Official Publication of the National Lipid Association LipidSpin · 2015. 2. 10. · Circa 2014 —Ralph LaForge, MSc, CLS, FNLA 22 Practical Pearls Selection of Dyslipidemia Guidelines

Volume 13 Issue 1 Winter 2015visit www.lipid.org

Also in this issue:

Translating Clinical Trial Evidence into Practical Medicine

Guidelines for the Guidelines — Impact and Controversies

This issue sponsored by the Southeast Lipid Association

Official Publication of the National Lipid Association

LipidSpin

Evaluating Published Clinical Trials and Translating Them into Practice

verb

1. to explain something in a way that is easier to understand

2. to change words from one language into another language

translate

NATIONAL LIPID ASSOCIATION


FEBRUARY 27–MARCH 1, 2015

DENVER, CO

SPRING CLINICAL

2015LIPID UPDATE

Hosted by the Paci�c and Southwest Chapters

Professional Development CoursesFebruary 26–27, 2015

Clinical Lipid UpdateFebruary 27–March 1, 2015

lipid.org/springclu

REGISTER NOW!

Featured Presentations ApoB in Risk Assessment and the Diagnosis and Treatment of the Atherogenic DyslipoproteinemiasAllan D. Sniderman, MD

Sunday, March 1 at 9:00 AM

Understanding the Molecular Biology of Atherosclerosis: The Future of Prevention and Intervention in Heart DiseasePaul N. Hopkins, MD, MSPH

Saturday, February 28 at 10:30 AM

The ApoC-III Story: Hypertriglyceridemia, Atherogenesis, and Therapeutic InhibitionFrank M. Sacks, MD

Saturday, February 28 at 1:45 PM

Keynote AddressWorking Together to Prevent One Million Heart Attacks and StrokesJanet Wright, MD

Friday, February 27 at 4:00 PM

HEIGHTS NEWLIPID MANAGEMENT

ACHIEVINGIN

2 From the NLA President Full Speed Ahead—Terry A. Jacobson, MD, FACP, FNLA

5 From the SELA PresidentResearching Progress —Lori A. Alexander, MSHS, RD, CCRC, FNLA

6 Letter from the LipidSpin EditorsHoliday Gifts—James A. Underberg, MD, MS, FACPM, FACP,

FNLA

7 Clinical FeatureTranslating Clinical Trial Evidence into Practical Medicine—Ralph Vicari, MD, FACC, FNLA

11 Guest EditorialGuidelines for the Guidelines — Impact and Controversies—Kahlid H. Sheikh, MD, MBA, FACC, FNLA

14 EBM Tools for PracticeClinical Trials of Alternative Medicine: Testing Whether Magic Works—Gregory S. Pokrywka, MD, FACP, NCMP, FNLA

16 Lipid LuminationsHPS2-THRIVE Commentary—Dave Dixon, PharmD, BCPS, CDE, AACC, FNLA—Evan Sisson, PharmD, MSHA, CDE, FAADE

18 Specialty CornerPhysical Activity and Lipid Disorders: Circa 2014—Ralph LaForge, MSc, CLS, FNLA

22 Practical PearlsSelection of Dyslipidemia Guidelines in Special Populations—Pamela Morris, MD, FACC, FACP, FACPM, FAHA, FNLA

25 Case StudyApplying Clinical Trial Data to Patient Management: A Case Study—Paul Ziajka, MD, PhD, FNLA

27 Chapter UpdateContributing to the NLA Mission—Lori A. Alexander, MSHS, RD, CCRC, FNLA

29 Member SpotlightDeborah S. Croy, NP, DNP, RN, ANP-BC, AGPCNP-BC, CLS, AACC

31 Education, News and Notes

33 Events Calendar

34 Foundation Update

35 References

37 Patient Tear Sheet

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

In This Issue: Winter 2015 (Volume 13, Issue 1)

EditorsJAMES A. UNDERBERG, MD, MS, FACPM, FACP, FNLA*Clinical Assistant Professor of MedicineNYU School of Medicine & NYU Center for Prevention of Cardiovascular DiseaseDirector Bellevue Hospital Lipid ClinicNew York, NY

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

Managing EditorMELISSA HEYBOER National Lipid Association

Executive DirectorCHRISTOPHER R. SEYMOUR, MBA National Lipid Association

Contributing EditorKEVIN C. MAKI, PhD, CLS, FNLA

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

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

Copyright ©2015 by the NLA. All rights reserved.

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

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

*indicates ABCL Diplomate status

Official Publication of the National Lipid Association 1

Clarification: In the Practical Pearls article titled “Lowering Triglycerides with Omega-3 Fatty Acids” from the Fall 2014 issue, the word “supplements” should have been used rather than “OTC.”

2 LipidSpin

Greetings, National Lipid Association members! I hope this holiday season has been a joyous one. As we look back on 2014, we can reflect on the many accomplishments the NLA has put forth. And, as we look toward the New Year, we are encouraged for what’s to come — both for the NLA as a whole and for the field of clinical lipidology.

Most recently, I had the opportunity to attend the American Heart Association’s Annual Scientific Sessions in Chicago in November, where the results of the IMPROVE-IT Trial were presented. I was very excited to hear the results, and as I hoped, the outcome reaffirms the NLA’s Part 1 Recommendations for the Patient-Centered Management of Dyslipidemia. The study also refocuses the emphasis back to the importance of reducing all atherogenic lipoprotein particles, and supports our position that lower is better.

It also reaffirms the importance of lower cholesterol goals and targets consistent with the 2012 Cholesterol Treatment Trialist’s (CTT) meta-analysis of all statin clinical trials.

As a result of requests by many NLA members, the NLA leadership has recently posted a slide set comparing the ACC/AHA Guidelines with the NLA Recommendations. The new slide presentation — created in large part by Carl Orringer, MD, FNLA, and reviewed by an NLA Recommendations Review Panel — compares and contrasts the perspectives provided by the ACC/AHA Guidelines and the NLA Recommendations. You can find the slide set by visiting, lipid.org/recommendations.

In addition, you will want to make sure to attend the NLA Spring Clinical Lipid Update (CLU) — sponsored by the Pacific Lipid Association and Southwest Lipid Association — Feb. 27– March 1, 2015, in Denver. One of the sessions will focus on the controversies in clinical lipid management, with presentations on the ACC/AHA Guidelines and the NLA

Recommendations. Janet S. Wright, MD, will be presenting the Keynote Address “Working Together to Prevent One Million Heart Attacks and Strokes.” She will be speaking about the Million Hearts initiative and how we can all work together to prevent an additional one million heart attacks and strokes. The full program, including those talks centered on the NLA Recommendations and the ACC/AHA guidelines, can be viewed online at lipid.org/springclu.

The Midwest Lipid Association will be hosting the 2015 Annual Scientific Sessions June 11–14, 2015, in Chicago. This is a great opportunity to submit your abstracts to be included in the poster hall. All accepted abstracts will be published in the Annual Scientific Sessions edition of the Journal of Clinical Lipidology (JCL) and up to five abstracts will be selected to be presented during the oral abstract presentation session during the annual meeting.

I especially urge all Young Investigators (in training students, residents, and fellows or members in practice for less than five

From the NLA President: Full Speed Ahead

Discuss this article at www.lipid.org/lipidspin

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

Diplomate, American Board of Clinical Lipidology


years) to submit an abstract. As lead author of an accepted abstract, Young Investigators also will have the chance to compete for the NLA’s enhanced Young Investigator Award. Cash prizes of $1,000 and $500 along with additional travel grants will be awarded to the top three finalists. The award winners will receive recognition at a special ceremony during the Annual Scientific Sessions. In addition, the first place winner will be selected to present his or her abstract during the live abstract session and have the poster published in the LipidSpin following the meeting. Also, all Young Investigator lead authors with accepted abstracts will receive complimentary registration to the Scientific Sessions. In addition, 4th and 5th place awardees will receive travel grants to get to and from the meeting. Make sure to inform any resident, fellow, or in-practice member of this great opportunity to get

their science published in the JCL. Also, lets get to see and acknowledge those NLA members who are providing effective mentorship of Young Investigators and supporting the development of future lipidologists. The submission deadline for all abstracts is Feb. 23, 2015. For more information, or to submit your abstract, visit lipid.org/abstracts.

We hope to see you at our upcoming meetings and appreciate your continued support of the NLA and the field of clinical lipidology.

Happy New Year! n

TUNE IN TO THE LIPID LUMINATIONS SERIES ON REACHMD.COM

ReachMD.com/LipidLuminationsLipid Luminations is brought to you by the National Lipid Association.

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A Series of Programs Focused on the Field of Lipidology.

• Recent advances in lipid management and heart disease

• Scientific and clinical research updates

• New treatment options

• Best practices in patient care

4 LipidSpin

What is your 2015 New Year’s Resolution?Expand your knowledge of Clinical Lipidology?Advance your personal standard of practice?Improve clinical decision making skills?






What is your 2015 New Year’s Resolution?

The National Lipid Association’sThe National Lipid Association’sThe National Lipid Association’sThe National Lipid Association’sThe National Lipid Association’sThe National Lipid Association’sThe National Lipid Association’sThe National Lipid Association’sThe National Lipid Association’sThe National Lipid Association’sThe National Lipid Association’sThe National Lipid Association’sThe National Lipid Association’s

can help you achieve your resolution and advance your career!can help you achieve your resolution and advance your career!can help you achieve your resolution and advance your career!can help you achieve your resolution and advance your career!can help you achieve your resolution and advance your career!can help you achieve your resolution and advance your career!can help you achieve your resolution and advance your career!

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

For more information, visit lipid.org/mastersonline

Features:Complete lectures synchronizedwith slides from the five courses

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Bonus online resources and tools to enhance your learning and practice

Topics:Advanced Lipidology: Cardiovascular Biomarkers, Atherosclerosis Imaging, and Evidence Based Practice Evidence Based Medicine, Cardiovascular Risk Assessment, and Practice Guidelines Vascular Biology and Atherosclerosis Pathogenesis Lipoprotein Metabolism, Genetics, and Familial Lipid Disorders Pharmacology: Lipid Lowering Drugs, Drug Interactions, Drug Safety, Randomized Controlled Trials, Evidence Based Treatment, and Combination Therapy Nutrition and Non-Pharmacologic Therapy Obesity, Metabolic Syndrome, and Diabetes Mellitus

Online Course

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 creditSee final activity program for specific details.

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

I am honored and excited to serve as President of the Southeast Lipid Association (SELA). My passion for lipids heralds back to the formation of the Florida Lipid Associates in 1994, led by Paul Ziajka, MD, PhD, FNLA, and some others interested in lipid research and treatment. It has been gratifying to see the progression of that passion over the years and the formation of SELA, and then the National Lipid Association (NLA).

One of the duties of a chapter president is to host an issue of the LipidSpin, choosing topics and authors. The theme for this LipidSpin is “Evaluating Published Clinical Trials and Translating Them into Practice,” and SELA members eagerly responded. I want to thank each author for rising to the task and sharing their expertise in the current articles. Many thanks as well to the expert guidance of Melissa Heyboer with the NLA, and the LipidSpin editors, James Underberg, MD, MS, FNLA, and Robert Wild, MD, MPH, PhD, FNLA.

One of the founders of the evidence-based

medicine movement described it as “the conscientious, explicit, and judicious use of current best evidence in making decisions about the care of individual patients.”1 A practitioner’s own knowledge and clinical experience is one aspect; understanding how relevant research applies to a specific patient is another. “Good doctors use both clinical expertise and the best available external evidence, and neither alone is enough.”1

As a clinical researcher myself, I believe this issue will prove valuable in helping to translate the evidence-based medicine of clinical trials to good use in caring for our patients. And as a Registered Dietitian, I have been afforded the best opportunity to care for and educate my patients — allowing them to be on the “cutting edge” of treatments in clinical trials, but also teaching them the importance of a healthy lifestyle. Many clinical trials are double-blinded, so if there is a placebo group, patients learn to appreciate how important diet and exercise can be to their overall health.

I want to thank our great Executive Board of Directors and all of the SELA members who have volunteered to help on committees, participate in projects, or have just offered support and guidance this year. In the Chapter Update on page 27, I highlight some of the ideas and initiatives we will be pursuing. I look forward to a fantastic 2015! n

References are listed on page 35.


From the SELA President: Researching Progress


LORI A. ALEXANDER, MSHS, RD, CCRC, FNLA Site Manager, St. John’s Center for Clinical Research

Ponte Vedra, FL

Diplomate, Accreditation Council of Clinical Lipidology

6 LipidSpin

I write this with the holiday season having just passed us. As I sit back and reflect on the past year, it occurs to me that we have much to be thankful for! This past year we embraced the extensive statin safety report from the National Lipid Association. This was followed in September by the release of our Recommendations for the Patient-Centered Management of Dyslipidemia.

Finally, just this past November in Chicago at the American Heart Association meeting, the long-awaited results of the IMPROVE-IT study were released. While purists might argue this was not a titrate-to-goal study, the results only strengthen the concept that atherogenic lipoproteins play a central causal role in the development of atherosclerosis and by extension targeting Non-HDL

cholesterol, apolipoprotein B, and/or LDL particle number to lower goals is key to the prevention of atherosclerotic cardiovascular disease.

Just recently, data published in the American Journal of Managed Care suggests that “increasing medication adherence was associated with improved LDL-C levels.”1 While IMPROVE-IT focused on a population of high risk patients at the very low end of the LDL cholesterol spectrum, when placed next to the accumulated data preceeding IMPROVE-IT, it would be hard not to extrapolate the inference to high risk patients not at goal, who by definition potentially can gain even greater benefit from larger absolute reductions in LDL-C, Non-HDL-C, ApoB, and LDLp.

For those of us who care for patients with inherited disorders of LDL metabolism such as Familial Hypercholesterolemia (FH), this further reinforces NLA’s Recommendations to reduce LDL-C to < 100 mg/dL in high risk patients with FH,

and it also suggests that using non-statin medications, such as ezetimibe, is an important part of this management.

Recent data from new medications in development, particularly PCSK9 inhibitors, also suggests that even at low attained LDL-C levels in high risk patients additional cardiovascular risk reduction may be achieved. This is an exciting time to practice clinical lipidology! The future is bright with hope and for even greater expectations for our patients. New and improved interventions are right around the corner; and our approach fits perfectly with the aggressive utilization of current and future pharmacologic interventions. Combining these options with our continued focus on lifestyle interventions and aggressive patient and physician education programs is our gift that keeps on giving — right now and in years to come.

Happy New Year to you and yours! n


Letter From the LipidSpin Editors: Holiday Gifts

JAMES A. UNDERBERG, MD, MS, FACPM, FACP, FNLA Clinical Assistant Professor of MedicineNYU School of Medicine & NYU Center for Prevention of Cardiovascular DiseaseDirector Bellevue Hospital Lipid ClinicNew York, NY




Over the course of my 36-year career, the practice of medicine has changed dramatically. When I was an intern at Georgetown University Hospital, we treated heart attacks with oxygen, morphine, and sometimes not much more than prayers. Barely anyone at that time could conceive of doing a cardiac catheterization on an acute myocardial infarction. The progress we all enjoy in medicine is based on two major factors: the rapid evolution of medical technology, and scientific evidence gleaned from clinical trials, particularly those trials powered adequately enough to reduce cardiovascular morbidity and mortality.1

Outcome-based clinical research in cardiovascular medicine has given birth to innumerable treatments that have been proven to reduce morbidity and, in some cases, total mortality. The Scandinavian Simvastatin Survival Study (4S)2 was the “grandfather study in lipidology” that was shown to decrease overall mortality. It is this type of research that has driven us to utilize pharmaceuticals and technology to ultimately benefit our patients. Our best clinical pathways and treatment

guidelines are derived from a generation of formidable clinical research. For instance, as of 2014, who would not consider using aspirin, beta blockers, and statins for patients with a recent myocardial infarction? From the Second International Study of Infarct Survival (ISIS-2)3 to the Beta-Blocker Heart Attack Trial (BHAT)4 and on to 4S, to mention a few, we have established clinical guidelines that benefit patient outcomes.

Having been a clinical trialist and clinician as well, I often ask myself if the patient before me whom I am asked to manage would have been included in one or more of the outcome studies based on the specific recruitment criteria.

Often, because of patient diversity, specific clinical trial data is not directly applicable. We are obliged to make clinical decisions for the patients’ maximum benefit based on experience and/or extrapolation of scientific outcome results. It is only with clear knowledge of specific trial inclusion and exclusion criteria, and endpoint results that we make clear evidence-based decisions.

For example, in 1995, the 4S trial randomized 4,444 male patients with coronary artery disease to receive an average dose of 33 mg of simvastatin versus placebo. The average pre-study low-density lipoprotein cholesterol (LDL-C) level was 188 mg/dl. So, going back to 1995, how should we have best managed a female coronary patient with an LDL-C level of 140? At that time, we were forced to make a decision that was not guided directly by patient-specific outcome data. Clinical judgment infused by clinical trial data guided our decision to use lipid-lowering therapy in this atypical patient. Clinical trial data often lags behind, or never will exactly answer how best to treat the vast majority of patients we treat. Fortunately, many statin trials since 1995 added diverse patients as compared to the

Clinical Feature: Translating Clinical Trial Evidence into Practical Medicine

RALPH VICARI, MD, FACC, FNLA Vice President, Foundation of the National Lipid Association

Founder, MIMA Century Research Associate Professor of Cardiovascular Medicine

Department of Medical Education University of Central Florida College of Medicine

Melbourne, FL Diplomate, American Board of Clinical Lipidology


8 LipidSpin

4S population, which make our decisions easier. In addition, safety data from many sources about statins in clinical trials and in practice makes us very comfortable with their use.5

We continually search to further reduce risk by combining statins with other medications both in practice and in randomized clinical trials. There have been four recent studies combining statins with other pharmaceutical agents to treat metabolic dyslipidemia.6-9 Two of the studies combined statins with fibrates and two combined statins with long-acting niacin.6,7 Intuitively, as lipidologists, we would like to believe that treatable risk exists for hypertriglyceridemia and low high-density lipoprotein cholesterol (HDL-C), and yet all of these RCT studies seemingly refute this belief. No study and no clinical trials are perfect both in design and/or implementation. In the following, I will dissect the recent studies that combine statins and fibrates/niacin for purposes of attempting to help the practicing clinician make rational decisions about the use of combination therapy in patients with metabolic dyslipidemia.

The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study6 randomized nearly 10,000 diabetic patients to receive fenofibrate versus placebo, usually in combination with statins. Of the randomized patients in the FIELD study, 80 percent had the metabolic syndrome, but only 38 percent had metabolic dyslipidemia, defined as a triglyceride level > 150 mg/dl, with a HDL-C level < 40mg/dl in males and < 50mg/dl in females. Inclusion criteria for participation in the FIELD study were a total cholesterol level from 116 mg/dl to 251mg/dl, a total cholesterol to HDL-C ratio (Chol/HDLc) > 4, and a triglyceride level > 89mg/dl. The mean LDL-C level prior to randomization was 119mg/dl. The mean HDL-C and triglyceride levels were 42mg/dl and

153mg/dl, respectively. It is well known that FIELD investigators were allowed to titrate statin doses in accordance with their clinical judgment based on unblinded LDL-C levels. Unfortunately, 17 percent of the placebo group in this trial were uptitrated on their statin therapy; whereas only 9 percent of the fenofibrate group received additive statin treatment. How much this influenced the negative trial outcome is unclear.

The outcomes of FIELD were somewhat disappointing for many of us. It showed no statistically significant reduction in the primary endpoint of cardiovascular morbidity and mortality. Overall mortality was higher in the fenofibrate group, but this was not statistically significant. The major benefit of fenofibrate in FIELD was on diabetic microvascular disease progression. This was seen in the retinal subpopulation group as well as in those with peripheral vascular disease and microalbuminuria. A clinical question that arises, based on the design flaws in FIELD, is what we should do with a statin-treated diabetic patient with coronary artery

disease who has an HDL of 30 mg/dl and has triglycerides of 300 mg/dl?

In the Helsinki Heart Study (HHS), there was a dramatic benefit seen in patients on a fibrate who had triglyceride levels greater than 204 mg/dl and an LDL/HDL ratio of >5.10 In the subpopulation of FIELD with true metabolic dyslipidemia, the outcomes were very favorable, with a significant reduction in cardiovascular morbidity and mortality. The pertinent clinical issue is: Can we rely on subpopulation data to make patient decisions? The statistical answer to this question is no; yet the majority of patients randomized to FIELD would not have been placed on combination therapy in my practice! Sometimes we are forced to rely on subpopulation results.

As clinicians, we are confronted with a quandary based on study design and overall outcomes in a diabetic population. Here is where we must, in my view, avoid generalization and treat the patient at hand, even without direct outcome data to perfectly support our best judgment. Would I treat a diabetic with coronary


disease who has an HDL of 30mg/dl and triglycerides of 300 mg/dl with fenofibrate when on statin therapy? For me, the answer is yes. And for those who would not treat this patient because the FIELD trial did not reach clear statistical differences in its primary outcome, a valid approach would be to consider the benefits of treatment on the outcome of microvascular disease alone. Many diabetics develop complications from retinopathy, nephropathy, or peripheral vascular disease, and this often results in blindness, dialysis, or amputation. While morbidity and mortality are the strongest outcomes to base clinical judgment; we also must have regard for a patient’s pain and suffering. Often, these components of patient care and judgment are not readily appreciated as critical components of evidence-based medicine.

The Action to Control Cardiovascular Risk in Diabetes (ACCORD) lipid trial7 was sponsored by the National Institutes of Health’s Heart, Lung and Blood Institute (NHLBI) to answer the question of whether adding a fenofibrate to a statin in diabetic patients influences cardiovascular outcomes. The diabetic population in ACCORD was at more risk for CVD than those entered into the FIELD study. Similar results were found however. After nearly five years of combined therapy, no significant differences in the primary outcome of myocardial infarction, ischemic stroke, and cardiovascular death were found in the comparator arms. Mean entry lipid levels of LDL-C in the ACCORD trial were 100 mg/dl, triglycerides of 162 mg/dl, and HDL-C of 38 mg/dl. These entry lipid values are not characteristic of the highest-risk group of diabetics with profound metabolic dyslipidemia. Microvascular outcomes, nevertheless, were favorably affected. Retinopathy progression was 6.5 percent of the fenofibrate group and 10.2 percent in the placebo group (P = .003). Progression of microalbuminuria also was

reduced with combination statin-fibrate treatment. And finally, a continuing theme is that in the ACCORD trial for participants with triglycerides >204 mg/dL and who also had an HDL-C<39 mg/dL, there was a 31-percent decrease in the primary combined endpoint.

The take-home message here is that, if we had chosen a higher-risk population to study in the first place, outcomes may have been different. Also, in my view, only a therapeutic nihilist would disregard the beneficial effects of fenofibrate on the progression of microvascular disease in diabetics based on combined FIELD/ACCORD results!

How about the recent niacin outcome studies — from trial data to practical use in clinical practice? The Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglyceride and Impact on Global Health Outcomes (AIM-HIGH) study8 was a prospective randomized clinical trial adding niacin ER therapy to high-risk statin-treated patients. Participants had mean entry LDL-C levels of 71mg/dl, mean baseline triglyceride levels of 161 mg/dl, and mean HDL levels of 35 mg/dl. Also, 1,500-2,000 mg of extended-release niacin was added to simvastatin based on pre-randomization tolerance and compared to no addition (placebo). The

placebo group was asked to take 250 mg of crystalline niacin to help maintain the blind due to flushing.

During the course of the AIM-HIGH study, investigators were allowed to manipulate statin doses to maintain LDL-C levels less than 80. There was considerably more statin-added therapy on trial in the placebo group. This could have influenced the trial outcome. The study (n = 3,414) was not large and a 25-percent dropout and down titration rate in the active treatment group occurred.

The results of AIM-HIGH showed no significant difference in cardiovascular morbidity or mortality at a mean follow-up time of 36 months in the niacin-treated patients. There was a tendency to more adverse events in the treatment group and a disturbing increase in stroke rate. Based on these findings the AIM-HIGH data and safety monitoring board (DSMB) discontinued the trial prematurely, with only 50 percent of predicted outcomes events recorded.

For most clinicians and trialists,7,8 the AIM-HIGH study results came as a surprise. We have all seen progression of coronary and vascular disease in patients with optimal LDL-C levels and significant metabolic dyslipidemia. These results left us with high hopes of positive results from the other niacin-statin mega trial Heart Protection Study 2 — Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE) trial.9

HPS-2 THRIVE randomized more than 25,000 high-risk vascular patients worldwide to compare niacin extended release (ER) plus laropiprant, an antiflushing agent, added to optimal statin therapy versus placebo. There were no specific HDL-C inclusion criteria in this study. Baseline mean lipid values in the HPS-2 THRIVE on simvastatin, with

“However, with any individual patient,

certainty from existing trial data does not

always directly apply to that individual.”

10 LipidSpin

or without Ezetimibe, were an LDL-C of 63 mg/dl, HDL-C of 44 mg/dl, and triglycerides of 125 mg/dl. There were 10,000 Chinese patients randomized to HPS-2 THRIVE.

The DSMB of HPS-2 STRIVE stopped the study prematurely because of a lack of benefit on the primary cardiovascular morbidity/mortality endpoint and an increase in adverse events. The majority of these adverse events were related to “minor hyperglycemic problems.” Specifically, the skin reaction rate was from four to five times as high and the rate of musculoskeletal events was nearly twice as high in the treatment (added niacin ER) group. The rate of serious myopathy was sixfold higher in the treatment group. Gastrointestinal side effects, overall bleeding and infection rates also were increased in the study patients on niacin/laropiprant. A disproportionate number of adverse events occurred in the Chinese cohort.

So, as trialist and clinicians scratch their heads about these results, what should we do practically for our high-risk patients with metabolic dyslipidemia and well-controlled LDL-C levels on statin therapy?

My own clinical judgment is as follows:(Note that most of my patients on statin therapy with metabolic dyslipidemia have demonstrated vascular disease and are, therefore, at high or highest NCEP risk.)11

1. Particularly in patients with mild metabolic dyslipidemia on statin therapy, diet, exercise, and weight loss are almost always effective at normalizing the lipid panel. Getting patients to consume less carbohydrate and fat calories and to participate in a programmed exercise regimen is extremely effective.

2. The majority of statin patients I have put on fibrates or niacin in the past 30 years have lipid profiles before treatment that are much worse than mean HDL and triglyceride levels in all of the aforementioned studies. I am not taking any of these patients off therapy unless they experience side effects. How do I rationalize this? There are four prior fibrate trials (HHS,10 Veterans’ Affairs — High-Density Lipoprotein Intervention Trial [VA-HIT],12 FIELD, and ACCORD), one prescription omega-3 study (Japan eicosapentaenoic acid Lipid Intervention Study [JELIS]),13 and two niacin trials (Coronary Drug Project [CDP]14 and AIM-HIGH) that show benefits in those patients in the lowest HDL and highest triglyceride groups.

3. In those high-risk patients with significant metabolic dyslipidemia (triglycerides>200mg/dl, HDL <35mg/dl in males, <45mg/dl in females), I am still prescribing both fibrates and niacin in combination with statins. I am particularly careful to monitor the use of niacin ER, especially during the titration phase. I monitor my patients’ fasting glucoses with each titration of niacin if they are diabetic and every other titration if they are non-diabetic.

4. I am diligent in educating the niacin ER-treated patients about side effects. With this caution, I am able to get more than 70 percent of patients on 1,000 mg or more.

5. I use fish oil (1,000 mg/day) in all patients with vascular disease, regardless of their lipid profile.

6. I believe it is reasonable to use fibrates in high-risk diabetics, particularly those with metabolic dyslipidemia, to reduce microvascular disease.

The practice of medicine should always be based on best evidence when there is proven outcome data relevant to patients meeting the inclusion and exclusion criteria of the trials. However, with any individual patient, certainty from existing trial data does not always directly apply to that individual. This is where the art of medicine and clinical experience are necessary to make therapeutic decisions. The hard endpoints of most CVD clinical trials are not all that should guide us in our treatment strategies. Pain and suffering are important in patient care, but are not common endpoints in cardiovascular trials. As a trialist and clinician, I believe the marriage of scientific knowledge and practical experience should guide our best decisions for patient care. n

Disclosure statement: Dr.Vicari has no disclosures to report.


This issue of LipidSpin is dedicated to “Evaluating Published Clinical Trials and Translating Them into Practice.” Clinical trials are the basis for advancing our knowledge of effective therapies in medicine. Well-conducted clinical trials, particularly those with results that can be replicated, traditionally have been used to develop practice guidelines.

Practice guidelines have far-reaching implications. They provide medical practitioners with guidance on the standard of care derived from evidence-based medicine. They also have economic impact, as they can promote and validate certain therapies and destroy others. They have administrative impacts, because they can form the basis of establishing payment, authorization, and regulatory policies by administrative agencies and health insurance plans. They have legal implications, because they can form the basis for medical standards of care used in peer review and medical malpractice issues.

Over the past 15 years, a plethora of practice guidelines have emerged, many

of which suffered from shortcomings in the development process. In response, the Institute of Medicine (IOM) assembled an expert committee to provide recommendations to ensure that practice guidelines would truly represent an unbiased and evidence-based compilation of knowledge and standards of therapy. A year in the making, in 2011, the IOM committee’s report, “Clinical Practice Guidelines We Can Trust,” was released.1

The IOM claims that its new standards will minimize the chances that important health decisions are based on information that may be biased or erroneous. However,

since their release, the IOM standards for practice guidelines have been met with praise, criticism, and controversy.

Review of IOM StandardsAfter an exhaustive process of research, review, and even public comment, the IOM committee outlined eight standards for clinical practice guideline development. (Table 1) The new standards addressed a variety of problems that were identified by the IOM committee. However, two major issues were given special emphasis.

One was the sheer number of guidelines available to clinicians. Many had conflicting recommendations and a process of development that was not transparent. A charge of the committee was to ensure that future guidelines are developed in a trustworthy, evidence-based process.


Guest Editorial: Guidelines for the Guidelines — Impact and Controversies

KHALID H. SHEIKH, MD, MBA, FACC, FNLA Director of Cardiology, Cape Canaveral Hospital

Assistant Professor, University of Central Florida College of Medicine Cocoa Beach, FL



“The new guidelines are silent with

respect to patients older than 75 and

those younger than than 40.”

12 LipidSpin

The second concern was addressing conflicts of interest. The committee found that many guidelines have been developed with fairly egregious conflicts of interest, such as instances when drug companies substantially fund guideline development. A more subtle, but potentially equally important, conflict of interest was recognized in which clinical experts involved in developing practice guidelines had inherent biases because of their affiliation with industry.

Validations of IOM StandardsThe assertions of the IOM committee regarding the problems it identified in clinical practice guidelines have been supported by objective and independent reviews. A recent report reviewed 130 randomly chosen clinical practice guidelines.2 Only 44 percent met the median number of IOM standards. Another report found that, in a review of 149 practice guidelines, only 46 percent incorporated a grading or classification system for their recommendations.3

Both of these studies found that more than half of the guidelines reviewed did not reveal conflict-of-interest statements. Of those that did, more than 70 percent disclosed that the writing committee chairperson(s) had conflicts of interest. Guidelines from non-U.S. groups and medical specialty societies were the least likely to include conflict-of-interest information or meet the other IOM standards.

These reports also found that the mean age of guidelines was more than five years. Thus, practice guidelines are not updated with sufficient frequency to reflect changes in clinical knowledge. Furthermore, guidelines were more likely to emphasize benefits of treatment rather than potential harms.

Criticisms of IOM StandardsThe IOM standards have been criticized as being impractical and inflexible. To be labeled trustworthy, the IOM states, a practice guideline must meet all eight standards. If most clinical practice guidelines already are not meeting IOM standards, then how practical are the IOM standards? We know we cannot have high-level evidence for everything we do in medicine. Do we leave clinicians unsupported in instances where high-quality evidence does not exist?A second criticism of the IOM report is the underlining belief system that working with industry to develop and commercialize new therapies is somehow inherently bad and should be managed or eliminated. The problem with this philosophy is that it fails to recognize the expertise and value from industry-academia collaboration.

Lastly, the IOM report fails to substantially meet its own standards.4 Subjected to scrutiny, the IOM document completely passed only two of its own standards, partially passed two and failed four. Therefore, one could question whether the new IOM standards were, in fact, trustworthy.

Impact of IOM Standards on Lipid GuidelinesAfter much delay and anticipation, last year the American College of Cardiology/American Heart Association (ACC/AHA) released the report of their expert panel task force, which was intended to be an updated set of guidelines for cholesterol management in the U.S.5 They were expected to provide a comprehensive review on both the science and clinical evidence linking atherosclerosis to disordered lipid metabolism and by incorporating recent clinical trials of lipid intervention; they also were expected to provide the most up-to-date recommendations for clinicians to evaluate and optimize cardiovascular risk as it relates to lipids. For most clinicians, the ACC/AHA report fell far short of these expectations, and ended up being another set of specialty society guidelines.

The ACC/AHA report acknowledged that it was influenced by the IOM’s 2011 report on the development of trustworthy clinical guidelines. The expert panel’s recommendations were derived primarily from randomized controlled trials (RCTs). The virtual exclusion of evidence other than that from RCTs restricted the scope of the new guidelines. No

Table 1.

Eight Standards for Clinical Practice Guidelines Published by the IOM

Establishing transparencyManagement of conflict of interestGuideline development group compositionClinical practice guidelines/systematic review intersectionEstablishing evidence foundations for and rating strength of recommendationsArticulation of recommendationsExternal reviewUpdating

Institute of Medicine. Practice Guidelines We Can Trust. National Academies Press, Washington, DC; 2011 http://iom.edu/Reports/2011/Clinical-Practice-Guidelines-We-Can-Trust.aspx (accessed September 1, 2014).


recommendations were formulated when sufficient evidence was not available. Thus, the new guidelines left clinicians in the position of having to use their own clinical judgment to arrive at many clinical decisions instead of having science-based and expert guidance to inform these clinical choices.

In addition to criticisms of its method-ology, the ACC/AHA report has been soundly criticized for many of its clinical recommendations, or lack thereof. One major criticism is that, with respect to lipid-lowering therapies, only statins were considered. Furthermore, the concept of low-density lipoprotein (LDL) goals for treatment was completely ignored. By not making LDL the centerpiece of the new guidelines, they largely disregarded the traditional lipid hypothesis.

More controversy arose from the new Pooled Cohort Risk assessment as a replacement for the Framingham risk calculator.6 The ACC/AHA risk algorithm has been purported to overestimate 10-year risk. As a result, an estimated 30 million to 40 million lower-risk Americans will be eligible for drug therapy.

The new guidelines place increased emphasis on lifestyle modifications. However, an interesting aspect of the new guidelines is that lifestyle is highly promoted without randomized clinical trial evidence. Thus, it seems that RCTs are only applied to drug therapy.

The new guidelines are silent with respect to patients older than 75 and those younger than 40. They do not comment on genetic dyslipidemias, metabolic syndrome, or primary prevention. They do not adequately address potential harm associated with statin use. Nontraditional risk factors, such as C-reactive protein

(CRP), calcium score, ApoB, and carotid intimal medial thickness, generally have been dismissed.

If the ACC/AHA document was intended to adhere to the IOM standards regarding conflict of interest, it failed to do so.7 Of the 13 authors in the main treatment guideline panel who were not NHLBI staffers, seven had financial relationships with pharmaceutical companies that manufacture statins. Of the 10 expert reviewers for the panel, three had financial relationships with pharmaceutical companies that manufacture statins. Of the 11 people on the risk prediction panel, five had financial relationships with pharmaceutical companies that manufactures statins.

Response to IOM StandardsThe National Lipid Association (NLA) has failed to endorse the new ACC/AHA guidelines. Likewise, the American Association of Clinical Endocrinologists (AACE) not only declined to endorse the guidelines but also recommended that its members continue to use AACE guidelines, which generally agree with Adult Treatment Panel 3 (ATP 3).

As a result, the NLA has put forth its new Recommendations for Patient-Centered Management of Dyslipidemia.8 The evidence base considered in the development of new consensus recommendations emphasized results from RCTs but also included subgroup assessments and pooled analysis for multiple trials, epidemiologic, genetic, metabolic, and mechanistic investigations. The panel acknowledged that the primary results from RCTs represent the strongest evidence from which to draw conclusions about the benefits and risks of treatment strategies. However, RCT evidence has limitations and often is incomplete or of uncertain relevance to patients with characteristics that may differ in important ways from those who participated in RCTs.

When it comes to practice guidelines, a reasonable question to pose to the IOM is whether, in our quest for trustworthy, we have compromised effectiveness. n

Disclosure statement: Dr. Sheikh received honorarium as a member of the speakers bureau from Amarin and Boehringer Ingelheim.


“When it comes to practice guidelines, a reasonable question to pose to the IOM is whether, in our quest for trustworthy, we have compromised

effectiveness.”

14 LipidSpin

I have in mind a prospective clinical trial in which I study a common children’s phenomenon, detailing the differences between genders, location, ethnicity, biometrics, dental data, monetary value, etc. It’s a common phenomenon that most parents have photos of and have experienced ourselves. I’m sure we could generate a lot of highly statistically significant data and make many useful insights.

I’m talking about what our children find left under their pillows by the Tooth Fairy. One problem — the Tooth Fairy doesn’t really exist.

This phenomenon, Tooth Fairy Science,1 happens daily throughout America, at many of our hospitals and institutions of higher learning. Under pressure from alternative medicine (Alt-Med or Complementary and Alternative Medicine [CAM])

practitioners and societies, and even Alt-Med-friendly government officials,2 such prescientific and long-discredited practices as homeopathy, acupuncture (“a theatrical placebo”), reiki, and others are infiltrating our medical schools and hospitals, without scientific proof of their efficacy and safety. These practices often come under the guise of integrative medicine, an attempt to “treat the whole patient” by integrating traditional medicine with Alt-Med.

Good clinicians attempt to treat the whole patient in the first place. However, many physicians, being rushed by the many pressures engendered by electronic medical records and volume-based reimbursement, have ceded to the Alt-Med practitioners the beneficial effects of talking to the patient and a more extended “laying on of hands” experience. As far as combining traditional medicine with Alt-Med, as a famous phrase goes,3 “Mixing apple pie with cow pie doesn’t make the cow pie taste better, it makes the apple pie taste worse.”

Two recent articles are pertinent. Maurizio Pandolfi and Giulia Carreras4 discuss

why “the type of inferential statistics used in medicine have intrinsic flaws to which CAM interventions appear to be particularly vulnerable.” When even a well-designed clinical trial is performed, the predictive power of the results is dependent on the prior plausibility of the phenomenon being studied. How to establish this prior plausibility? Conformity to scientific laws and principles is one criterion – the Tooth Fairy, homeopathy (in which the “treatment” is so diluted that it contains not even one molecule of the original substance!), “energy medicine,” reiki, Bach Flower Therapy, acupuncture (there is no identifiable “chi” nor “meridian”), and many others all fail to meet this criteria. Another criterion is “falsifiability”: Science aims to produce falsifiable hypotheses; pseudoscience often cannot. Another criterion is “Ockham’s razor,” according to which if two models describe the observations equally well, the simpler one is more likely to be true, e.g. the placebo effect in Alt-Med interventions. Applying Bayes’ theorem, that is the probability of an inference’s being true is dependent on prior plausibility — Bayes’ theorem provides a

EBM Tools for Practice: Clinical Trials of Alternative Medicine: Testing Whether Magic Works

GREGORY S. POKRYWKA, MD, FACP, NCMP, FNLA Assistant Professor of General Internal Medicine Johns Hopkins University School of Medicine Director, Baltimore Lipid Center Baltimore, MD

Diplomate, American Board Clinical Lipidology



principled way of combining new evidence with prior beliefs — it is inopportune to interpret P values at face value, especially when they are calculated from results obtained by testing hypotheses with low prior probability/plausibility. Clinicians tend to be easily swept up in P values, often neglecting how heavily dependent they are on prior probability/plausibility of hypotheses being tested. (This is very low for Alt-Med modalities such as those mentioned above.) It is critical to realize that the P value tends to exaggerate support for the hypothesis tested, especially if the scientific plausibility of the hypothesis is low. Any difference can be shown to be statistically significant if the numbers are large enough. What counts is clinically meaningful clinical differences found to be statistically significant.

David Gorski and Stephen Novella5 lament that the usual process of evidence-based medicine (EBM), wherein treatments proceed to randomized clinical trials after biological plausibility is determined and compelling evidence from preclinical studies has been amassed, has been upended in the case of Alt-Med treatments, for which clinical trials are conducted prematurely. Some of these trials will have “positive P values” but, as explained above, the low prior plausibility undermines the

trials’ support for the tested hypothesis. It is important to note that “biologically plausible” does not mean “knowing the exact mechanism.” It means that the mechanism should not be so scientifically implausible as to be reasonably considered impossible and not violate well-established laws of biology, chemistry, and physics (as reiki, homeopathy, and acupuncture do, for example).

“Extraordinary claims require extraordinary evidence,” as philosopher David Hume once said.6 Many clinical trials are imperfect and bias-prone and should not be weighted as superior evidence of truth in circumstances where prior plausibility is low. In RCT’s testing modalities with low plausibility, confounding bias effects are very much magnified, producing a high false-positive rate.7 Despite their lack of biological plausibility and pre-clinical studies, Alt-Med clinical trials are, in fact, often driven by popularity with the public and funding sources. The authors have distinguished science-based medicine (SBM) from EBM by the recognition that, before doing a clinical trial on a medical treatment, there must be a reasonably high prior plausibility that the treatment will work.8

An example perhaps familiar to many

readers is the Trial to Assess Chelation Therapy (TACT), the $30 million multi-center trial funded by tax dollars and the National Center for Complementary and Alternative Medicine (NCCAM) to determine the safety and efficacy of ethylenediaminetetraacetic acid (EDTA) chelation therapy for individuals with coronary artery disease (CAD) and prior myocardial infarction (MI). The trial was conducted despite a lack of prior plausibility, possible mechanism of action and preclinical trial data, as well as multiple failed smaller trials. Many study sites were dubious alternative medicine clinics, and the treatment itself poses risks to patients.9 When finally reported, results were negative except for one subgroup (diabetics), and all results have come under much deserved and damning criticism.10

An esteemed lipidology colleague, when engaged in debate over these issues, accused those of us practicing SBM of being biased and closed minded in our assessment of prior plausibility for Alt-Med treatments. He’s certainly correct. SBM is biased in favor of science because science works. Science also does not pretend to know everything. Who knows what pharmacologic treatments await discovery out there? But unless new treatments are consistent with the laws of science, their assessment in clinical trials is unrevealing, predicts little, and is even unethical.

“Keep your minds open and stay thirsty my friends, but don’t let your brains fall out!” — The Most Interesting Scientist in the World. n

Disclosure statement: Dr. Pokrywka received consulting fees from Amarin and AstraZeneca. He received speaker honoraria from Amarin, AstraZeneca, Daiichi Sankyo Inc., Kowa Pharmaceuticals, LipoScience Inc., Health Diagnostics Labs, Genzyme, Metagenics, and Genentech.


Key Points:

“Alternative Medicine” practices (e.g. homeopathy, acupuncture, reiki, and many others) are infiltrating our medical schools and hospitals without scientific proof of their prior plausibility and efficacy.

Applying Bayes’ theorem, that is the probability of an inference’s being true is dependent on prior plausibility, it is inopportune to interpret P values at face value, especially when they are calculated from results obtained testing hypotheses with low prior probability/plausibility.

Science-based medicine (SBM) is distinguished from EBM by the recognition that, before doing a clinical trial on a medical treatment, there must be a reasonably high prior plausibility that the treatment will work.

Unless new treatments are consistent with the laws of science, their assessment in clinical trials is unrevealing, predicts little, and is even unethical.

16 LipidSpin

The Heart Protection Study 2 — Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE) trial was a randomized, double-blind, multicenter clinical trial.1 Enrolled subjects were between ages 50 and 80 and had a history of vascular disease. After a four-week run-in phase with simvastatin 40mg daily (ezetimibe was added if total cholesterol remained >135 mg/dL), subjects were randomized to extended-release niacin-laropiprant or matching placebo. Laropiprant, a prostaglandin D2 inhibitor, may improve niacin tolerability by reducing

the incidence of flushing. After a median follow-up of 3.9 years, niacin-laropiprant did not reduce the primary outcome of first major vascular event but did increase the risk of niacin-related serious adverse events.

Some have suggested that increasing high-density lipoprotein cholesterol (HDL-C) with niacin is ineffective at reducing cardiovascular risk based on the results from HPS2-THRIVE; however, the stated purpose and study design do not fully support this conclusion.2 The study did not establish specific entry criteria for lipoprotein levels or target patients with low HDL-C. HPS2-THRIVE primarily included patients with an HDL-C >43 mg/dL (49.2 percent) and only 19.1 percent of the study population had a baseline HDL-C <35 mg/dL.

The overall lack of benefit with niacin-laropiprant is difficult to reconcile with earlier niacin trial data. Although niacin was the primary target drug, the observed effects may have been influenced by the addition of laropiprant. Similarly, patients receiving ezetimibe plus simvastatin achieved lower low-density lipoprotein cholesterol (LDL-C) levels than those taking simvastatin alone (53 mg/dL vs. 56 mg/dL, respectively), potentially masking any additional benefits from niacin.

A more likely explanation for the lack of benefit is related to the ethnicity of the population (57.4 percent from Europe and 42.6 percent from China). The first impact of combining these two groups was observed during the run-in phase. During this period, fewer anticipated differences in lipid levels (12 percent LDL-C reduction

Lipid Luminations: HPS2-THRIVE Commentary

DAVE DIXON, PharmD, BCPS, CDE, AACC, FNLAAssistant Professor, VCU School of PharmacyRichmond, VA


EVAN SISSON, PharmD, MSHA, CDE, FAADEAssociate Professor, VCU School of PharmacyRichmond, VA



from baseline in Europe, 7 percent in China) prompted the steering committee to increase study enrollment from 20,000 to 25,000. Although the overall incidence of major vascular events was not significantly different between groups, patients from Europe receiving niacin had fewer events compared with placebo (11.3 percent versus 12.4 percent), but no difference existed for patients from China (15.8 percent versus 15.5 percent).

The incidence of niacin-associated serious adverse effects also was influenced by the population demographics. Patients in China receiving niacin-laropiprant were 10 times as likely to experience myopathy compared with those in Europe. Although patients with active peptic ulcer disease were excluded, those with a history of peptic ulcer disease were allowed to enroll. Because the mechanism of niacin-related gastrointestinal bleeding is due

to prostaglandin-mediated vasodilation, the observed study incidence represents a major strike against laropiprant. As expected, patients receiving niacin were more likely to experience worsening insulin resistance. The increased incidence of glucose-related hospitalization in patients with pre-existing diabetes was not observed in other studies. Although a subgroup analysis by ethnicity was not provided, it is possible that this increase was influenced by the Chinese population and related to increased niacin sensitivity or health-system custom for care of patients with glucose excursions.

The authors concluded that the addition of niacin-laropiprant “to statin-based LDL-C lowering therapy did not significantly reduce the risk of major vascular events.” A key omission from this conclusion is that the patients achieved a mean non-HDL-C of 84 mg/dL prior to randomization, a

level that would not traditionally warrant additional intervention. Consequently, these results may validate the benefit of aggressive cholesterol management, especially in patients who are male, smoked, or are from Europe. Although the sample size of this study is impressive, characteristics of the study population from which the data were derived must be considered before applying the findings to individual patients in clinical practice. n

Disclosure statement: Dr. Dixon received speaker honorarium from Sanofi. Dr. Sisson received speaker honorarium from AADE.


Complex Lipid ManagementSelf-Assessment Program

Hypertriglyceridemia: Diagnosis, Pathophysiology,Clinical Significance and Treatment

An online, innovative, evidence-based, self-directed CME/CE program for health care professionals who treat patients with lipid disorders

*NLA members only.

FREECME/CEActivity!

For more information visit

lipid.org/education/clmsap

• Objective validate and enhance your clinical knowledge of hypertriglyceridemia

• Complete the program at your own pace – whenever and wherever you choose

• Real-time feedback after each question – includes access to mobile applications designed for iPad and Android devices*

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.

This activity is supported by educational grants from Amarin and AstraZeneca.

CE credit provided by Advancing Knowledge in Healthcare, Inc.

Jointly provided by AKH, Inc., Advancing Knowledge in Healthcare and the National Lipid Association.This activity is eligible for ACPE and ANCC credit.Full accreditation information available at www.lipid.org.For questions about this educational activity contact the NLA at 904-998-0854.

18 LipidSpin

Specialty Corner: Physical Activity and Lipid Disorders: Circa 2014

Blood Lipid Response to Physical Activity and Exercise Training A prevailing myth among patients and many healthcare providers is the notion that physical exercise “burns” or oxidizes cholesterol or cholesterol-rich particles similar to the utilization of fatty acids and glucose. This doesn’t happen. Cholesterol is a sterol, a lipid molecule biosynthesized by all animal cells because, among other purposes, it is an essential structural component of animal cell membranes that is required to maintain both membrane structural integrity and fluidity. In other words, it is not an oxidizable substrate fuel supporting exercise energy. Thus, unlike adipose tissue or even carbohydrate utilization during prolonged exercise, there is at best a minimal relationship between total exercise energy expenditure and

diminished total cholesterol or low-density lipoprotein cholesterol (LDL-C). Still, regardless of how you rationalize physical activity, we don’t “burn” off cholesterol. With that said, and for numerous metabolic and genetic reasons, an individual’s lipid and lipoprotein profile is nearly always improved with sufficient weekly physical activity. When all of the many exercise training-lipoprotein trials are taken into consideration, the overall recommendation for the quantity and quality of physical activity necessary for lipid and lipoprotein improvement is provided by the 2014 guidelines on exercise and dyslipidemia by the American College of Sports Medicine:1

Aerobic exercise, five or more days a week, 30 to 60 minutes per day, at 40 to 75 percent of aerobic capacity.

Although this guideline is somewhat nonspecific, it is helpful to know that this amount of physical activity is consistent with recommendations for long-term weight control, i.e. 200 to 300 minutes/week of moderate physical activity or ≥ 2,000 kcal/week of activity. This physical activity volume may be accumulated with repeated exercise bouts of ≥ 10 minutes.

LDL-C Response Although exercise programs have the best chance of reducing LDL-C when there is associated body-weight reduction, they also can favorably alter lipoproteins in the absence of body-weight changes when appropriate exercise training volumes are used. Most studies evaluating the total cholesterol and/or LDL-C response to exercise training have found very little to only moderate decreases in LDL-C. Many studies used inadequate exercise volumes and/or energy expenditure or failed to control for confounding variables such as training-induced changes in plasma volume, dietary habits, or seasonal variation in cholesterol and lipoproteins. On average, sufficient volume exercise training by itself will reduce LDL-C by 4 to 7 percent but the response can be quite variable.2,3 The percent reduction depends on baseline lipid values, the total energy expenditure of the exercise program plus a host of other variables (Figure).3,4

Very few controlled exercise trials have been conducted on patients with dyslipidemia, with most evaluating those with normal or modestly elevated

RALPH LAFORGE, MSC, CLS, FNLA Managing Director, Duke Lipid Clinic Preceptorship Program Durham, NC




triglycerides and/or LDL-C. An often quoted meta-analysis of 13 studies by George Kelley and co-workers found a non-significant decrease of less than 1 percent in LDL-C, independent of changes in body weight.5 The problem with this finding, as is often the case in interpreting meta-analysis findings, is that there was a wide range in training modalities (e.g. running, swimming, stationary cycling, dance), often at energy expenditures not reliably reported and an average training stimulus of ~40 minutes per session, 3.9 times a week, at mostly moderate-intensity exercise levels. This weekly volume of exercise, approximately 1,600-1,800 kcal/week, is insufficient by current recommendations (≥ 2,000 kcal/week) to demonstrate meaningful reductions in LDL-C and, of course, at that volume of physical activity most adults are likely to lose some body weight, and experience a reduction in adiposity.

The use of nuclear magnetic resonance imaging technology (NMR) to assess the low-density lipoprotein particle concentration (LDL-P) response to exercise training has demonstrated efficacy.6-8 Moderate volumes and intensities (e.g., walking ~12 miles per week at 40 to 55 percent of aerobic capacity) significantly reduced LDL-P when total cholesterol and Friedewald-predicted LDL-C remained essentially unchanged.8 Such patients on a return clinic visit would be considered unresponsive to exercise therapy when a conventional lipid profile was used to score the patient’s progress. Thus, advanced lipoprotein measures, such as the determination of LDL-P by NMR technology, may improve the ability to track exercise-associated responses.

HDL-C Response The high-density lipoprotein cholesterol (HDL-C) response to exercise training is under considerable genetic influence, with underlying genetic polymorphisms

(e.g., lipoprotein and hepatic lipase, apolipoprotein (apo) CII, III) explaining up to 50 percent of the variation in HDL-C.9,10 For this reason, healthcare providers should be cautious in predicting the HDL-C response in clients, because there is a considerable variation in the magnitude of changes in HDL-C. There also are individuals with genetic variants of very low HDL-C (hypoalphalipoproteinemia: HDL levels <30 mg/dL) and, in general, they will respond minimally to even high volumes of exercise training. On average, exercise training by itself can increase HDL-C by 3 to 25 percent, depending on baseline lipid values, triglyceride response, and total exercise volume (i.e., added weekly energy expenditure) but, as a rule, the HDL-C response to training is quite moderate.3 The increase in HDL is likely linked to triglyceride reduction (via the action of cholesterol ester transfer protein).11 Most exercise trials support between 700 and nearly 2,000 kcal of exercise per week to significantly alter HDL-C.12 Kodama performed a large meta-analysis of 25 randomized controlled trials of exercise alone, without diet or drug therapy, and found that aerobic exercise at an intensity of ~5.3 MET’s (65 percent of max aerobic capacity) significantly

increased HDL-C by 6 percent. Among exercise variables, exercise duration was found to be the most important determinant of increase in HDL-C on multivariate analysis.13 There have been mixed findings among studies investigating the relationship between exercise intensity and increases in HDL-C, with some studies reporting the necessity for more vigorous exercise intensities.14

Resistance training also may generate increases in HDL-C. There are reports that from six to nine weeks of resistance training (eight to 10 exercises) three times a week can significantly increase HDL-C — from 4 to 9 percent — in men and women.15,16 At least one study demonstrated greater HDL-C increases with higher-intensity resistance training (80 to 90 percent at one-repitition maximum) compared to moderate-intensity training.16 However, not all studies demonstrate significant increases.17

Non-HDL ResponseAs important as non-HDL-C is to managing atherosclerotic risk, there is very little research that has exclusively evaluated the response to exercise training. However, at least one meta-analysis retrospectively

20 LipidSpin

looked at non-HDL responsivity and found a decrease of approximately 6 mg/dL in response to aerobic exercise training programs between 10 and 104 weeks.18 This meta-analysis included male as well as pre- and postmenopausal females.The majority of subjects included in the studies were white, however, blacks, Hispanics, Japanese, and Asians were also represented. The greatest non-HDL response apparently is observed when dietary and exercise interventions are combined.

Triglyceride ResponseCompared to other lipids, such as LDL-C, elevated baseline triglycerides (TG) (e.g. >150 mg/dL) are generally more responsive to exercise training of sufficient volume. Triglyceride mobilization and utilization appear to be in direct proportion to exercise energy expenditure. Unlike LDL-C, triglycerides generally decrease immediately after a session of high-volume endurance exercise (e.g., greater than 45 minutes of sustained effort), and remain lower for up to 48 hours after the session. Several facts stand out after reviewing scores of exercise-triglyceride metabolism trials:19

• Exercise-induced TG-lowering is acute, in that it manifests after just a single bout of exercise and is not the result of repeated exercise sessions (i.e., training), and it is short-lived, in that it is readily reversed when exercise is withdrawn.

• Numerous studies have confirmed the initial hypothesis that the magnitude of the decrease in plasma TG concentration after a single exercise session and after training is the same (i.e., 15 to 50 percent).

• These observations suggest that chronic exercise does not have an equally sustainable effect

on plasma triacylglycerol (TAG) concentration, i.e., beyond that attributed to acute exercise; hence, exercise should be performed on a regular and uninterrupted basis to maintain lower TG.

Overall, exercise training programs also have been shown to decrease fasting triglycerides by 4 to 37 percent (approximate mean change of 24 percent).20 Overall, exercise is most effective in lowering triglycerides when baseline levels are elevated (i.e., >150 mg/dL), activity is moderate to intensive, and total caloric intake is reduced.21 The same exercise-generated response holds true for exercise training and very low density lipoprotein (VLDL) because VLDL’s carry most of the triglyceride in plasma — the VLDL triglyceride and plasma triglyceride levels are almost the same.19

Inactivity and LipidsBeing sedentary, particularly daily sitting time, has been associated with elevated

triglycerides and decreased HDL-C, as well as other cardiometabolic risk factors.22 A modest amount of exercise training can prevent the deteriorating lipid profile that is seen with inactivity.23 This is particularly true for LDL and HDL size, LDL-P, and total HDL cholesterol. In fact, it appears that only seven to 10 miles of walking a

week will prevent inactivity-associated deterioration in these lipid parameters.23

Exercise and Postprandial LipemiaPostprandial lipemia is essentially the blood lipid, particularly triglyceride (and associated triglyceride-rich particles), response to a meal, particularly a fatty meal. Depending on how much fat or sugar is consumed in a meal, a person with normal fasting triglycerides will increase their triglycerides by 100 to 200+ mg/dL for two to six hours after a high fat meal.24 Those with visceral obesity, the metabolic syndrome or type 2 diabetes can have much larger increases in post-meal triglycerides. The problem of prolonged, elevated postprandial triglyceride states is that, for the amount of time triglycerides

Figure 1.


are elevated much above 250-300 mg/dL, there is diminished arterial function, lower HDL-C and exposure of the arterial wall to atherogenic lipoprotein particles (e.g., intermediate-density lipoprotein (IDL) and VLDL remnant particles). Over the past 15 years, there has been abundant research supporting the finding that sufficient exercise timed anywhere from several hours to 12 hours before a fat-rich meal will reduce postprandial lipemia by 20 to 40 percent.25 This also was observed in men with baseline hypertriglyceridemia, who experienced a 30 to 39 percent reduction in postprandial triglycerides with prior moderate and vigorous exercise, respectively.26 The relative suppression of triglycerides can last up to 36 hours after a significant bout of exercise, e.g., >400 kcal. Some investigators report that women may be more responsive than men to reducing postprandial TG with exercise.27 This somewhat blunted triglyceride response to high-fat or high-glycemic meals is one of the benefits of engaging in aerobic physical activity every day. There also are reports that higher-intensity exercise may be more effective than moderate intensity exercise at reducing postprandial TG, even when both are matched for the same total energy expenditure.28 Having patients exercise at least every other day is an excellent way to keep triglycerides and associated triglyceride-rich atherogenic particles reasonably suppressed.

Resistance Training and Lipid DisordersResitance training (RT) has shown some promise as a means to improve the blood lipid profile, but the effect is modest at best. It is not recommended as the primary form of exercise therapy for people with dyslipidemia but RT certainly can play a supportive role. The lipid and lipoprotein response to RT largely depends on the energy expenditure of the resistance training session, which essentially means

that each session (e.g., 30+ minutes) includes an abundance of contraction repetitions versus, for example, just three sets of 10 to 12 repetitions of four or five exercises. A recent review of 13 published RT and lipid response trials reinforced the requirement of higher repetition RT doses for a sufficient stimulus lipid and lipoprotein response.29 The review concluded that it consistently has been shown that the increased volume of movement via increased numbers of sets and/or repetitions has a greater impact on the lipid and lipoprotein parameters than increased RT intensity (e.g. high-weight, low-repetition training) a view also supported by other recent studies.30

Final WordAlthough there is wide individual variation in the lipid and lipoprotein response to a given amount of exercise training, nearly all studies have demonstrated some improvement in the lipid profile. The greatest exercise-induced changes in lipoproteins occur when there are significant reductions in adiposity. Lastly, it is important to note that there are numerous variables that control the lipid response to exercise training, not the least of which are baseline lipid values, net energy cost (in kcal) of the exercise program, gender, and a host of genetic influences (e.g., Apo CII and III genotypes, to name but a few). The precise mechanisms responsible for these changes remain to be elucidated but very likely include those denoted in Figure 1. n

Disclosure Statement: Mr. LaForge received speaker honorarium from AstraZeneca.


“...nearly all studies have demonstrated

some improvement in the lipid profile.”

22 LipidSpin

Atherogenic lipoproteins play a critical role in the initiation and progression of vascular atherosclerosis, and decades of research have clearly demonstrated the benefits of lipid-lowering therapy for prevention of atherosclerotic cardiovascular disease (ASCVD) events. However, despite the publication of guidelines for management of dyslipidemia by numerous professional societies, there still are inadequate numbers of patients receiving evidence-based therapy. One factor contributing to this gap in care is confusion among healthcare providers regarding selection and implementation of appropriate guidelines, particularly for special patient populations.1 In addition, not all at-risk patients clearly match one of the defined statin-benefit groups as identified by the 2013 American College of Cardiology/American Heart Association (ACC/AHA)

cholesterol guidelines.2 Awareness of additional published guidelines for statin non-benefit groups will help clinicians make individualized decisions with patients.

Case Presentation: The patient is a 52-year-old white woman with Stage IV polycystic kidney disease who is seen for cardiovascular risk assessment and recommendations for ASCVD prevention. She follows a heart-healthy diet and has a body mass index (BMI) of 17.69 kg/m2. She participates in spin class three days a week and walks five miles two days a week. She has known hypertension, which is well controlled on amlodipine 10 mg daily. She smoked cigarettes for three to four years when she was in high school. She has no history of diabetes. She was told several months ago that she has mild hyperlipidemia and seeks further recommendations for management. Her only history of cardiovascular disease or

symptoms is a diagnosis of mitral valve prolapse associated with occasional palpitations. She is, otherwise, completely asymptomatic. She is not dialysis-dependent.

A physical exam was unremarkable. Laboratory analysis revealed creatinine 2.4 mg/dl, eGFR 23 ml/min/1.73 m2, total cholesterol 228 mg/dl, high-density lipoprotein cholesterol (HDL-C) 56 mg/dl, low-density lipoprotein cholesterol (LDL-C) 141 mg/dl, and triglycerides 155 mg/dl. Liver function studies are normal.

Practical Pearls: Selection of Dyslipidemia Guidelines in Special Populations

PAMELA B. MORRIS, MD, FACC, FACP, FACPM, FAHA, FNLA Director, Preventive Cardiology Co-director, Women’s Heart Care Charleston, SC



High- or very high-risk patient groups

Quantitive risk scoring is not necessary for initial riskassessment in patients with the following conditions:*

• Diabetes mellitus, type 1 or 2

• Chronic kidney disease, stage ≥3B

• LDL-C ≥190 mg/Dl: severe hypercholesterolemia phenotype,

which includes FH

• ASCVD

ASCVD, atheroslerotic cardiovascular disease; FH, familial hypercholesteremia; LDL-C, low-density lipoprotein cholesterol. *Patients in these categories are all at high or very high risk for an ASCVD event and should be treated accordingly.

Table 1. NLA Recommendations


To determine preventive therapy for ASCVD risk reduction in this patient with chronic kidney disease (CKD), an appropriate assessment of risk and selection of treatment guidelines must be considered. The new ACC/AHA CV Risk Calculator has not been validated in patients with CKD and this algorithm cannot be accurately used to predict this patient’s 10-year or lifetime risk of ASCVD events.3 The recently published National Lipid Association (NLA) Recommendations for Patient-Centered Management of Dyslipidemia identifies patients with CKD Stages 3B and 4 as high- or very high-risk and indicate that quantitative risk scoring is not necessary for initial risk assessment. (Table 1)4 Similarly, according to the 2013 Clinical Practice Guideline for Lipid Management in CKD, published by the Kidney Disease: Improving Global Outcomes (KDIGO) panel, the relationship between LDL-C and ASCVD events is weaker in CKD patients than in individuals with normal renal function.5 This may be related to the atherogenic dyslipidemia often present in CKD, characterized by near-normal levels of LDL-C, elevated LDL particle number, reduced HDL-C, and elevated triglycerides. Therefore, therapy is not guided by the LDL-C level but rather by the absolute risk of coronary events based on the patient age and stage of CKD or eGFR. (Table 2)

The 2013 ACC/AHA Guideline on the

Treatment of Blood Cholesterol to Reduce Atherosclerotic Risk in Adults includes an evidence statement that patients with manifest clinical ASCVD and CKD Stages I-IV benefit from high-intensity statin therapy. The panel examined a sub-analysis of patients with ASCVD and moderate CKD (eGFR <60 ml/min/1.73 m2) from the Treating to New Targets study.6 Atorvastatin 80 mg significantly reduced the incidence of major cardiovascular events compared to atorvastatin 10 mg in patients with moderate CKD (HR=0.68;

95 percent CI 0.55 to 0.84, p=0.0003). The ACC/AHA guidelines do not make specific recommendations for primary prevention in patients with moderate CKD.

The KDIGO panel provides recommenda-tions for patients at all stages of CKD. However, the experts acknowledge

that only a few large, randomized controlled trials and post-hoc analyses of the subgroup of CKD patients from statin trials in the general population are available to inform the guidelines. Specific statins and statin or ezetimibe doses are recommended for each stage of CKD and dose titration to a specific LDL-C goal is not recommended. (Table 3) Neither ACC/AHA nor KDIGO guidelines recommend initiation of statin therapy or combination treatment with statin and ezetimibe in dialysis-dependent patients on

the basis of results from the AURORA (A Study to Evaluate the Use of Rosuvastatin in Subjects on Regular Hemodialysis: An Assessment of Survival and Cardiovascular Events), Deutsche Diabetes Dialyse Studie (4-D), and Sorafenib HCC Assessment Randomized (SHARP) trials.7-9 However, patients already on lipid-lowering therapy

Table 2. KDIGO5

Age >40 years (eGFR G1-G4) 14.0 (14.6–15.3) 17.4 (16.9–17.9) 12.7 (12.3–13.1) eGFR G3a-G4 19.0 (18.8–19.8) 23.4 (22.6–24.2) 16.4 (15.8–17.0) eGFR G1-G2 9.7 (9.3–10.0) 12.0 (11.4–12.6) 6.7 (6.3, 7.2)Age >50 years (eGFR G1-G4) 17.3 (17.0–17.7) 20.2 (19.6–20.8) 14.8 (14.3–15.3) eGFR G3a-G4 19.9 (19.4–20.4) 24.3 (23.4–25.2) 16.9 (16.3–17.5) eGFR G1-G2 12.9 (12.4–13.4) 15.2 (14.5–16.0) 9.7 (9.0–10.5)Age >40–50 years (eGFR G1-G4) 3.2 (2.9–3.6) 4.7 (4.2–5.4) 1.6 (1.2–2.0) eGFR G3a-G4 4.7 (3.7–6.0) 5.9 (4.3–8.1) 3.6 (2.5–5.3) eGFR G1-G2 3.0 (2.6–3.3) 4.6 (4.0–5.3) 1.2 (0.9–1.6)

Overall Male Female

Rate (95% CI) of coronary death or non-fatal MI (per 1000 patient-years)

Rate of coronary death or non-fatal MI (by age and eGFR)

Table 3. KDIGO5

Statin eGFR G1-G2 dialysis or with a kidney transplant

Lovastatin GP nd

Fluvastatin GP 801

Atorvastatin GP 202

Rosuvastatin GP 103

Simvastatin/Ezetmibe GP 20/104

Pravastatin GP 40

Simvastatin GP 40

Pitavastatin GP 2

eGFR G3a-G5, including patients on

Recommended doses (mg/d) of statins in adults with CKD

24 LipidSpin

at the time of progression to dialysis may continue treatment. In agreement, the NLA Recommendations state that the evidence in this patient population is limited and inconsistent. Thus, therapy and goals for atherogenic lipoprotein levels in CKD

Stage V are considered to be a matter of clinical judgment.

The current patient with Stage IV CKD has a high rate of coronary death or nonfatal myocardial infarction as assessed in Table 2 (16.9 per 1,000 patient years, 95 percent CI 16.3 to 17.5). KDIGO guidelines recommend therapy with either fluvastatin 80 mg, atorvastatin 20 mg,

rosuvastatin 10 mg, simvastatin/ezetimibe 20/10 mg, pravastatin 40 mg, simvastatin 40 mg, or pitavastatin 2 mg daily. (Table 3) The NLA Recommendations specify goals of non-HDL-C <130 mg/dl and LDL-C <100 mg/dl for this high-risk patient.

She would, therefore, require at least moderate-intensity statin to achieve these goals, which is consistent with KDIGO recommendations. (Table 4)

Clinicians are faced daily with at-risk patients and patients in special populations who do not clearly fall into one of the four statin-benefit groups identified by the ACC/AHA cholesterol guidelines. The NLA Recommendations and guidelines for special populations are of great help in more personalized ASCVD risk reduction for the diverse patients that providers must care for each day. n

Disclosure statement: Dr. Morris has received speaker and/or advisory board honoraria from AstraZeneca, LipoScience, Aegerion, and Genzyme.


Table 4: NLA Recommendations (Table 12)

bid, twice per day; LDL-C, low-density lipoprotein cholesterol.*Individual responses to statin therapy should be expected to varyin clinical practice. Moderate- or high-intensity statin therapy ispreferred unless not tolerated.

Intensity of Statin therapy*

High-intensity daily Moderate-intensity dailydosage LDL-C ≥50% dosage LDL-C 30% to <50%

Atorvastatin 40–80 mg Atorvastatin 10–20 mgRosuvastatin 20–40 mg Fluvastatin 40 mg bid Fluvastatin XL 80 mg Lovastatin 40 mg Pitavastatin 2–4 mg Pravastatin 40–80 mg Rosuvastatin 5–10 mg Simvastatin 20–40 mg

© 2013, By National Lipid Association, Jacksonville, Florida. All Rights Reserved.

C onsultativ e I ssues in C lin ical L ipido logy


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


Case:The patient was a 62-year-old Caucasian woman when she was first seen at the Florida Lipid Institute in 2010. She had hypertension that was treated with losartan/HCTZ. She had no other significant past medical history. She had a family history of hypertension and diabetes and one brother who developed angina at the age of 48. Her review of systems was negative — specifically, she had no complaints of chest pain, transient ischemic episodes, or claudication. Her only medication was the losartan/HCTZ and she had no known drug allergies. She had never been on lipid-modifying therapy.

On physical exam, the patient’s height was 5-foot-4, her weight was 180 pounds, her waist circumference was 38 inches, and her blood pressure on treatment was 130/86. Her temperature, respiratory rate, and pulse were normal. Her cardiac, pulmonary, abdominal, neurological, dermatological, and vascular exams were all normal.

A fasting lipid panel obtained by her referring physician showed total cholesterol of 205 mg/dL, a low-density

lipoprotein cholesterol (LDL-C) of 126 mg/dL, triglycerides of 156 mg/dL, and a high-density lipoprotein cholesterol (HDL-C) of 48 mg/dL — non-HDL was 157 mg/dL. Her high-sensitivity C-reactive protein (hs-CRP) was elevated at 3.6 mg/L, and her fasting blood sugar was 112 mg/dL. All other values on her complete blood count (CBC), comprehensive metabolic panel, urine analysis (UA), and TSH were within normal limits.

She was specifically referred by her internist with the question, “Should this woman be on a statin?”

JUPITER Study:The Justification for the Use of Statins in Primary Prevention (JUPITER) study was published in 2008.1 The study enrolled 17,802 apparently healthy men over 50 years old and women over 60 years old who had an LDL less than 130 mg/Dl, and an hs-CRP >2.0 mg/L. They were randomized 1:1 to rosuvastatin 20 mg or placebo once daily. The study’s primary outcome was a reduction in an aggregate endpoint of myocardial infarction (MI), stroke, revascularization, hospitalization for unstable angina, and death from any

cardiovascular cause. It was designed for a treatment duration of five years but was terminated at a median observation period of only 1.9 years by the data safety monitoring committee because of an overwhelming benefit seen in the rosuvastatin group. At termination, the active treatment group had a hazard ratio of 0.56 for the aggregate endpoint, 0.46 for MI, 0.52 for stroke, and 0.80 for death from any cause. When the study ended, the rosuvastatin arm had an average LDL-C reduction of 50 percent and an hs-CRP reduction of 37 percent.

The study received some criticism2 following publication focused primarily on the early termination and the definition of “apparently healthy.” Critics pointed out that, in JUPITER’s “apparently healthy” population, 25 percent had hypertension (systolic BP>145), 50 percent were

Case Study: Applying Clinical Trial Data to Patient Management: A Case Study

PAUL ZIAJKA, MD, PhD, FNLADirector, Florida Lipid Institute

Winter Park, FL

Director, American Board of Clinical Lipidology


26 LipidSpin

overweight, 25 percent were obese, 41 percent met the clinical criteria for the metabolic syndrome, and less than 17 percent were taking a daily aspirin.

In 2010, based on the results from JUPITER, the U.S. Food and Drug Administration (FDA) approved rosuvastatin for the “primary prevention of cardiovascular disease in individuals without clinically evident coronary heart disease but with an increased risk of cardiovascular disease based on age >50 years old in men and >60 years old in women, hsCRP> 2 mg/L and the presence of at least one additional cardiovascular risk factor.” (Crestor Package labeling)

Back to the Case:After I first saw the patient, I repeated the lipid panel and hs-CRP. Her repeat labs showed TC = 203 mg/dL, LDL-C = 124 mg/dL, triglycerides 160 mg/dL, HDL-C = 47 mg/dL, non-HDLC 156 mg/dL, and an hs-CRP = 3.8.

According to ATP guidelines, her LDL goal was <130 and, based on that criteria, she clearly did not warrant statin therapy. But the patient could easily have been a “poster child” for the JUPITER study population, meeting all of the criteria identified in the FDA’s expanded indication for rosuvastatin. She also met all of the

ATP criteria for the diagnosis of metabolic syndrome, a diagnosis found in a significant portion of the JUPITER study population.

In the spirit of the patient-centered approach emphasized by the new NLA Recommendations,3 I met with the patients and her husband to discuss treatment options. She decided, based in large part on the JUPITER study results, to start rosuvastatin 20 mg once daily. She also was referred to the clinic’s dietitian for weight and CVD risk reduction dietary interventions.

Case Follow-Up:The patient most recently was seen at the Florida Lipid Institute in August. She remains free from cardiovascular disease. Her most recent lipid profile — on TLC plus rosuvastatin 20 mg once daily — showed TC = 136 mg/dL, LDL = 60 mg/dL, triglycerides = 80 mg/dL, HDL = 60 mg/dL, and nonHDLC 76 mg/dL. Her hs-CRP is <1.0. After meeting with the dietitian a total of four times since her initial presentation, AT’s weight is down 20 pounds, her waist circumference is 34 inches, her fasting blood sugar is 88, and she no longer meets any of the criteria defining the metabolic syndrome.

Her care was patient-centered and I was delighted to work with an informed, compliant patient. n

Disclosure statement: Dr. Ziajka received speaker honoraria from Kowa Pharmaceuticals, Abbott Laboratories, Merck and Co., Atherotech Inc., Hunter Heart Lab and AstraZeneca. He’s received a research grant from Genzyme and consulting fees from Hunter Heart Lab. a.


“She was specifically referred by her

internist with the question, ‘Should

this woman be on a statin?’”


Chapter Update: Contributing to the NLA Mission

It was an honor and privilege for the Southeast Lipid Association (SELA) to host the National Lipid Association (NLA) Scientific Sessions in Orlando, Fla. this past May 2014. Excellent topics and presenters offered practical knowledge for integrating the latest clinical research guidelines into practice. I was pleased to chair the Abstracts Committee, and was impressed with all the submissions. Marisa Schoen, BA, was recognized with the First Place Young Investigator Award. Her poster was titled “Statins and Cognitive Function: A Systematic Review.” All of the scientific posters abstracts were published in the June 2014 Journal of Clinical Lipidology. I hope you will encourage all Young Investigators to begin thinking about submitting their abstracts for this year’s NLA Scientific Sessions held in Chicago in June 2015.

One of the projects SELA is pursuing is being led by SELA Secretary Deborah Croy, DNP, RN, ANP-BC, AGPCNP-BC, CLS, AACC. Dr. Croy recognized the need for improving lipid management in underserved areas, especially in the southern region of the U.S. Patients in the south across the stroke belt have

higher rates of modifiable risk factors such as hyperlipidemia, obesity, diabetes, hypertension, and smoking. Dr. Croy has reached out to Virginia’s Federally Qualified Health Centers to see how SELA members can collaborate with them to provide and encourage education and advocacy. She has also contacted the Virginia Community Health Care Association about planning a SELA educational conference, possibly in March 2015. This is a wonderful way to involve interested SELA members in spreading the word about the importance of lipid management. For more information, see the Member Spotlight section of this LipidSpin (Page 29), which features her contributions!

Another SELA initiative being proposed, prompted by Dr. Harold Bays’ ideas and leadership, is a project geared toward improving patient care. This is another opportunity to engage the many extraordinary talents of volunteer SELA members to craft an educational review, with plans for publication in a peer-reviewed journal. Many clinicians are deficient in their knowledge of nutrition intervention and the lipid effects of

common diets, which should be a core skill of anyone managing patients with dyslipidemia. The publication is to be titled “Nutritional Intervention and Dyslipidemia: Review of the Contents and Lipid Effects of Common Diets.” The creation of illustrated color figures representing common diets are planned for a number of ongoing and future NLA initiatives. This project is best integrated with others at the NLA who have an interest in nutrition interventions to further the overall goals of the organization.

I also want to share the initiatives of the Florida (FLA) Committee, led by President Sandra Kreul, ARNP. Each year the committee selects a topic and develops a presentation for its members to use in the community, for speaking and educating. This year Dr. Paul Zaijka has put together a talk on “The Evolution of Cholesterol

LORI A. ALEXANDER, MSHS, RD, CCRC, FNLA Site Manager, St. John’s Center for Clinical Research

Ponte Vedra, FL



28 LipidSpin

Management Guidelines” for members to use in talks throughout their communities. Other projects of the FLA Committee include furthering relationships with other organizations, such as the Florida Chapter of ACC and the Florida Dietetic Association. FLA Committee member and SELA Board Member Dr. Greg Cohn is participating in an Internal Medicine Residency Program at Florida Atlantic University in Boca Raton, Fla. Residents rotate among three hospitals, and spend one day each month at Dr. Cohn’s office focusing on cardiovascular disease prevention. He emphasizes the difference between lipids and lipoproteins, utilization of advanced lipid testing, and diseases such as PCOS. He will be lecturing to the residents on “Lipids, Lipoproteins

and Atherosclerosis,” and providing them with valuable and current information on managing their patients’ lipid issues.

SELA is a very active, creative, and energetic organization that is always looking to involve more of its members. If you have a particular interest or passion and want to become involved, email [email protected] at the NLA and let us know! We’ll take it from there. n

Disclosure statement: Ms. Alexander has no

disclosures to report.

Palmer House HotelChicago, IL

Scientific SessionsJune 11–14, 2015

Professional Development CoursesJune 10–11, 2015

SCIENTIFIC SESSIONSNATIONAL LIPID ASSOCIATION

lipid.org/sessions

REGISTER NOW

CME Credit Provided by National Lipid Association

This activity has been approved for AMA PRA Category 1 Credit™.Full accreditation information is available at www.lipid.org/sessions

Hosted by the Midwest Lipid Association


“Security is mostly a superstition. It does not exist in nature, nor do the children of men as whole experience it. Avoiding danger is no safer in the long run than outright exposure. Life is either a daring adventure or nothing.” – Helen Keller

This quote is a favorite of Deborah S. Croy, DNP. She says, “If one female who was blind and deaf could make such a contribution to humanity, if we who have no or limited disabilities apply ourselves, think of what we can do.” This is Dr. Croy’s philosophy when it comes to treating underserved patients in rural Virginia and West Virginia.

Dr. Croy has known since the age of 8 that she wants to treat and help find a cure for heart disease. As a young girl, she witnessed her coal mining father become disabled due to cardiovascular disease and suffer multiple myocardial infarctions. At that time, she vowed to dedicate her life to finding a cure for heart disease so that other young children would not lose quality time with their parents. Dr. Croy grew up in an unincorporated community

called Abbs Valley in the Virginia coalfields and remained in the rural Virginia area to treat and advocate for the underserved populations. She received her Masters in Nursing from Duke University and most recently earned her Doctor of Nursing Practice degree from Johns Hopkins School of Nursing. She noted that this was a far cry from the first school she attended as a child that had an outhouse and used a potbelly coal stove for heat!

Dr. Croy is an Adult Nurse Practitioner employed in a Federally Qualified Community Health Center where she treats patients with dyslipidemia and metabolic disorders on a daily basis. Many of her patients are either uninsured or underinsured and, without their clinic, would go without medical care. The Health Center has a contract so it can obtain labs at cost. This allows patients to receive basic labs, including their lipid profiles, at an affordable cost. The patients in the rural population that Dr. Croy sees have a higher than national incidence of diabetes and dyslipidemia. This, coupled with the fact that many suffer from a lack

of income, makes treatment for them more challenging. In addition, many of Dr. Croy’s patients have been diagnosed with bipolar disorder and depression, and are on medications known to increase their risk of dyslipidemia.

Despite these various setbacks, Dr. Croy and her coworkers have become advocates for her underserved patients. Past SELA President, Ralph LaForge, urged Dr. Croy to become involved with the National Lipid Association (NLA). Not long after she also became a certified Clinical Lipid Specialist. She says, “I found in the NLA there are many like-minded practitioners and was invited to take a leadership role and join the SELA board.”

Dr. Croy is also very involved with the

Member Spotlight: Deborah S. Croy, DNP, RN, ANP-BC, AGPCNP-BC, CLS, AACC

DEBORAH S. CROY, DNP, RN, ANP-BC, AGPCNP-BC, CLS, AACC Nurse Practitioner, Bland County Medical Clinic

Bastian, VA


30 LipidSpin

American College of Cardiology, serving on three committees and is their incoming Cardiac Care Associate liaison for the state of Virginia. She uses her roles in both organizations to act as a voice for the underserved population and to create awareness. She says that “many people do not know that they can get free medication for the indigents through pharmaceutical programs.” Her goal for the field of lipidology would be to see more collaboration and funding for the study of rural, underserved patients and those with different ethnicities. She would also like to see the development of medications with fewer adverse drug reactions so her patients can continue to take them.

Despite the everyday challenges she faces in her rural area, Dr. Croy says her favorite part of her job is having the opportunity to get to know her patients and their families. She is able to form a relationship with them and, in return, they treat her as part of the family. Outside of work and volunteering, Dr. Croy loves traveling, photography, and dancing. She also enjoys taking nature walks looking for Native American artifacts. n

Deborah Croy with her staff at Bland County Medical Clinic.

A view of Dr. Croy’s hometown, Pocahontas, Va.


Education and Meeting News and Notes

NLA Achieves Accreditation with Commendation from ACCME The National Lipid Association (NLA) was surveyed this year by the Accreditation Council for Continuing Medical Education (ACCME) and awarded Accreditation with Commendation for the next six years as a provider of continuing medical education for physicians. The NLA’s new accreditation term expires Nov. 30, 2020. ACCME accreditation seeks to assure the medical community and the public that NLA provides physicians with relevant, effective, practice-based continuing medical education that supports U.S. healthcare quality improvement. The ACCME employs a rigorous, multilevel process for evaluating institutions’ continuing medical education programs according to the high accreditation standards adopted by all seven ACCME member organizations. These organizations of medicine in the U.S. are the American Board of Medical Specialties, the American Hospital Association, the American Medical Association, the Association for Hospital Medical Education, the Association of American Medical Colleges, the Council of Medical Specialty Societies, and the Federation of State Medical Boards of the US, Inc.

The ACCME’s decision was based on a survey of the NLA’s written self-study report of CME processes and procedures, evidence of performance in practice through CME activity files, and an interview with NLA staff and volunteers. Accreditation with Commendation is a significant achievement in CME and is awarded to providers that demonstrate compliance in all criteria and

policies of the ACCME and also positions itself as a leader in its field. This designation is only awarded to approximately 20 percent of ACCME accredited providers. Support was provided to the NLA staff during the ACCME survey process by Dr. Robert Wild, Chair-CME Committee, and Dr. Peter Jones, Chief Science Officer.

New Slide Set Available Comparing ACC/AHA Guidelines vs. NLA Recommendations View and download the new slide presentation that compares and contrasts the perspectives provided by the ACC/AHA Guidelines and the NLA Recommendations for the Patient-Centered Management of Dyslipidemia. Many NLA members requested a slide set that compares these viewpoints, and Carl Orringer, MD, FNLA, took the initiative to develop them. It was reviewed by an NLA Recommendations panel for accuracy, content, and balance and includes the latest discussion of the recent IMPROVE-IT Trial results. This new slide set is one of many tools on the NLA Recommendations available on the website at lipid.org/recommendations.

Membership CompetitionDoes your chapter have what it takes to be a VIP? Join your fellow colleagues in the Member Recruitment Competition for 2015 to see

which chapter has what it takes to win a VIP Lounge at the 2015 Annual Scientific Sessions in Chicago. If your chapter recruits the most new members by May 15, 2015, every member of that chapter who is

attending the annual meeting will have all-day access to a private lounge with free wi-fi, soft drinks, and snacks – not to mention bragging rights! Your chapter needs your help! If you want your chapter to win, make sure to reach out to your colleagues who are not NLA members yet and tell them why they should join the NLA. To request membership and marketing materials, email Membership Manager, Britney Caldwell at [email protected]. Visit lipid.org/competition2015 for more information and current winning chapter.

Register Now for the NLA’s Spring Clinical Lipid Update in Denver

There’s still time to register for the National Lipid Association’s Spring Clinical Lipid Update. The 2015 Spring CLU will take place in Denver Feb. 27–March

1, 2015, at the Grand Hyatt Denver. Based on this year’s theme, “Achieving New Heights in Lipid Management,” you will learn about the latest controversies in lipid management, the impact of public policy in health care, evolving strategies for prediction and treatment, and emerging targets for atherosclerosis prevention. If you miss pre-registration, onsite registration is also available. Visit lipid.org/springclu for more information. Use promo code DSCLU15 for a $50 discount toward meeting registration.

Submit your Abstracts for the NLA Annual Scientific Sessions in Chicago The National Lipid Association is currently accepting abstracts for the Annual Scientific

32 LipidSpin

Sessions in Chicago June 11–14, 2015. This is your opportunity to submit your science for inclusion in the NLA’s 2015 Poster Hall. The NLA Poster Hall will cover a vast array of topics in 16 categories including clinical applications of biomarkers, epidemiology of cardiovascular disease, management of statin intolerance, and imaging in atherosclerosis. All accepted abstracts will also be published in the 2015 Annual Scientific Sessions edition of the Journal of Clinical Lipidology. Visit lipid.org/abstracts to submit online and for more information.

Pay Your Dues for 2015The 2015 NLA dues statements and membership cards have been mailed. In addition to paying your 2015 dues, this is a great opportunity to donate to the Foundation of the NLA. Donate online or add your end of year contribution when you pay your 2015 NLA dues. To pay your dues online, visit lipid.org/dues. For more information or questions regarding dues, contact Membership Manager Britney Caldwell at [email protected].

Mentors Needed for Mentor/Mentee Program Did you know that the NLA has established a mentoring program to help develop the next generation of clinical, academic, and administrative leaders in the field of lipidology by pairing early career members with established members? We hope you will take the time to get involved in this wonderful initiative. More details about the Mentor/Mentee program and application are available on lipid.org/education/fellows.

NLA and Chapter Board NominationsNominations for At-Large and Officer positions will open up in the end of January. An email will go out to all NLA members

detailing the process and deadlines. Board members with expiring terms have been contacted directly to notify them if they are eligible to serve another term. A complete nomination application includes at least two letters of recommendation, a CV, and an updated financial disclosure. Nominees may submit additional supporting material for the Nominating Committee to consider. Please check the NLA website for additional information.

Call for Honors and Awards NominationsThe NLA Honors and Awards nomination window is now open. The deadline to nominate is Friday, March 6, 2015. The NLA has established several types of recognition: Fellow of the NLA, NLA Distinguished Achievement Award, and NLA Honorary Lifetime Membership Award. To view the awards criteria and requirements or to submit a nomination, visit lipid.org/awards.

NLA Releases Annual Summary of Clinical Lipidology 2015Have you received your copy of the Annual Summary of Clinical Lipidology with the latest issue of the Journal of Clinical Lipidology? This annual summary is intended to be a ‘‘living document,’’ with future annual updates that will be based on emerging science, clinical considerations, and new NLA position and consensus statements. The goal is to provide clinicians an ongoing resource that translates the latest advances in medical science toward the evaluation and treatment of patients with dyslipidemia. To learn more, visit lipid.org/nla/national-lipid-association-releases-annual-summary-clinical-lipidology-2015.

Upcoming ISA 2015 MeetingThe 17th International Symposium on Atherosclerosis (ISA) is scheduled for May 23-26, 2015, in Amsterdam, Netherlands. The scientific program is designed in a novel format, organized in four major themes: Dyslipidemia, Pathogenesis, Prevention, and Epidemiology of atherosclerosis. The abstract submission deadline has been extended to Feb. 1, 2015. For more information, visit isa-2015.com.

Masters in Lipidology Course Available Online SoonThe Masters in Lipidology Course, traditionally offered as an ancillary course prior to NLA meetings, will be released as an online course in early 2015! This comprehensive program provides physicians, physician assistants, pharmacists, nurse practitioners, nurses, dietitians, and other healthcare professionals with an interest in lipid management, with complete lectures synchronized with slides from the live course. The Masters in Lipidology online course provides an intensive curriculum covering lipoprotein metabolism, genetics, vascular biology, atherosclerosis, biomarkers, imaging, Cardiometabolic disorders, lifestyle interventions, and pharmacologic therapies. The curriculum is designed for healthcare professionals who desire to practice at an advanced level within the field.

Available via computer, laptop, or iPad/tablet, the program provides participants with the flexibility to complete modules from virtually anywhere. Participants receive access to online resources and tools to enhance learning and practice. For full Accreditation information, visit lipid.org/mastersonline.


NLA Events Calendar

2015 National Lipid AssociationClinical Lipid Update—Spring Hosted by the Pacific and Southwest ChaptersFebruary 27–March 1, 2015 Grand Hyatt Denver Denver, COlipid.org/springclu

2015 National Lipid AssociationScientific Sessions Hosted by the Midwest Lipid AssociationJune 11–14, 2015 Palmer House HotelChicago, ILlipid.org/sessions

2015 National Lipid AssociationClinical Lipid Update—Fall Hosted by the Northeast and Southeast ChaptersSeptember 18–20, 2015 Omni William Penn HotelPittsburgh, PAlipid.org/fallclu

SPRING CLINICAL

2015


LIPID UPDATE

FEBRUARY 27–MARCH 1, 2015

DENVER, CO

Palmer House HotelChicago, IL

June 11–14, 2015SCIENTIFIC SESSIONSNATIONAL LIPID ASSOCIATION

Lipid AcademyFebruary 26–27, 2015 Denver, CO

June 10–11, 2015 Chicago, IL

September 17–18, 2015Pittsburgh, PA

Masters in LipidologyFebruary 26–27, 2015 Denver, CO

June 10–11, 2015 Chicago, IL

September 17–18, 2015Pittsburgh, PA

Lipidologist Needed to Take Over Practice in Tallahassee, Fla.

There is an excellent opportunity for an internist, family physician, cardiologist, or endocrinologist to take over a referral practice of lipidology. The applicant must be a diplomate of the American Board of Clinical Lipidology. The Tallahassee Memorial Lipid Center has been in operation for more than five years and has approximately 100 referring physicians, for a total of more than 500 annual referrals. J. Orson Smith, MD, FACC, is the current director, working with Nancy Smith, RD, CDE, CLS. They were joined in December 2014 by Elizabeth Ford, ARNP-BC. The Lipid Center is in the same building as the Tallahassee Memorial Diabetes Center and the Tallahassee Memorial Bariatric Center. Current plans are to eventually move into a larger building,

which will allow for the addition of three endocrinologists. Dr. Smith wishes to retire in 2015 but will remain on as a consultant to the new director for a period of time. The work environment is pleasant, academic, and rewarding. The salary, which is based on RVUs, is negotiable and the present conversion factor is quite good.

Telephone: (850) 431-5474Fax: (850) 431-4711Address: 1981 Capital Circle NE, Tallahassee, FL 32308Website: TMH.org/LIPIDCenterEmail: [email protected]

JOB LISTING

34 LipidSpin

I hope everyone had a wonderful Holiday Season and a Happy New Year! To kick off the New Year, the Foundation of the National Lipid Association (FNLA) is hard at work with new projects and partnerships.

Most recently, the FNLA collaborated with Sanofi US and Regeneron Pharmaceuticals Inc. in their launching of an unbranded cholesterol awareness campaign, “Cholesterol Counts” on Dec. 15, 2014. The campaign consists of polling patients on their base knowledge of cholesterol, lipid disorders, and their own risk associated with LDL-C. The poll is being disseminated through an unbranded website, CholesterolCounts.com, and through a market research firm — Harris, a Nielsen company.

Ralph M. Vicari, MD, FACC, FNLA, will act as the Foundation’s program spokesman in this effort. The FNLA will help market

the campaign via media interviews and publications and the FNLA’s social media accounts. The final results of the poll will provide a snapshot of cholesterol awareness levels across the country and will be revealed in a full paper to be released in December 2015. This collaboration is focused on helping to address the unmet needs of cardiovascular health and the role cholesterol plays. It is our hope to provide resources to help patients better understand and take control of their heart health.

In addition, the Foundation will be sponsoring a special abstract award at the 2015 NLA Annual Scientific Sessions in Chicago from June 11–14, 2015. In honor of Donald B. Hunninghake, MD, a pioneer in lipid research, the Foundation is offering The Foundation of the National Lipid Association Donald Hunninghake Familial Hypercholesterolemia Abstract Award for the best submitted abstract specifically in the area of familial hypercholesterolemia (FH) research.

Dr. Hunninghake — a graduate of the University of Kansas Medical School — had an illustrious career dedicated to the

causes and prevention of heart disease. In addition to his work in lipids, Dr. Hunninghake served as the director of the Heart Disease Prevention Clinic at the University of Minnesota. He contributed to numerous clinical trials of important lipid-lowering medications as well as outcomes trials involving lipid lowering.

The Foundation has had a significant focus geared toward patient awareness and education concerning disorders such as FH, and this award has been created in order to continue that focus and to further encourage clinicians in their research and study of familial hypercholesterolemia. The winner will be determined by the Foundation of the NLA Board of Directors once the abstract committee has approved the abstracts in this category. The award — $1,500 and a $1,000 travel grant — will be presented to the winner at the Honors and Awards Ceremony at the NLA 2015 Annual Scientific Sessions. Please check lipid.org/abstracts for more information on submitting an abstract in this category for consideration of this award. The Foundation is looking forward to seeing exciting research in this very important area. n

Foundation Update

ANNE C. GOLDBERG, MD, FNLAPresident, Foundation of the National Lipid AssociationAssociate Professor of MedicineWashington University School of MedicineSt. Louis, MODiplomate, American Board of Clinical Lipidology



From the SELA President

1. Sackett DL, Rosenberg WM, Gray JA, Haynes RB, Richardson WS. Evidence-based Medicine: What it is and What it isn’t. BMJ. 1996; 312:71.

Letter from the LipidSpin Editors

1. Am J Manag Care. 2014;20(4):e105-e112

Clinical Feature

1. Antman E. Tools for Guiding Clinical Practice from the AHA and the ACC. Circulation. 2009;119:1,180-1,185.

2. Wright RA. Scandinavian Simvastatin Study. The Lancet. 1995;344:1,765-1,768.

3. ISIS-2 Collaborative Group. Randomized Trial of Intravenous Streptokinase, Oral Aspirin, Both, or Neither in Suspected Acute Myocardial Infarction. The Lancet. 1988;332:349-360.

4. Beta-Blocker Heart Attack Study Group. Beta Blocker Heart Attack Trial. JAMA. 1981;246(18):2,073-2,074.

5. McKenney J. Final Conclusion and Recommendations of the National Lipid Association Statin Safety Assessment Task Force. Journal of Clinical Lipidology. 2006;97(8A):11C-52C

6. FIELD Study Investigators. Effect of long-term fenifibrate therapy on cardiovascular events in 9,795 people with type 2 diabetes mellitus: randomized clinical trial. The Lancet. 2005;366(9,500):1,849-1,861.

7. The ACCORD study group. Effects of Combination Lipid Therapy on Type 2 Diabetes Mellitus. NEJM. 2010: 1,563-1,574.

8. Boden WE. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. NEJM. 2012;367(2)2,255-2,267.

9. The HPS-2 THRIVE collaborative Group. Effects of extended-release niacin with laropiprant in high-risk patients. NEJM. 2014;371:203-212.

10. Nernonen OP. The Helsinki Heart Study: coronary heart disease incidence during an extended follow up. Journal of Internal Medicine. 1994;235:41-49.

11. Villalobos A. Application of the cholesterol guidelines. NEJM. 2014;371:1.

12. Coronary Drug Project Group. Coronary Drug Project. JAMA. 1970;(7):1,303-1,313.

13. Yokoyama M. Effects of EPA on major coronary events in hypercholesterolemic patients (JELIS): a randomized open-label, blinded endpoint analysis. The Lancet. 2007;369:1,090-1,098.

14. Robins JT. Targeting low HDL cholesterol for therapy: lessons from the VA HIT Study. AJC. 2001;88(12A):19N-23N.

Guest Editorial

1. Institute of Medicine. Practice Guidelines We Can Trust. National Academies Press, Washington, DC; 2011 http://iom.edu/Reports/2011/Clinical-Practice-Guidelines-We-Can-Trust.aspx (accessed September 1, 2014).

2. Kung J, Miller RR, Mackowiak PA. Failure of Clinical Practice Guidelines to Meet Institute of Medicine Standards: . Arch Intern Med. 2012;172(21):1,628-1,633.

3. Feuerstein JD, Akbari M, Gifford AE. et al. Systematic Analysis Underlying the Quality of the Scientific Evidence and Conflicts in

Interventional Medicine Subspecialty Guidelines. Mayo Clin Proc. 2014;89:16-24.

4. Young BK, Greenberg PB. Are the Institute of Medicine’s Trustworthiness Guidelines Trustworthy? Rhode Island Medical J. 2013;8:13-14.

5. Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults; a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2014;63(25 Pt B):2889-2934.

6. Ridker PM, Cook NR. Statins: New American Guidelines for Prevention of Cardiovascular Disease. Lancet. 2013;382:1762-1765.

7. Health Care Renewal: Confused Thinking about New Cholesterol Guidelines-Were Conflicts of Interest to Blame? http://hcrenewal.blogspot.com/2013/11/confused-thinking-about-new-cholesterol.html (accessed September 1, 2014).

8. Jacobson TA, Ito MK, Maki KC, et al. National Lipid Association Recommendations for Patient-Centered Management of Dyslipidemia: Part 1 – Executive Summary. J Clin Lipidology. 2014;8:473-488.

EBM Tools for Practice

1. Hall, H. http://www.csicop.org/specialarticles/show/tooth_fairy_science_part_1

2. In 2014 in the State of Maryland, Legislators and opponents were told by the Governor’s office that legislation to license Naturopaths would be passed “whether we like it or not” – so efforts were shifted to heavily regulating these practitioners instead of trying to defeat the bill.

3. www.sciencebasedmedicine.org blogger Dr. Mark Crislip.

4. Pandolfi M, Carreras G. The faulty statistics of complementary alternative medicine (CAM). Euro Jnl of Internal Medicine 2014. http://dx.doi.org/10.1016/j.ejim. 2014.05.014.

5. Gorski D, Novella S. Clinical trials of integrative medicine: testing whether magic works? Trends in Molecular Medicine. September 2014;20(9):473-476.

6. In his famous 1748 essay Of Miracles, by the great skeptic David Hume.

7. Goodman S.N. (1999) toward evidence-based medical statistics. 2: The Bayes factor. Ann Intern Med 130, 1,005-1,013.

8. http://www.sfsbm.org/

9. Nissen S.E. Concerns about reliability in the Trial to Assess Chelation Therapy (TACT). JAMA. 2013;309:1,293-1,294.

10. When the author attempted to question the TACT lead author (at Am Soc Prev Cardiology meetings) about these problems with the study he wasn’t even allowed to finish his questions before dismissive answers were given. To my knowledge the many concerns about this trial have not been answered in print.

Additional Resources

http://www.sciencebasedmedicine.org/ Exploring issues and con-troversies in the relationship between science and medicine.

http://www.sciencebasedmedicine.org/prior-probability-the-dirty-little-secret-of-evidence-based-alternative-medicine-2/

http://sfsbm.org The Society for Science-Based Medicine.

Science-Based Medicine Anthology, available on Amazon.com

Do You Believe in Magic? The Sense and Nonsense of Alternative Medicine, by Paul Offit, MD. HarperCollins Publishers, 2013

Snake Oil Science. The Truth about Complementary and Alternative Medicine, by R Barker Bausell. Oxford University Press, 2007.

Lipid Luminationss

1. The HPS2-THRIVE Collaborative Group. Effects of Extended-Release Niacin with Laropiprant in High-Risk Patients. N Engl J Med. 2014;371:203-212.

2. Lloyd-Jones DM. Niacin and HDL Cholesterol — Time to Face Facts. N Engl J Med. 2014;371:271-272.

Specialty Corner

1. Pescatello L (senior editor) American College of Sports Medicine. Guidelines for Exercise Testing and Prescription, 9th Edition. In: Whaley M, ed. Philadelphia: Lippincott Williams and Wilkins; 2014.

2. Durstine JL, Grandjean PW, Davis PG, et.al. Blood lipid and lipoprotein adaptations to exercise: a quantitative analysis. Sports Med. 2001;31:1033-1062.

3. Mestek ML. Physical Activity, Blood Lipids and Lipoproteins. Am J Lifestyle Med. 2009;3:279-283.

4. La Forge R. American Council on Exercise Medical Exercise Specialist Manual. Chapter 8. Blood Lipid Disorders. American Council on Exercise. San Diego, 2014.

5. Kelley GA, Kelley KS, Tran ZV. Aerobic exercise, lipids and lipoproteins in 24 overweight and obese adults: a meta-analysis of randomized controlled trials. Int. J. Obes. (Lond). 2005;29:881-893.

6. Greene NP, Martin SE, Crouse SF. Acute Exercise and Training Alter Blood Lipid and Lipoprotein Profiles Differently in Overweight and Obese Men and Women. Obesity. 2012;20:1,618-1,627.

7. Halverstadt A, Phares DA, Wilund KR, Goldberg AP, Hagberg JM. Endurance exercise training raises high-density lipoprotein cholesterol and lowers small low-density lipoprotein and very low-density lipoprotein independent of body fat phenotypes in older men and women. Metabolism. 2007;56(4):444-450.

8. Kraus W, Houmard JH, Duscha BD, et al. Effects of the amount and intensity of exercise on plasma lipoproteins. New England Journal of Medicine. 2002;347(19)1,522-1,524.

9. Blazek A, Rutsky J, Kwame Osei, et al. Exercise-mediated changes in high-density lipoprotein: Impact on form and function. Am Heart J. 2013;166:392-400.

10. Teslovich TM, Musunuru K, Smith AV, et al. Biological, clinical and population relevance of 95 loci for blood lipids. Nature. 2010;466:707-13.

11. Ginsberg HN. Diabetic dyslipidemia: basic mechanisms underlying the common hypertriglyceridemia and low HDL cholesterol levels. Diabetes. 1996 Jul;45 Suppl 3:S27-30.

12. Bays H, Toth P, Kris-Etherton P, et al. Obesity, adiposity and dyslipidemia: A consensus statement from the National Lipid Association. Journal of Clinical Lipidology. 2013;7:304-383.

13. Kodama, S., S. Tanaka, K. Saito, M. et.al. (2011). Effect of aerobic exercise training on serum levels of high-density lipoprotein cholesterol: a meta analysis. Arch. Intern. Med. 167:999-1008.

14. Paoli A, Pacelli Q, Moro T, et.al. Effects of high-intensity circuit training, low-intensity circuit training and endurance training on blood pressure and lipoproteins in

References

middle-aged overweight men. Lipids in Health and Disease 2013, 12:131

15. Costa RR, Alberton C, Tagliari M, et al. Effects of resistance training on the lipid profile in obese women. J Sports Med Phys Fitness. Mar 2011;51(1):169-77.

16. Sheikholeslami VD, Ahmadi S, et al. Changes in cardiovascular risk factors and inflammatory markers of young, healthy, men after six weeks of moderate or high intensity resistance training. J Sports Med Phys Fitness. Dec 2011;51(4):695-700.

17. Wooten JS, Phillips MD, Mitchell JB, et al. Resistance exercise and lipoproteins in postmenopausal women. Int J Sports Med. Jan 2011;32(1):7-13.

18. Kelley GA, Kelley KS, Tran ZV. Walking and Non-HDL-C in adults: a meta-analysis of randomized controlled trials. Prev. Cardiol. 2005;8:102-107.

19. Magkos F. Very low-density lipoprotein metabolism in response to exercise: Mechanisms of hypotriacylglycerolemia. Progress in Lipid Research. 2009;48:171-190.

20. Trejo-Gutierrez JF and Fletcher G. Impact of exercise on blood lipids and lipoproteins. Journal of Clinical Lipidology. 2007;1:175-181.

21. Durstine JL, Grandjean PW, Cox CA, and Thompson PD. Lipids, lipoproteins and exercise. Journal of Cardiopulmonary Rehabilitation. 2002;22:385-398.

22. Staiano A, Harrington D, Katzmarzyk P, et al. Sitting time and cardiometabolic risk in U.S. adults: associations by sex, race, socioeconomic status and activity level. Br J Sports Med. 2014;48:213-219.

23. Slentz CA, Houmard JA, Johnson JL, et al. Inactivity, exercise training and detraining, and plasma lipoproteins. Journal of Applied Physiology. 2007;103:432-442.

24. Cohen JC, Noakes TD, Benade AJ. Serum triglyceride responses to fatty meals: effects of meal fat content. Am J Clin Nutr. 1988 May;47(5):825-7.

25. Malkova D, Gill J. Effects of exercise on postprandial metabolism. Future Lipidology. 2006;1:743-755.

26. Zhang JQ. Effect of exercise on postprandial lipemia in men with hypertriglyceridemia. European Journal of Applied Physiology. 2006;98:575-582.

27. Henderson GC, Krauss RM, Fattor JA, et al. Plasma triglyceride concentrations are rapidly reduced following individual bouts of endurance exercise in women. Eur J Appl Physiol. 2010;109:721-730.

28. Trombold JR, , Christmas KM, Machin DR, et al. Acute high-intensity endurance exercise is more effective than moderate-intensity exercise for attenuation of postprandial triglyceride elevation. J Applied Physiol. 2013;114:792-800.

29. Mann S, Beedie C, Jimenez A. Differential Effects of Aerobic Exercise, Resistance Training and Combined Exercise Modalities on Cholesterol and the Lipid Profile: Review, Synthesis and Recommendations. Sports Med. Feb 2014;44(2):211-21.

30. Lira F, Yamashita A, Uchida M, et al. Low and moderate, rather than high, intensity strength exercise induces benefit regarding plasma lipid profile. Diabetol Metab Syndr. 2010;2:31.

Practical Pearls

1 Morris PB, Ballantyne CM, Birtcher KK, et al. Review of clinical practice guidelines for the management of LDL-related risk. J Am Coll Cardiol. 2014;64:196-206.

2 Stone NJ, Robinson J, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2014;63:2,889-2,934.

3 Goff DC Jr., Lloyd-Jones DM, Bennett G, et al. 2013 ACC/AHA guideline on the assessment of cardiovascular risk: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2014;63:2,935-2,959.

4 Jacobson TA, Ito MK, Maki KC, et al. National Lipid Association recommendations for patient-centered management of dyslipidemias: Part 1 – executive summary. J Clin Lipidol. 2014;8:473-488.

5 Kidney Disease: Improving Global Outcomes (KDIGO) Lipid Work Group. KDIGO clinical practice guideline for lipid management in chronic kidney disease. Kidney Int Suppl. 2013;3:259-305.

6 Shepherd J, Kastelein JJP, Vera Bittner, et al. for the Treating to New Targets Investigators. Intensive lipid lowering with atorvastatin in patients with coronary heart disease and chronic kidney disease: TNT (Treating to New Targets) Study. J Am Coll Cardiol. 2008;51:1,448-1,454.

7 Fellström BC, Jardine AG, Schmieder RE, et al. for the AURORA Study Group. Rosuvastatin and cardiovascular events in patients undergoing hemodialysis. N Engl J Med. 2009;360:1,395-1,407.

8 Wanner C, Krane V, März W, et al. for the German Diabetes and Dialysis Study Investigators. Atorvastatin in Patients with Type 2 Diabetes Mellitus Undergoing Hemodialysis. N Engl J Med. 2005; 353:238-248.

9 Baigent C, Landray MJ, Reith C, et al. for the SHARP Investigators. The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): a randomised placebo-controlled trial. The Lancet. 2011;377(9784):2,181-2,192.

Case Study

1. Ridker PM, Danielson E, Fonseca FA, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein; NEJM. 2008;359:2,195-2,207.

2. Kappagoda CS and Amsterdam EA. Another look at the results of the JUPITER Trial; AJC. 2009;104:1,603-1,605.

3. National Lipid Association recommendations for patient-centered management of dyslipidemia: Part 1 – executive summary Terry A. Jacobson, Matthew K. Ito, Kevin C. Maki, Carl E. Orringer, Harold E. Bays, Peter H. Jones, James M. McKenney, Scott M. Grundy, Edward A. Gill, Robert A. Wild, Don P. Wilson, W. Virgil Brown DOI: http://dx.doi.org/10.1016/j.jacl.2014.07.007 Journal of Clinical Lipidology, Vol. 8, Issue 5 473-488

Genetic Testing and CholesterolFOR YOUR PATIENTS

Health Care Providers—access this tear sheet at www.learnyourlipids.com

Cynthia G. Rodriguez, DNP, ARNP, FNP-BC, CLS, FNLA

Genetic Testing What does it tell you? What does it affect?

Apolipoprotein E (apoE) Genotype Your risk of having a disorder called “dysbetalipoproteinemia”

• The way your body makes and stores cholesterol and triglycerides.

• People with this disorder are at risk for heart disease.

Familial Hypercholesterolemia (FH) If you have genetic mutations, such as in the LDL Receptor, PCSK9 or ApoB genes, that cause FH

• The way your body makes and processes cholesterol.

• People with FH are at risk for heart disease.

Familial Chylomicronemia Syndrome (FCS)

If you have genetic mutations, such as in the Apo C II and LPL genes, that cause FCS.

• The way your body forms and processes triglycerides.

• People with FCS are at risk for pancreatitis.

SLCO1B1 Genotype (Statin Myopathy) Your risk of having muscle side effects from a group of cholesterol lowering medications called Statins.

• Your ability to take Statins.

Discuss the need for genetic testing with your healthcare provider. It is not necessary for most.

If you have a genetic test, the result may help determine the best treatment and if any of your

family members should be tested.

ReferencesCleveland Heart Lab. http://www.clevelandheartlab.com/Health Diagnostic Laboratory Inc. http://www.hdlabinc.com/

6816 Southpoint PkwySuite 1000Jacksonville, Florida 32216

Documents

Official Publication of the National Lipid Association LipidSpin · 2015. 2. 10. · Circa 2014 —Ralph LaForge, MSc, CLS, FNLA 22 Practical Pearls Selection of Dyslipidemia Guidelines