Official Publication of the National Lipid Association LipidSpin

Theme: Statin Intolerance— Facing Adversity

Also in this issue: Evidence-Based Approach to the Use of CoQ10 to Deal with Statin Intolerance Vitamin D Deficiency and Statin Intolerance This issue sponsored by the Southeast Lipid Association

Volume 11 Issue 4 Fall 2013 visit www.lipid.org Elsvier MauiAd.Full Page8.13:Maui Ad 8/30/13 9:08 AM Page 1

MORETHANA MEETING IN MAUI

Join us for the opening session of the 2014 Clinical Lipid Update Meeting as world renowned thought leaders discuss Lipid Management and Metabolic Syndrome in various populations from around the world. W.Virgil Brown,MD,FNLA Cesare R. Sirtori,MD,PhD Yuji Matsuzawa,MD,PhD GeraldWatts,DSc,MB,BS,PhD This meeting features evidence-based sessions that include: A debate from John Brunzell,MD and Sekar Kathiresan,MD How Close are we to Personalizing CVD Prevention with Genetics?

Other key sessions include: HDL Analytics & Functionality Debate: Is it time to Stop using Benjamin Ansell, MD, FNLA Fibrates Combined with Statins? Jocelyne R. Benatar, MD, MBChB Cardiovascular Risk inAsians Eliot Brinton, MD, FNLA and Pacific Islanders Beatriz Rodriguez, MD, PhD Dietary Issues and Supplements Keawe’aimoku Kaholokula, PhD Kathleen Wyne, MD, PhD, FNLA Nathan Wong, PhD Terry Jacobson, MD, FNLA Latha Palaniappan, MD, MPH Forrest Batz, PharmD Geeta Sikand, RD, FNLA

See you in Maui! Visit www.lipid.org/springclu to register now.

To book your room, call 800-888-6100 and ask for the National Lipid Association room rate. Get the NLA room rate starting at $235/night plus tax if you book your room by February 11, 2014. Delta Airlines discount code: NMGR6 WALDORF ASTORIA GRANDWAILEA HOTEL WAILEA, MAUI, HAWAII

CME Credit provided by the National Lipid Association This activity has been approved for AMA PRA Category 1 Credit™ This activity is eligible for CDR credit

CE credit provided by Postgraduate Institute for Medicine This activity is eligible for ACPE and ANCC credit See final activity program for specific details In This Issue: Fall 2013 (Volume 11, Issue 4)

Editors 2 From the NLA President JAMES A. UNDERBERG, MD, MS, FACPM, FACP, FNLA* Spreading the Word Preventive CV Medicine, Lipidology and Hypertension —Matthew K. Ito, PharmD, CLS, FNLA Clinical Assistant Professor of Medicine NYU Medical School and Center for CV Prevention New York, NY 3 From the SELA President and Immediate Look for the NLA Community logo to discuss Past President articles online at www.lipid.org ROBERT A. WILD, MD, PhD, MPH, FNLA* Clinical Epidemiology and Biostatistics and Statin Intolerance Clinical Lipidology Professor —Ralph La Forge, MSc, CLS, FNLA Oklahoma University Health Sciences Center —Paul E. Ziajka, MD, PhD, FNLA* Oklahoma City, OK Managing Editor 4 Letter from the Lipid Spin Editors 21 Practical Pearls EMILY T. PARKER, MA NLA CME: A Culture of Policing Vitamin D Deficiency and Statin National Lipid Association Ourselves Intolerance Executive Director —Robert A. Wild, MD, PhD, MPH, FNLA* —Debra A. Friedrich, DNP, ARNP, FNP-BC, CHRISTOPHER R. SEYMOUR, MBA FNLA National Lipid Association 5 Clinical Feature Contributing Editor An Update on Statin Safety with an 23 Case Study KEVIN C. MAKI, PhD, CLS, FNLA Muscle-Related Statin Intolerance Emphasis on Differences —Nicole Gaskins Greyshock, MD* Associate Editor for Patient Education —Demir Baykal, MD, FACC, FASE, CCT* VANESSA L. MILNE, MS, NP, CLS —John R. Guyton, MD, FNLA* Cardiac Vascular Nurse and Family Nurse Practitioner Bellevue Hospital Lipid Clinic Guest Editorial New York, NY 9 Member Spotlight: Managing the Statin-Intolerant 26 Barbara Wiggins, PharmD Lipid Spin is published quarterly by the Patient: Low-Dose/Low-Frequency National Lipid Association Treatment Regimens 6816 Southpoint Parkway, Suite 1000 —Mary Honkanen, MD, ABIM, FNLA* 27 Education, News and Notes Jacksonville, FL 32216 Phone: 904-998-0854 | Fax: 904-998-0855 Foundation Update Copyright ©2013 by the NLA. 13 EBM Tools for Practice 28 All rights reserved. Evidence-Based Approach to the 29 References Visit us on the web at www.lipid.org. Use of CoQ10 to Deal with Statin Intolerance The National Lipid Association makes every effort to —Jennifer M. Welding, PharmD, CTTS 32 Events Calendar provide accurate information in the Lipid Spin at the —Bishoy Ragheb, PharmD, BCACP, CDE, CTTS time of publication; however, circumstances may alter certain details, such as dates or locations of events. 33 Provider Tear Sheet Any changes will be denoted as soon as possible. Lipid Luminations The NLA invites members and guest authors to 16 provide scientific and medical opinion, which do not Lowering LDL Using Non-Statin necessarily reflect the policy of the Association. Regimens ­—Casey Elkins, DNP, NP-C, CLS

19 Specialty Corner Tolerability of Statin Therapy in Children *indicates ABCL Diplomate status ­—Jessica Lilley, MD

1 From the NLA President: Spreading the Word

Matthew K. Ito, PharmD, CLS, FNLA National Lipid Association President Professor of Pharmacy Practice Oregon State University/Oregon Health and Science University Portland, OR Diplomate, Accreditation Council for Clinical Lipidology

during National Cholesterol Education treatment, develop the best treatment plan Month this September. between you and your patient, provide optimal patient education to ensure patient As a Doctor of Pharmacy and President adherence and persistence to therapeutic Discuss this article at www.lipid.org/lipidspin of the National Lipid Association (NLA) lifestyle changes and pharmacotherapy, this year, I am committed to raising and continue to assess for subclinical awareness about this disorder. I want atherosclerosis to further guide the As a teen, I did all the things other both patients and health care providers to intensity of therapy. In the near future, 14-year-old boys did: played sports, know exactly how important early diagnosis if emergent therapies in clinical trials hung out with friends, and raced dirt and aggressive treatment is—from my are approved, these therapies added to bikes. But around that time I learned I personal—and life-threatening--experience. maximum tolerated statin combination inherited a genetic disorder called Familial therapy could provide important reductions Hypercholesterolemia (FH). I encourage you to continue to educate in cardiovascular risk to our FH patients. your patients about FH through the When I was diagnosed with FH in 1974, many resources the National Lipid In addition, please spread the word about the medical community didn’t have ideal Association offers, including lipid.org, the FH Foundation’s new patient registry. guidance or treatment for it, especially for lipidfoundation.org and You can find more information at children and teens. In fact, I wasn’t treated learnyourlipids.com. www.thefhfoundation.org. for FH until my late 20s, just after statins were introduced. The only thing standing It is important to know that although I hope to see you at one of our upcoming between me and a life-changing—or life- not curable, FH and other dyslipidemias meetings. Best wishes to you and your ending—heart attack was a semi-strict diet are treatable. The aim of treatment is to families this holiday season. n and exercise. reduce your cholesterol to an acceptable level, thereby preventing or delaying That is why I was pleased to help ischemic vascular disease. As a lipidologist, spread the word, along with so many you can implement cascade screening in of my colleagues, about FH and other all first-degree relatives of the FH index dyslipidemias and cholesterol disorders case to help facilitate early detection and

2 LipidSpin From the Chapter President and Immediate Past-President: Statin Intolerance

RALPH LA FORGE, MSc, CLS, FNLA President, Southeast Lipid Association Durham, NC Diplomate, Accreditation Council for Clinical Lipidology

PAUL E. ZIAJKA, MD, PhD, FNLA Immediate Past-President, Southeast Lipid Association Director, Florida Lipid Institute Winter Park, FL Diplomate, American Board of Clinical Lipidology

The SELA board decided to devote this Also, patients with statin intolerance are issue of Lipid Spin to the problem of statin at a clinical and economic disadvantage. In intolerance. In formal clinical trials statin patients with a history of coronary heart intolerance is reported in 2 to 3 percent disease statin intolerance is associated of study subjects, but longer term follow with an 80 percent relative risk increase Discuss this article at www.lipid.org/lipidspin up studies report a more realistic rate of for myocardial infarctions and a 53 15 to 20 percent. In an informal survey of percent relative risk increase for all cause the past-president’s (PZ) private practice mortality compared to similar patients lipid clinic 24 of the most recent 30 new able to tolerate statins. Dyslipidemic patients were referred because of statin patients unable to take statins have been intolerance. reported to incur a $400 to $900 greater total health care cost over an 18 month The most common problems reported observation period compared to similar by statin intolerant patients are muscle patients able to tolerate statin therapy. complaints (about 80%), but the full spectrum of statin intolerance includes This issue of Lipid Spin will examine some increased liver enzymes, allergic reaction, of the clinical strategies used to deal with headache, neuropathy, alopecia, memory statin intolerance, including switching to disturbances, glucose intolerance, statins with a better tolerability profile, gastrointestinal disturbances, insomnia, use of very low dose - low frequency statin arthralgias, exercise intolerance, administration, vitamin D supplementation, depression and dizziness. CoQ10 supplementation and the use of non-statin lipid lowering regimens. n

Official Publication of the National Lipid Association 3 Letter From the Lipid Spin Editors: NLA CME: A Culture of Policing Ourselves

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

lowest form of evidence. Often the stronger presentations are reviewed for compliance. the opinion the least amount of data behind We ask that everyone help in this effort. If the opinion! a potential conflict of interest arises, real or perceived, for any of our educational Discuss this article at The educational efforts of the NLA are offerings, let us know so that we can look www.lipid.org/lipidspin undergoing a massive structural change into it. for peer review to deal with issues of subjectivity and/or potential conflicts of We feel strongly as an educational Lipid Spin is but one NLA educational interest. We recognize that all of us have organization that we all benefit from offering. As editors we are pleased to bring ‘bias’. We all have our likes, dislikes and this effort to strive to be the premier these issues to clinicians on a regular basis. each of us has a relatively limited view organization for the clinician in the practice Lipid Spin is peer reviewed. The subject of the world of science around us given of Clinical Lipidology. Help us all by doing matter is always trying to address how we the massive differences, experiences and your part. Help us move to clarity and can better take care of the patients/clients individuality as we apply the information we give us feedback. Not until we know how we serve. Our focus is prevention. Because learn about. we can help you can we learn how best we are always trying to prevent ravages to provide what is useful and meaningful of CVD for everyone, by definition some As a professional educational organization to each of you. We welcome your input. of what we offer will always be useful for we are guided by governing bodies that try Be part of this culture. Let your regional some and not useful for others. We need to assure that all professional organizations president know if you have any concerns, to remind everyone from time to time that do their best to avoid conflicts of interest. and most importantly, you have suggestions many of the articles here provide clinical In short we have national guidelines regarding how best to improve our efforts. opinions. Peer review is not a perfect that we adhere to as we strive to make There are a number of considerations process. There is always an element of our educational efforts second to none. that we have to deal with: logistics, costs, subjectivity involved. However it is the The NLA has many educational offerings feasibility, relevance, timeliness, etc. Rest best way we have to try to avoid conflicts and the process of peer review requires assured however that our hearts are in the of interest. We strive to bring you useful our own policing. Fortunately, we have right place. Help us move to excellence. information from a clinical perspective. unanimous opinions amongst the leadership Always be aware that articles presented that this is a priority for the NLA. As you We hope that you enjoy this publication and are opinions of the authors and as such do attend the regional and national meetings recognize that it has a place. Also recognize not imply NLA endorsement. One of my please be aware that presenters are given that helping us by giving us feedback in the favorite maxims is that strong opinion is the guidance as to acceptable content and their long run will allow us to serve you better. n

4 LipidSpin Clinical Feature: An Update on Statin Safety with an Emphasis on Differences

DEMIR BAYKAL, MD, FACC, FASE, CCT Gwinnett Consultants in Cardiology Medical Software LLC Diplomate, American Board of Clinical Lipidology

the upper-limit normal (ULN) associated Abbreviations with myalgia or rhabdomyolysis. The ULN = upper-limit normal incidence of myopathy was (0.1%) for CAD = coronary artery disease lovastatin 40mg/day and (0.2%) for MMSE = Mini-Mental State Examination lovastatin 80mg/day in the Evaluation of Discuss this article at LFT = liver function test Xience Prime™ versus Coronary Artery www.lipid.org/lipidspin Bypass Surgery for Effectiveness of Left Statin drugs have been studied in Main Revascularization (EXCEL) trial.¹ numerous controlled trials involving patients – nine of them on simvastatin There were no cases of myopathy or hundreds of thousands of study 80mg/day – developed myopathy in the rhabdomyolysis in three major pravastatin participants. Their use has resulted in high-risk-CAD A to Z trial.7 The highest trials.² None of the three cases of reduced coronary artery disease (CAD) incidence of statin-related myopathy rhabdomyolysisin patients on 10mg/day mortality, morbidity and, in several was encountered in the seven-year, dose or the two cases on 80mg/day dose of studies, all-cause mortality. Even though randomized, double-blind SEARCH study. atorvastatin in the Treating to New Targets clinical trial evidence and clinical practice Fifty-two patients (0.9%) in the 80mg (TNT) trial was felt by investigators to experience have demonstrated extremely group versus one patient (0.02%) in the be casually related to atorvastatin.³ In an low incidence of adverse effects, safety 20mg group developed myopathy, defined analysis of 27 Phase 2/3 controlled clinical concerns have existed, mostly on the basis as unexplained muscle weakness or pain trials of rosuvastatin, CK elevation>10X of case reports and data from clinical trials. with a serum CK >10 times ULN.8 This ULN occurred in 0.02% to 0.04% in a The U.S. Food and Drug Administration was higher than the labeled risk (based on dose-independent manner. No cases of (FDA) provided updates on statin labels clinical trial data) of 0.53%. Twenty-two rhabdomyolysis was reported.4 regarding side effects in 2011 and 2012. patients (0.4%) in the 80mg group versus no patient in the 20mg group developed Clinical trial assessment of muscle The incidence of CK elevations is reported rhabdomyolysis. The risks for myopathy adversities as 0.03% on 40mg/day fluvastatin and and rhabdomyolysis with simvastatin 80mg No conclusive comparative evidence exists 0.00% on fluvastatin 80mg/day and were highest in the first 12 months of to indicate that currently available statins there have been no reported cases of treatment; older age and female gender differ in regard to their risks of myopathy, rhabdomyolysis. Therefore, fluvastatin both increased the risk of myopathy. defined as otherwise unexplained marked may have the least propensity to cause In SEARCH, the risk of myopathy was creatine kinase (CK) elevation >x10 myotoxicity.6 On the other hand, 10 approximately doubled in patients taking

Official Publication of the National Lipid Association 5 4 a calcium channel blocker, in particular elevations 1 in liver injury tests (defined diltiazem.8 as > 3 X ULN) is between 0.5% and 5%; and liver enzyme elevations are dose Clinical hepatotoxicity The findings from the SEARCH trial dependent. There is little relationship are supported by analyses of the FDA’s between the magnitude of low-density is exceedingly rare, Adverse Event Reporting System (AERS) lipoprotein (LDL) reduction and the mild to moderately database, which show that the level degree of enzyme elevation at lower of reporting of fatal rhabdomyolysis doses; in other words, there are no elevated LFT associated with the 80mg dose of differences between more potent statins simvastatin has been higher in comparison and less potent ones. Instead, when a abnormalities with lower doses of simvastatin or most statin dose is doubled from the second other statins, leading to a recommendation highest to maximum allowed dose, blood are higher-dose to limit the initiation of an 80mg/day dose. transaminase levels increase. In one comparative head-to-head, six-week study dependent and almost involving 2,431 participants, there were always self-limited. The incidence only five cases of two consecutive-visit aspartate transaminase (AST) elevations of statin-related on atorvastatin 80mg (n=1), atorvastatin endocytosis and is physiological because myopathy varies 20mg (n=2), simvastatin 40mg (n=1), of HMG-CoA reductase inhibition. simvastatin 80mg (n=1), and none on Hematuria seen with statin use in clinical little between rosuvastatin 40mg daily dose.9 The clinical trials commonly has other explanations. significance of these often transient, To address the question of whether different statins, self-limited elevations is unclear. The urinary abnormalities with statin use baseline measurements of liver function are detrimental to long-term renal except the highest tests are useful for future comparisons. function, an open-label atorvastatin study Pretreatment liver enzyme levels have not was conducted. It was concluded that incidence is seen been predictive of clinically meaningful atorvastatin reduced the proteinuria and with the initiation acute hepatocellular reactions. Therefore, progression of chronic kidney disease routine continued monitoring of liver (CKD) additive to angiotensin-converting- of simvastatin 80mg enzymes at lower doses of statins is enzyme (ACE) Is or angiotensin-receptor not necessary except for patients on blockers (ARBs). This particular beneficial daily and lowest concomitant medications, with co-morbid or safety profile of atorvastatin may be conditions or otherwise felt to be at high contributed by minimal renal excretion, (none reported) with risk. On Feb. 28, 2012, the FDA approved <2% as opposed to 10% with rosuvastatin, crucial changes to the safety label for 13% with simvastatin and 20% with fluvastatin 80mg daily. statins, removing the recommendation pravastatin. In the atorvastatin-based Die for periodic monitoring of liver enzymes. Deutsche Diabetes Dialyse (4D) study, no Drug interactions and metabolic pathways According to the new labels, the FDA case of rhabdomyolysis was reported in are major considerations. Because they recommends that such tests be conducted 619 hemodialysis patients.¹¹ are not metabolized significantly via before starting therapy and as clinically the cytochrome P450 (CYP) pathway, indicated thereafter. Potential neurological adverse pravastatin and rosuvastatin may be experiences administered in a safer fashion if given Adverse renal experiences The level of evidence supporting potential concomitantly with drugs known to be CYP Preclinical animal studies have neurological adverse effects of statins is inhibitors. demonstrated renal tubular toxicities listed in Table 1. related to high-dose statin intake. Potential liver adversities Mild proteinuria seen clinically is the Case reports and clinical trials have Overall, statin trials have demonstrated result of impairment of renal tubular suggested that statins may impair cognitive that the incidence of significant protein absorption by receptor-mediated function, which may be of safety concern,

6 LipidSpin Level of Evidence Potential Statin-Adverse Experience with peripheral nervous system adverse experiences. However, from a review of A Statins reduce the risk of ischemic stroke12 the literature, it is reasonable to conclude B A decrease in cognition or memory 13,14,15 that any potential risk of peripheral 16 F Statins may worsen dementia, Alzheimer’s disease neuropathy with statin use is very small. 17 B Statins may improve dementia, Alzheimer’s disease A stepwise approach to the patient with U Some statins are safer than others in regard to adverse neurological events a potential statin-related peripheral C Peripheral neuropathy is a potential adverse effect18,19 neuropathy adverse experience may be to, Table 1. first, ensure that other secondary causes particularly in older individuals. trial conducted specifically in older study have been evaluated; second, to perform participants, 5,804 men and women ages a neurologic physical examination and In a double-blind study of 209 generally 70 to 82 years with a history of or risk attempt to objectively quantify abnormal healthy hypercholesterolemic adults, factors for vascular disease were evaluated neurologic physical findings; and third, to randomly assigned to six-month for mental changes. After an average obtain appropriate diagnostic neurologic treatment with lovastatin 20 mg or of 3.2 years, pravastatin 40mg/day was studies; and, fourth, to stop administering a placebo, lovastatin did not cause found to have no significant effect on the statin. If objective abnormalities psychological distress or substantially cognitive function or disability compared alter cognitive function, but it did result with a placebo, as assessed by diagnostic in small performance decrements on instruments such as the Mini-Mental Neurotoxicity neuropsychological tests of attention State Examination (MMSE). With specific and psychomotor speed, which were regard to dementia (which may include seems to originate concluded to be of uncertain clinical Alzheimer’s disease), nested case-control from idiosyncratic importance. In a similar follow-up study designed studies revealed that individuals of 308 adults with hypercholesterolemia, who were prescribed statins actually had reaction, reversible a randomized, double-blind, placebo- a substantially lowered risk of developing controlled trial of simvastatin 10mg or dementia. However, a meta-analysis based upon discontinuation 40mg for six months provided partial on the Cochrane database review (pooling support for minor decrements in cognitive the studies providing a change in MMSE with little difference functioning with statins. In the Pravastatin from baseline) of the effect of statins on in Elderly Individuals at Risk of Vascular dementia concluded that, while there was between different Disease (PROSPER) trial, the largest statin insufficient evidence to recommend statins statins. for the treatment of dementia, statins were The incidence of new not detrimental to cognitive function. diabetes development An FDA review concluded that data from are found on physical examination and the observational studies and clinical diagnostic neurologic testing, and if the appears to be a class trials did not suggest that cognitive neuropathic symptoms resolve upon changes associated with statin use were discontinuing the statin, then it may be effect and appears common or led to clinically significant useful to repeat the objective evaluations cognitive decline, but information about to see whether the resolution of symptoms to be more common the potential for generally non-serious and correlates with the resolution of objective reversible cognitive side effects (memory neurologic findings. If resolution of with moderate or loss, confusion, etc.) was added to the symptoms or objective neurologic testing statin labels. does not occur after withdrawal of statin higher doses, but a therapy, then the diagnosis of idiopathic causal relationship is Peripheral nervous system peripheral neuropathy unrelated to statin In case reports, and in a small number use should be considered. Conversely, if unproven. of case-control and cohort studies it is symptoms and objective neurologic testing suggested that statins may be associated resolve, then the clinician can best decide

Official Publication of the National Lipid Association 7 whether the benefits of a re-challenge of a analysis by Sattar, et al., reported that of statin therapy and the incidence of statin drug exceeds the potential risks. statin therapy was associated with a 9% diabetes development was observed. increased risk for incident diabetes (odds However, the selection bias of a higher-risk Increases in glycosylated hemoglobin ratio [OR] 1.09[1.02-1.17]), with little population requiring more intense statin (HbA1c) and fasting plasma glucose heterogeneity (I2=11%) between trials.19 A therapy could not be excluded.²³ In the FDA’s review of the results from meta-analysis by Rajpathak also reported a the Justification for the Use of Statins in small increase in diabetes risk (relative risk Based on clinical trial meta-analyses and Primary Prevention: an Intervention Trial [RR] 1.13[1.03-1.23]) with no evidence epidemiological data from the published Evaluating Rosuvastatin (JUPITER) trial, it of heterogeneity across trials.²¹ A recent literature, information concerning an was reported that there was a 27% increase study by Culver, et al., using data from effect of statins on incident diabetes and in investigator-reported diabetes mellitus the Women’s Health Initiative, reported increases in HbA1c and/or fasting plasma in rosuvastatin-treated patients compared that statin use conveys an increased risk glucose was added to statin labels. n to placebo-treated patients. High-dose of new-onset diabetes in postmenopausal atorvastatin also has been associated women and noted that the effect appears Disclosure statement: Dr. Baykal has received consulting fees from Actelion Pharmaceuticals Ltd. with worsening glycemic control in the to be a medication-class effect, unrelated References are listed on page 29. Pravastatin or Atorvastatin Evaluation to potency or to individual statin type²² and Infection Therapy – Thrombolysis in contrary to the findings of Carter.²³ In this Myocardial Infarction 22 Investigators 14-year observational study, a relationship (PROVE-IT TIMI 22) substudy. A meta- between the potency (and duration)

8 LipidSpin Guest Editorial: Managing the Statin-Intolerant Patient: Low-Dose/Low-Frequency Treatment Regimens

MARY HONKANEN, MD, ABIM, FNLA Director of The Cholesterol and Lipid Treatment Center Mobile Diagnostic Center Providence Hospital Mobile, AL Diplomate, American Board of Clinical Lipidology

A patient recently told me the story of her lipid lowering medications. The average statin-intolerant sister, who was referred to low-density lipoprotein (LDL) reduction a cardiologist she had seen for chest pain in these patients was 50.8%. So the crux a few years earlier. When he entered the of therapy for our statin-intolerant room, she explained that she could hardly patients is STATIN, but often dosed Discuss this article at www.lipid.org/lipidspin walk or even get out of bed on atorvastatin. in an unconventional manner in unusual The doctor simply stated there was nothing combinations with other lipid-lowering he could do for her and walked out, agents. years of statin therapy3 compared to the leaving her confused and hurt. We can do 360 lives saved per 100,000 person- something for these patients and it starts Following is our approach to the SI patient. years of statin therapy in 17 secondary with listening. prevention trials. A little pain is worth a lot First, listen to the patient. Just listening of gain. Statin clinical trials suggest an incidence with a compassionate ear will make the of adverse muscular events of ~ 1.5 - 3%, patient more receptive to at least try Third, rule out other causes of but the true incidence of statin intolerance another statin at a very low dose. myopathy and evaluate potential (SI) is likely between 10% and 15%.1, 2 exacerbating factors by checking a In a recent one-month chart review of Second, educate the patient on the TSH, B12, vitamin D level. A baseline 393 patients seen in our lipid clinic, 185 benefits of statin therapy. The patient’s CK should be established and monitored (47%) were originally seen for statin- perception of these drugs often comes with symptoms as recommended by the related adverse events, and 145 (37%) of from the evening news, a friend’s report National Lipid Association Statin Safety these had a history of SI related solely to of some statin horror story or the hungry Task Force.3 musculoskeletal complaints. lawyer ads on T.V. They rarely hear the good news. A favorite “one-liner” for this Finally, we initiate drug therapy by: So, what can we do for these patients? Of purpose: “For every one high-risk person (1) Switching to another statin, one with the 145 SI patients from our review, 90% on statin who has died from an adverse a different metabolism or to an extended- (129 patients) are actually on a statin today muscle event, 1,188 people DIDN’T release preparation (fluvastatinXL or – 14% on a statin alone and 83% on statins DIE because they took their statin,” a lovastatin XR-Altoprev). dosed at very low doses and/or dosed 2-4 calculation based on the incidence of fatal times weekly, in combination with other rhabdomyolysis of 0.3/100,000 person- (2) Initiating very low doses (Ld) of

Official Publication of the National Lipid Association 9 triglyceride monitoring, niacin for LDLs Myalgia not at goal and NOT for those with severe expressions of metabolic syndrome,

Check CK monitoring platelets and symptoms of Rule out other causes of myopathy. ulcers and gout. Address exacerbating factors.

Rhabdomyolysis Since most patients referred to lipid clinics CK>10,000 or Tolerable pain Tolerable pain Intolerable pain have already failed multiple attempts with CK<10xULNa a >10XULN+ Cr CK>10xULN Without elevated CK requiring medical attention multiple statins, proceeding directly to

options 2 and 3 above is reasonable. We Continue statin. Reduce dose/ change Discontinue statin until symptoms resolve almost always start with rosuvastatin 2.5mg statin as symptoms dictate -5mg, taken on Mondays, Wednesdays Carefully reconsider and Fridays (MWF), with directions Rechallenge with risk/ benefit of statin • Same statin at reduced dose to add ezetimibe 5mg (1/2 10mg pill) therapy • Statin with different metabolism on Tuesdays, Thursdays and Saturdays • Extended release statinb OR (TuThSa). Providing samples for this first cycle definitely improves compliance. If symptoms recur, consider: • Very low doses of potent statin A normal week’s supply lasts a month (rosuva 2.5-5mg or atorva 5-10mg QD) with the pill splitting and QOD dosing. • Low-dose / low-frequency (Ld/Lf) long half -life statins rosuva 5-10 mg or atorva 10-20mg 1-4x/week (i.e. M, MF, MWF, QOD) We repeat labs after six weeks. Once pitavastatin 1-2mg QOD • Combination of ezetimibe (also at low dose QD or QOD) with very low doses the patients see the usually significant of weaker statins or Ld/Lf regimens improvements, they are encouraged i.e.pravastatin 10-20mg + ezetimibe 5-10mg QD rosuva 2.5-5mg or atorva 5-10mg 3x/week – QOD (MWF), alternating enough to continue and even increase the with ezetimibe 5-10mg (Tues/ Thurs/ Sat) medications. We advance the statin very gradually, as tolerated, by increasing the

Tolerable symptoms, but Very few symptoms and If symptoms recur: try dose first, not the frequency. For insurance symptoms present and lipids not at goal, slowly non-statin drugs: BAS, purposes, we often switch to atorvastatin lipids not at goal, consider advance statin dose. fibrate, niacin, ezetimibe adding non-statin Increase the dose, not the in varying combinations 5-10mg dosed at the same frequency or medications: BAS, fibrate, frequency in Ld/Lf niacin, ezetimibe regimens change to very low doses of weaker statins (i.e. pravastatin 10-20mg) daily. From Figure 1: Algorithm for managing statin-intolerant patients* there, it’s a slow process of tweaking, Adapted from Arca and Pigna15and NLA Task Force3 determined by other lipid abnormalities, comorbidities and cost. a NLA taskforce recommends 10xULN; some clinicians use 5xULN b fluvastatinXL (Lescol) or lovastatinXR (Altoprev) Following is a summary of studies *This protocol is not the recommendation of the NLA but the personal protocol of the author evaluating the efficacy and tolerability long half-life statins at a low frequency full doses cause a reduction in high-density of low-dose/low-frequency (Ld/Lf) (Lf), i.e. once a week to every other day lipoprotein (HDL). dosing strategies with statins: (QOD), using primarily rosuvastatin (19 (1) Piamsomboon et al.4—In 61 patients hours) and atorvastatin (14 hours) or (4) Combining the above (statin treated with atorvastatin 10mg QOD, pitavastatin (11 hours) QOD. +/- ezetimibe) or ezetimibe alone LDL was reduced 30%. with other non-statin lipid-lowering (2) Juszczyk et al.5—In 25 patients treated medications (BAS, niacin, fibrates) with (3) Combining very low daily doses of with atorvastatin QOD (mean dose an intense effort to choose a drug that weaker statins or alternate-day dosing 18.8mg) or rosuvastatin QOD (mean dose has some clinical trial evidence of benefit of long half-life statins with ezetimibe 9.7mg), LDL reductions were 43% and for that individual patient, i.e. fibrate for – also used at a low-dose/low-frequency 28%, respectively. (5-10mg daily, QOD or 3 times weekly) triglycerides>200mg/dl and HDL<40mg/ 6 – for reduced symptoms, lower cost or if dl, colesevelam for diabetics with close (3) Wongwiwatthanaukit et al. —In 81 patients treated with rosuvastatin 10mg

10 LipidSpin qd vs. QOD, LDLs were reduced 48% Lipid-Lowering Agent No. of patients % a and 39%, respectively, and 85% vs 70% on medications achieved NCEP targets, neither statistically Statins b 129 90 significantly different. Single- agent 19 14 + ezetimibe alone 44 29 (4) Jafari et al.7—In 54 patients, there + ezetimibe + other agents (below) 49 35 were no statistically significant differences + other agents (no ezetimibe) 20 14 Non-daily dosing (low-dose/ low-frequency) c 29 21 in LDL reductions between atorvastatin dosed at 10mg qd, 10mg QOD or 20mg Ezetimibe (5-10mg) 90 64 Non-daily dosing d 48 35 QOD after 6 weeks of treatment; all tolerated treatment. Fibrate e 63 45 Fenofibrate 48 34 (5) Keles et al.8—In 61 patients treated 1/3-2/3 max dose 27 19 with atorvastatin 20mg qd vs QOD, Gemfibrozil 15 11 there was no significant differences in ER Niacin 14 10 the reductions of LDL or hsCRP after 3 BAS (Welchol) 5 3.5 months. Table 1. Usage of Lipid-Lowering Medications in 140 Patients with Myalgia-Related Statin Intolerance; A One- Month Chart Review. Similar trials performed in STATIN a 145 of 393 patients were SI; 2 had stopped all medications, 3 had no results following initial visits; the denominator INTOLERANT patients include: used to calculate percentages was 140. (1) Backes, et al.9—In 51 patients treated b Statins used: rosuvastatin 48% (average dose: 7.4mg/d); atorvastatin 27% (average dose: 13.5mg/d); pravastatin 14% with rosuvastatin 2.5-10mg QOD, (average dose: 35mg/d); pitvastatin 3% (average dose: 2mg/d); fluvastatin XL 2% (average dose: 80mg/d); simvastatin 3.5% (average dose: 24mg/d); lovastatin 0.7% (average dose: 40mg/d). (mean dose 5.6mg), LDL was reduced c Statins used for non-daily dosing: rosuvastatin 2.5mg (7pts), 5mg (13pts), 10mg (4pts) and 20mg (2pts) dosed twice 34.5%, 50% achieved National Cholesterol weekly (M&F), MWF, MWF p.m. + Sun a.m.; atorvastatin 5mg (5pts), 10mg (1pt), 20mg (4pts) dosed M:F, MWF or QOD Education Program goals and 72.5% d Ezetimibe was used at 5-10mg, dosed 2-4 times/week (Tues/Sat, Tues/Thurs/Sat or Tues/Thurs/Sat/Sun) usually tolerated therapy. alternating with statin MWF e 75% of 393 lipid patients reviewed had TG>200; 22% had TG>500mg/dl. Gemfibrozil was used only with very low 10 (2) Gardala, et al. —In 40 lipid patients doses of rosuvastatin and pravastatin in very carefully selected patients who were educated extensively on the signs/ receiving rosuvastatin 5-10mg twice symptoms of rhabdomyolysis weekly (Mondays and Thursdays); LDLs were reduced 26% and 80% tolerated (2) Reddy, et al.13—In 23 patients doses of statins, and 44 were on statin treatment. intolerant of atorvastatin or rosuvastatin in combination with ezetimibe alone receiving the same drug dosed twice with an average LDL reduction of 52%. (3) Rusinger, et al.11—50 patients receiving weekly plus ezetimibe twice weekly Many of these were on non-daily low rosuvastatin 2.5-20mg once a week; plus colesevalam 6 pills a day, LDLs doses of ezetimibe (5mg 2-4 times per LDLs were reduced 23%, 74% tolerated were maintained at the level produced by week). An additional 33 patients were treatment, but only 27% reached their daily dosing, but 87% of patients tolerated on statin+ezetimibe+other non-statin NCEP goal. treatment, and HDLs went up in the drugs and had an average LDL reduction of rosuvastatin patients. 62%. Coincidentally, 62% of the patients Studies evaluating Ld/Lf or extended- were below the more aggressive NCEP release statin therapy in SI patients in (3) Stein, et al.14—In patients receiving targets; 79% of those not at goal had combination with ezetimibe include: daily fluvastatin XL 80mg, ezetimibe 10mg or both, LDLs were reduced 33%, >40% LDL reductions. (1) Athyros, et al.12—In 54 patients 16% and 41%, NCEP targets were achieved receiving ezetimibe 10mg QD for three in 59%, 29% and 84%, and muscle-related Following statins and ezetimibe, fibrates months and subsequently receiving side effects occurred in 17%, 24% and 14%, were the drugs used at the next highest atorvastatin 10mg twice weekly respectively. frequency. This is not surprising, because for three months, LDLs were reduced 295 of 393 (75%) of our patients had TGs 34%, 84% achieved LDL goals vs. only Results from our chart review are >200, and 22% were referred with severe 9% on ezetimibe alone, and only one consistent with the above reports: 29 hypertrigyceridemia (TG>500). Even so, patient could not tolerate the addition of of 140 SI patients were on non-daily less than half of these patients were on atorvastatin. full-dose fenofibrate. Fenofibrate can help

Official Publication of the National Lipid Association 11 lower the LDL further and often results in Treatment % of patients % LDL % HDLc % TG c a dramatic LDL reduction when combined on regimen reduction increase reduction with ezetimibe alone, a very consistent Statin alone 13.7 42 28 30 finding in the completely statin-intolerant patient. If fenofibrate lowers HDL and Statin + Ezetimibe 29.5 53 29 44 increases creatinine, especially enough to Statin + Ezetimibe + Fenofibrate 17.3 52 26 60 preclude the use of metformin, we reduce Statin + Ezetimibe + Gemfibrozil 6.5 57 41 68 the dose or stop it. Table 1 summarizes Statin + Ezetimibe + ER+ Niacin 5.5 60 56 44 the drugs used and Table 2 the lipid values Statin + Ezetimibe + BAS+ d 1.4 60 21 34 achieved with various drug combinations. Only 20% of the patients were on a Ld/ Statin + Ezetimibe + Fenofibrate + ER 1.4 72 34 73 Niacin Lf statin-dosing schedule, but most were Statin + Ezetimibe + Fenofibrate + BAS 2.9 62 41 68 originally started on rosuvastatin (2.5mg) three days a week. Most patients tolerate a very gradual increase in the statin dose – Statin + Gemfibrozil 4.3 46 44 72 to a point. The art is knowing when to Statin + Fenofibratee 5.8 48 21 69 stop. Statin + Fenofibrate + ER Niacin 0.7 37 63 31 Statin + ER Niacin + BAS 0.7 49 9 47 While all of these results of alternate-day statin dosing, especially in combination Statin + ER Niacin 2.2 36 48 41 with other lipid drugs, are quite Statin + ER Niacin + BAS 0.7 51 47 55 remarkable and encouraging, these are non-approved strategies and no clinical trial Ezetimibe Alone 0.7 11 0 -2 evidence for cardiovascular risk reduction Ezetimibe + Fenofibrate 5.0 41 72 58 exists. Therefore, these strategies should be reserved for those patients who have Ezetimibe + Fenofibrate + BAS 0.7 58 22 45 failed recurrent attempts of conventionally Table 2. Efficacy of Various Treatment Regimens Used in Statin-Intolerant Patients; A Chart Review of 140 dosed statins. Designing a clinical trial Patients a,b to evaluate these kinds of treatments in SI patients would be a monumental a Results were calculated by comparing the most recent lipid values to the worst corresponding lipid value on record. For example, LDLs were compared to the highest LDL observed after correcting chylomicronemia. Some baseline values task. However, if one were designed so were not available, because patients often were referred while on some lipid therapy medications were meticulously tailored for b 62% of patients achieved the more aggressive NCEP/ADA LDL target, i.e. <70mg/dl with documented disease or DM + the individual patient – the way most of us 1 risk factor. Of the 38% not at goal, 79% had LDL reductions > 40%. treat these SI patients – compared to those c Triglyceride and HDL responses were likely confounded by changes in other medications (i.e. addition of pioglitazone, other diabetic agents and omega-3 fatty acids [10 pts] or discontinuation of thiazides, atenolol etc.) and significant treated with statin alone, these patients lifestyle modifications. just might come out ahead – or at least d BAS bile acid sequestrant they could get out of a chair! n e 4 of 8 patients also were started on high-dose omega-3 fatty acids in the fenofibrate group, none in the gemfibrozill group. Disclosure statement: Dr. Honkanen is on the speaker’s bureau for Merck & Co., Inc., Astra-Zeneca and Amarin Pharma, Inc.

References are listed on page 29.

12 LipidSpin EBM Tools for Practice: Evidence-Based Approach to the Use of CoQ10 to Deal with Statin Intolerance

JENNIFER M. WELDING, PharmD, CTTS Clinical Pharmacist PharMerica Fort Lauderdale, FL

BISHOY RAGHEB, PharmD, BCACP, CDE, CTTS Clinical Pharmacy Specialist Residency Coordinator Veterans Affairs Health Systems Tallahassee, FL

Statins reportedly are the most effective Statins, CoQ10 and Myopathies of the lipid-modifying drugs in primary CoQ10 is essential in cellular and secondary prevention of coronary bioenergetics, because it participates heart disease.1-6 Yet, many patients are in the electron transport chain during deprived of the benefits of statins because oxidative physphorylation, leading to Discuss this article at of their associated complications. The adenosine triphosphate (ATP) production.13 www.lipid.org/lipidspin most common statin-related complication Depletion of CoQ10 is known to result is myopathy, which was underreported in mitochondrial dysfunction, which is in clinical trials because of the exclusion theorized to result in myopathy.10,14 et al., who published the first double- of patients with a previous history of The theory of CoQ10 depletion blind study assessing the effect of statins myalgia.1,7,8 Studies specifically designed involvement in statin-induced myopathy on plasma CoQ10 levels. Since then, the to assess the rate of statin-related was first proposed in the late 1980s.14 relationship of statins and reduced myalgia have estimated muscle-related CoQ10 is an end-product of the CoQ10 plasma levels has been well complications occur in between 9% and mevalonate pathway. Statins are believed documented. 8,10,12,17-36 22% of patients – or 1.5 million people – to reduce CoQ10 biosynthesis and each year.9-12 This ultimately leads to the cause myopathy by interfering with this Conventional wisdom would suggest that, discontinuation of statins in between 5% pathway via the inhibition 3-hydroxy- given the role of CoQ10 in muscle-energy and 10% of patients.11 Practitioners have 3-methylglutaryl coenzyme A [HMG- production, reversing CoQ10 depletion via been searching for strategies capable of CoA].7,10,14,16 supplementation would resolve cases of alleviating statin-induced myopathy to statin-induced myopathy. The evidence to facilitate the continued use of statins. CoQ10 Depletion Studies date has been, at best, controversial.10 The most prevalent of these strategies is The theory of statin-induced CoQ10 CoQ10 supplementation.9 depletion was supported by Ghirlandaio

Official Publication of the National Lipid Association 13 Updated and Revised CoQ10 Outcomes and mitochondrial myopathy, because up to 600mg/day.8,10,12,45,54 There is strong September 2013 The two most widely cited studies, by intramuscular CoQ10 levels have not evidence based on the observed safety 7,10,42,45 Young et al. and Caso et al., have produced consistently decreased with statins. level of CoQ10 that doses up to 1,200mg/ How it Works equivocal results. In a double-blind Two studies observed intramuscular dl are very safe.53 Based on the safety data 1. Assess your knowledge by placebo-controlled pilot study, Young et CoQ10 increases of 46% and 9% in statin- alone, several authors have suggested answering multiple-choice questions 46,47 al. concluded that, despite a significant treated patients. CoQ10 should be considered in statin- 2. Submit answer sheets and receive a increase in plasma CoQ10 levels, intolerant patients, even if only to induce score report* supplementation with 200mg/day CoQ10 a placebo effect, arguing minimal risk with 3. Review the critiques for each did not improve statin tolerance and CoQ10 should be possible benefit.10,12,45 question with cited references* myalgia after 12 weeks in patients with *Online activity provides real-time prior statin-induced myalgia.37 considered in statin- Conclusion Self-Assessment Program scoring and critiques on each question To date, there is inconclusive evidence to 4. Claim CME/CE credit for Caso et al. performed a double-blind, intolerant patients, prove if CoQ10 can reduce statin-induced participation randomized pilot study assessing the effect myopathy in all patients. Some research, even if only to induce Benefits of Participation of 100mg/day CoQ10 versus 400IU/day however, suggests that it may provide Completely Revised Edition Now Available • Learn from the experience of Vitamin E on the degree of muscle pain a placebo effect, some benefit in certain patients who have leading practitioners, clinical and its interference with daily activities. CoQ10-depleting conditions. Additionally, Now also available as an ONLINE activity! researchers and experts in lipidology the remarkable safety profile makes After 30 days, pain intensity decreased arguing minimal risk • Identify areas of strengths and significantly from baseline in the CoQ10 CoQ10 an attractive low-risk option for opportunities for further study group. Those in the Vitamin E group did with possible benefit. practitioners who are aggressively trying Order Today at lipid.org/nlasap • Complete the NLA Self-Assessment not experience a significant difference in to maintain statin use in their patients. Program anywhere–no travel costs and 38 pain. More data are needed to determine if no time away from your patients and Where do we go from here? CoQ10 is an effective treatment in statin- family Adding to the dilemma, more recent Because of inconsistent results, the induced myopathy. Many are eagerly • Earn up to 150 CME/CE credits studies – such as those by Bookstaver et al., National Lipid Association (NLA) has anticipating the release of the Parker et al. • Activities available in print format Zlatohlavk et al., and Fedacko et al. – also not endorsed the use of CoQ10 for trial later this year in the Journal of Clinical or as online activity** 39-41 failed to produce consistent results. prophylaxis to reduce statin-induced Lipidology, hoping it will shed more light **Online activity includes access to Several clinical reviews have assessed myalgias.48 However, some researchers on this ongoing debate.55 n mobile app designed for iPad and these studies and have been unable to have suggested that CoQ10 may still android tablets definitively conclude that CoQ10 improves have a place in treating statin-induced Disclosure statement: Dr. Welding has no disclosures to report. Dr. Ragheb has no disclosures to report. statin-induced myopathy. 8,9,42-44 myalgia, particularly in the setting of CoQ10-depleting conditions such as References are listed on page 29-30. The five-volume series provides more than 500 board-review style questions with advanced age, multisystem diseases, Rethinking Plasma CoQ10 robust, evidence-based critiques. Inconsistencies in the research data multisystem inherited metabolic disease, have led some to call into question the mitochondrial encephalomyopathies and 1 The Science of Lipidology: Lipid Metabolism, Pathogenesis of certain movement disorders, including significance of reduced plasma CoQ10 Atherosclerosis and Genetic Disorders levels on myalgia. Parkinson’s disease and some cerbebellar 2 ataxias.7,45 There also is research to suggest Cardiovascular Disease Risk Stratification: Identification of Risk Factors and Management of Patients at Risk Researchers suggest that, rather than the benefits of CoQ10 in patients with indicating a true inhibition of CoQ10 cancer. 49,50 3 Contemporary Management of Dyslipidemia: Therapeutic Lifestyle Change synthesis, a reduction in plasma CoQ10 4 Contemporary Management of Dyslipidemia: Pharmacologic Therapy levels should be expected because of Additionally, CoQ10 may be beneficial the statin-induced reduction of low- in patients who have a genetic or 5 Consultative Issues in Clinical Lipidology density lipoprotein (LDL) particles, neuromuscular predisposition to statin- the primary transporter of CoQ10 in induced myopathies.51,52 plasma.8 Additionally, while the statin- induced depletion of CoQ10 is well The use of CoQ10 may be considered CME credit provided by the National Lipid Association CE credit provided by Advancing Knowledge in Healthcare, Inc. documented, research has not established because of its remarkable safety record, a firm association between statin use because there are no known risks in doses These activities have been approved for AMA PRA Category 1 CreditTM. This activity is eligible for ACPE, ANCC and AANP credit; See final CE activity announcement for details. These activities are eligible for CPEUs by the Commission on Dietetic Registration Co-provided/Co-sponsored by Advancing Knowledge in Healthcare (AKH Inc.) This activity is approved for Maintenance of Certification Points by: Full accreditation information and details regarding order fulfillment available at www.lipid.org/nlasap 14 LipidSpin For questions about this educational activity contact the NLA at 904-998-0854. Updated and Revised September 2013

How it Works 1. Assess your knowledge by answering multiple-choice questions 2. Submit answer sheets and receive a score report* 3. Review the critiques for each question with cited references* *Online activity provides real-time Self-Assessment Program scoring and critiques on each question 4. Claim CME/CE credit for participation

Benefits of Participation Completely Revised Edition Now Available • Learn from the experience of leading practitioners, clinical Now also available as an ONLINE activity! researchers and experts in lipidology • Identify areas of strengths and opportunities for further study Order Today at lipid.org/nlasap • Complete the NLA Self-Assessment Program anywhere–no travel costs and no time away from your patients and family • Earn up to 150 CME/CE credits • Activities available in print format or as online activity** **Online activity includes access to mobile app designed for iPad and android tablets

The five-volume series provides more than 500 board-review style questions with robust, evidence-based critiques.

1 The Science of Lipidology: Lipid Metabolism, Pathogenesis of Atherosclerosis and Genetic Disorders 2 Cardiovascular Disease Risk Stratification: Identification of Risk Factors and Management of Patients at Risk 3 Contemporary Management of Dyslipidemia: Therapeutic Lifestyle Change 4 Contemporary Management of Dyslipidemia: Pharmacologic Therapy

5 Consultative Issues in Clinical Lipidology

CME credit provided by the National Lipid Association CE credit provided by Advancing Knowledge in Healthcare, Inc.

These activities have been approved for AMA PRA Category 1 CreditTM. This activity is eligible for ACPE, ANCC and AANP credit; See final CE activity announcement for details. These activities are eligible for CPEUs by the Commission on Dietetic Registration Co-provided/Co-sponsored by Advancing Knowledge in Healthcare (AKH Inc.) This activity is approved for Maintenance of Certification Points by: Full accreditation information and details regarding order fulfillment available at www.lipid.org/nlasap

For questions about this educational activity contact the NLA at 904-998-0854. Lipid Luminations: Lowering LDL Using Non-Statin Regimens

CASEY ELKINS, DNP, NP-C, CLS Assistant Professor University of South Alabama, College of Nursing Mobile, AL Director/Founder The Lipid Center at Cooper Family Med Center Pascagoula, MS Diplomate, Accreditation Council for Clinical Lipidology

to bile acid in the intestines and prevent fewer cardiovascular events and decreased recirculation of cholesterol-decreasing mortality with niacin, and these benefits LDL-C by 15%-26%,2,3 achieving maximal persisted for up to 15 years after induction LDL-C reductions within two weeks. or therapy.6 Niacin reduces LDL-C by 25%, Discuss this article at Colesevelam has a higher specificity for increases high-density lipoprotein (HDL-C) www.lipid.org/lipidspin bile acids than the two older bile acid by 15%-30% and decreases triglycerides sequestrants, and consequently there are by 35%-50%3 with more pronounced Although statin therapy is a cornerstone fewer gastrointestinal side effects and benefits in patients with metabolic of cardiovascular disease prevention, drug interactions.2 Colesevelam has been syndrome. Some clinicians erroneously and although it achieves the largest noted to decrease hemoglobin A1C by eliminate niacin from dyslipidemia reduction of low-density lipoprotein (LDL- about 0.5%,3,4 and is more frequently being treatment options because of results of C),1 and has one of the safest overall used in diabetic patients. Because bile acid several recent randomized clinical trials side-effect profiles among lipid-lowering sequestrants are not absorbed systemically, without an overall understanding of medications, some patients are unable to large doses are required. They do not have aggregate literature. In addition to the tolerate statins because of one or more any systemic drug interactions but they lipoprotein changes associated with niacin side effects. When this clinical scenario can interfere with drug absorption.2, 5 This administration, there are several other is present, alternative risk-reduction requires constant vigilance, monitoring and pleotropic effects, including associated strategies are needed to achieve target adjustments to ensure therapeutic levels of anti-oxidative and anti-inflammatory LDL-C goals. Clinicians should be familiar concomitant medications are maintained to properties, improved endothelial function, with alternative pharmacological therapies, improve outcomes. reduced high-sensitivity C-reactive protein, non-pharmacologic therapy and intensive and regression of carotid intima-media therapeutic lifestyle modifications that Nicotinic acid thickness. This makes niacin a more reduce atherosclerosis progression when Although recent clinical trials have compelling option.1, 7 statin therapy is not an option. shown no benefit from nicotinic acid when LDL cholesterol is therapeutically Cholesterol-absorption inhibitors Bile acid Sequestrants low, there are many research studies Ezetimibe, a cholesterol-absorption Bile acid sequestrants – colestipol, demonstrating LDL-C reduction.5 The inhibitor, can be used alone or in cholestyramine and colesevelam – bind Coronary Drug Project found significantly combination with other medications to

16 LipidSpin reduce LDL-C (by 15%-20%).3,8,9 This several commercially available forms of forming a viscous matrix and trapping amount of reduction in LDL-C does not sterols and stanols, including margarine cholesterol and bile acids. National meet the 30% reduction proven to reduce spreads, juices, smoothies, and chews. Cholesterol Education Program Adult cardiovascular events, and routinely Treatment Panel III (NCEP ATP III) clinicians use ezetimibe in combination recommends a daily intake of 10-25 g/day with other medications. Based on the All patients receiving of viscous fiber. Grains, prunes, apples available data, ezetimibe appears to be and legumes are natural sources of viscous safe but has not been proven to provide lipid-lowering fiber. Psyllium-containing products are significant long-term cardiovascular supplemental sources of viscous fiber benefit.3,9,10 Ezetimibe and colesevelam medications should that provide patients with a convenient combination therapy has been noted to be counseled method to increase daily fiber intake. It is provide a 30%-40% reduction in LDL-C.11 important to instruct patients to gradually on the benefits increase their daily dosage of fiber to Alternative therapies promote gastrointestinal tolerance and to Red yeast rice is a traditional Chinese and importance increase adherence. Combining decreased supplement that is procured after red saturated fat and dietary cholesterol with yeast is grown on rice. It combines of aggressive weight reduction and increased levels of monounsaturated fatty acids, sterols, viscous fiber and plant sterols/ stanols can isoflavones, Monacolin K (a form of therapeutic lifestyle provide a cumulative LDL-C reduction of lovastatin) and other ingredients, whereby modifications. 20%-30%.16 it is reported to lower LDL-C by 10%-20% in several small population studies.3,12 Conclusion This level of LDL-C reduction does not Lifestyle modifications Statin therapy is first line pharmacologic equal the potency of the weakest statin, All patients receiving lipid-lowering interventions for patients with increased and long-term safety and decreased medications should be counseled on the LDL-C; however, some patients experience cardiovascular mortality are not clearly benefits and importance of aggressive untoward side effects and are unable to documented, leading some clinicians to therapeutic lifestyle modifications.3 continually adhere to this therapy. As object to its use. It has been used for In general however, knowledge and clinicians we need to be familiar with centuries in China and it does lower implementation of these lifestyle effective strategies that lead to better LDL-C to some degree, and therefore modifications are under-used or under- lifestyle modifications and we need to be remains non-statin option to reduce LDL- utilized in clinical practice. The current able to employ alternative pharmacologic C, primarily in combination with other ACSM guidelines for exercise and and non-pharmacologic therapies to therapies. dyslipidemia are: Aerobic exercise, 40-75% reduce cardiovascular risk and to improve of aerobic capacity, for 5-7 days a week, healthcare outcomes in our patients in Plant sterols occur naturally and have for 30-60 minutes per day or ≥ 2000 kcal/ need of CVD risk reduction. n a similar structure to cholesterol. Plant week of leisure-time physical activity.15 Disclosure statement: Dr. Elkins is a member of the stanols are “saturated sterols” and do not Therapeutic lifestyle changes have the speakers bureau for LipoScience Inc. have double bonds. Between 150-400 best chance of reducing LDL-C when both References are listed on page 30. mg/d of sterols and stanols are provided physical activity and dietary changes are by the typical Western diet. However, made together. A 4.5kg weight loss has much higher intakes (1-3 g/d) are needed been documented to reduce LDL-C by 5%- to decrease atherogenic lipoprotein 8%.3 Decreasing the intake of cholesterol, properties. Plant sterols and stanols saturated fat, trans-saturated fat, and using are underutilized in the treatment of dietary adjuncts aids in LDL-C reduction.3,9 dyslipidemia. At doses of 2 grams per day, they can lower LDL-C by about 10%- Increasing viscous fiber to at least 5%-10 15%; and these benefits are often additive grams per day can lower LDL-C by 6%- to lifestyle modifications.13-14 There are 13%9. Water-soluble viscous fiber acts by

Official Publication of the National Lipid Association 17

Online AcademyAd.6.13:Layout 1 6/12/13 12:14 PM Page 1 L

Introducing an Interactive Online Training Program in Clinical Lipid Management

Ⅲ Lipid Academy Online is a user-friendly, tech-savvy adaptation of the NLA’s live training course.

Ⅲ This series of seven interactive modules provides a

L comprehensive indoctrination to lipid science and

essential information for the systematic management L of dyslipidemia and the metabolic syndrome.

An iPad-friendly version of Lipid Academy Online will be available soon.

This activity has been approved for AMA PRA CATEGORY 1 CREDIT™

CME credit provided by the National Lipid Association

This activity is Co-provided by Postgraduate Institute for Medicine

This activity is eligible for ACPE, ANCC and CDR credit; see final CE activity for specific details. Full accreditation information is available online at nlalipidacademy.com/

For more information, visit www.nlalipidacademy.com

L 18 L LipidSpin Specialty Corner: Tolerability of Statin Therapy in Children

JESSICA LILLEY, MD Assistant Professor of Pediatrics Blair Batson Children’s Hospital University of Mississippi Medical Center Jackson, MS Acknowledgements: Written with the mentorship and guidance of Sergio Fazio, MD, PhD, Vanderbilt University School of Medicine.

The National Heart, Lung and Blood management of lipid disorders, particularly Institute (NHLBI) recommends universal pharmacotherapy. pediatric lipid screening to identify and treat children with serious genetic Hesitation to use this class of drugs is dyslipidemias.1 Primary care providers unfortunate, because statins have proven Discuss this article at should certainly identify children who highly effective and safe in adult primary www.lipid.org/lipidspin will be candidates for statin therapy. One and secondary prevention trials4,5 and in 500 people are heterozygous for the improve carotid medial thickness in autosomal co-dominant mutations causing children with FH.6 Furthermore, a recent lowering LDL-C than the prior mainstay familial hypercholesterolemia2 (FH), meta-analysis of 135 studies involving of pediatric treatment, bile-acid-binding making it one of the most common genetic ~250,000 adult patients showed that resins. diseases in Western populations. Still, a side effects of statins were rare.7 They are very low number of the children tested far more palatable and more effective at Regardless of the agent used, reducing will reach the threshold for treatment.3 cholesterol in the pediatric population Statin therapy is recommended for has caused concerns about decreasing otherwise healthy children older than Statins are well the available substrate to form hormones 10 years with low-density lipoprotein that orchestrate pubertal development, cholesterol (LDL-C) > 190 mg/dL; tolerated in children and initiating a low-fat diet in at-risk this high cutpoint include only those when prescribed children has been questioned because with severe dyslipidemias such as FH.1 of the necessity of fats for healthy brain Regardless of the low number of children by specialists as development. These concerns remain who will require treatment, obstacles theoretical; a well-designed meta-analysis remain for these pediatric patients. recommended by of six studies examining a total of 798 Medications commonly associated with children showed no pubertal or growth grandparents and secondary prevention of the conservative concerns in children treated with statins.8 further cardiovascular disease may seem Smaller studies showed efficacy and safety out of place in a child’s medicine cabinet. guidelines given by of other agents, though none was powered Even for willing prescribers, pediatricians the NHLBI. to detect rare events.9-12 Reversible historically have had little training in the elevations in transaminases were reported

Official Publication of the National Lipid Association 19 in from 1% to 5% of children in trials of brief medication holiday, she has had no disease later in life. Routine clinic simvastatin or atorvastatin, but none had complaints with rosuvastatin treatment for visits with appropriate screening and clinical signs of liver injury.11,12 years now. A survey of our colleagues at counseling regarding adverse drug effects three other pediatric lipid clinics at tertiary are necessary, but the knowledge of Infrequent but significant adverse effects academic referral centers similarly revealed these potential rare complications should of statin therapy have been reported, no knowledge of adverse effects requiring not limit the use of these powerful including severe muscle injury leading discontinuation of statin therapy. and effective lipid-lowering agents in to rhabdomyolysis. However, the more appropriate patients. n common issue in practice is statin intolerance, an inability to stay on the Recent studies Disclosure statement: Dr. Lilley has no disclosures to report. medication because of muscle complaints without objective signs or blood marker showing a slight but References are listed on page 30-31. changes. Furthermore, recent studies statistically significant showing a slight but statistically significant increase in risk for new onset diabetes increase in risk for have given many prescribers pause about statin use in patients of all ages.7,13 Acute new onset diabetes kidney injury with high doses,14 increased muscle injury and strains,15 reversible have given many memory problems16 and decreased exercise tolerance17also have been reported. prescribers pause Furthermore, the possible cumulative about statin use in effect of statins is unknown. Young patients who start statin therapy for FH patients of all ages. will likely take a pill for the rest of their lives. Statins are classified as a Category X medication for their potential teratogenic One potential explanation for low rates of effects18 and should be used carefully in adverse effects in young patients is that women of childbearing age, including children are generally healthy, without teenage girls. concomitant kidney or muscle disease. Furthermore, children are not usually In the Vanderbilt University Medical taking other medications known to cause Center pediatric lipid program, we first serious interactions, including gemfibrozil present lifestyle measures for lowering and digoxin.19 Polypharmacy increases the LDL-C and improving overall cardiovascular risk of toxicity because of competition health, and each family meets with our with other cytochrome P450 isoform 3A4- dietitian. Following six months of optimal metabolized substances.19 Lipid specialists lifestyle efforts, we offer low-dose statin also treat to less aggressive goals in therapy and transparently discuss the children and use lower doses than for high- risks and benefits of pharmacotherapy if risk adult patients, and lower doses are LDL-C remains above the recommended associated with fewer adverse effects.7 threshold and continue close follow-up in our clinic. Only one patient in our practice, In summary, statins are well tolerated in an obese but active girl, discontinued children when prescribed by specialists simvastatin based on complaints of muscle as recommended by the conservative pain while performing ballet. There was guidelines given by the NHLBI. Early no evidence of serious muscle injury, and identification and treatment of serious a creatine phosphokinase level was normal dyslipidemias provide an important at 114 IU/L (normal 26-140); following a opportunity to prevent atherosclerotic

20 LipidSpin Practical Pearls: Vitamin D Deficiency and Statin Intolerance

DEBRA A. FRIEDRICH, DNP, ARNP, FNP-BC, FNLA Director, West Florida Lipidology Assistant Professor, University of South Florida Tampa, FL Diplomate, Accreditation Council for Clinical Lipidology

Studies specifically designed to evaluate of vitamin D at the cellular and genomic prevalence of statin-related myalgia levels may explain the hormone’s possible have shown that approximately 22% of role in diseases such as multiple sclerosis, patients on statins have some degree depression, tuberculosis, CVD, asthma Discuss this article at of musculoskeletal pain.1 As clinicians, and cancer.5,6 It is reported that vitamin www.lipid.org/lipidspin we know it is difficult for patients to D deficiency is more prevalent than discern between pain related to statin previously recognized and may be present intolerance and that associated with aging, in 50% of the adult population.7 as part of a retrospective chart review osteoarthritis or autoimmune disorders. of lipid outcomes in patients seen in my Many patients with these symptoms lipid clinic. This allowed me to track my discontinue their statin medication Vitamin D presumption that an association may exist without consulting their primary care insufficiency may between a deficiency in vitamin D and provider. This likely leads to increased intolerance to statin medications. This cardiovascular disease (CVD) risk related potentiate statin- association led to a review of the literature to medication non-compliance. and a closer look of patients already induced myalgia enrolled in a six-month pilot study within Low serum concentrations of my practice. 25-hydroxyvitamin D (< 20 ng/ml) are and/or statins independently associated with myalgia2,3 From this literature review there appears and there is a possible connection themselves may to be different concepts related to the between statin intolerance and vitamin D contribute to vitamin potential mechanisms by which vitamin D deficiency. Bioactive vitamin D, or and statins may be connected to patient calcitriol (1, 25-(OH) 2D3), is a steroid D deficiency. intolerance. Vitamin D insufficiency may hormone that has an essential role in potentiate statin-induced myalgia and/ bone mineralization. However, recent or statins themselves may contribute to data shows that vitamin D receptors In my own clinical practice dealing vitamin D deficiency. As of this review, have been identified in a wide variety of with lipid disorder patients, I began there have been several non-blinded cells, demonstrating that this hormone’s seeing an association between vitamin studies that support the concept that biological involvement may well extend D deficiency and reported intolerance to vitamin D deficiency may be directly beyond mineral metabolism.4 The function statins. Vitamin D levels were measured

Official Publication of the National Lipid Association 21 patients who are already at increased CVD 47 (44%) risk. Statins are the cornerstone for the prevention and treatment of coronary Number of vitamin D de cient patients in pilot study heart disease. Strategies to improve tolerance of and compliance with these medications are essential; thus, supporting the suggestion that vitamin D may be is an 28 (59%) excellent option for this statin intolerant patients with inadequate Vitamin D, thus, Number of vitamin D de cient patients intolerant to statins supporting the suggestion that vitamin D may be an excellent option for statin intolerant patients with inadequate vitamin D. n 18 (64%) Disclosure statement: Debra Friedrich has received honoraria from Amarin Corporation. Number of de cient and intolerant patients who tolerated a statin re-challenge after vitamin D levels were normalized References are listed on page 31.

Figure 1. Vitamin D Levels Related to Statin Tolerance. related to statin-induced myalgia. Ahmed had vitamin D levels of less than 30 ng/ et al.8 reported in 2009 the resolution of dl. The number of vitamin D-insufficient statin-induced myalgia in 92% of vitamin patients intolerant to statins was 28 (59%). D-deficient patients after vitamin D Most notably, the number of vitamin supplementation. In a small case series D-deficient and -intolerant patients who published in 2010 by Dr. David Bell,9 four – after achieving normal vitamin D levels of six patients with statin-induced myalgia with supplementation – were able to and vitamin D deficiency who were re- tolerate the re-challenge of a statin for at challenged with the same statin dosage least six months was 18 (64%). after the correction of vitamin D levels tolerated the statin for at least six months. The data are certainly evolving related to In a review, Lee et al.10 also highlighted vitamin D deficiency and it relationship to the association of vitamin D insufficiency CVD risk as a whole. Vitamin D deficiency with statin-induced myalgia, demonstrating potentially is associated with hypertension, successful re-introduction of statin diabetes and the metabolic syndrome, therapy in a subgroup of patients following left ventricular hypertrophy, congestive appropriate repletion of vitamin D levels. heart failure and chronic vascular Literature also reports that insufficient inflammation.12,13 In a recent meta-analysis cytochrome P450 (CYP) enzyme activity of 18 randomized controlled trials of related to vitamin D deficiency may be 57,000 subjects, a vitamin D intake of > responsible for inactivity and increased 500 IU/day was associated with lower all- toxicity of CYP-metabolized statins in cause mortality, in part by association with some patients, leading to the need for fewer CV deaths.14 possible statin dose adjustments.11 This information, along with the small Reviewing the data from my own six- non-blinded studies and anecdotal month pilot study (Figure 1), I found observations that repletion of 25 (OH) D that 106 (70%) of 151 lipid patients had levels predictably improves or resolves vitamin D levels assessed as part of their statin-related myalgia, certainly warrants initial workup. Of these patients, 47 (44%) a further look at how we treat our lipid

22 LipidSpin Case Study: Case Study: Muscle-Related Statin Intolerance

NICOLE GASKINS GREYSHOCK, MD Endocrinology Fellow Division of Endocrinology, Metabolism and Nutrition Duke University Medical Center Durham, NC Diplomate, American Board of Clinical Lipidology

JOHN R. GUYTON, MD Associate Professor of Medicine Division of Endocrinology, Metabolism and Nutrition Duke University Medical Center Durham, NC Diplomate, American Board of Clinical Lipidology

Our patient is a 67-year-old African unable to perform her activities of daily American female referred to the Duke living (ADLs). At her initial visit, when Lipid Clinic for hypercholesterolemia she was off all lipid medications, her lipid and elevated creatine kinase (CK). She profile results were: total cholesterol 287 Discuss this article at has a history of coronary heart disease mg/dL, low-density lipoprotein cholesterol www.lipid.org/lipidspin with a prior non ST-elevation myocardial (LDL-C) 209 mg/dL, triglycerides 108 mg/ infarction (NSTEMI) and stent placement. dL; her high-density lipoprotein (HDL) was She has a former 40-packs-a-year smoking 56 mg/dL. patients who receive statin therapy,2 mild history, hypertension, lumbar degenerative to moderate muscular symptoms are quite disk disease and constipation. She How common are statin-related muscle common. The Prediction of Muscular had lower extremity muscle pain with complaints? Risk in Observational conditions (PRIMO) atorvastatin with elevated CK in the low There is little doubt that Statins are highly study, a large observational study of 300s (reference 20-200 U/L). Her mild effective for cholesterol lowering. Clinical primary care patients on high-dose statin CK elevation persisted when she was off of trials have demonstrated that they reduce therapy, demonstrated that 10.5% of study statin therapy. She was unable to tolerate the risk of ischemic heart disease events, patients had mild to moderate muscular a statin re-challenge with pravastatin coronary procedures and stroke by about symptoms.3 because of lower extremity muscle one third.1 Clinical trials and experience cramping that started within a few weeks have demonstrated that statin therapy is What are risk factors for muscular of beginning statin therapy and stopped generally safe and well tolerated. However, symptoms? after statin discontinuation. CK levels muscle symptoms and associated myopathy The PRIMO study highlights certain never rose above her baseline of 290-330 can limit their use in clinical practice. patient characteristics that are likely to be U/L on statin therapy. However, her quality While the incidence of severe myopathy associated with muscle side effects from of life was impaired to the point of being is low, occurring in less than 0.1% of statin therapy. In PRIMO, the strongest

Official Publication of the National Lipid Association 23 independent risk factor for muscular exam, medicine reconciliation and focused a low-fat, low-glycemic-index diet. Her symptoms was a personal history of muscle laboratory evaluation. Our history focuses medications consisted of Tylenol, tramadol, pain with another lipid-lowering therapy on the timing of muscle effects related to aspirin, carvedilol, lisinopril and a bowel (statins or fibrates).This prior history statin initiation or dose titration, unusual regimen. Her blood pressure was 133/58, was associated with a 10-fold increase physical activity or concurrent illness, her body mass index (BMI) was 27 kg/m,2 in the risk of muscular symptoms. Other as well as historical features that would and her physical examination was within significant, independent risk factors in the point to a secondary cause of muscle pain normal limits, including the ability to PRIMO study were unexplained cramps (hypothyroidism, vitamin D deficiency, rise from a chair without using her arms. (odds ratio [OR] 4.14), a history of CK and family history of autoimmune or There was no other muscle weakness or elevation (OR 2.04), a family history neuromuscular disease, symptoms of pain. Her basic metabolic profile, albumin, of muscular symptoms (OR 1.89) and systemic illness). Medication reconciliation phosphorus, liver function and TSH hypothyroidism (OR 1.71). Treatment with particularly focuses on drugs that inhibit were all within normal limits. She had statins for more than three months and cytochrome P450 3A4, fibrate therapy, an erythrocyte sedimentation rate (ESR) concomitant antidepressant medication use drugs independently considered a risk of 22 mm/h and CK 305 U/L off of statin were associated with a significantly lower factor for myopathy (i.e. glucocorticoids, therapy. prevalence of muscular symptoms (OR cyclosporine, daptomycin, zidovudine) 0.28 and 0.51, respectively). Importantly, and diet history (daily consumption Rosuvastatin 2.5 mg twice weekly was no greater prevalence was found amongst of grapefruit juice). During physical prescribed5 but, within three weeks, she patients with impaired kidney function or examination, we look for signs of systemic developed crampy lower-extremity pain older age. Patients with muscle symptoms illness or inflammatory myositis (rash, and weakness that made it difficult for were more physically active and the joint effusions, fever, muscle redness or her to walk up the stairs in her home and incidence of muscle pain increased with edema) as well as muscle weakness and take care of her other ADLs. Symptoms the level of physical activity. pain. In a younger person, the ability to do resolved several weeks after discontinuing six deep knee bends without using arms rosuvastatin. Clinical features of statin-induced and hands to assist the legs is reassuring myalgia that proximal motor weakness is absent; Based on National Cholesterol Education Usual Statin-related muscular pains are in an older person, the ability to rise from Program Adult Treatment Panel III (NCEP proximal, symmetric muscle weaknesses a chair without using arms and hands is ATP III), our patient’s LDL-C goal is less and soreness. In the PRIMO study, reassuring. A standard laboratory workup than 100mg/dL. Given her intolerance of pains were most commonly described as includes renal and liver function tests, low-dose pravastatin and even low-dose heaviness, stiffness or cramps. However, and measurement of CK and thyroid- rosuvastatin twice weekly with symptoms weakness, loss of strength during exertion stimulating hormone (TSH). Based on that interfered with her ability to carry out and tendon-associated pain were also the history and physical examination, ADLs, she was felt to be statin intolerant. frequently reported. Symptoms were serum calcium, albumin, phosphorus, Other medication possibilities include most commonly in the lower extremities; 25-hydroxyvitamin D, CBC, erythrocyte fibrates, bile acid sequestrants, niacin however, upper extremity, truncal and sedimentation rate (ESR), autoantibodies and cholesterol-absorption inhibitors. diffuse pain also were also found.3 On (such as antinuclear antibodies [ANA] for Given her severe constipation, bile acid physical exam, patients may have muscle suspected lupus, rheumatoid factor [RF] sequestrants were not an option. She tenderness and impairment in motor for suspected rheumatoid arthritis, etc.), was counseled on therapeutic lifestyle function, such as difficulty rising from a electromyogram or possibly muscle biopsy changes and started on ezetimibe 10mg seated position or raising arms above the may be obtained. daily with immediate-release niacin titrated head. Most patients have no elevation – or up to 1,000 mg twice daily. A mortality only minor elevation – in serum CK.4 Let’s get back to our patient. At her initial benefit from niacin was suggested from appointment, off statin therapy for several the follow-up of the Coronary Drug Project How do you evaluate a patient with months, she had intermittent, chronic low which demonstrated an 11% decrease in statin intolerance? back pain. She denied systemic complaints mortality in patients who received niacin Our approach to patients with statin other than severe constipation. She rode after a myocardial infarction.6 Ezetimibe intolerance because of muscle side effects a stationary bike for 30 minutes three has been demonstrated to reduce LDL-C by consists of a detailed history, physical times weekly without difficulty. She ate 25% when added to niacin therapy.7

24 LipidSpin Over a period of about nine months, our we will continue current medications. We patient lost weight, reaching a BMI of 25 suggest that adding psyllium to her bowel kg/m2 and increasing her exercise to an regimen may reduce LDL-C further.9 n hour five times weekly. She tolerated her Disclosure statement: Dr. Greyshock has no disclosures medications and had no medical event. to report. Dr. Guyton has received consulting fees from Merck & Co. Inc. and research grants from Merck & She recently had the following lipid profile: Co. Inc., Abbott Laboratories, GlaxoSmithKline, Amarin total cholesterol, 198; LDL-C, 102; HDL-C, Corporation, Regeneron Pharmaceuticals, Inc., Amgen 89; triglyceride, 36 mg/dL. The decrement Inc., and Genzyme Corporation, A Sanofi Company. He is a stockholder in Eli Lilly and Company. in her LDL-C is surprisingly large for References are listed on page 31. niacin-ezetimibe combination therapy; however, individual patient responses are variable. During a period of active weight loss, LDL-C can drop transiently for several months, and we warned her that long-term results may not sustained at this level.8 She is not at her NCEP ATP III goal; nevertheless, she has had vast improvement and, for the next six months,

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Official Publication of the National Lipid Association 25 Member Spotlight: Barbara S. Wiggins, PharmD

BARBARA S. WIGGINS, PharmD, BCPS, CLS, FNLA, FCCP, FAHA, AACC Clinical Pharmacy Specialist Cardiology Medical University of South Carolina Adjunct Associate Professor South Carolina College of Pharmacy Charleston, SC Diplomate, Accreditation Council for Clinical Lipidology

development of what is now known as the competed in the Olympic trials in the ACCL. marathon, and was at one time nationally ranked for the 5 and 10 kilometer “I think it is easy to just think of lipidology distances. She continues to race and is Discuss this article at in terms of HDL, LDL, triglycerides, etc.,” www.lipid.org/lipidspin looking forward to running in the U.S. Dr. Wiggins said, “through my involvement Army 10- miler in Washington, D.C., this with the NLA and the ACCL, I have October. n For Barbara Wiggins, PharmD, a typical acquired a greater depth of knowledge work day involves working up patients, regarding the various aspects of lipid managing medication reconciliation, management that I incorporate into my verifying doses, compliance, and everyday practice.” completing rounds as a member of an She has gradually become more involved interdisciplinary health care team. Her with the NLA, starting first with spare time is divided into providing input involvement with the ACCL and then on patient management, counseling and moving on to serve on the NLA and teaching. Southeast Lipid Association (SELA) boards. Before she became a clinical pharmacy In the future, Dr. Wiggins would like to specialist in cardiology, Dr. Wiggins had see lipid management focus on methods deferred going into clinical practice and to increase medication compliance, served in the United states Navy for 6 particularly with statin therapy, and years. She then continued her education she would also like to someday see a by obtaining her PharmD, and made the breakthrough on HDL-raising agents that transition to clinical practice. She enjoys show reduced cardiovascular outcomes. all aspects of patient care. Outside of the office, Dr. Wiggins likes to Dr. Wiggins first became interested in spend time with her husband, her three Clinical Lipidology through a colleague children, three dogs, and loves running. who invited her to get involved with Something surprising that most people the National Lipid Association where don’t know about Dr. Wiggins is that she participated in the naming and she is a former professional runner who

26 LipidSpin Education and Meeting News and Notes

Save the Date! NLA Clinical Lipid Update disorders. Developing patient registries is management of statin intolerance, and in Maui: March 13-16, 2014 crucial to this mission by pooling patient imaging in atherosclerosis. Submit your Save the date for breathtaking Maui! data concerning more rare dyslipidemias so abstract using the online abstract submission The NLA’s Spring CLU is scheduled for that epidemiologic and/or clinical research system. All accepted poster abstracts will March 13-16, 2014 at the Grand Wailea can be more focused. Your participation also be published in the 2014 Annual Hotel in Maui, HI. Be there as world in this specific patient registry will assist Scientific Sessions edition of the Journal of renowned thought leaders discuss lipid researchers in the planning of clinical trials Clinical Lipidology. management and metabolic syndrome in that will assess the efficacy of new therapies. Thank you Dr. Swartz various populations from around the world. The NLA and the Foundation of the NLA The Lipid Spin co-editors wish to thank Other sessions include HDL analytics & are pleased to announce the formation ToniMarie Swartz, PharmD, for her work functionality and cardiovascular risk in of this new registry specific patients with supplying keywords so each issue of Lipid Asians in Pacific Islanders. You can earn 18.5 hypertriglyceridemia. For information on Spin is conveniently accessible in the search CME/CE credits for attending. Please check the registry and how to get patients added, function on www.lipid.org. www.lipid.org/springclu for the latest go to www.connect.patientcrossroads. details. org/?org=fnla Pediatric Dyslipidemia Questionnaire

As a member of the NLA, your expertise Adherence Toolkit Available Introducing the Clinical Lipidology and knowledge of dyslipidemia is a valued Resource Center This issue of Lipid Spin includes a opinion for a pediatric dyslipidemia survey. supplemental Clinician’s Toolkit: A Guide The Clinical Lipidology Resource Center is Please follow the link to the questionnaire to Medication and Lifestyle Adherence. The now available. This resource center aims on the homepage of www.lipid.org. Your goals of the toolkit are to define adherence to support lipidologists and other health participation is voluntary and all responses and the various types of non-adherence, care professionals through its expert are anonymous. Even though you may identify common barriers to adherence provision of peer-reviewed, evidence-based not screen or medically manage pediatric and predictors of non-adherence, describe educational content from the Journal of populations, but your participation is still the role of all health care professionals in Clinical Lipidology and the National Lipid valued. the identification and management of non- Association. You can access the resource adherence, summarize current methods center directly from the NLA website or by Research Study Request from University used to assess adherence and review visiting this link: www.nlaresourcecenter. of Pennsylvania evidence-based, innovative strategies to lipidjournal.com We are looking for patients with HDL-C improve adherence. Access this toolkit levels consistent with a confirmed or online and let us know how it has helped Abstracts now Invited for NLA Annual suspected genetic cause (apoA-I, ABCA1, you in your practice: www.lipid.org/ Scientific Sessions May 1-4, 2014 LCAT, CETP deficiency) interested in practicetools/tools/adherence. The National Lipid Association is now participating in a study assessing reverse accepting abstracts for the Scientific cholesterol transport using a radiotracer New Patient Registry Available for Sessions in Orlando, FL May 1 – 4, 2014. technique developed by our team at the Patients with High Triglycerides This is your opportunity to submit your University of Pennsylvania. Subjects are As a professional organization, the National science for inclusion in the NLA’s 2014 required to have one overnight stay in our Lipid Association’s mission has been to Poster Hall. Visit lipid.org/abstracts to research unit. Travel and lodging costs are reduce the morbidity and mortality from submit. The NLA Poster Hall will cover covered. If you are interested in receiving cardiovascular disease by increasing the a vast array of topics in 16 categories, more information, please contact Marina understanding of the pathophysiology, and including clinical applications of biomarkers, Cuchel, MD, PhD at 215-746-2834; detection and optimal treatment of lipid epidemiology of cardiovascular disease, [email protected].

Official Publication of the National Lipid Association 27 Foundation Update

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

lipidjournal.com), FH specialist member • Foundation members assisted highlights on lipid.org, and public relations with a patient survey to launch outreach to local and regional media a new registry for patients with affiliates. high triglycerides. Go to http:// Discuss this article at Other Foundation highlights include: connect.patientcrossroads. www.lipid.org/lipidspin org/?org=fnla for more • Hosting a food tour in the historic information on the registry. September is National Cholesterol Fell’s Point Neighborhood of Education Month. In recognition of this, Baltimore at our Fall Clinical the Foundation of the NLA has supported Lipid Update in Baltimore, MD. As always, we are extremely grateful for an important campaign called “ARE YOU Thank you to everyone who your support of the Foundation! THE ONE?” To help call attention to supported the Foundation of the familial hypercholesterolemia (FH), the NLA through this event. Please Foundation has provided two copies stay tuned for more information of a poster and handout to all NLA about the Foundation event in Two new patient registries: members and more than 40,000 members Maui, which will be inspired by Hypertriglyceridemia patient of the American Academy of Family the traditional luau, perfect for registry, visit: Physicians. This campaign furthers one our Pacific location during this http://connect.patientrcrossroads. of our priorities: to educate clinicians— meeting! org/?org=fnla especially primary care providers—on FH and other cholesterol disorders to • Lifetime Membership has been a Familial Hypercholesterolemia facilitate proper diagnosis and treatment successful membership campaign patient registry, visit: of patients. and it is not over yet! Remind www.thefhfoundation.org your colleagues that Lifetime Additional FH awareness efforts for Membership to the NLA is only National Cholesterol Education Month available through December include a series of FH-themed broadcasts 2013. To show your support, on ReachMD, an FH content area on the please visit lipid.org/membership/ newly created Clinical Lipidology Resource lifemember and register today! Center (http://nlaresourcecenter.

28 LipidSpin References

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Risk of Diabetes Mellitus in Postmenopausal Women in the Wom- muscle-related side effects with other statins. Am J Cardiol. Feb 15 en’s Health Initiative. Arch Intern Med. 2012;172(2):144-152. 3. LaRosa JC, Grundy SM, Waters DD, et al. Intensive lipid lowering 2008;101(4):490-496. with atorvastatin in patients with stable coronary disease. N Engl J 23. Carter AA, Gomes T, Mamdani MM. Risk of incident diabetes 15. Arca M, Pigna G. Treating statin-intolerant patients. Diabetes Metab Med. 2005;352:1425-1435. among patients treated with statins: population based study. BMJ. Syndr Obes.4:155-166. 2013;346:f2610. 4. U.S. Food and Drug Administration. Alert for Healthcare Profession- als: Crestor (Rosuvastatin Calcium). [US Food and Drug Administra- Guest Editorial tion Website.] United States Department of Health and Human EBM Tools for Practice 1. Bruckert E, Hayem G, Dejager S, Yau C, Begaud B. Mild to Services, Center for Drug Evaluation and Research March 2005. moderate muscular symptoms with high-dosage statin therapy in 1. Abd TT, Jacobson TA. Statin-induced myopathy: a review and up- 6. De AG. The influence of statin characteristics on their safety and hyperlipidemic patients – the PRIMO study. Cardiovasc Drugs Ther. date. Expert Opin Drug Saf. 2011;10(3):373-387. tolerability. Int J Clin Pract. 2004;58:945-955. Dec 2005;19(6):403-414. 2. Ghirlanda G, Oradei A, Manto A, et al. Evidence of plasma CoQ10- 7. de Lemos JA, Blazing MA, Wiviott SD, et al. Early intensive vs. a 2. Cohen JD, Brinton EA, Ito MK, Jacobson TA. Understanding Statin lowering effects by HMG-CoA reductase inhibitors: a double-blind, delayed conservative simvastatin strategy in patients with acute cor- Use in America and Gaps in Patient Education (USAGE): an Internet- placebo-controlled study. J Clin Pharmacol. 1993;33:226-9. onary syndromes: Phase Z of the A to Z trial. 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Official Publication of the National Lipid Association 29 17. Mabuchi H. the Hokuriku Lipid Research Group. Effects of CoQ10 36. Littarru GP, Langsjoen P. CoQ10 and statins: biochemical and clini- of dyslipidemia: A scientific review. South Med Jour. 2006;99:257- supplementation on plasma lipoprotein lipid, CoQ10 and liver and cal implications. Mitochondrion. 2007 Jun;7 Suppl:S168-74. 273. muscle enzyme levels in hypercholesterolemic patients treated 37. Young J, Florkowski C, Molyneux S, et al. Effect of CoQ10 3. Sikka P, Kapoor S, Bindra VK, Sharma M, Vishwakarma P, Saxena with atorvastatin: a randomized double-blind study. Atherosclerosis. supplementation on simvastatin-induced myalgia. Am J Cardiol. KK. Statin intolerance: Now a solved problem. Jour Postgrad Med. 2007;195:E182-E189. 2007;100(9):1400-3. 2011;57:321-328. 18. Ghirlanda G, Oradei A, Manto A, et al. Evidence of plasma CoQ10- 38. Caso G, Kelly P, McNurlan MA, Lawson WE. Effect of CoQ10 on 4. 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7. Tangpricha V, Pearce EN, Chen TC, Holick MF. Vitamin D deficiency among free-living healthy young adults.Am J Med. 2002;112:659-62.

Official Publication of the National Lipid Association 31 Events Calendar

2013 Scientific Meeting 2014 Scientific Meetings American Heart Association 2014 National Lipid Association Scientific Sessions 2013 Clinical Lipid Update—Spring November 16–20, 2013 Hosted by the Pacific Lipid Association Dallas, Texas and the Southwest Lipid Association March 13–16, 2014 Grand Wailea Hotel Maui, Hawaii

2014 National Lipid Association Scientific Sessions Hosted by the Southeast Lipid Association May 1–4, 2014 Hyatt Regency Grand Cypress Hotel Orlando, Florida

2014 National Lipid Association Clinical Lipid Update—Fall Clinical Hosted by the Midwest Lipid Lipid Association Update and the Northeast Lipid Association National Lipid Association August 22–24, 2014 JW Marriott Hotel • Indianapolis, IN August 22–24, 2014 JW Marriott Hotel Indianapolis, Indiana

32 LipidSpin This information is intended for providers. Always assess risk/benefit of statin therapy. Author: Paul E. Ziajka, MD, PhD, FNLA Strategies to Deal with Muscle-Related Statin Intolerance

1. Switch statins • if muscle symptoms developed on a lipophyllic statin, switch to a hydrophyllic one (see hydrophyllic vs. lipophyllic listing below) • if muscle symptoms developed on CYP3A4 metabolized statin, switch to one metabolized by a different pathway (see metabolic pathways in table below) • if muscle symptoms developed on a long half-life statin, switch to a short half-life statin and vice versa (see half lives in table below) • if statin therapy is thought to objectively and consistently interfere with exercise tolerance (e.g., compromised exercise capacity, extended recovery and/or muscle pain) consider another statin with different pharmacokinetics 2. Use a statin at a dose and/or frequency that is below the FDA approved lowest dose • try half of the lowest FDA approved dose every day and then consider every other day or 2 to 3 times a week 3. Consider checking for 25 (OH) vitamin D deficiency • if the level is less than 30 ng/ml, hold the statin until vitamin D has been replaced to greater than 30 ng/ml, then rechallenge Replacement Protocol #1: • 50,000 IUs of prescription vitamin D2 qweek for 8 weeks, then recheck the 25(OH) vitamin D level • repeat as needed until 25(OH) vitamin D is greater than 30 ng/ml • then switch to over-the-counter vitamin D3 at 2000 IUs daily Replacement Protocol #2: • 5000 IUs of vitamin D3 for 8 weeks, then recheck the 25(OH) vitamin D level • repeat as needed until 25(OH) vitamin D is greater than 30 ng/ml • then switch to vitamin D2 at 2000 IUs daily 4. Consider supplement with 200 mg of CoQ10 daily, although randomized trials haven’t been uniformly supportive 5. Lower the LDL to goal using a non-statin treatment regimen • especially in patients with the SLCO1B1 Val/Ala or Ala/Ala variations

Generic Name lovastatin pravastatin simvastatin fluvastatin atorvastatin rosuvastatin pitavastatin Brand Name Mevacor Pravachol Zocor Lescol Lipitor Crestor Livalo Year Introduced 1987 1991 1991 1993 1997 2003 2010 Generic Available Yes Yes Yes Yes Yes No No FDA approved dose range (mg/day) 10 to 80 10 to 80 10 to 40 20 to 80 10 to 80 5 to 40 1 to 4 LDL reduction range (%)1 24 to 40 18 to 37 27 to 47 14 to 35 35 to 60 52 to 63 31 to 44 Hydrophyllic/Lipophyllic Lipo Hydro Lipo Hydro Lipo Hydro Lipo Primary mode of metabolism2 CYP3A4 nonCYP CYP3A4 CYP2C9 CYP3A4 nonCYP nonCYP Half-life (hours)3 2 to 3 1 2 to 3 0.5 13 to 16 19 12

(1) per FDA approved package labelling (2) lists the primary mode of metabolism; most statins have alternate modes as well (3) lists half life of the active drug, not metabolites

Definitions: Myalgias: muscle pain without an increase in CPK Lipophyllic statin: a statin that is primarily soluble Organic Anion Transport Polypeptide 1B1 levels or with an increase that is less than 10 times in oil (i.e. the oil/water separation coefficient (OATP1B1): the main transporter responsible for the upper limit of normal is greater than 1.0). In order of most to least extracting all statins from the portal circulation into lipophyllic: simvastatin > lovastatin > atorvastatin the hepatocyte. Many of muscle statin side effects Myositis/myopathy: muscle pain with a CPK > pitavastatin are related to the concomitant use of drugs that increase equal to or greater than 10 times the inhibit CYP3A4 and/or OATP1B1 upper limit of normal SLCO1B1 174 Ala variant – single nucleotide polymorphism associated with statin induced CYP3A4 inhibitors: itraconazole, ketoconazole, Rhabdomyolysis: myopathy (as defined above) muscle side effects posaconazole, voriconazole, erythromycin, with renal compromise (i.e. increase in serum clarithromycin, telithromycin, HIV protease creatinine) Cytochrome p450 3A4 (CYP3A4): primary mode inhibitors, cyclosporine, danazol, verapamil, of metabolism of lovastatin, simvastatin and diltiazem, dronedarone, amiodarone, amlodipine, Hydrophyllic statin: a statin that is primarily atorvastatin ranolazine soluble in water (i.e. the oil/water separation coefficient is less than 1.0). Includes: pravastatin, OATB1B1 inhibitors: rifampin, clarithromycin, rosuvastatin and fluvastatin indinavir, ritonavir, cyclosporine, nelfinavir, erythromycin, atazanir

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