and appeared20000 source of nutrition. 959–968. shown to interact with cholesterol crystals. 6000 on atherosclerotic compared to normal non-atherosclerotic normal (gray) and atherosclerotic (black) aorta segments destabilizing the plaque leading it to rupture. Figure 2. Washer with exposed arterial intima. with Staphylococcus aureus for 1 or 3 hours. Bars = 㼼 SD. 3. Izadi M et al. Helicobacter species in atherosclerotic plaques of patients with crystals are noted perforating the intimal surface 18000 4000 arteries in a rabbit model. coronary artery disease. Cardiovasc Pathol 21:307-311.

to be dissolving them (Fig. 5). Normal count colony Bacterial • Further studies on the mechanism of just below the plaque rupture site (1). Objective 1µ 16000 2000 arterial wall References • Ten samples were obtained from 5 0 1µ 1. Abela GS, Aziz K. Cholesterol Crystals Rupture Biological Membranes and Human 14000 Atherosclerotic interaction between bacteria and cholesterol • Bacteria have been reported present in humanIn this study we investigate if arteries with 1 3 Plaques During Acute Cardiovascular Events: A Novel Insight into Plaque Rupture dissolving and crystalspitting byneed Scanning toElectron be Microscopy. performed. Scanning 2006; 28:1However,-10. a atherosclerotic plaque rich in cholesterol 12000 Incubation time (hours) atherosclerotic rabbits andatherosclerotic 5 normal plaques controls. (3). Both gram positive 2. Abela GS et al. Effect of cholesterol crystals on plaques and intima in arteries of crystals will enhance bacterial growth Figure 4: Bacterial colony counts following incubationplausible of patients explanation with acute coronary andfor cerebrovascular our findings syndromes. Am mayJ Card 2009;103: be 10000 the crystals. 959–968. (Staphylococcus aureus) and gram negative compared to normal non-atherosclerotic normal (gray) and atherosclerotic (black) aorta segmentsrelated to bacteria utilizing cholesterol as a Figure 2. Washer with exposed 8000arterial intima. with Staphylococcus aureus for 1 or 3 hours. Bars = 㼼 SD. 3. Izadi M et al. Helicobacter species in atherosclerotic plaques of patients with • For each group, five samples(Pseudomonas were aeruginosa incubated) bacteria in have beenarteries in a rabbit model. source ofcoronary nutrition. artery disease. Cardiovasc Pathol 21:307-311. shown to interact with cholesterol crystals. 6000 broth for 1 h and another five samples were 4000 Objective 1µ count colony Bacterial 2000 References incubated for 3 h. Bacterial colony counts were 0 1µ 1. Abela GS, Aziz K. Cholesterol Crystals Rupture Biological Membranes and Human In this study we investigate if arteries with 1 3 Plaques During Acute Cardiovascular Events: A Novel Insight into Plaque Rupture measured at each time interval. Incubation time (hours) by ScanningConclusion Electron Microscopy. Scanning 2006; 28:1-10. atherosclerotic plaque rich in cholesterol 2. Abela GS et al. Effect of cholesterol crystals on plaques and intima in arteries of crystals will enhance bacterial growth Figure 4: Bacterial colony counts following incubation of patients with acute coronary and cerebrovascular syndromes. Am J Card 2009;103: 959–968. • Bacterial presence on thecompared intimal to normal surface non-atherosclerotic was normal (gray) and atherosclerotic (black)• This aorta segments study demonstrates that bacteria have a Figure 2. Washer with exposed arterial intima. with Staphylococcus aureus for 1 or 3 hours. Bars = 㼼 SD. 3. Izadi M et al. Helicobacter species in atherosclerotic plaques of patients with arteries in a rabbit model. Figure 3. (left) Bacterial growth from normal artery coronary artery disease. Cardiovasc Pathol 21:307-311. examined by scanning electron microscopy as control inoculum. (right) Bacterial growth from high affinity to cholesterol crystals in arterial (SEM) from additional arterial samples exposed atherosclerotic artery inoculum. tissues rich in cholesterol crystals. . Scanning electron micrograph (SEM) of Figure 1 to bacteria. • The presence and growth of bacteria in left anterior descending artery in a patient who atherosclerotic plaques have the potential of died with acute cardiovascular event. Cholesterol 20000 crystals are noted perforating the intimal surface 18000 destabilizing the plaque leading it to rupture. • just below the plaque rupture site (1). 16000 Normal Further studies on the mechanism of Atherosclerotic interaction between bacteria and cholesterol • Bacteria have been reported present in human 14000 12000 crystals need to be performed. However, a atherosclerotic plaques (3). Both gram positive plausible explanation for our findings may be 10000 (Staphylococcus aureus) and gram negative related to bacteria utilizing cholesterol as a 8000 (Pseudomonas aeruginosa) bacteria have been source of nutrition. shown to interact with cholesterol crystals. 6000 4000 Objective 1µ count colony Bacterial 2000 References 0 1µ 1. Abela GS, Aziz K. Cholesterol Crystals Rupture Biological Membranes and Human In this study we investigate if arteries with 1 3 Plaques During Acute Cardiovascular Events: A Novel Insight into Plaque Rupture Incubation time (hours) by Scanning Electron Microscopy. Scanning 2006; 28:1-10. atherosclerotic plaque rich in cholesterol 2. Abela GS et al. Effect of cholesterol crystals on plaques and intima in arteries of crystals will enhance bacterial growth Figure 4: Bacterial colony counts following incubation of patients with acute coronary and cerebrovascular syndromes. Am J Card 2009;103: 959–968. compared to normal non-atherosclerotic normal (gray) and atherosclerotic (black) aorta segments Figure 2. Washer with exposed arterial intima. with Staphylococcus aureus for 1 or 3 hours. Bars = 㼼 SD. 3. Izadi M et al. Helicobacter species in atherosclerotic plaques of patients with arteries in a rabbit model. coronary artery disease. Cardiovasc Pathol 21:307-311.

Official Publication of the National Lipid Association 35 Red Yeast Rice as an Alternative Therapy for Hyperlipidemia

RAM Y. GORDON, MD Cardiac Specialists Yale-New Haven Health System Fairfield, CT Diplomate, American Board of Clinical Lipidology

DAVID J. BECKER, MD Division of Cardiology Temple University Hospital Philadelphia, PA

tolerate it well while lowering their low- average LDL-C and a history of myocardial density lipoprotein cholesterol (LDL-C) infarction who were randomized to RYR to goal levels. Rather than dismiss this versus placebo.6 Discuss this article at supplement as naturopathic “snake oil,” www.lipid.org/lipidspin we decided to perform randomized, Red yeast rice may be a useful adjunct to double-blinded, placebo-controlled trials diet and exercise in patients who prefer Some patients refuse statin therapy or to formally evaluate its efficacy and safety. not to take statin therapy,3 but it also cannot tolerate its side effects. Many of A decade after renewed interest in this may have a much bigger role for patients these patients seek alternative therapies, product, we provide a brief overview of who develop statin-associated myalgias including red yeast rice (RYR), a widely its use, especially in patients who cannot (SAMs). The incidence of SAMs may be available herbal supplement made by tolerate or refuse statin therapy. We also as high as 15 percent7,8, and may affect culturing a yeast, Monascus purpureus, summarize regulatory and safety issues approximately 1.3 million people in the on rice. This process produces 14 that continue to make the use of RYR U.S.9 There is no consensus on optimal monacolins, compounds that inhibit HMG- controversial for both practitioners and therapy for patients with SAM, but CoA reductase, the rate-limiting step in patients. there are many approaches for treating hepatic cholesterol synthesis.1 One of hyperlipidemia in this population (Table the monacolins produced is monacolin K, Several clinical trials have documented 1). There has been increased interest in which is chemically identical to lovastatin. RYR’s efficacy in lowering total cholesterol, SAM with the introduction of proprotein LDL-C, and triglycerides.2-4 A recent meta- convertase subtilisin/kexin type 9 (PCSK-9) We began our research on RYR a analysis found that RYR lowered LDL-C an inhibitors into clinical practice. The Goal decade ago, after we heard anecdotes average of 21 to 30 percent, depending on Achievement After Utilizing an Anti-PCSK9 from patients about its efficacy and dose and formulation used.5 One secondary Antibody in Statin Intolerant Subjects 3 tolerability. Patients who previously had prevention trial found significantly fewer (GAUSS-3) trial recently examined the been prescribed statins had, on their deaths, revascularizations, and cardiac use of evolocumab in this population and own, started taking RYR and seemed to events in 4,870 Chinese patients with suggested that these agents may present

36 LipidSpin • Volume 14, Issue 4 • August 2016 0.001) and week 24 (P = 0.011). Adverse yeast rice’s potency is likely explained by Approach to Patients with a History of Statin-Associated Myalgias1,2 events were similar, with no difference in the presence of monacolins other than incidence of myalgias. monacolin K that may act synergistically 1. Initiate or intensify therapeutic lifestyle changes3 2. Decrease statin dose to inhibit HMG-CoA reductase. Red 3. Discontinue statin and re-challenge at a later Another study enrolled 43 patients with yeast rice also contains fiber, sterols, date SAMs and randomized them to RYR, isoflavones, isoflavone glycosides, and 4 4. Reduce dose of statin and add ezetimibe 2,400 mg twice daily (Sylvan Bioproducts, monounsaturated fatty acids, all of which 5. Use a different statin or statin-like supplement Kittaning, PA) or pravastatin, 20 mg/d also may contribute to its lipid-lowering a. Fluvastatin XL 80 mg daily5 for 12 weeks, in addition to a lifestyle effects.4 b. Rosuvastatin at a low dose (5 or 10 mg/day)6 12 c. Rosuvastatin once weekly,7 twice weekly,8 or modification program. LDL-C levels every other day9 decreased 30 percent in the RYR group Unfortunately, the major criticism of RYR d. Atorvastatin 10-40 mg 3 times weekly10 and 27 percent in the pravastatin group, is its status as an unregulated, over-the- e. Red yeast rice 1800 mg twice daily and there were no significant differences counter supplement and there remain 6. Pulse statin therapy2 between groups in other serum lipid valid concerns about efficacy and safety. In 7. Switch class of lipid-lowering agent levels. There were also no differences in 2010, we found that 12 widely available a. Use ezetimibe alone4 b. Combine ezetimibe and colesevelam11 incidence of myalgias (P = 0.99). RYR products had marked variability of 16 8. Check Vitamin D levels and replete if low12 monacolin content, corroborating similar 9. Add co-enzyme-Q10 (ubiquinone) 200 mg/day to The third trial evaluated the combination results published by Heber, et al. almost a 13 statin therapy of RYR and phytosterols in 187 patients decade earlier.17 Up to 80 percent of RYR 10. Initiate PCSK-9 inhibitor14 with statin-intolerance or statin refusal.13 products may contain citrinin, a potentially 11. LDL-C apheresis in qualified patients2 All patients took RYR, 1,800 mg twice nephrotoxic mycotoxin produced by LDL-C – Low-density lipoprotein cholesterol daily, (Sylvan Bioproducts, Kittaning, PA) several yeast species.17,18 Because of PCSK-9 - Proprotein convertase subtilisin/kexin type 9 and mean LDL-C decreased from 150 mg/ these issues, there are no reliable Table 1. References available on page 47. dL at baseline to 111 mg/dL at week 12, methods for physicians and patients to an effective, albeit expensive, alternative 110 mg/dL at week 24, and 113 mg/dL at know the true content of commercial treatment for SAM in the future.10 week 52 (all P<0.001). Four participants RYR products. Red yeast rice has been The most recent American College of experienced myalgias necessitating reported to have serious side effects, Cardiology/American Heart Association cessation of RYR, with no objective including myopathy,19-24 rhabdomyolysis,25 (ACC/AHA) Guidelines state that “it is evidence of myositis. hepatoxicity,26 and anaphylaxis.27 reasonable to use non-statin cholesterol- lowering drugs that have been shown to A fourth study, published by Paul So the question remains: Should doctors reduce ASCVD events in (randomized Thompson, et al., was a retrospective recommend RYR to their patients? In our controlled trials) if the ASCVD risk- analysis of 1,400 charts of patients with a practice, we advocate a trial of RYR for reduction benefits outweigh the potential history of statin intolerance.14 The authors patients who refuse statins or prefer a for adverse effects.”11 found 17 patients with a history of SAMs “natural” approach to pharmacotherapy, who were treated with RYR for at least and for patients with a history of statin- We conducted three trials to evaluate four weeks. In those patients, LDL-C associated myalgias, and we provide close RYR for patients with SAMs. The first decreased 19 percent and 15/17 tolerated monitoring and follow-up. Until there is examined 62 statin-intolerant patients with the treatment with no adverse effects. improved regulation and standardization an average LDL-C of 164 mg/dL.2 All were of RYR, its use will remain controversial, enrolled in a 12-week lifestyle modification Most studies noted similar rates of and physicians should remain cautious in program and randomized to RYR, 1,800 mg adverse events between RYR and recommending this promising and popular twice daily (Sylvan Bioproducts, Kittaning, placebo2,3,6,13 in a population intolerant alternative therapy for hyperlipidemia. n PA) or placebo for six months. Mean of statins. Participants in RYR studies percentage change in LDL-C in the RYR took the equivalent of only 5 mg/d to 6 Disclosure statement: Dr. Gordon has received honorarium as a Medical Advisory Board Member for group was -27.3 percent at week 12 and mg/d of lovastatin, with resultant LDL-C Regeneron. Dr. Becker is a consultant for Nutrasource -21.3 percent at week 24 with significant reductions of 25 to 40 percent, equivalent Diagnostics Inc. decreases in LDL-C in the RYR compared to reductions seen with 20 mg/d to 40 References are listed on page 47. with the placebo group at week 12 (P < mg/d of lovastatin in other trials.15 Red

Official Publication of the National Lipid Association 37 Foundation Update

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

attended the event “A Night at the gathered for dinner and a live showing of Museum.” The night started off with the Johnny Cash Experience. It was a fun cocktails, where attendees had a chance night, and another successful event for the to mingle and view the exhibit “Road to Foundation. Discuss this article at Berlin,” which had been opened only for www.lipid.org/lipidspin Foundation event guests. After the cocktail In addition, the Foundation will once again hour and exhibit viewing, everyone launch an awareness campaign to coincide with National Cholesterol Education The National Lipid Association and the Month this September. The objective Foundation are thankful once again for of the 2016 Rare Disease Education and another successful year of meetings and Awareness Campaign is to establish a fundraising. But we still have much work national patient outreach program that to do. will enable the Foundation to address the medical community and educate both If you are onsite at the Fall CLU in Amelia healthcare professionals and patients with Island, make sure to purchase a ticket to the latest knowledge and information the Foundation Event for an evening of regarding rare lipid disorders. miniature golf on Aug. 27 from 6:30–8:30 p.m. Engage your peers in a friendly Until now, publicly available information competition through 18 holes on the has tended to focus on low-density Heron Cove Adventure Golf course located lipoprotein (LDL) cholesterol as the at the Omni Amelia Island Plantation key element of cardiovascular health Resort. The winning team will take home risk Rare lipid disorders significantly prizes and bragging rights, and a portion affect individuals and their families. We of your ticket will be donated to the hope to improve the physician-patient Foundation. For more information, stop by relationship by using information and the registration desk onsite. education to increase patient awareness of disorders such as familial chlyomicronemia During the Scientific Sessions in New syndrome (FCS), lysosomal acid lipase Orleans last May, more than 80 people deficiency (LAL-D), lipodystrophy, and

38 LipidSpin • Volume 14, Issue 4 • August 2016 heterozygous and homozygous familial donated to the Foundation. The store hypercholesterolemia (HeFH and HoFH, offers shirts, polos, and many other respectively). items branded with the NLA logo. Show your support of the NLA and visit This national education program intends the store online at logosoftwear.com/ to inform patients and healthcare shareandsell/?store=nlastore. professionals about ways to improve the identification and management of these As always, thank you for your continued rare lipid disorders and to better the support to the Foundation and to another overall quality of care delivered to patients successful year! n who might be identified as having a rare lipid disorder. Ultimately, the best level of healthcare is achieved when consumers are better educated and have a deeper grasp of the essential issues regarding their health and plans for treatment.

Another way to support the Foundation is to continue shopping at the newly opened NLA store. All proceeds will be

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Official Publication of the National Lipid Association 39 The National Lipid Association (NLA) would like to acknowledge and thank our longtime members for their commitment to the NLA and the field of lipidology. The strength and longevity of our organization is only possible because of the dedication and contributions of our members. Below is a list of our committed members who have helped shape the NLA.

5+ YEAR MEMBERS

George Abela, MD Ralph Buckley, MD Gregory Dressel, MS Cheri Hayes, MSN Loriann Lofaro, PharmD Ralph Abraham, PhD Randy Burden, PharmD P. Barton Duell, MD Robert Hegele, MD Amale Lteif, MD Mohammad Abuannadi, MD Kenneth Burman, MD Danielle Duffy, MD Elizabeth Helden, BSN Henry Lui, MD Dominique Adair, MS Dale Burwen, MD Robert Dufour, MD Shannon Hemenway, APRN Michelle Lyon, PharmD James Adams, MD Edward Busick, MD Jack DuShey, MD Stephen Henry, MD Rachel Mackey, PhD Jim Aderhold, PA-C Richard Butcher, MD Julie-Ann Dutton, RD Luis Herrera-Behr, MD Luis Mackrizz, MD Allen Adolphe, MD Michael Butler, MD Wael Eid, MD Richard Herrington, MD Kevin Maki, PhD Monica Agarwal, MD Randolph Byrd, MD Tony Eid, PharmD Tetsuya Hirano, MD Michael Makover, MD Mahtab Ahmed, MD Armando Camara, MD Robert Ellis, MD Andrea Hirsch, PharmD Sanjay Malhotra, MD Hardeep Ahuja, MD John Gerald Canto, MD Raul Enad, MD Eileen Hoffman, MD Louis Malinow, MD Firas Al Badarin, MD Carla Cappadoro, ARNP Kristin Fabbio, PharmD Marc Hofley, MD Mary Malloy, MD Khalid Al Rasadi, MD Becky Captain, DNP Jamshid Faraji, MD Jerome Hojnacki, PhD Benedict Maniscalco, MD Ahmad Al-Sarraf, MD Chris Caraang, MD James Farrens, MS James Holton, MD Dan Manning, PharmD Omar Albustami, MD Nacu Caracas, MD Leslie Feigin, MD Ronnie Holuby, PharmD Werther Marciales, MD Khalid Alghofaili, MD Curtis Carothers, MD Kenneth Feingold, MD John Homan, MD Chad Martell, PharmD Sarah Ali, MD Paige Carson, PharmD Mary Felando, MS Dana Houser, MD Lisa Martin, MD Wael AlJaroudi, MD Paul Casanova-Romero, MD Regis Fernandes, MD Judith Hsia, MD Barbara Martin, ACNP Naji Aljohani, MB, ChB Michael Cecil, MD Maria-Luz Fernandez, PhD Stanley Hsia, MD Anuritha Marumganti, MD Thomas Allison, PhD George Chaconas, MD Bobby Fields, PA-C LisaHudgins, MD R. Mason, PhD Saadah Alrajab, MD James Chaney, DO Diego Fiorentino, DO Robert Hurst, MD Bassem Masri, MD Scott Altmann, PhD Ku Juey Chang, MD Herbert Fischer, MD Vanessa Hurta, NP Marvin Matlock, MD Rolf Andersen, MD Mary Katherine Cheeley, PharmD Edward Fisher, MD Andrey Ilyasov, MD Janet Maxson, PhD Joan Anderson, MSN Rebecca Cheung, PharmD Richard Flanigan, MD Joseph Ingrassia, MD Heidi May, PhD Bruce Andrus, MD Stephen Chiavetta, MD Michael Flynn, MA Terry Irwin, MD Patrick McBride, MD David Ange, MD Valentine Chikwendu, MD Tisha Fonce, RD Marc Israel, PharmD Brown McCallum, MD Luis Aparicio, MD Samuel Church, MD Sonja Fontana, DNP Ramamurthi Iyer, MD Brian McCrindle, MD Esmeraldo Arada, RN Nicole Ciffone, ANP-C Christopher Forman, MD Zaid Jabbar, MD Peter McCullough, MD Jim Arter, MD Sarah Clauss, MD Reginald Fowler, MD Muhammad Janjua, MD Kellie McLain, ANP-C Brian Asbill MD Jenny Cleary, NP Debra Friedrich, DNP Daniel Jass, MD Vicky Mennenga, PhD Ambika Ashraf, MD David Cochran, DO Susan Fujii, PharmD Bhavani Jeereddy, MD John Merenich, MD Colleen Astles, NP Ronald Codario, MD Margaret Furman, MD Manohar Jethani, MD Jim Metropoulos, MD John Attokaren, MD Floyd Cohen, MD Ramprasad Gadi, MD Harry Jimenez, MD Debra Metzler, DNP Eric Auerbach, MD Mark Colligan, MD Claude Gagne, MD Lewis Johnson, MD Gay Meyers, PA-C Zuhier Awan, MD Judith Collins, MSN Om Ganda, MD Dennis Johnson, MD James Mickle, MD Khalid Aziz , MD Michael Conlin, MD Shylesh Ganta, MD Ancil Jones, MD Gerald Miele, MD Alexis Baass, MD Stacy Conner, PharmD Jose Garcia, MD Carlos Jorge, MD E. J. Milas, BSN James Backes, PharmD Sonja Connor, RD Daniel Gaudet, MD Bipin Joshi, MD Walter Miller, MD Mhd. Motaz Baibars, MD Gary Conrad, MD Eugenia Gianos, MD Bill Joswig, MD Margo Minissian, MS Virginia Bailey, RN John Contois, PhD Samuel Gidding, MD Renee Julien, BSN Guy Mintz, MD Sridhar Banuru, MD Travis Cork, PharmD Richard Gillett, MD Hepsi Kalapala, MD Sean Miran, DO Ana Barac, MD Patrick Couture, MD Peter Gillies, PhD Melissa Kalt, MD Cres Miranda, MD Walid Barbour, MD Steven Cox, DO Daniel Ginsberg, MD Ahmad Kamme, MD Rudi Mirian, FNP Marie Barthelemy, CFNP William Craig, MD Carmella Gismondi-Eagan, MD Soteria Karahalios, MD Virginia Mitchell, PharmD Theodore Bash, DO James Crandell, MD Robert Gleeson, MD Youssef Kardouh, MD Jon Miyakawa, MD Dennis Bassetti, MD Denise Crawford, LPN John Glomset, MD Sultan Khan, MD Jasmine Moghissi, MD Christy Beaver, PharmD Deborah Croy, DNP Jyothi Gogineni, MD Pramod Khosla, PhD Howard Monsour, MD Paul Bekx, MD Ada Cuevas, MD Stanley Goldberg, MD Sandeep Khurana, MD Mahesh Moolani, MD Maria Bella , RD Jorge Cusco, MD Kari Gondeck, FNP Leonard Kinland, MD James Moore, MD Blair Beltzer, MD Charles Dahl, MD Julian Gonzalez, MD Carol Kirkpatrick, PhD Matthew Moran, PharmD Brian Berelowitz, MD H. Leon Daneschvar, MD Alberto Gonzalez-Alvarez, MD Josh Knowles, MD Bertrand Mukete, MD Richard Berger, MD Stephen Daniels, MD Dennis Goodman, MD Durga Komaragiri, MD Karl Nadolsky, DO Jean Bergeron, MD Seshadri Das, MD Ralph Goodman, MD Kris Komosa, MSN Michael Nagel, MD Richard Berquist, MD Indranil Dasgupta, MD Mark Goodman, MD George Kondos, MD Charlene Naimo, BS Kenneth Bescak, MD Judith Deckert, ARNP Joel Goozh, MD Richard Kones, MD Sanjeev Nair, MD Steven Bescak, NMD Khaleel Deeb, MD Caroline Graham, ANP-BC Constantine Kosmas, MD Alisa Nance, MD Lee Besen, MD William Delp, DO Jonathan Greco, MD David Kovacich, MD Al Narraway, DO Sayeeda Bilkis, MD Nicholas DePace, MD Herbert Green, MD Gerald Kovar, MD Gregg Neithardt, MD George Bittar, MD Sondra DePalma, PA-C E. James Greenwald, MD Sistla Krishna, MD Lidia Nelkovski, MD Ronald Bjarnason, DO James Devlin, PhD Nicole Greyshock, MD Spencer Kroll, MD Richard Nemiroff, MD M. Louis Blettel, MD Stephen Devries, MD Enrique Griego, MD Vladimir Kryzhanovski, MD Connie Newman, MD Richard Blum, MD Shawn Dhillon, MD Alex Grinberg, BS Darwin Labarthe, MD Dzung Nguyen, MD William Boden, MD Stephen DiBlasi, DO Larry Grogan, PharmD John Lacorazza, DO Allen Nichol, PharmD Armen Bogosian, MD Mary Dicklin, PhD Luigina Guasti, MD Shannon Lahn Prabhjot Nijjar, MD Julie Bolick , RD Andres Digenio, MD Steven Gubin, MD Donald Lamprecht, PharmD Sean Nikravan, MD Richard Bond, DO Susan Dimick, MD Eric Gupta, PharmD John Larry, MD Julia Nordgren, MD William Borden, MD Stewart Dismuke, MD Stuart Haigler, MD Julia Larsen, BSN Philip O'Donnell, MD Kenneth Borow, MD Kathleen Dively, MSN Susan Halli Demeter, DNP Steve Lasater, MD Jessica O'Neill, PharmD Cynthia Bosch, ARNP Dave Dixon, PharmD Jee-Young Ham, MD Michael Lenz, MD Eleanor O'Rangers, PharmD Ariel Brautbar, MD Damon Dixon, MD James Hancock, MD David Leonardi, MD Oyebimpe Oguntola, PharmD Craig Brett, MD Evan Dixon, MD Yehuda Handelsman, MD Edgar Lerma, MD Anders Olsson, MD Marc Brickman, DO Burt Dobson, MD Douglas Hansen, MD Cheung (Tom) Leung, MD Bassam Omar, MD Bridget Briggs, MD Julianne Doherty, PA-C Ashraf Harahsheh, MD Jeff Lewis, PharmD Philip Oranburg, MD John Brown, DO Andrew Don-Wauchope, MD Kira Harris, PharmD Stephen Li, MBBS Renata Ordon, MS Stephen Bruce, MD Marina Donahue, NP Sean Harvey, DO Joshua Liberman, MD Diane Osborn, ARNP Philippe Brudi, MD Joanne Donovan, MD Eranga Haththotuwa, MD Robert Lichtenberg, MD Steven Owens, MD Barbara Bruton, MD Michael Doyle, MD Krista Havlin, ANP Randy Lieberman, MD Quinn Pack, MD

40 LipidSpin • Volume 14, Issue 4 • August 2016 Stephen Pandolph, MD Ian Riddock, MD Arsalan Sheikh, DO Kimberley Stout, RN Thomas Vinson, MD Rodolfo Paoletti, MD Susan Robinson, PA-C Khalid Sheikh, MD Deborah Stuck, MD Laura Waite, PharmD Pathmaja Paramsothy, MD Kristen Rodeheaver, APN Doyle Shelton, PA-C Savitha Subramanian, MD Robert Warren, MD Steve Parcell, NMD Merideth Rodgers, PharmD Mounir Shenouda, MD Mihail Subtirelu, MD Carla Weidner, NP John Pasquini, MD Brenda Rodi, FNP J. Mark Sherman, PhD Andrey Susekov, MD Ned Weiss, MD Dharmesh Patel, MD Ghislaine Roederer, MD Viral Sheth, MD AnnMarie Swanson, NP-C Barry Welge, MD Shipra Patel, MD Kellie Rolph, ANP-C Susan Shoemaker, PhD Tonimarie Swartz, PharmD James Wertz, PharmD Susan Peacock, MS Jose Rosado-Vega, MD Eric Shoup, PA-C Richard Taw, MD Malia West, MSN Rade Pejic, MD Robert Rosenstein, MD Vinu Shrestha, MD Michelle Taylor, ACNP Randall West, DO Barbara Pellegrin, MSN Leslie Ruppe, PharmD Suzanne Shugg, DNP Matthew Teltser, MD Donald Westbie, MD Nimalie Perera, MBBS Eugene Ryan, MD Arthur Silverstein, DO Darcy Theisen, NP Randal White, MD Rolando Perez, MD David Ryan, DO A J Vinaya Simha, MD Robert Thompson, MD Anthony Wierzbicki, MD Randy Perrin, MS Ahmad Sabbagh, MD Ann Sims, RD Paul Thompson, MD John Wikle, MD Wayne Peters, MD Richard Safeer, MD Santosh Sinha, MD K. Douglas Thrasher, DO Gisela Wilcox, MBBS Francis Peterson, PhD Donald Sally, PA-C Daniel Siniawski, MD Joseph Tokaruk, MD Jacki Wildeman, NP Binh An Phan, MD Robert Saltman, MD Hicham Siouty, MD Lynn Toll, RN Kaye-Eileen Willard, MD Thomas Phiambolis, MD Leonard Sanders, MD Barrett Skandera, MSN Cornelius Toma, MD Geoffrey Williams, MD Gregory Phillips, MD Sanjay Sarin, MD Ronald Skowsky, MD Joanne Tomassini, PhD Vicki Williams, PharmD Anthony Pick, MD Anpalakan Sathasivam, MD Robert Slama, MD Emily Traub Huntley, PA-C Steven Winiarski, DO John Pino, DO Susan Satterfield, MD Jeremy Smart, PharmD Elizabeth Triana, MD Nathan Wong, PhD Otis Plunk, MD Morton Saunders, DO Nancy Smith, RD James Trippi, MD Amy Wren, MSN Venkateshwar Polsani, MD Roger Savonen, PhD Melissa Snider, PharmD Kamini Trivedi, DO Min-Shung Wu, MD Mohinder Poonia, MD Michelle Scanlan, MD Ashok Sonnad, MD Janet Troski, RN Eric Yang, MD Indu Poornima, MBBS Arthur Schantz, MD Nicoleta Sora, MD Jan Troup, PhD Elizabeth Yeung, MD Robert Pordy, MD Laura Schmelz, PharmD Nicole Spaeth, MSN Michael Truong, MD Philippe Yostos, MB, ChB Sathyavani Prabhakar, MD Friedhelm Schneider, MD Mark Speakman, MB ChB Peggy Tun, MD Gerald Youker, MD Thomas Quinn, MD Peter Scivoletti, MD Sheila Stadler, PharmD Aaron Turkish, MD Stephen Young, MD Anwer Qureshi, MD Lynn Scott, ARNP Allan Stahl, MD Traci Turner, MD Rabani Zaheer, MD Mohammed Rais, MD Joseph Scott, MD Thomas Starc, MD Sherri Turner-Lloyd, PA-C Suzana Zamecnik, NP Santiago Ramirez, MD Sabyasachi Sen, MD Julia Steinberger, MD Cecile Upchurch, RN Frances Zappalla, DO Richard Rapp, MD Terry Sensing, RN Jeff Steinhoff, MD Elaine Urbina, MD Atanaz Zargar, PharmD Stephen Raskin, MD Joshua Septimus, MD Christopher Stephenson, MD Santos Uy, MD Geoffrey Zarrella, DO Heather Rasmussen, PhD Reem Shafeh, MD Jerzy Sterkowicz, MD Byron Vandenberg, MD Jahan Zeb, MD Sudha Ravilla, MD Prediman Shah, MD Sean Stewart, PharmD Daniel VanHamersveld, MD Kristine Ziemba, APNP Michael Ravotti, ScD Chandrakant Shah, MD Sarajane Stirling, MD Ernesto Vazquez, MD Matthew Zimmerman, MD Rajesh Reddy, DO Reena Shah, PharmD Richard Stober, MD Jose VazQuez-Tanus, MD Thomas Zoch, MD Pulla Reddy, MBBS Samir Shah, MD Eric Stocker, MD Marc Vengrove, DO David Reich, MD Michael Shapiro, DO Thomas Stoiber, MD Suneet Verma, MD Melvin Richardson, MD Mrinal Sharma, MD Kimber Stout, MD Elisa Vila, RPh

10+ YEAR MEMBERS Nicola Abate, MD Harold Bays, MD Anthony Busti, PharmD Thomas Dayspring, MD Elaine Feldman, MD Peter Abel, MD Cassie Benge, PharmD Robert Buynak, MD Emil deGoma, MD Keith Ferdinand, MD Rajaratnam Abraham, MD Victor Benson, MD Tami Buzzard, NP Rolando deGoma, MD Edwin Ferguson, MD Azhar Afaq, MD David Berger, MD Galileu Cabral, MD Julio Delgado, MD Jonathan Fialkow, MD Aryan Aiyer, MD Thomas Bersot, MD Richard Campbell, MD Patrick Demare, DO Thomas Ficho, MD C. David Akin, MD Krishna Bhaghayath, MD Robert Carida, MD Dennis DeSilvey, MD Carolyn Finocchiaro, ARNP Moutasim Al-Shaer, MD Karan Bhatia, MD Sanford Carimi, MD Julie Diaz, NP Norman Fishman, MD Peter Alagona, MD Rajat Bhushan, MD Lawrence Carter, MD John Diaz, MD Barbara Fletcher, RN Sidney Alexander, MD Gary Birnbaum, MD William Castelli, MD Martha Dickens, MD Gerald Fletcher, MD Lori Alexander, MSHS Kim Birtcher, PharmD Maria Castro, MD Susan Dietz, RN Christopher Foley, MD Fad Alfayoumi, MD Vera Bittner, MD Manisha Chandalia, MD Peter Dionisopoulos, MD Elizabeth Ford, RN Diane Allen, MSN Piers Blackett, MD Scott Charland, PharmD Douglas Doctor, MD Grant Fowler, MD James Aller, MD David Blank, MD Brian Chesnie, MD Amy Doneen, ARNP Laura Fox, MD Hisham Alrefai, MD Thomas Blevins, MD Jagan Chintamaneni, MD John Dormois, MD Andrea Frank, DO Claudia Amidon, PharmD Howard Bliman, MD Sin-Ching Chiu, MD George Douglass, MD Perry Frankel, MD Grant Anderson, MD Michael Bloch, MD Elizabeth Choate, MSN Robert DuBroff, MD Howard Frauwirth, MD Benjamin Ansell, MD Robert Block, MD Mark Christman, ARNP Ralph Duda, MD Sonja Fredrickson, MD Eduardo Antezano, MD Conrad Blum, MD Ellie Chuang, MD Carlos Dujovne, MD Jeffrey Freeman, DO Hal Applebaum, MD Roger Blumenthal, MD Dellie Clark, MD Richard Dunbar, MD Karen Friday, MD Maryann Arce, RN Martha Bogart, PhD Michael Clearfield, DO Fredrick Dunn, MD John Frierson, MD Jane Arey, PharmD Adolphus Bonar, MD Michael Cobble, MD Daniel Duprez, MD John Frownfelter, MD Joseph Arulandu, MD Sabyasachi Bose, MBBS Lynn Cofer-Chase, RN Jessica Durham, ARNP Mamatha Gadarla, MD Marie Ashen, PhD B Alan Bottenberg, DO Rallie Cogburn, PA-C Honey East, MD Drew Garcia, PA-C Karen Aspry, MD Michael Bottorff, PharmD Jerome Cohen, MD James Ebert, MD Christine Garza, PhD Carlos Ayers, MD J. Chris Bradberry, PharmD Gregory Cohn, MD Robert Eckel, MD Raymond Gaskins, MD Arnold Baas, MD Michael Brady, MD Cindy Conroy, RD Brian Edwards, MD James Gault, MD Jerry Back, MD Dean Bramlet, MD John Corbelli, MD Jeff Eggart, MD Mark Geller, MD Karen Badellino, PhD Howard Brand, MD Wilfredo Corredera, MD Scott Eisenberg, DO Joseph Giancaspro, MD Joshua Bailey, PA-C Lyn Brant, ARNP Anthony Cossell, MD Steven Eisenberg, MD Ruth Gibson, FNP-C Gobivenkata Balaji, MD Lynne Braun, PhD Stephen Crespin, MD Julie Ellis, RD Edward Gill, MD Ajay Bali, MD Eliot Brinton, MD William Cromwell, MD Florencio Ello, MD Henry Ginsberg, MD Christie Ballantyne, MD James C. Brocoum, MD John Crouse, MD Enas Enas, MD Laxmana Godishala, MD Robin Balthis, RN Scott Brodarick, MD Anthony Curiale, PA Kent Erickson, MD Ira Goldberg, MD Sarang Baman, MD Robert Brook, MD Steven Curland, MD Ramon Espaillat, MD Anne Goldberg , MD Steven Baron, MD Clinton Brown, MD Kenneth Cusi, MD Robert Evans, MD Ronald Goldberg, MD Jeffrey Baron, MD Katherine Brown, PA-C Mark Cziraky, PharmD Wendy Everhart, PharmD Edward Goldenberg, MD Elizabeth Barrett-Connor, MD Finley Brown, MD Nancy Dagefoerde, NP Nabil Fahmy, MD Mark Goldstein, MD Thomas Barringer, MD Lawrence Brown, MD Tara Dall, MD James Falko, MD Antonio Gotto, MD Ginnie Barringer-Collins, RD Alan Brown, MD Elliot Davidson, MD Sergio Fazio, MD Connie Grantham, RN Michael Bartell, MD W. Virgil Brown, MD Michael Davidson, MD W. E. Feeman, Jr, MD Melanie Greene, MD Mark Bartz, MD Osvaldo Brusco, MD Ashley Davila, RN Adam Feldman, MD Robert Greenfield, MD Seth Baum, MD Jenny Buccicone, RD Tina Davis, CRNP Jeffrey Feldman, MD Raymond Grenfell, MD

Official Publication of the National Lipid Association 41 Keith Griffin, MD Vinod Lala, MD Vincent Murphy, MD Melvyn Rubenfire, MD Helen Trahan, MSN Vicki Groo, PharmD John LaRosa, MD Jay Murphy, MD Lawrence Rudel, PhD Douglas Trenkle, DO Chris Guerin, MD Michael Ledet, MD Walter Myalls, MD Giacomo Ruotolo, MD Nathan Trentham, MD W. Barrett Gunter, MD Wai Hung Lee, MD Merle Myerson, MD Todd Sandroni, PharmD Douglas Triffon, MD Avinash Gupta, MD Peter Lehmann , MD Anne Nafziger, MD Joseph Saseen, PharmD Wayne TRUE, MD Richard Guthrie, MD Richard Leighton, MD Tome Nascimento, MD Carlos Say, MD Thomas Tulenko, PhD Peter Gutschenritter, MD Robert Lending, MD Stephen Nash, MD Cindy Schabert, MSN Mohammad Tulimat, MD Adina Gutstein , MSN James Lichon, RPh, DDS David Neff, DO Ernst Schaefer, MD George Tzanis, MD John Guyton, MD Ann Liebeskind, MD Gregory Nelligan, MD Gary Schaffel, MD Gail Underbakke, RD Rodolfo Guzman, MD John Lien, MD John Nelson, MD Judith Schipper, MS James Underberg, MD Thomas Haffey , DO Joseph Lillo, DO Lori Neri, CRNP Michael Schloss, MD Allen Unger, MD Clark Hampe, MD William Linn, PharmD German Neri, MD Robert Schmidt, MD Kari Uusinarkaus, MD Pauline Hariri , APN MacRae Linton , MD Yen Nguyen, PharmD Jon Schragez, MD Ernesto Uy, MD Robert Harner, MD Larry Lipidologist, MD Robert Norris, MD Paulette Schreiber, MSN Wendy VanWootten, RD Charles Harper, MD Bradford Lipman, MD Kathleen O'Keeffe, RD Robert Schubert, MD Michael Varveris, MD William Harris, PhD William Littman, MD Ahmed Okba, MD Charles Schulman, MD Jose Venero, MD Howard Harrison, MD Janet Long, MSN Mark Oldendorf, MD Jeffrey Schultz, MD Carmelo Venero, MD K. Craig Hart, MD Maria Lopes-Virella, MD Trevor Orchard , MD Michael Schwartz, MD Josef Vesely, MD William Hazzard, MD J. Antonio Lopez, MD Carl Orringer, MD Cranford Scott, MD Ralph Vicari, MD Murray Heimberg, MD Albert Lopez, DO Randy Orsborn , PA-C Simone Scumpia, MD Krishnaswami Vijayaraghavan, MD Robert Heinig, MD Jonathan Lown, MD John Osborne, MD Paul Segal, DO Luis Villamon, MD Alan Helmbold, DO John Luoma, PharmD James Otvos, PhD Barry Seidman, MD Yoel Vivas, MD Ahdy Helmy, MD Susan Lynch, MD Michael Ozner , MD Munni Selagamsetty, MD Sanjay Vohra, MD Linda Hemphill, MD Leslie Machos, PharmD Lee Brian Padove, MD M. Saleem Seyal, MD Steven von Elten, MD Marcia Hendricks, MSN Phillip Madonia, MD Casey Page, MD Charlie Shaeffer, MD G. Russell Warnick, MS Jeffrey Hershkowitz, DO Robert Maguire, MD Anthony Pagedas, MD Edward Shahady, MD Wayne Warren, MD Rhonda Hettinger, DNP R. Clarke Maiocco, MD Robert Panther , MD Burton Shelton, MSN Karol Watson, MD Margueritte Hevezi, PharmD Deidre Mallak Ashish Patel, MD Mark Sherman, MD Perry Weinstock, MD Kathleen Hill, CRNP Martha Mangan, RN Ramesh Patel, MD Scott Shurmur, MD Howard Weintraub, MD Daniel Hilleman, PharmD Chadi Mansour, MD Rakesh Patel, MD Jeffrey Siegel, MD Martha Weintraub, RD Bob Hillert, MD Steven Margolis, MD Shailesh Patel, MD Geeta Sikand, RD John Weisenberger, MD John Hoekstra, MD Basil Margolis, MD Thomas Pearson, MD Livia Silva, MD John West, MD David Hoisington, MD David Maron, MD Jane Pearson, MD Debra Simmons, MD Thomas Whayne, MD William Hollins, MD Joel Marrs, PharmD James Petre, MD Frederick Simonie, MD Thomas White, MD Mary Honkanen, MD Nancy Martin, PhD Margaret Pfeiffer, RD John Sink, PA-C Libby Whitley, RN Paul Hopkins, MD William Martin, MD Karl Pfuetze, MD Bridget Sinnott, MD Ryan Whitney, MD Patrick Hornig, NP Sloan Martin, MD Daniel Phillips, MD Stephen Sisselman, DO Michelle Wien, RD Barry Horowitz, MD Carol Mason, ARNP Jack Pieniazek, DO Evan Sisson, PharmD Barbara Wiggins, PharmD Wm. James Howard, MD Patrick Mathias, MD Roda Plakogiannis, PharmD Sally Sloboda, BS Robert Wild, MD Melissa Hull, PharmD Robert Matthews, MD Jorge Plutzky, MD J. Orson Smith, MD Mary Beth Wiles, MD Glenn Huth, MD Maureen Mays, MD Gregory Pokrywka, MD Steve Smith, MD Robert Williams, MD Joseluis Ibarra, MD Donald McAlexander, MD Donna Polk, MD Donald Smith, MD Phyllis Williamson, MSN Thomas Isaacson, MD Jan McAlister, NP Susan Pope, NP Allan Sniderman, MD John Willis, DO Michael Isaacson, MD Anthony McCall, MD Stacey Porterfield, DO Abigail Snow, RN Stuart Willson, MD Matthew Ito, PharmD Lawson McClung, MD Judith Potter, MSN Frank Snyder, MD Don Wilson, MD Ramakrishnan Iyer, MBBS Sandra McCrary, PA-C Daniel Preud'Homme, MD Diane Sobkowicz, MD Kevin Winfield, MD Elizabeth Jackson, MSN Patrick McCullough, MD Suzanne Proulx, RD Daniel Soffer, MD Daniel Wise, MD Terry Jacobson, MD Donald McElroy, MD Chandrakant Pujara, MD Richard Sokol, MD Joseph Witztum, MD Douglas Jacoby, MD Chris McElroy, MD Gerald Pytlewski, DO David Southren, MD Gordon Wolfe, MD Denise Janosik, MD Mary McGowan, MD Daniel Rader, MD Chris Sparkman, MD Michael Wong, MD Bradley Johnson, MD Michael McGuire, PharmD Maureen Rafferty, MD Laurence Sperling, MD John Wood, MD Frank Johnson, MD Bernard McGuire, MD Mojgan Rahmani, MD Robert St. Amant, MD Milford Wyman, MD Peter Jones, MD Michael McIvor, MD Sridhar Ramachandran, MD Valerie Stanard Steele, PharmD Kathleen Wyne, MD Jila Kaberi-Otarod, MD James McKenney, PharmD Ramanujapuram Ramanujan, MD John Stein, MD Frank Yanowitz , MD John Kane, MD Catherine McNeal, MD Shiloh Ramos, MD James Stein, MD Hasan Zakariyya, MD Dean Karalis, MD Adi Mehta, MD Saleem Raslan, MD John (Jack) Stevens, MD Allan Zelinger, MD Wahida Karmally, RD Philip Mellen, MD Danielle Raymer, PharmD W.W. Stoever, DO Michael Zema, MD Moti Kashyap, MD Stephanie Melnyk, PharmD Khaled Reheem, MD Neil Stone, MD Paul Ziajka, MD JoEllen Kaufman, MS Phil Mendys, PharmD Alan Reichman , MD Tamara Strassell, CNP Sandra Zieve, MD Sukhdeep Kaur, MD Scott Merryman, MD Connie Reifenberger, CNP Abhay Suda, MD Franklin Zieve, MD Jill Keast, RN Donald Meyer, DO James Reifschneider, MD Andrew Sumner, MD Kenneth Kellick, PharmD David Meyers, MD Thomas Repas, DO H. Robert Superko, MD Douglas Kelling, MD Steven Mickley, MD Katherine Rhodes, PhD Mary Sweeney, MD Salman Khan, MD Thomas Mieras, MD James Rhyne, MD Brian Swirsky, MD Amit Khera, MD Douglas Miller, BS Santuccio Ricciardi, MD Andrew Tagle, NP George Kichura, MD Carl Miller, BS Nicholas Ricculli, DO Robert Talbert, PharmD Jane Kienle, MD Andrew Miller, MD Lucian Rice, MD Peter Tan, MD Peter Klementowicz, MD Deborah Miller, MSN Michael Richman, MD Jerry Tanner, DO Mandy Klingenberg, PharmD Michael Miller, MD Charles Riley, MD Joseph Tannous, MD Peter Knight, MD Basant Mittal, MD Elvira Rios, MD John Tapp, MD Deborah Koehn, MD Richard Moe, MD Antonio Rios, MD Phillip Tarkington, MD Richard Koffend, PA-C B. Krishna Mohan, MD Ashley Robaina, MD Felix Tarm, MD Walter Kohut, MD Malec Mokraoui, MD Mark Roberts, MD Alacia Tarpley, MD Habib Komari, MD Jeanette Moleski, DO James Roberts, MD Barry Tarpley, MD Raymond Kordonowy, MD Michael Monroe, MD David Robertson, MD Ralph Teague, MD Dawn Koselleck, PharmD Daniel Montero, MD Adela Robinson, MN Barry Tedder, MD John Kostis, MD Samia Mora, MD Melissa Robledo, MD James Thomas, MD Ronald Krauss, MD Terrance Moran, MD Cynthia Rodriguez, DNP Kimberly Tibbs, MD Sandra Kreul, ARNP Glen Morgan, MD Brian Rose, MD John Tidwell, MD Penny Kris-Etherton, PhD Patrick Moriarty, MD Susan Roseberg, RN Mary Tilak, MD Jeffrey Kuch, MD Pamela Morris, MD Joseph Rosenblatt, MD Richard Timmons, MD Dharamjit Kumar, MD David Moss, MD Paul Rosenblit, MD Karen Tisdel, PharmD Mariananda Kumar, MD Richard Mueller, MD Robert Rosenson, MD Richard Torricelli, MD Richard Kunis, MD Linda Muhonen, MD Joyce Ross, MSN Peter Toth, MD Ralph La Forge, MSc Marty Mullins, PA Eli Roth, MD Robert Touchon, MD

42 LipidSpin • Volume 14, Issue 4 • August 2016 Education and Meeting News and Notes

Save the Date for 2017 NLA Meetings Cohen, MD; Barbara Wiggins, PharmD; Julie sites for qualified patients. If you have Make sure you save the date for the NLA’s St. Pierre, MD; and much more. patients who could benefit from enrollment 2017 meetings. The 2017 Spring Clinical in this trial or would like to receive Lipid Update — hosted by the Pacific and Certification in Lipidology more information, contact Liz Masson at Southwest Chapters — will take place Feb. Preparing to become certified in lipidology [email protected] or 508-769- 24–26, 2017, at the Hyatt Regency Phoenix. through either the American Board of 9630. In addition, the 2017 NLA Scientific Clinical Lipidology or Accreditation Council Sessions will be held May 18–21, 2017, for Clinical Lipidology? The deadline to Research Initiative Launched to at the Philadelphia Marriott Downtown. apply for the Fall Testing Window is Sept. Characterize Disease Burden of FCS The annual meeting will be hosted by the 16. Applications must be postmarked by this Akcea Therapeutics has launched an IRB- Northeast Lipid Association. Finally, the date. For more information, visit lipid.org/ approved research study to understand 2017 Fall CLU — hosted by the Southeast education/certification or contact Nicole the multi-dimensional impact of Familial and Midwest Chapter — will take place Woodsmall at [email protected]. Chylomicronemia Syndrome (FCS) on adults Aug. 11–13, 2017, at the JW Marriott living with the disease. FCS, also known Indianapolis. Check lipid.org/conferences Resource Toolbox Available Online as lipoprotein lipase deficiency (LPLD) for more information and regular updates as The Clinician’s Lifestyle Modification or type I hyperlipoproteinemia, is a rare they become available. Toolbox includes patient education material hereditary condition in which individuals based on the NLA Recommendations lack properly functioning lipoprotein lipase NLA Meeting Highlights Now Available for Patient-Centered Management of (LPL), an enzyme that clears triglycerides Slide presentations and audio recordings Dyslipidemia: Part 2. It is a resource from plasma. Through this study, called the from the Spring CLU in San Diego and designed to assist clinicians and healthcare INvestigation of Findings and Observations the Scientific Sessions in New Orleans are professionals in beginning a conversation Captured in bUrden of Illness Survey in FCS now available. To view these highlights, with patients about achieving successful Patients (IN-FOCUS), adults affected by FCS and others, visit lipid.org/education/ lifestyle changes that promote their lipid can anonymously share information about highlights. health. Visit lipid.org/clmt to view the their experience living with FCS using a resources. simple Web-based survey. FCS patients may JCL Sees Increase in Impact Factor access the survey at fcsinfocus.com. The 2015 Impact Factors were recently NLA Mentoring Program released and the Journal of Clinical The NLA is accepting applications to 2016 Young Investigator Competition Lipidology (JCL) saw yet another increase become mentors for our early career Congratulations to Imran Baig, MD, an — from 3.904 (2014) to 4.906 (2015). members. The mentoring program was academic hospitalist at Mclaren Hospital The JCL is now ranked 23rd out of 253 established to help develop the next in Flint, Mich., who authored the abstract journals in its category (pharmacology and generation of clinical, academic, and “Atherosclerotic Arteries with Cholesterol pharmacy). The Thomson-Reuters Impact administrative leaders in lipidology. Crystals Enhance Bacterial Growth: Risk for Factor represents the ratio of articles For more information, visit lipid.org/ Plaque Destabilization” and placed first in quoted in other scientific publications education/trainees/mentoring or contact the Sanofi Regeneron Young Investigator compared to the total qualifying articles Amanda East at [email protected]. Award Competition at the 2016 NLA during the years 2013 and 2014. Scientific Sessions in New Orleans, May Patients Needed for Clinical Study 19–22. You can view this abstract on Check Out the Latest ReachMD Gemphire Therapeutics Inc., a clinical-stage Page 34 of this issue of the LipidSpin. In Recordings biotech based in Michigan, is currently addition, you can view a downloadable Lipid Luminations host, Alan Brown, MD, recruiting adult patients with homozygous version of this abstract online at lipid.org/ welcomed several guests at the NLA’s 2016 FH for their Phase 2 clinical study. There util/eposters/PDF/177.pdf. The Young Scientific Sessions in New Orleans this past are currently two investigatory sites in the Investigator Competition was sponsored by May. Visit lipid.org/communications/ U.S. accepting new subjects. Funds are an educational grant from Sanofi U.S. and reachmd to hear the lastest from David available for transportation to investigative Regeneron Pharmaceuticals.

Official Publication of the National Lipid Association 43 NLA Events Calendar

2017 National Lipid Association clinicallipid Clinical Lipid Update—Spring Hosted by the Pacific and Southwest Chapters update February 24–26, 2017 FEBRUARY 24–26 Hyatt Regency Phoenix Lipid Academy Phoenix, AZ February 23–24, 2017 2017 Phoenix, AZ PHOENIX May 17–18, 2017 Philadelphia, PA

August 10–11, 2017 NATIONAL LIPID ASSOCIATION 2017 National Lipid Association Indianapolis, IN SCIENTIFIC Scientific Sessions Hosted by the Northeast Lipid Association SESSIONS May 18–21, 2017 May 18–21 Philadelphia Marriott Downtown

PHILADELPHIA 2017 Philadelphia, PA

Masters in Lipidology 2017 National Lipid Association February 23–24, 2017 clinicallipid Clinical Lipid Update—Fall Phoenix, AZ update Hosted by the Southeast and Midwest Chapters AUGUST 11–13 August 11–13, 2017 May 17–18, 2017 JW Marriott Indianapolis Philadelphia, PA Indianapolis, IN 2017 August 10–11, 2017 INDIANAPOLIS Indianapolis, IN

44 LipidSpin • Volume 14, Issue 4 • August 2016 References

From the NLA President 7. Kronenberg F, Lingenhel A, Lhotta K, et al. Lipoprotein(a)- and 12. Brown BG, Zhao XQ, Chait A, et al. Simvastatin and Niacin, low-density lipoprotein-derived cholesterol in nephrotic syndrome: Antioxidant Vitamins, or the Combination for the Prevention of 1. Adapted from: http://www.acc.org/latest in cardiology/ten points to Impact on lipid-lowering therapy? Kidney Int. 2004;66(1):348-54. Coronary Disease. N Engl J Med. 2001;345:1583-92. remember 2016. 8 Radhakrishnan J, Cattran DC. The KDIGO practice guideline on 13. Jacobson TA, Ito MK, Maki KC, et al. National Lipid Association 2. Http://www.lipid.org/nla/acc16-american college cardiology scientific glomerulonephritis: reading between the (guide)lines – application Recommendations for Patient-Centered Management of sessions highlights to the individual patient. Kidney Int. 2012;82(8):840-56. Dyslipidemia: Part 1 – Full Report. J Clin Lipidol. 2015;9:129-69. 9. Chatrath H, Vuppalanchi R, Chalasani N. Dyslipidemia in pa- 14. Colhoun HM, Betteridge DJ, Durrington PN, et al. Primary From the LipidSpinEditor tients with nonalcoholic fatty liver disease. Sem Liver Disease. Prevention of Cardiovascular Disease with Atorvastatin in Type 1. Lloyd-Jones DM, Morris PB, Ballantyne CM, et al. 2016 ACC Expert 2012;32(1):22-9. 2 Diabetes in the Collaborative Atorvastatin Diabetes Study Consensus Decision Pathway on the Role of Non-Statin Therapies 10. Gaggini M, Morelli M, Buzzigoli E, DeFronzo RA, Bugianesi E, (CARDS): Multicentre Randomised Placebo-Controlled Trial. Lancet. for LDL-Cholesterol Lowering in the Management of Atherosclerotic Gastaldelli A. Non-alcoholic fatty liver disease (NAFLD) and its con- 2004;364:685-96. Cardiovascular Disease Risk. J Am Coll Cardiol 2016;68:92–125. nection with insulin resistance, dyslipidemia, atherosclerosis and 15. Martin SS, Blaha MJ, Elshazly MB et al. Comparison of a Novel 2. Yusuf S, et al. 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Modeling the primary oxidation atherosclerotic cardiovascular risk in adults: a report of the and p.(Gln4494del), causing Familial Hypercholesterolaemia in commercial fish oil preparations. Lipids. 2011;46(1):87-93. American College of Cardiology/American Heart Association Task provides novel insights into variant pathogenicity. Sci Rep. 12. Garcia-Hernandez VM, Gallar M, Sanchez-Soriano J, Micol V, Force on Practice Guidelines. J Am Coll Cardiol. 2014;63:2889- 2015;5:18184. Roche E, Garcia-Garcia E. Effect of omega-3 dietary supplements 2934. 12. Muller PY and Miserez AR. Large heterogeneity of mutations in the with different oxidation levels in the lipidic profile of women: a 12. Halbert SC, French B, Gordon RY, et al. Tolerability of red yeast gene encoding the low-density lipoprotein receptor in subjects with randomized controlled trial. Int J Food Sci Nutr. 2013;64(8):993- rice (2,400 mg twice daily) versus pravastatin (20 mg twice familial hypercholesterolaemia. Atheroscler Suppl. 2004;5:1-5. 1000. daily) in patients with previous statin intolerance. Am J Cardiol. 13. Gaffney D, Reid JM, Cameron IM, et al. Independent mutations at 13. Nogueira MS, Kessuane MC, Lobo Ladd AA, Lobo Ladd FV, Cogliati 2010;105:198-204. codon 3500 of the apolipoprotein B gene are associated with hyper- B, Castro IA. Effect of long-term ingestion of weakly oxidised 13. Becker DJ, French B, Morris PB, Silvent E, Gordon RY. Phytosterols, lipidemia. Arterioscler Thromb Vasc Biol. 1995;15:1025-9. flaxseed oil on biomarkers of oxidative stress in LDL-receptor red yeast rice, and lifestyle changes instead of statins: a randomized, 14. Fouchier SW, Kastelein JJ and Defesche JC. Update of the molecular knockout mice. Br J Nutr. 2016:1-12. double-blinded, placebo-controlled trial. Am Heart J. 2013;166:187- basis of familial hypercholesterolemia in The Netherlands. Hum 14. Kleiner AC, Cladis DP, Santerre CR. A comparison of actual versus 196. Mutat. 2005;26:550-6. stated label amounts of EPA and DHA in commercial omega-3 14. Venero CV, Venero JV, Wortham DC, Thompson PD. Lipid-lowering 15. Palacios L, Grandoso L, Cuevas N, et al. Molecular characterization dietary supplements in the United States. J Sci Food Agric. efficacy of red yeast rice in a population intolerant to statins.Am J of familial hypercholesterolemia in Spain. European Heart Journal. 2015;95(6):1260-1267. Cardiol. 2010;105:664-666. 2012;221:137-42. 15. Albert BB, Derraik JG, Cameron-Smith D, et al. Fish oil supplements 15. Bradford RH, Shear CL, Chremos AN, et al. Expanded Clinical 16. Brusgaard K, Jordan P, Hansen H, Hansen AB and Horder M. Mo- in New Zealand are highly oxidised and do not meet label content Evaluation of Lovastatin (EXCEL) study results: two-year efficacy and lecular genetic analysis of 1053 Danish individuals with clinical of n-3 PUFA. Sci Rep. 2015;5:7928. safety follow-up. Am J Cardiol. 1994;74:667-673. signs of familial hypercholesterolemia. Clin Genet. 2006;69:277-83. 16. Ritter JC, Budge SM, Jovica F. Quality analysis of commercial fish oil 16. Gordon RY, Becker DJ. Marked Variability in LDL-Cholesterol 17. Miserez AR and Muller PY. Familial defective apolipoprotein B-100: preparations. J Sci Food Agric. 2013;93(8):1935-1939. Lowering Using Two Readily Available Red Yeast Rice Formulations. a mutation emerged in the mesolithic ancestors of Celtic peoples? 17. Mason R, Sherratt S. Analysis of omega-3 fatty acid dietary J Am Coll Cardiol. 2009;53:A206 (abstract). European Heart Journal. 2000;148:433-6. supplements with respect to content: are they appropriate 17. Heber D, Lembertas A, Lu QY, Bowerman S, Go VL. An analysis 18. Chiou K-R and Charng M-J. Genetic diagnosis of familial hypercho- for patients? [abstract E21]. J Manag Care Spec Pharm. of nine proprietary Chinese red yeast rice dietary supplements: lesterolemia in Han Chinese. 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South Med 1. De Castro-Oros I, Cenarro A, Tejedor MT, et al. Common genetic 22. Morton DH, Morton CS, Strauss KA, et al. Pediatric medicine and J. 2003;96:1265-1267. variants contribute to primary hypertriglyceridemia without the genetic disorders of the Amish and Mennonite people of Penn- 23. Vercelli L, Mongini T, Olivero N, Rodolico C, Musumeci O, differences between familial combined hyperlipidemia and isolated sylvania. Am J Med Genet C Semin Med Genet. 2003;121C:5-17. Palmucci L. Chinese red rice depletes muscle coenzyme Q10 and hypertriglyceridemia. Circ: Card Genet. 2014;7:814-821. 23. Newborn Child Testing Act (Pennsylvania State Legislature). 1965. maintains muscle damage after discontinuation of statin treatment. 2. Berglund L, Brunzell JD, Goldberg AC, et al. Evaluation and 24. Kastelein JJ, Robinson JG, Farnier M, et al. Efficacy and safety of J Am Geriatr Soc. 2006;54:718-720. treatment of hypertriglyceridemia: An Endocrine Society Clinical alirocumab in patients with heterozygous familial hypercholesterol- 24. Vicari R, Roa-Sugura MN. Lipid Luminations: A Case of Covert Practice Guideline. J Clin Endo Met. 2012;97(9): 2969-2989. emia not adequately controlled with current lipid-lowering therapy: Use of Red Yeast Rice Resulting in Severe Myositis. LipidSpin. 3. Backes JM, Dayspring T, Mieras T, Moriarty PM. design and rationale of the ODYSSEY FH studies. Cardiovasc Drugs 2016;14:16-17. Pseudohypertriglyceridemia: Two cases of probable glycerol kinase Ther. 2014;28:281-9. 25. Prasad GV, Wong T, Meliton G, Bhaloo S. Rhabdomyolysis due to deficiency. J Clin Lip. 2012;6:469-473. 25. Raal FJ, Stein EA, Dufour R, et al. PCSK9 inhibition with evolocumab red yeast rice (Monascus purpureus) in a renal transplant recipient. 4. 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Official Publication of the National Lipid Association 47 2. Siddiqi SA, Thompson PD. How do you treat patients with myalgia who take statins? Curr Atheroscler Rep. 2009;11:9-14. 3. Stone NJ, Robinson JG, Lichtenstein AH. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. JACC. 2013;63:2889-2934. 4. Gazi IF, Daskalopoulou SS, Nair DR, Mikhailidis DP. Effect of ezetimibe in patients who cannot tolerate statins or cannot get to the low density lipoprotein cholesterol target despite taking a statin. Curr Med Res Opin. 2007;23:2183-2192. 5. Stein EA, Ballantyne CM, Windler E, et al. Efficacy and tolerability of fluvastatin XL 80 mg alone, ezetimibe alone, and the combination of fluvastatin XL 80 mg with ezetimibe in patients with a history of muscle-related side effects with other statins. Am J Cardiol. 2008;101:490-496. 6. Glueck CJ, Aregawi D, Agloria M, et al. Rosuvastatin 5 and 10 mg/d: a pilot study of the effects in hypercholesterolemic adults unable to tolerate other statins and reach LDL cholesterol goals with nonstatin lipid-lowering therapies. Clin Ther. 2006;28:933-942. 7. Backes JM, Moriarty PM, Ruisinger JF, Gibson CA. Effects of once weekly rosuvastatin among patients with a prior statin intolerance. Am J Cardiol. 2007;100:554-555. 8. Gadarla M, Kearns AK, Thompson PD. Efficacy of rosuvastatin (5 mg and 10 mg) twice a week in patients intolerant to daily statins. Am J Cardiol. 2008;101:1747-1748. 9. Backes JM, Venero CV, Gibson CA, et al. Effectiveness and tolerability of every-other-day rosuvastatin dosing in patients with prior statin intolerance. Ann Pharmacother. 2008;42:341-346. 10. Juszczyk MA, Seip RL, Thompson PD. Decreasing LDL cholesterol and medication cost with every-other-day statin therapy. Prev Cardiol. 2005;8:197-199. 11. Rivers SM, Kane MP, Busch RS, Bakst G, Hamilton RA. Colesevelam hydrochloride-ezetimibe combination lipid-lowering therapy in patients with diabetes or metabolic syndrome and a history of statin intolerance. Endocr Pract. 2007;13:11-16. 12. Lee JH, O’Keefe JH, Bell D, Hensrud DD, Holick MF. Vitamin D deficiency an important, common, and easily treatable cardiovascular risk factor? J Am Coll Cardiol. 2008;52:1949-1956. 13. Marcoff L, Thompson PD. The role of coenzyme Q10 in statin- associated myopathy: a systematic review. J Am Coll Cardiol. 2007;49:2231-2237. 14. Nissen SE, Stroes E, Dent-Acosta R. Efficacy and tolerability of Evolocumab vs. Ezetimibe in patients with muscle-related statin intolerance. JAMA. 2016;315:1580-1590.

48 LipidSpin • Volume 14, Issue 4 • August 2016 Patient Tear Sheet

Healthy Sleep Habits for Your Heart Advice from the National Lipid Association Clinician’s Lifestyle Modification Toolbox

Sleep and Your Health Not sleeping enough hours each night or not sleeping well can cause many health problems. Poor sleep habits may be linked to obesity, high blood pressure, type 2 diabetes, heart disease, atrial fibrillation (irregular heart beat), stroke, and heart failure. Having healthy sleep habits is healthy for your heart!

“How Long Should I Sleep Each Night?” The “<” means less than. The “>” means greater than. The “h” means hours. Newborns Infants Toddlers Preschoolers Children Teenagers Young Adults Adults Elderly Age (0–3 months) (4–11 months) (ages 1–2) (ages 3–5) (ages 6–13) (ages 14–17) (ages 18–25) (ages 26–64) (age ≥65) Achieve 14–17 h 12–15 h 11–14 h 10–13 h 9–11 h 8–10 h 7–9 h 7–9 h 7–8 h Avoid <11, >19 h <10, >18 h <9, >16 h <8, >14 h <7, >12 h <7, >11 h <6, >11 h <6, >10 h <5, >9 h

“What Can I Do for Healthy Sleep Habits?” DO DON’T  Try to be in bright light during the day.  Drink alcohol. Drinking too much will make  Have a daily physical activity routine. your sleep restless.  Exercise in the morning and/or afternoon.  Use products that have caffeine (for example:  Set aside a “worry” time during the day so coffee, soda, energy drinks), nicotine, and you can relax at bedtime. other stimulants.   Make the area where you sleep Have exposure to bright light during the comfortable. night.   Enjoy a relaxing activity before bedtime Exercise within 2–4 hours of bedtime. like light reading or listening to calming  Have heavy meals within 2–3 hours of music. bedtime. If you are hungry, eat only a light  Avoid screen time (TV, computer, tablet, snack. smartphone) 2 hours before bedtime.  Nap, if you are not a shift worker.  Enjoy a warm bath.  Watch the clock. This can make you more  Use bed only for sleeping or intimacy. anxious about not sleeping.   Establish a regular sleep pattern. Go to Keep trying to sleep. Instead, get out of bed bed and get up about the same time every and do a relaxing activity until you feel tired. day, even on weekends.  Have your bedroom too hot or too cold.  Allow excessive noise. Signs and Symptoms You May have a Sleep Problem The symptoms of a condition called “sleep apnea” are listed below. If you or a family member notice any of these symptoms, talk with your healthcare provider.  Snoring  Large neck size (greater than 17 inches for  Temporarily stop breathing during sleep men, greater than 16 inches for women)  Gasping/choking during sleep  Middle-of-the-night waking or insomnia  Unexplained daytime sleepiness  Non-refreshing sleep

This information is provided as part of the Clinician’s Lifestyle Modification Toolbox courtesy of the National Lipid Association. 6816 Southpoint Pkwy Suite 1000 Jacksonville, Florida 32216