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The Official Publication of the National Lipid Association LipidSpin

Clinical Feature ACCORD–Lipid: Does Adding a to a Prevent in ?

Also in this issue: EBM Tools for Practice: A Positive Approach for Cardioprotective Eating with the Mediterranean Clinical Use of Pedometers in Cardiometabolic Risk Reduction Programs

Volume 8 Issue 3 Summer 2010 visit www.lipid.org In This Issue: Summer 2010 (Volume 8, Issue 3)

18 EBM Tools for Practice Editors A Positive Approach for James A. Underberg, MD, MS, FACPM, FACP, FNLA Preventive CV Medicine, and Cardioprotective Eating with the Look for the NLA Community logo to discuss Mediterranean Diet Clinical Assistant Professor of Medicine — Mary Felando, MS NYU Medical School and Center for CV Prevention articles online at www.lipid.org New York, NY Diplomate, American Board of Clinical Lipidology 22 Lipid Luminations Robert A. Wild, MD, PhD, MPH Draws Curiosity and 1 From the NLA President Professor of Reproductive Endocrinology and An Exciting Year Ahead Questions Gynecology — Craig Williams, PharmD Oklahoma University Health Sciences Center — Michael H. Davidson, MD Oklahoma City, OK Diplomate, American Board of Clinical Lipidology Case Study No. 1 2 From the PLA Immediate Past–President 23 Co-Editor Practice Insights ACCORDing to PLA Change We Can Believe In? Kevin C. Maki, PhD, CLS Board of Directors — Neel K. Gupta, MD President and Chief Science Officer — Edward A. Gill, Jr., MD Provident Clinical Research — Matthew K. Ito, PharmD Glen Ellyn, IL Case Study No. 2 Clinical Lipid Specialist From the PLA President 26 3 Creatine Phosphokinase Elevations Staff Editor Greetings from the PLA in African-American Patients Megan Seery — Edward A. Gill, Jr., MD National Lipid Association — Adela Robinson, RN Executive Director 4 Editor’s Corner Specialty Corner Christopher R. Seymour, MBA 29 National Lipid Association Clarification Clinical Use of Pedometers in — Robert A. Wild, MD, PhD Cardiometabolic Risk Reducation Lipid Spin is published quarterly by the Programs National Lipid Association Clinical Feature 6816 Southpoint Parkway, Suite1000 5 — Ralph La Forge, MSc Jacksonville, FL 32216 ACCORD-Lipid: Does Adding Phone: 904-998-0854 | Fax: 904-998-0855 a Fibrate to a Statin Prevent 32 PLA Chapter Update Copyright ©2010 by the NLA. Atherosclerosis in Diabetes? Prescription Fish Oil and Blue Cross All rights reserved. — Eliot A. Brinton, MD of Idaho — Paul D. Rosenblit, MD, PhD — Matthew K. Ito, PharmD Visit us on the web at www.lipid.org. — J. Antonio G. Lopez, MD The National Lipid Association makes every 9 Guest Editorial effort to provide accurate information in the 35 In Memoriam Lipid Spin at the time of publication; however, Differential Pharmacokinetics and circumstances may alter certain details, such as Adverse Effects of , dates or locations of events. Any changes will 36 News and Notes be denoted as soon as possible. The National , and Fenofibric Acid Lipid Association invites members and guest — P. Barton Duell, MD authors to provide scientific and medical 37 Education and Meeting Update opinion, which do not necessarily reflect the policy of the Association. 13 Practical Pearls ER and Pioglitazone–The 38 Annual Scientific Sessions Dynamic Combination — Drew Garcia, PA-C 39 Foundation Update — John R. Nelson, MD 40 Honors and Recognition 16 Member Spotlight Thomas Hirose, MD, Cleansing the 43 Meetings and Courses Calendar of ‘Bad’ From the NLA President: An Exciting Year Ahead

MICHAEL H. DAVIDSON, MD, FACC, FACP, FNLA National Lipid Association President Professor and Director of Preventive Cardiology University of Chicago Pritzker School of Medicine Chicago, IL President, Chief Executive Officer and Executive Medical Director Chicago Center for Clinical Research Radiant Research Chicago, IL Diplomate, American Board of Clinical Lipidology

I am honored and thrilled to serve as the We hope to spearhead symposia that next president of the National Lipid As- will enhance the educational mission of all sociation. The organization has been well three associations and grow the “big tent” served by Dr. Vera Bittner, whose leader- philosophy that has enhanced our member- ship during the past year kept strong the ship during the past five years. Discuss this article at www.lipid.org NLA’s mission of education and promoting Go to “Topics” and look for the professionalism of lipidology, despite Secondly, our educational programs have “An Exciting Year Ahead.” challenging economic times. achieved national acclaim. It is time to take these programs “on the road” to be launched in India and Australia. The There are three key objectives I wish to ac- the 100,000-plus primary care profes- Polish Lipid Association was founded in complish during my 12-month term. First, sionals who deal with lipid disorders on May and wants to affiliate with us. The we must reach out to organizations that a daily basis. While the majority of these NLA’s success serves as a model for other share overlapping interests with the NLA. professionals may not want to focus their countries seeking to create professional We must continue to build our wonderful careers on lipidology, most are interested organizations that incorporate the entire partnership with the Preventive Cardio- in learning about common cardiometabolic healthcare team into the management of vascular Nurses Association (PCNA) to . In next 12 months, we will con- lipid disorders. reach allied health professionals interested duct half- and full-day lipidology programs in lipidology. I encourage our members in conjunction with family practice CME Lipidology has been an exciting field during to join PCNA and participate in its meet- symposiums. These will enhance our edu- the past decade and emerging therapies, ings. Many members already belong to the cational mission and member outreach. risk markers and guidelines will require American Society of Hypertension (ASH) new adjustments in clinical care. The or the Obesity Society. The NLA has estab- Lastly, the NLA needs to expand interna- NLA has been the leader in bringing this lished educational programs that focus on tionally. Our self-assessment programs information to practitioners so it can result cardiometabolic disorders and we should (SAPs) and website activities are used in outcome improvements. This will be continue to work with other groups that worldwide. An International Masters another exciting year, and I am grateful to target obesity and metabolic syndrome. Course is in development and will soon serve as your president. n

The Official Publication of the National Lipid Association 1 From the PLA Immediate Past–President: Practice Insights ACCORDing to PLA Board of Directors

MATTHEW K. ITO, PharmD, FCCP, FNLA, CLS Pacific Lipid Association Immediate Past–President Professor of Pharmacy Practice Oregon State University/Oregon Health and Science University Portland, OR

lipid-lowering therapy. Practical pearls of over-the-counter fish oils” be used as on the use of pioglitazone and extended- a substitute. The PLA leadership was at release niacin in patients with low HDL odds with this recommendation. In our cholesterol, type II diabetes and coronary article and Q&A sidebar, Dr. J. Antonio G. Discuss this article at www.lipid.org artery are offered by Dr. John López and I inform you about our chapter’s Go to “Topics” and look for “Practice Insights Nelson and Drew Garcia, PA-C. As many as efforts regarding this issue and differences ACCORDing to PLA Board of Directors.” 81 percent of patients undergoing cardiac between prescription omega-3 fatty acid surgery use some form of complementary ethyl esters and supplement fish oils. The Pacific Lipid Association is thrilled to medicine, and red yeast rice supplements present this issue of the Lipid Spin, with are used by many patients. Dr. Thank you for the honor of serving this a clinical feature based on the ACCORD Craig Williams presents a brief review on past year as PLA president. We met trial in which Drs. Eliot Brinton and the lipid-lowering effects of these products the educational needs of our members, Paul Rosenblit offer perspective on the and whether they contain HMG-CoA as illustrated by the overwhelmingly study’s major findings. Because there reductase inhibitors. positive comments from attendees at our may be discrepancies between in annual meeting in San Francisco. We also terms of their effects on clinical events, We all understand the ongoing battle increased educational opportunities at the Dr. Bart Duell discusses the differences to keep patients adhering to a healthy local level with tremendous help from Drs. between gemfibrozil and fenofibrate in diet. Mary Felando, RD, MS, reviews the Paul Rosenblit, Rob Greenfield, Nathan terms of pharmacokinetics and how they Mediterranean diet and offers positive Wong and John Nelson. Their well-attended may influence how we use these in eating messages to share with patients. events were partially funded through a selected patients. Drs. Ed Gill and Neel Helping patients reduce and maintain their generous grant from the Foundation of the Gupta discuss the clinical considerations weight through can be enhanced NLA. when using fibrates in combination with by use of pedometers. Ralph La Forge, a statin. A level of complexity exists MSc, provides an overview of these devices Finally, we conducted a live virtual journal when managing patients taking in and offers instructions for their use. club on the ACCORD trial in which Dr. combination with other that Henry Ginsberg reviewed the study findings can increase the risk of muscle-related side In July 2009, Blue Cross of Idaho notified and Dr. Eliot Brinton discussed how they effects and in her article, Adela Robinson, its providers that they would no longer affect managing dyslipidemia patients. RN, MN, NP, offers clinical guidance provide coverage for Lovaza® (prescription We remain committed to enhancing the for interpreting levels in omega-3 fatty acid ethyl esters) and quality of patient care by exceeding your African-American patients who receive suggested that “four capsules per day educational needs. n

2 LipidSpin From the PLA President: Greetings from the PLA

EDWARD A. GILL, JR., MD, FNLA, FAHA, FACC, FASE Pacific Lipid Association President Professor of Medicine (Cardiology) University of Washington School of Medicine Seattle, WA Director of Echocardiography Harborview Medical Center Seattle, WA Diplomate, American Board of Clinical Lipidology

Thanks go to all who contributed to this University of Washington, has been added informative edition of the Lipid Spin. to our board as a fellow representative and I am excited to lead the PLA for the will attend the regional PLA meeting in next year and help our membership’s March 2011. continuous development. It is not without Discuss this article at www.lipid.org challenges—significant uncertainties about Despite clear advancements in the Go to “Topics” and look for the future of health care and the growth treatment of , cardiovascular “Greetings from the PLA.” of the U.S. economy, in general—that disease continues to be the No. 1 we move forward this year. It is also a cause for death in the U.S. But there is the Pacific region with assistance from time when we face difficulties within evidence that we are making progress. the Foundation of the NLA. This goal the academic community with regard to In the June 10 issue of the New England will follow in the wake of the past year’s funding and regulatory issues. Despite Journal of Medicine, Yeh et al. show that increased educational opportunities made that, the PLA and the NLA remain strong the incidence of possible by a number of talented members. organizations and have established goals and, particularly, ST elevation MI, has At our annual meeting, which will be to help us become more financially dramatically decreased in the past decade.1 conducted jointly with the Southwest Lipid independent while providing increased Association, Dr. Kathleen Wyne and I will insight into the care of patients with There are several goals I would like to attempt to bring some third-party payors to coronary disease and coronary disease see the organization attain during my the table to discuss reimbursement for lipid equivalents as well as risks for the same. term as president. We will re-visit the disorders. In March we held our strategic planning Lovaza® payment issue with Blue Cross of committee meeting in Austin, Texas. The Idaho. I’d like to see significant progress Finally, I look forward to seeing you at our goals put forth from that meeting included: toward guidelines for lipid management, next national meeting, Annual Scientific 1) Decreasing reliance on industry for especially related to HDL therapy. I am Sessions, from May 19–21 in New York. n funding; 2) Expanding leadership; and 3) anxious to see the anticipated statement Developing international outreach. from the American Association of Clinical References listed on Page 44. Endocrinologists. I will strive to develop Andrew Cheng, a cardiology fellow at the additional educational programs throughout

The Official Publication of the National Lipid Association 3 Editor’s Corner: Fluvastatin Clarification

ROBERT A. WILD, MD, PhD, MPH Professor of Reproductive Endocrinology and Gynecology Oklahoma University Health Sciences Center Oklahoma City, OK Diplomate, American Board of Clinical Lipidology

red yeast rice; Level 2—Moderate, In our view it is best to check for possible which includes cholestyramine, fibric acid interactions through the computer derivatives and cyclosporine; and Level when prescribing any statin. Instructing 3—Mild, which includes common agents patients regarding the possibility of drug Discuss this article at www.lipid.org such as digoxin, , phenytoin, interactions also is a good idea. Often Go to “Topics” and look for “Fluvastatin niacin, and fluoxetine. Substrates reported our patients are under the care of many Clarification.” as “clinically significant for interactions” physicians, which can be a risk for drug are NSAIDs, glipizide, glyburide, interactions given our current healthcare amitryptoline, rosiglitazone, tamoxifen, environment. Another caution is to We do appreciate the comments about and warfarin among others. Anti-retroviral remember that it is possible to run into a fluvastatin XL discussed in the Spring inhibitors, clopidogel and, of ‘poor metabolizer’ and this can contribute 2010 issue of the Lipid Spin. We would be course, alcohol are among many other to atypical unwanted side effects. Please remiss, however, if we did not point out a agents to think about when considering note, too, that fluvastatin is scheduled to few things regarding fluvastatin XL. possible interactions. In controlled studies, come off patent soon. n is reported as 5 percent with Described interactions include: Level Lescol, 3.8 percent with Lescol XL, and 4.5 1—Severe, which includes statins and percent with .

4 LipidSpin Clinical Feature: ACCORD–Lipid: Does Adding a Fibrate to a Statin Prevent Atherosclerosis in Diabetes?

ELIOT A. BRINTON, MD, FAHA, FNLA PAUL D. ROSENBLIT, MD, PhD, FACE, FNLA Director, Section Clinical Professor in the Division of Endocrinology, Cardiovascular Genetics Diabetes, Metabolism Associate Professor University California at Irvine School of Medicine University of Utah School of Medicine Irvine, CA Salt Lake City, UT Diabetes Clinic Co-Director Diplomate, American Board of Clinical Lipidology University of California at Irvine Medical Center Orange, CA Director, Diabetes/Lipid Management & Research Center Huntington Beach, CA Diplomate, American Board of Clinical Lipidology

Fibrates activate Peroxisome Proliferator- as and fenofibrate, markedly activated receptor (PPAR)-alpha improve the over statin use receptors in many cells and tissues. alone, as demonstrated by the SAFARI They mediate the expression of at least study.3 The safety of this combination has 14 genes involved in lipid metabolism. been shown in many studies, including the Discuss this article at www.lipid.org Prominent effects include reduced newly completed ACCORD-Lipid trial (see Go to “Topics” and look for (TG) and increased LDL below). “ACCORD-Lipid: Adding a Fibrate to a Statin.” particle size, and increased synthesis of HDL . Fibrates appear to In ACCORD-Lipid,4 5,518 patients, mean increase reverse cholesterol transport and age of 62.3, with diabetes mellitus type fasting triglyceride (<700 mg/dL off and to reduce inflammation.1 Because there 2 and at high risk of having a CVD event, <450 on TG-lowering treatment) levels. is consensus that most, if not all, high- were treated with an average dose of 22.3 Baseline TG levels were 162 mg/dL, HDL-C risk diabetic patients should be receiving mg open-label Simvastatin. They were was 38 mg/dL, LDL-C was 101 mg/dL, statin therapy,2 the Action to Control randomized to blinded 160 mg fenofibrate non-HDL-C was 137 mg/dL and the total Cardiovascular Risk in Diabetes Lipid Study or placebo. Subjects were selected for cholesterol/HDL-C, LDL-C/HDL-C and TG/ (ACCORD-Lipid) was designed to test the HDL cholesterol (HDL-C) <55 mg/dL in HDL-C ratios were 4.59, 2.64 and 4.25, (CVD) efficacy of blacks and women, and <50 in all others. respectively. fenofibrate when added to ongoing statin Entry criteria were very broad for LDL use. Statin-fibrate combinations, such cholesterol (LDL-C) (60-180 mg/dL) and After a median follow-up of 4.7 years,

The Official Publication of the National Lipid Association 5 the annual rate of the primary outcome (first occurrence of nonfatal myocardial infarction, nonfatal , or CV death) trended non-significantly downward with fenofibrate (2.2 percent in the fenofibrate group and 2.4 percent in the placebo group, hazard ratio [HR] fenofibrate vs. placebo 0.92; 95 percent confidence interval [CI], 0.79 to 1.08; P=0.32). No secondary outcomes (components of the primary outcome) were reduced, although, surprisingly, congestive failure trended downward 22 percent (HR 0.78, p=0.1). Annual mortality trended slightly downward with fenofibrate [1.5 percent in the fenofibrate group and 1.6 percent in the placebo group Figure 1. ACCORD-Lipid: Primary Outcome in High TG (>204 mg/dL) and Low HDL-C (<34 mg/dL) vs. All Others in Entire Cohort. (HR 0.91; 95 percent CI, 0.75 to 1.10; P=0.33)]. One pre-specified subgroup baseline level of HDL-C (bottom tertile, did not differ by sex. analysis—gender—showed heterogeneity <34 mg/dL), (P=0.057 for interaction). in the primary endpoint with a benefit for The overall eight percent RRR associated The fact that patients with high TG, fenofibrate in men and possibly for harm in with fenofibrate treatment was almost low HDL-C are indeed at high CVD risk women (P=0.01 for interaction). Potential entirely confined to this subgroup has been confirmed in several studies, mechanisms for such a sex-specific effect population, comprising only 17.6 percent such as the Copenhagen Prospective are unknown, and since it has not been (n=941) of the total trial population Cardiovascular (Male) Study,5 in which observed in other fibrate studies, this may (Figure 1). In these patients, the CVD approximately 35 percent of the popula- be a chance occurrence. event risk with placebo (on statin alone) tion-attributable risk was associated with was highest for any pre-specified subgroup, high TG and low HDL-C levels (Figure 2). Another pre-specified subgroup analysis 17.32 percent, while it was only 12.37 showed a strong trend to benefit for percent (an adjusted 31 percent lower, CI Surprisingly, although it has been well- patients with both a high baseline TG not overlapping one) in those randomized known for several decades both that high level (top tertile, >204 mg/dL) and a low to simvastatin plus fenofibrate. This finding TG patients are at high CVD risk and that the greatest lipid effect of fibrates is their ability to lower TG levels, none of the major CVD event-based fibrate trials has targeted subjects with substantially elevated TG levels. The HHS (1988), the Veterans’ Affairs HDL Intervention Trial (VA-HIT) (1999), the Intervention Program (BIP) (2000), the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial (2005), and ACCORD-Lipid studied subjects with average baseline TG levels of 169, 161, 145, 154, and 162 mg/dL, respectively, barely into the borderline elevated range and well below the lowest conventional TG 6-10 Figure 2. Copenhagen Prospective Cardiovascular Study: High TG and Low HDL-C Increase IHD Risk treatment cutoff of >200 mg/dL. Independent of LDL-C.

6 LipidSpin Despite the low average TG levels in of statin use. This makes it much more these studies, subgroups with high TG relevant to contemporary practice than and low HDL-C (HHS, BIP and FIELD) the earlier fibrate studies, since high-risk “CVD benefit with were found to have significant CVD event patients are usually treated with a statin fenofibrate was not reduction (Table 1).11-13 In VA-HIT14 before consideration of additional lipid where all subjects had HDL-C <40 mg/ therapy. seen in the overall dL (mean 32 mg/dL), CVD event reduction was also demonstrated in the whole A meta-analysis of fibrate trials has found ACCORD-Lipid cohort subject population (Table 1). Thus, there a lack of reduction in fatal CHD and total is considerable evidence that fibrates mortality, but a reduction in nonfatal MI.18 but did appear in the lower CVD primarily, if not exclusively, in The authors reported the suggestion of patients with high TG and low HDL-C. greater benefit in patients with high TG subgroup with High or low HDL-C, but this was based only on TG/Low HDL-C.” Main results and key sub analyses were all study design rather than pooled analysis published for HHS, BIP and VA-HIT before of subgroups. Interestingly, there was a the design of ACCORD-Lipid was finalized non-significant trend toward decreased follow-up. Unfortunately with regard to in November 2002. These prior data might CHD mortality in ACCORD-Lipid (Table CVD mortality and fenofibrate use, the well have persuaded the ACCORD-Lipid 1). Of interest, the 13-year post-study other major fenofibrate study, FIELD, investigators that a positive study result follow-up of HHS study patients found a showed a non-significant trend toward was unlikely without a focus on high TG/ 32 percent RRR in CHD mortality in the increased CVD mortality during the trial low HDL-C patients, especially given the group originally randomized to gemfibrozil (possibly reflecting a large disparity in anticipated difficulty of showing added 18 years prior during the original study statin drop-in therapy), and no follow-up benefit on top of statin therapy. A lower period.19 This observation of a “memory” data have been reported to date. TG limit should have been set for study or “legacy” effect is reminiscent of the entry to exclude normotriglyceridemic statistically significant reduction in total Although statin monotherapy can subjects, already known to respond mortality (of 11 percent) observed with substantially reduce CVD risk, especially poorly to fibrates. The resulting increased niacin at the 15-year follow-up of the at high doses, considerable residual risk difficulty in subject recruitment would Coronary Drug Project,20 also not seen persists. This residual risk may be partially have been overcome by a need for fewer during the randomized trial period. If the attributable to residual low HDL-C and/or subjects. HHS study had been extended beyond its high TG levels. 21, 22 The findings in earlier five-year duration, this effect might have fibrate trials outlined in this review appear Clearly in retrospect, the negative primary been even more striking and might have to confirm the suggestion, given in 2001 results of ACCORD-Lipid were due to its been seen even sooner than the 18-year in ATP III2 and reaffirmed in its update,23 lack of focus on high TG and low HDL-C subjects. Nevertheless, it has become the fifth large randomized to show CVD event reduction with fibrates specifically in subjects with high TG and/ or low HDL-C, with or without diabetes mellitus (Table 1) (In FIELD and ACCORD- Lipid, all subjects had diabetes, while only a minority of subjects in HHS, BIP and VA- HIT had diabetes). Although none of these studies by itself proves fibrate CVD benefit in patients with high TG and/or low HDL- C, consistency among the five studies in this population is impressive. Importantly, ACCORD-Lipid is the first CVD study done Table 1. Comparison of ACCORD subgroup results with those from prior fibrate studies (After HN Ginsberg, with a fibrate against a uniform background ACC Meeting presentation, March 2010).

The Official Publication of the National Lipid Association 7 that adding adjunctive therapy of a fibrate addition, when statin use is impossible, in patients with diabetes, relatively un- or niacin to a statin should be considered due to myalgia or ,7 fibrate selected for specific lipid disorders. for CVD risk reduction, especially in the therapy seems to be a reasonable option However, in a pre-specified subgroup setting of residual dyslipidemia (elevated with high TG and low HDL-C, although, analysis, it appeared to reduce the primary non-HDL-C or TG, or low HDL-C) after again, no trials have specifically explored CVD composite by 31 percent in diabetic statin monotherapy. ACCORD-Lipid this situation. men and women with high TG and low provides new evidence supporting this HDL-C. Essentially all of the eight percent point, that CVD events may be reduced The novel finding that fenofibrate may RRR trend in the overall study population by the addition of fenofibrate to a statin reduce microvascular complications in was confined to this subgroup, which in patients with DM-2 who have high TG DM-2 has been reported in the FIELD trial comprised only 941 patients (about 17 and low HDL-C. Given the consistency of for the endpoints of microalbuminuria, percent of the total number of subjects). CVD benefit in this patient type among the retinopathy, and lower extremity various fibrate trials including ACCORD- amputation in the absence of evident This is in keeping with similar findings Lipid, we believe that the evidence is macrovascular disease.9, 10 from sub-group analyses of four prior strong enough to recommend fenofibrate fibrate studies. ACCORD-Lipid suggests, as a reasonable statin adjunct in that Only microalbuminuria results have been for the first time, that fenofibrate can lipid subgroup. Although the two large reported for ACCORD-Lipid so far, but reduce CVD events when it is added to fenofibrate trials, FIELD and ACCORD- if the FIELD results are corroborated, statin therapy in patients with high TG Lipid, studied only patients with diabetes, microvascular disease prevention may and low HDL-C. ACCORD-Lipid supports other fibrate studies which included become established as another important the NCEP-ATP III recommendation that subjects with and without diabetes found benefit of fenofibrate. fibrates, and particularly fenofibrate, similar results between them. Thus, we be considered as an adjunct to statin believe that fenofibrate is a reasonable Summary and Conclusion monotherapy in such patients.2, 23 n consideration for CVD reduction when ACCORD-Lipid failed to show statistically non-diabetic patients have high TG and significant CVD event reduction with References listed on Page 44. low HDL-C after statin monotherapy. In the addition of fenofibrate to simvastatin

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8 LipidSpin Guest Editorial: Differential Pharmacokinetics and Adverse Effects of Gemfibrozil, Fenofibrate, and Fenofibric Acid

P. BARTON DUELL, MD Director, Lipid-Atherosclerosis Laboratory Director, Lipid Disorders Clinic Division of Endocrinology, Diabetes, and Clinical Nutrition Oregon Health and Science University Portland, OR

Fibric acid derivatives, commonly referred metabolites are primarily excreted in the to as fibrates, have been used for the urine. treatment of hyperlipidemia for decades. Prior to the clinical availability of statin Fenofibrate [2-[4-(4-chlorobenzoyl) medications nearly 25 years ago, fibrates phenoxy]-2-methyl-propanoic acid, Discuss this article at www.lipid.org were often used to achieve modest LDL 1-methylethyl ester] was initially FDA- Go to “Topics” and look for cholesterol lowering as an adjunct to approved in 1993 under the brand name “Guest Editorial.” other medications such as niacin, bile acid Tricor but recently became available as a sequestrants, and . The typical generic . It is marketed under others). Fenofibrate is well absorbed and targets of more recent fibrate therapy several brand names (Tricor, Antara, is hydrolyzed by esterases (mostly in the have been , low HDL Lofibra, Triglide, Fenoglide, Lipofen and intestine) to form the active metabolite cholesterol, and small dense LDL. fenofibric acid, which subsequently Older fibrates, such as , have A. Fenofibrate undergoes hepatic glucuronidation. been supplanted by newer fibrates Approximately 60 percent of DRUG DOSES (mg) such as gemfibrozil, fenofibrate, administered fenofibrate is excreted Antara 43, 130 bezafibrate and . This Fenoglide 40, 120 in the urine, mostly as fenofibric acid article will focus on gemfibrozil and Lipofen 50, 100, 150 and its glucuronate conjugate, and fenofibrate, the fibrates currently Lofibra tablets 54, 160; about 25 percent is excreted in the being prescribed in the U.S. capsules 67, 134, 200 feces. The half-life of fenofibric acid Tricor 48, 145 is approximately 20 hours. Fenofibric Gemfibrozil Triglide 50, 160 acid [2-[4-(4-chlorobenzoyl) phenoxy]- [5-(2,5-dimethylphenoxy)­2,2- Unbranded generics various doses 2-methyl-propanoic acid] (Trilipix) was dimethylpentanoic acid], is well (not 48 and 145) FDA-approved in 2008 for treatment absorbed from the gastrointestinal of hyperlipidemia in the United States. tract and undergoes extensive hepatic B. Fenofibric Acid Another version of fenofibric acid conjugation. It was approved by DRUG DOSES (mg) (Fibricor) was approved in 2009. The the FDA in 1981 and was formerly Fibricor 35, 105 pharmacokinetics of fenofibric acid marketed under the brand name Trilipix 45, 135 appear to be similar to fenofibrate, Lopid. It has a plasma half-life of since fenofibrate is rapidly hydrolyzed approximately 1.5 hours and its Table 1. Preparations of fenofibrate and fenofibric acid. to form fenofibric acid in vivo. The

The Official Publication of the National Lipid Association 9 doses of various preparations of fenofibrate cholesterol concentration and fenofibric acid are inconsistent due to may be achieved in patients Gemfibrozil Fenofibrate differences in formulation, bioavailablity with normal or mildly Triglyceride lowering ++ ++ and manufacturer (Table 1). Several elevated plasma triglyceride Decreased remnants ++ ++ preparations are reportedly roughly concentrations who are Raising HDL + + bioequivalent when administered as treated with fibrates, Increased apo A-I + + approved (i.e., with or without food), but LDL cholesterol Increased LDL size + + but therapeutic equivalence cannot be concentrations often Increased ? + assumed for all products. increase among patients Fibrinogen decrease +/- + with hypertriglyceridemia as PAI-1 decrease +/- + Fibrates exert lipid-modifying effects a consequence of increased Uric acid decrease - + through several mechanisms, some of conversion of VLDL to LDL. Regression of albuminuria ? + which involve activation of peroxisome The efficacy of gemfibrozil in diabetes proliferator-activated receptor α (PPARα). and fenofibrate in lowering Beneficial changes mediated by fibrates and raising HDL Table 2. Effects of fibrates that may have anti-atherogenic benefits. include decreased hepatic lipogenesis cholesterol concentrations hepatotoxicity and myopathy when and VLDL secretion, increased fatty acid may be comparable in many settings, but administered as monotherapy.2,6 As a oxidation in and muscle, increased the results of some studies have suggested possible consequence of the high protein lipoprotein lipase activity (increased that one drug may be more efficacious than binding of the drugs, fibrates increase activity and decreased inhibition due the other in selected groups of patients. the international normalized ratio (INR) in patients treated with coumarin-type Potential anti-atherogenic benefits of , requiring a 25 percent “The results of fibrates are related in part to changes in to 35 percent reduction in the dose of lipoprotein metabolism, but other possibly . Gemfibrozil may be more some studies have beneficial effects include decreases in likely to cause symptoms of dyspepsia and plasma concentrations of PAI-1, fibrinogen abdominal pain. The drugs also seem to suggested that one and uric acid (Table 2). It appears that differ in their effects on serum creatinine, drug may be more fenofibrate may have some superiority in cystatin C and homocysteine. Fenofibrate these effects, but the clinical relevance and, less commonly, gemfibrozil are efficacious than the of these changes is unclear. Despite the recognized to reversibly increase serum beneficial effects of fibrates on PAI-1 concentrations of creatinine and cystatin other in selected and fibrinogen, fenofibrate and clofibrate C without causing a decrement in have been associated with a small creatinine clearance.2,7,8 Accordingly, these groups of patients.” but statistically significant increase in changes are not believed to represent venothromboembolic disease, which could renal damage. Moreover, data from the be related to other adverse effects such as FIELD trial suggests that treatment with to reduced apo C-III concentrations), homocysteine elevation.2,3 fenofibrate may help prevent progression increased transcription of apo A-I and to albuminuria and may induce regression A-II, increased transfer of phospholipid Gemfibrozil and fenofibrate have of albuminuria in patients with type 2 and cholesterol to HDL, and remodeling comparable risks of causing several diabetes.2 Fenofibrate and some other of LDL particles.1 As a consequence of potential adverse effects when they are fibrates have been shown to increase these and other effects, fibrates effectively administered in monotherapy, but there plasma concentrations of homocysteine lower concentrations of triglycerides, are some differences (Table 3). Both by 40 percent to 55 percent, presumably VLDL cholesterol and VLDL particles, fibrates are known to comparably increase because of PPARα-mediated mechanisms.9 and remnant lipoproteins in plasma. They the risk of cholelithiasis by causing Gemfibrozil may have a lower propensity also raise plasma HDL concentrations increased lithogenicity of bile resulting for raising plasma homocysteine and mediate a shift in small, dense LDL from a rise in the ratio of cholesterol concentrations,10,11 but a homocysteine to more buoyant, larger LDL particles. to phospholipids and bile salts.4,5 Both elevation of 18 percent after treatment Modest lowering of the plasma LDL drugs also have a low risk of inducing with gemfibrozil was noted in one study.12

10 LipidSpin The implications of fibrate-mediated of when administered with with fibrates and statins, alone or in elevation of plasma homocysteine and a 15-fold higher risk when combination, include increased age, female concentrations on cardiovascular risk are administered with other statins.21 The sex, renal insufficiency, , unknown, despite the known association results of other studies have demonstrated , diabetes, dehydration, between plasma homocysteine and low rates of creatine kinase elevation and intercurrent illness, heavy exercise cardiovascular risk.13,14 rhabdomyolysis among patients treated and a variety of predisposing genetic with fenofibrate in combination with polymorphisms. The toxicities of gemfibrozil and moderate doses of statins,23 which suggests fenofibrate are distinctly different when that treatment with the combination of The effects of fibrates on cardiovascular they are administered in combination fenofibrate and a moderate dose of statin endpoints have been variable, with with statins (Table 3). This difference may be a safe option for patients with gemfibrozil demonstrating cardiovascular in toxicity is related in part to the .24 Fenofibric benefit in the Helsinki Heart and VA capacity of gemfibrozil to inhibit both acid (Trilipix) was FDA-approved in 2009 HIT studies, but fenofibrate showing glucuronidation and for use in combination with moderate benefit only in secondary and post hoc oxidative metabolism of many statins.15,16 doses of statins in Accordingly, gemfibrozil, but not appropriate patients. Gemfibrozil Fenofibrate fenofibrate, increases the plasma area It is unclear Dyspepsia and abd pain ++ + under the curve (AUC) and peak plasma whether fenofibric Hepatotoxicity + + concentrations (Cmax) of , acid is actually safer + + , simvastatin, , in combination with Increased INR in coumarin- + + , and cerivastatin by two- a statin compared treated patients to threefold.17,18 Neither gemfibrozil to fenofibrate plus Increased creatinine +/- + nor fenofibrate appears to influence a statin because Increased cystatin C +/- + the pharmacokinetics of fluvastatin.19 definitive studies Increased homocysteine +/- + have not been done, Worsening creatinine - - but the clinical clearance “Patients who are data reviewed by Rhabdomyolysis the FDA indicated Monotherapy + + treated with fibrates that treatment with With statins +++ + fenofibric acid in need to be monitored combination with Table 3. Potential adverse effects of fibrates. moderate doses of for potential statins was associated with an acceptable cardiovascular endpoints in the FIELD and risk of myopathy. For these reasons, ACCORD studies. The failure to achieve complications of fenofibrate and fenofibric acid are the benefit in the primary cardiovascular therapy.” preferred fibrates for administration in endpoint in the FIELD study may have combination with a statin. If treatment been related to a high rate of drop-in with gemfibrozil cannot be avoided, and statin use in the placebo group. In both statin plus fibrate therapy is deemed the FIELD and ACCORD studies, the The results of several lines of evidence necessary, treatment in combination with magnitude of dyslipidemia in many subjects indicate that gemfibrozil is associated fluvastatin may be an acceptable option, also may have been insufficient to achieve with a substantially increased risk of but fluvastatin has limited efficacy for the greatest benefit from fibrate treatment. rhabdomyolysis compared to fenofibrate lowering LDL cholesterol. If fibrates are It appears that the cardiovascular benefits when it is administered in combination administered in combination with statins, of fibrates may occur predominantly among with statins.20,21,22 On the basis of a review only low or moderate doses of statins patients with hypertriglyceridemia greater of cases of rhabdomyolysis reported should generally be used to minimize than approximately 200 mg/dL and HDL to the FDA between 1998 and 2002, the risk of myopathy and hepatotoxicity. cholesterol concentrations less than 35-40 gemfibrozil in comparison to fenofibrate Additional factors that may increase mg/dL. was associated with a 33-fold higher risk the risk of myopathy in patients treated

The Official Publication of the National Lipid Association 11 In summary, gemfibrozil, fenofibrate and the associated risk of myopathy to be monitored for potential complications and fenofibric acid are drugs with favor fenofibrate and fenofibric acid over of therapy, and healthcare providers need demonstrated efficacy for triglyceride gemfibrozil, particularly when they are to be aware of factors that may increase lowering, HDL cholesterol raising, and administered in combination with statins. the risk of toxicity. Further studies are inducing positive changes in LDL size and Gemfibrozil has the advantage of lower required to define the most appropriate composition. The cardiovascular benefits cost, in some cases, and may have less of uses of fibrates in the endeavor to prevent of fibrate therapy may be mostly limited an effect on serum creatinine and plasma cardiovascular events. n to patients who have hypertriglyceridemia homocyteine concentrations, but the latter and low HDL cholesterol. Differences effects have unknown clinical significance. References listed on Page 44. in the pharmacokinetics of these drugs Patients who are treated with fibrates need DREW GARCIA, PA-C, CLS Lipid Clinic Specialist Saint Alphonsus Regional Medical Center Boise, ID

JOHN R. NELSON, MD, FACC, FNLA Director California Cardiovascular Institute Fresno, CA Diplomate, American Board of Clinical Lipidology

12 LipidSpin Practical Pearls: ER Niacin and Pioglitazone– The Dynamic Combination

DREW GARCIA, PA-C, CLS Lipid Clinic Specialist Saint Alphonsus Regional Medical Center Boise, ID

JOHN R. NELSON, MD, FACC, FNLA Director California Cardiovascular Institute Fresno, CA Diplomate, American Board of Clinical Lipidology

The lack of treatment of low HDL-C , oxidative stress, and the in high risk patients is of epidemic rates of atherosclerosis and recurrent proportions despite multiple guideline CV events should be utilized in treating recommendations. This alarming trend patients with type 2 DM with CAD and exists across all levels of high risk patients low HDL-C. We believe that extended Discuss this article at www.lipid.org and particularly for those with type release niacin (ER niacin) and pioglitazone Go to “Topics” and look for “ER Niacin and Pioglitazone–The Dynamic 2 diabetes mellitus (type 2 DM) and are an outstanding and underutilized Combination.” coexistent (CAD). drug combination in these very high It was recently demonstrated that only 18 risk patients. ER niacin and pioglitazone percent(p=.0002).7 Both ER niacin and percent of men and 16 percent of women both improve all components of diabetic pioglitazone improve endothelial function with type 2 DM, CAD, and low HDL-C dyslipidemia—including lowering as measured by mediated were treated with non-statin therapy, triglycerides, raising HDL-C, reducing endothelial .8, 9 ER niacin has despite American Diabetic Association small dense LDL, and LDL particle been shown to ameliorate the worsening (ADA) Guidelines stating that HDL-C in number while increasing LDL size.2,3 in HDL peroxidation and HDL associated men and women should be greater than The increase in HDL-C by pioglitazone myeloperoxidase activity seen in patient’s 40 mg/dL, 50 mg/dL respectively.1 Thus, has been demonstrated to predict the with type 2 DM and low HDL-C.8 from epidemiologic estimates there is anti-atherosclerotic effects in the carotid Studies consistently show both niacin tremendous opportunity for reducing circulation.4 Both pioglitazone and ER and pioglitazone slow the progression cardiovascular (CV) events and mortality niacin lower CRP and raise adiponectin.5,6 or regress both carotid and coronary rates by treating low HDL-C in these very In patients with metabolic syndrome and atherosclerosis.10–13 high risk patients. low HDL-C, 2000 mg of ER niacin with the additional 45 mg of pioglitazone further We believe that focusing on only LDL-C Drug combinations which not only treat increase adiponectin by an additional in this patient population is not enough. dyslipidemia and , but also 200 percent (p<.0001) and HDL-C was Intravascular ultrasound (IVUS) studies improve endothelial function, reduce further increased by an additional 13 in patients on statins have shown that

The Official Publication of the National Lipid Association 13 intensive LDL-C lowering decreases the In a meta-analysis of 19 rate of plaque progression but only to trials involving 16,390 the level observed in non-DM patients patients with type 2 with suboptimal lipid control.14 This is DM, pioglitazone was especially important in type 2 DM where shown to have an 18 patients have higher re-stenosis rates than percent relative risk non– type 2 DM patients for both bare- reduction of death, MI metal stents (BMS) and also drug-eluding or stroke (p=0.005).18 stents (DES).15 Pioglitazone has been The Coronary Drug shown to decrease both in-stent neointimal Project (CDP) evaluated proliferation and the clinically important the effects of 5 lipid endpoint of target legion revascularization modifying agents, in a (TLR). In one study, the TLR in 6 months randomized doubleblind was decreased by 58 percent (12.5 placebo controlled design percent versus 29.8 percent, P = 0.04) in in 8,341 men with prior patients with type 2 DM randomized to MI. Niacin was shown spironolactone.22, 23 Obese patients or 16 pioglitazone post BMS implantation. to reduce the combined endpoints of patients with left ventricular systolic or CHD death and nonfatal MI (15 percent, diastolic dysfunction NYHA functional Adverse CV event rate reduction has been p<0.05), nonfatal MI (26 percent, class I or II should be seen frequently reported with both pioglitazone and niacin. p<0.05), and stroke or transient ischemic for monitoring and additional counseling 19 attack (24 percent, p<0.05). on lifestyle modification and reduction in sodium intake. Regarding the slight “The underutilized ER niacin is well tolerated in patients increase in distal fracture reported with with type 2 DM. In the Advent Trial pioglitazone (an additional increase of 0.8 drug combination (Assessment of Diabetes control and fractures per 100 patient-years in distal eValuation of the Efficacy of Niaspan Trial), upper arm or distal lower leg in women), it pioglitazone and a 16-week double blind, placebo-control is known that patients with type 2 DM are ER niacin reduce trial, 148 patients were randomized at increased risk of fracture.24, 25 This issue to placebo, 1000 mg or 1500 mg of requires further evaluation. cardiovascular event ER niacin.20 At the end, there was no significant increase in glucose or HgA1c In summary, low HDL-C in patients with rates and improve in the 1000 mg ER niacin dose group. type 2 DM and CAD remains one of the Even at the 1500 mg dose, the HgA1c least treated lipid goals. Pioglitazone and revascularization in only increased 0.29 percent. In this ER niacin is a powerful, underutilized trial patients were not allowed to use drug combination, to not only treat patient’s post PCI.” thiazolidinediones (TZDs). While flushing diabetic dyslipidemia but also to improve was reported in two-thirds of the patients, endothelial function, reduce inflammation, only three discontinued ER niacin due to and resistance. These therapies The PROactive trial was a double blind this side effect. Mild ER niacin-induced also reduce progression and promote placebo controlled trial of 5,238 patients impairment of glucose homeostasis can regression of atherosclerosis. They reduce with type 2 DM and macrovascular disease be prevented with concomitant use of cardiovascular event rates and improve 21 who were randomized to pioglitazone pioglitazone, insulin sensitizing effects. revascularization in patient’s post–PCI. n or placebo. In the subgroup of 2,445 In the Proactive trial, pioglitazone was patients who had a previous myocardial associated with increased congestive heart References listed on Page 44. infarction, pioglitazone reduced the pre- failure (CHF), which was not associated specified secondary endpoint of fatal and with death.17 The excess fluid associated nonfatal MI (28 percent risk reduction, with CHF is secondary to the increased p=0.045) and sodium reabsorption due to TZDs and (37 percent risk reduction, p=0.035).17 has been shown to be mitigated by

14 LipidSpin The Official Publication of the National Lipid Association 15 Member Spotlight: Thomas Hirose, MD Cleansing the Blood of ‘Bad’ Cholesterol

Thomas G. Hirose, MD Chairman and Chief Medical Officer Transfusion Medicine Associates Torrance, CA Assistant Clinical Professor University of California at Los Angeles School of Medicine Los Angeles, CA

familial hyperlipidemia patients die of percent of the patients Dr. Hirose sees are cardiovascular events while still in their heterozygous or have an unknown genetic teenage years. background.

Discuss this article at www.lipid.org Today, LDL apheresis is more common and Patient eligibility criteria include failure Go to “Topics” and look for “Member Spotlight– its centrifugal process often is compared to to respond to changes in diet, increased Thomas Hirose, MD.” dialysis, even though patients only need to exercise and cholesterol-lowering receive the therapy twice a month. medications when LDL is >300 without During treatment, blood flows into an heart disease, or LDL >200 with evidence The use of an LDL apheresis machine in apheresis machine and cholesterol- of heart disease. People suffering Dr. Thomas Hirose’s practice has afforded containing plasma is separated from the or liver toxicity from statin medication also his team the honor of caring for two of the red cells. After the cholesterol is removed are candidates for the treatment. therapy’s longest-standing U.S. patients; by absorption onto a sugar or heparin each has undergone the specialized column, the red cells and “cleared” plasma Dr. Hirose became interested in this form treatment for more than a decade. are returned to the patient. of therapy while a resident at Cedars-Sinai Medical Center, where he was mentored “These patients would have died from Both heterozygous and homozygous by Dr. Dennis Goldfinger, chairman for heart disease many years ago without this familial hyperlipidemia patients benefit the Transfusion Medicine Department. therapy,” Hirose said. “It is very gratifying from LDL apheresis, but more than 90 Working there, and later for Dr. Walter to provide this type of healthcare in the Dzik during a fellowship with Harvard community.” Medical School’s New England Deaconess Hospital, increased his interest in While licensed in the United States for management. about 15 years, LDL apheresis has a slightly longer practice history in Japan “Coagulation is a broad, interesting area and Europe, where public demand for the of medicine that may lead to dramatic treatment was greater in the 1980s, Dr. responses in medical therapy if correct Hirose said. diagnosis and timely intervention are provided,” Dr. Hirose said. “Necessity is the mother of invention,” Apheresis patient Cynthia Moore and her son, Dylan. he said, noting that the era saw Today, Dylan is two years old.

16 LipidSpin A third-generation Californian, he brought nature of the recent cardiovascular events, is what stands out as being most important his interest in transfusion medicine back especially given that she had to stop her during that time and, now that I have my to Los Angeles, where he began his private statin regimen while expecting. baby, I would do it all over again.” practice in 1994. In addition to overseeing five locations for Transfusion Medicine Pregnant women are advised against taking Despite positive feedback from patients Associates, Dr. Hirose also serves as an statins because the medication increases such as Moore, the public’s awareness assistant clinical professor at the University the risk of birth defects. But when Moore’s of LDL apheresis remains relatively low, of California–Los Angeles School of primary lipid specialist, Dr. Thomas Bersot, which is especially problematic because Medicine and as an attending physician at recommended the LDL apheresis therapy, hyperlipidemia is considered a “silent Harbor–UCLA Medical Center. she gained the invaluable opportunity to disease.” carry her pregnancy to full term. One of his patients, Cynthia Moore, “It will be an upstream battle if the first described LDL apheresis as a life-changing For the last eight months of her pregnancy, heart attack has occurred,” Dr. Hirose said. opportunity that allowed her to fulfill her Moore received apheresis treatment every “We need to get the word out because, for dream of becoming a mother. two weeks at a Transfusion Medicine patients who really need apheresis therapy, Associates clinic in anticipation of her it is essential that they are treated sooner “I had a heart attack followed by C-section. Although she left each rather than later.” n emergency open heart bypass surgery at treatment feeling tired, the fatigue was age 40 and unexpectedly became pregnant well worth her chance at motherhood, she For more information about LDL apheresis eight weeks later as a result of having to said. or Transfusion Medicine Associates, please stop birth control,” Moore said. contact Dr. Hirose’s office at (877) 393-5700 “My heart surgery is no longer at the or via e-mail at [email protected]. Her treating cardiologist advised her not forefront of what I went through during to carry the pregnancy due to the high-risk that period,” Moore said. “My pregnancy

The Official Publication of the National Lipid Association 17 EBM Tools for Practice: A Positive Approach for Cardioprotective Eating with the Mediterranean Diet

MARY FELANDO, MS, RD, CLS Clinical Dietitian Heart Institute Cedars-Sinai Medical Center Los Angeles, CA

limited to less than 200 mg daily with 20 of yogurt and cheese, weekly fish, poultry to 30 grams of fiber.2 In addition to TLC and eggs, and an infrequent intake guidelines, the American Heart Association of sweets and red meat. Wine is also Diet and Lifestyle Recommendations call consumed with meals.4 Discuss this article at www.lipid.org for a limitation on trans fat (up to one Go to “Topics” and look for “EBM Tools for percent of calories), sodium (from 1,500 Keys et al. were the first to determine Practice.” to 2,300 mg daily), minimization of added a positive relationship between a sugars, and a recommendation for omega-3 Mediterranean diet and CHD.5 Since then, fatty acids.3 numerous studies have provided further Encouraging cardiac patients to eat evidence for the cardioprotective effect of healthily is an ongoing challenge. For Within the framework of these two a Mediterranean diet. A meta-analysis of people accustomed to traditional American dietary guidelines, it is appealing that the nine cohort studies has shown that greater fare, veggie burgers and tofu can be a Mediterranean diet can be used as a model to the Mediterranean diet is hard sell. In a study of patients one year for healthy eating. The Mediterranean diet associated with a significant reduction in after diagnosis of coronary heart disease is about abundance and flavor and less cardiovascular and overall mortality.6 In a (CHD), researchers found that dietary focused on restriction and deprivation. It is randomized two-year trial in patients with quality was poor, with less than 12.4 not just a “diet” but a way of life. metabolic syndrome, a group following percent of patients meeting the daily the Mediterranean diet was compared to recommendations for fruit and vegetable The traditional Mediterranean diet is based a control group receiving general healthy intake.1 on the eating habits of Crete, Greece, and food information. Results found that the southern Italy in the 1960s, a time when Mediterranean diet group had significant Adult Treatment Panel III recommends a they enjoyed low rates of chronic disease reductions in hs-CRP and insulin resistance lifestyle approach, Therapeutic Lifestyle and high life expectancy. The overall diet with improved cardiovascular endothelial Changes (TLC), to lower the risk of CHD. is high in total fat (up to 40 percent of function scores. After two years, the The nutrient composition of the TLC Diet calories) but low in saturated fat (less than prevalence of metabolic syndrome in includes from 25 percent to 35 percent 8 percent of calories) It is characterized patients randomized to the Mediterranean of calories as total fat with less than seven by an abundance of fresh and minimally diet was reduced by one-half.7 percent saturated fat, up to 20 percent processed plant foods (vegetables, fruits, monounsaturated fat and up to ten percent whole grains, potatoes, beans and nuts), The Prevencion con Dieta Mediterranea polyunsaturated fat. Cholesterol intake is olive oil as the primary fat, small amounts (PREDIMED) study is an ongoing four-year

18 LipidSpin omega-6 polyunsaturated fatty acids for heart health.9 Patients can be advised to use virgin olive oil (virgin having higher phenol content) more often but not exclusively; other oils include canola, corn, safflower, sunflower and soybean. 2) Wine: The evidence does not suggest a benefit of wine over other types of alcohol, nor has it been determined whether there is a clear benefit with or without meals.10 In addition, a decision to use alcohol must be carefully weighed against risks. 3) Egg yolks and cheese: Intake should be individualized to stay within the saturated fat and cholesterol restrictions outlined in the TLC diet.

The Mediterranean diet, for cardioprotective eating, has a substantial research base and proven track record. Not only is it an attractive option for patients, it combines both the TLC and AHA guidelines and can be used as a teaching tool when discussing a healthful lifestyle Mediterranean Diet Pyramid to reduce future cardiac events. Positive Source: 2009 Oldways Preservation & Exchange Trust eating messages can include: “Enjoy a handful of nuts daily.” “Fill half of your clinical trial of 9,000 high-risk individuals cholesterol-to-HDL ratio than those plate with vegetables.” “Eat fruit at every 8 randomized to follow the Mediterranean randomized to the prudent control group. meal.” “Use avocado as a spread for whole diet plus one liter of free virgin olive oil grain bread.” provided weekly, the Mediterranean diet Although the TLC and AHA dietary plus one ounce of free mixed nuts daily, or guidelines can blend with the A referral to a registered dietitian for a low-fat diet group. The results, expected Mediterranean diet, there are three areas medical nutrition therapy (MNT) can in 2011, will add to the current research. of discordance: facilitate a patient’s successful transition In an interim analysis of the PREDIMED 1) Olive oil: Research does not confirm to Mediterranean eating with the use of study, it was found that patients the superior and sole use of olive oil, a behavioral strategies, shopping lists and randomized to either of the Mediterranean monounsaturated fat. The 2010 AHA recipes.11 diets had lower mean glucose, lower Science Advisory supports an intake of (See Editor’s Note on following page.) systolic blood pressure and a lower total five percent to ten percent of energy as References listed on Page 45.

About the Mediterranean Diet “His midday meal is of eggplant; with large mushrooms, crisp vegetables and country bread dipped in golden olive oil. Once a week, there is a bit of lamb. Once a week, there is chicken. Twice a week, there is fish fresh from the sea. Other meals are hot dishes of legumes seasoned with meats and condiments. The main meal is followed by a tangy salad, then by dates, Turkish sweets, nuts or fresh fruit. A sharp local wine completes the meal.”

– Henry Blackburn, MD Co-Investigator, Seven Countries Study, Professor of Public Health and Medicine, University of Minnesota

The Official Publication of the National Lipid Association 19 Editor’s Note about EBM Tools for Practice article—

Mary Felando provides a practical article in which she differences). By strict evidence–based practice the RCT is reports evidence for practice regarding the Mediterranean a stronger study design needed to help us change practice. diet. Even better would be a meta-analysis of randomized clinical trials to pool the evidence. Of interest is how observations of reduced risk for CVD when compliant with this lifestyle were found and how To incorporate this evidence into practice we should this was evaluated using longitudinal cohort studies. Of understand this science, understand our patients’ values, the observational study designs the longitudinal cohort and use our judgment as to whether it is good practice is the strongest analytical study (with a control group) to prescribe for any given patient. For example, there design. The next step was to synthesize the evidence may be other diets with better evidence, some patients’ using a meta-analysis of observational studies. The forest religious beliefs may prohibit its use, or patients may plot from this work is shown in the figure. Of the 4 have strong feelings about alcohol. This might suggest studies included there was a 9 percent risk reduction that the need for alternatives or modifications to the basic was found significant. The authors reported a random Mediterranean lifestyle. effects model (a conservative estimate with greater ability to generalize the wider confidence intervals). There was I like this diet because one can still eat a lot, drink a little non significant heterogeneity among studies (I2 was 32.6 and be merry! I applaud her review of how evidence can percent and Chi-square was 0.2). This means that there improve practice. n is still a possibility of heterogeneity due a possible type II error. In other words there could be heterogeneity — Robert Wild, MD, PhD, MPH between the studies, it just wasn’t detected. The evidence Editor, Lipid Spin was next assessed by organizing a randomized clinical trial and Felando noted the reporting of early surrogate findings from the RCT (not hard outcomes like CVD death

Figure 1. Risk of mortality from cardiovascular diseases associated with two point increase in adherence score for Mediterranean diet. Squares represent effect size; extended lines show 95 percent confidence intervals; diamond represents total effect size. Source: Sofi, F. et al. BMJ 2008;337:a1344.

20 LipidSpin Visit Our New Website! In June, the National Lipid Association launched an improved website. Our new website provides an expanded platform for participating in the conversation about lipid management.

The enhanced website provides numerous resources for visitors, members and partner organizations-including our lipid specialist database, member blogs, ReachMD podcasts, policy statements and much more. While open to all visitors, lipid.org also features certain members-only privileges, such as access to our publications, slides, discussion forum and the NLA Virtual Clinic.

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The Official Publication of the National Lipid Association 21 Lipid Luminations: Red Yeast Rice Draws Curiosity and Questions

CRAIG WILLIAMS, PharmD Clinical Associate Professor College of Pharmacy Oregon State University/Oregon Health and Science University Portland, OR

unsaturated fatty acids, average reductions animal models have documented an increase in LDLc rarely exceed 15 percent with these in bile acid excretion with red yeast rice, an agents and the HMG-CoA inhibiting effects effect which might lower LDLc but which is Discuss this article at www.lipid.org of red yeast rice almost certainly play a role not known to occur from the inhibition of in the LDLc lowering effects that are seen.6 the HMG-CoA reductase.11 Additionally, the Go to “Topics” and look for “Red Yeast Rice Draws Curiosity and Questions.” One of the monacolins present in red yeast documented presence of could rice is identical in structure to lovastatin.7,8 reasonably be expected to contribute at least Alterations in the process have somewhat to the LDLc reduction with differ- Chinese red yeast rice (also known as koji, been shown to be able to alter the concen- ent red yeast rice preparations. Thus, while anka, angkak and ben-koji) is produced tration of lovastatin in red yeast rice by as it is irrefutable that one mechanism of LDLc by fermenting white rice with the yeast much as 20-fold.7 The presence of lovastatin lowering with red yeast rice is at least some Monascus purpureus. This produces many and several reports of myositis from red degree of HMG-CoA reductase inhibition, compounds including a family of substances yeast rice prompted the U.S. Food and Drug other mechanisms are likely involved and known as monacolins, some of which are Administration to release a public warning in have yet to be fully explained in the current known to inhibit HMG-CoA reductase.1 Yet, 2007.9, 10 literature. despite this known effect of red yeast rice, many other compounds are present which Despite the documented presence of may account for some of the lipid modulat- Given the unknown aspects of the mecha- ing effect of this dietary supplement.2 These monacolins which can inhibit HMG-CoA nisms of action of the various red yeast include phytosterols and various unsaturated reductase, the concentrations of these com- products and the lack of an FDA-approved fatty acids. Other compounds also present pounds have generally been considered to be product in the US, there are currently no include dimerumic acid, gamma aminobu- too low to fully account for the LDLc reduc- recommendations from any major societies 1,5 tyric acid (GABA), and novel compounds tion that is seen with red yeast rice. In fact to incorporate red yeast rice into a compre- with yet unknown physiologic effects.1, 3 some preparations have been found to con- hensive lipid management plan. While the tain no monacolins at all.8 A comprehensive NLA acknowledges the potential benefits of A recent report with red yeast rice in 25 study of different red yeast rice products red yeast rice, it does not condone its use statin-intolerant patients found an average to ascertain the degree of LDLc lowering until ongoing research is completed and an reduction in total cholesterol of 15 percent relative to monacolin concentrations has assessment of available products can be un- with an LDLc reduction of 21 percent.4 This not been done. Thus, it is not possible to dertaken. To read the NLA's red yeast rice is similar to previous findings.5 While reduc- conclude whether or not red yeast rice policy, go to www.lipid.org/policy. n tions of LDLc in this range are conceivable preparations which lack any monacolins still with higher doses of phytosterols and mono- retain LDLc lowering properties. However, References listed on Page 45.

22 LipidSpin Case Study No. 1: Change We Can Believe In?

NEEL K. GUPTA, MD Resident, Department of Internal Medicine University of Washington School of Medicine Seattle, WA

EDWARD A. GILL JR., MD, FNLA, FAHA, FACC, FASE Professor of Medicine (Cardiology) University of Washington School of Medicine Seattle, WA Director of Echocardiography Harborview Medical Center Seattle, WA Diplomate, American Board of Clinical Lipidology

We admitted a 73-year-old East Indian increase his HDL. man to the Cardiac Intensive Care Unit (CICU) for unstable . He was Because of multiple comorbidities and known to have three-vessel coronary poor coronary artery bypass targets, he disease, mellitus (A1c 6.8 was thought to be an unsuitable surgical Discuss this article at www.lipid.org percent), stage 3 chronic kidney disease candidate. In addition, there were no Go to “Topics” and look for “Case Study No. 1.” (CKD), and dyslipidemia. A fasting lipid obvious coronary lesions thought to be panel approximately three weeks prior to amenable to percutaneous intervention. of concern for statin-fibrate-induced admission was notable for the following: We, therefore, focused our attention on total cholesterol 123 mg/dL, triglycerides relieving his symptoms through maximal myopathy. 143 mg/dL, LDL 67 mg/dL, HDL 27 mg/dL, medical management and emphasized and non-LDL 96 mg/dL. His medications secondary prevention in this very high-risk Clinical Questions: What is the risk/ included simvastatin 40mg, metoprolol XL, individual. Three days after his admission, benefit profile of combination statin- losartan, , clopidogrel, and long- gemfibrozil 300 mg BID was added based fibrate therapy in this individual? What is acting insulin twice daily. Simvastatin was on a repeat lipid panel with a serum HDL the relative efficacy of fenofibrate versus changed to atorvastatin 80mg on admission level of 25 mg/dL (Table 1). His renal gemfibrozil in raising HDL? What other with acute coronary syndrome (ACS), function remained stable and he did not potential side effects of fenofibrate should and a fasting lipid panel was obtained report any or muscle weakness be considered in this case? the following day (Table 1). He had been on the combination of gemfibrozil and taking lovastatin 20mg daily for two years high-dose atorvastatin. However, per the Myopathy is a feared consequence of and was switched to simvastatin during a recommendation of our clinical pharmacist, statin-fibrate combination therapy and is prior inpatient stay in an attempt to more he was sent home on rosuvastatin 20mg generally not recommended in higher risk aggressively treat his LDL and possibly along with fenofibrate 67mg daily out patients (e.g., age >70; chronic kidney

The Official Publication of the National Lipid Association 23 disease; and multiple medications).� information, coupled with data indicating not fit the typical profile of patients in However, in at least one review of 36 that atorvastatin (along with fluvastatin studies evaluating the effect of fibrates on clinical trials published between 1988 and pravastatin) has the lowest rate of cardiovascular disease, there is established and 2000 looking at 1,674 patients, the fatal rhabdomyolysis at .04 deaths per data demonstrating the efficacy of million prescriptions,� gemfibrozil in dyslipidemic patients. In the would seem to provide well-known Veterans Affairs High-Density some reassurance when Lipoprotein Cholesterol Intervention Trial assessing the risk/ Study Group (VA-HIT, 1999) investigators benefit profile of this observed a six percent increase in serum particular statin-fibrate HDL levels in the 1,264 men assigned combination. to receive 1,200 mg gemfibrozil per day, as compared to the 1,267 men receiving If the risk of a placebo. Notably, the investigators atorvastatin-fibrate- also observed a 24 percent reduction in associated myopathy is the combined outcome of death from relatively low and serum coronary heart disease, nonfatal myocardial levels of atorvastatin infarction and stroke (P<0.001).� incidence of statin-fibrate-associated are affected equally by gemfibrozil and Concentrating more on coronary events, myopathy (defined as myalgia with CK fenofibrate, the decision to use one agent there was a 22 percent reduction in non- elevated 10 x upper-limit normal) was 0.12 versus the other comes down to efficacy. fatal MI plus coronary death. A multivariate percent, or 20 cases total, spanning all In addition to ongoing efforts aimed analysis of the trial showed that coronary trials.� Moreover, many of the earlier case at maintaining low serum LDL levels, heart disease events were reduced by series reporting statin-associated myopathy 11 percent with gemfibrozil for every (alone or in combination with fibrates) increase in HDL of 5 mg/dL (p-0.02). Most were tied to the use of cerivastatin, which “We focused notably, despite the fact that the impact has long since been pulled off the market. on triglycerides was more substantial than our attention on the HDL, the 6 percent increase in HDL In our patient’s case there was particular cholesterol significantly predicted a lower concern for myopathy secondary to the use on relieving his risk of CHD events. Neither LDL levels of gemfibrozil and high-dose atorvastatin. symptoms through nor baseline or on treatment triglyceride Review of the literature shows some levels predicted the lower risk of coronary discordance between this prevalent maximal medical heart disease. The Helsinki Heart Study clinical concern and the underlying similarly compared 2,051 asymptomatic pharmacokinetics. One in vitro study management and men receiving 1,200 mg gemfibrozil per examining the interaction between statins day with a matched group of 2,030 men and fibrates demonstrated only minimal emphasized secondary receiving placebo. Gemfibrozil caused a increase (1.2– to 1.4-fold) in atorvastatin marked increase in HDL cholesterol and area-under-the-curve (AUC) plasma levels prevention in this very persistent reductions in serum levels of via non-selective glucuronidation in the high-risk individual.” total, LDL and non-HDL cholesterol and setting of concomitant gemfibrozil or triglycerides when compared to serum lipid fenofibrate administration.� Contrast levels in the placebo group. A reduction of this with the two- to threefold increase maintaining reasonable glycemic control, 34.0 percent in the incidence of coronary and near sixfold increase in AUC for and effective blood pressure management, heart disease was observed between the simvastatin/lovastatin/pravastatin and this patient’s persistently low serum HDL two arms. cerivastatin, respectively. Notably, this level was another important and potentially study also demonstrated near identical modifiable risk factor. In contrast, recent findings from the increase in atorvastatin AUC when ACCORD trial suggest that treatment with comparing co-administration with With the caveat that this 73-year-old fenofibrate in addition to statin therapy gemfibrozil versus fenofibrate. That East Indian man with CKD likely did in type 2 diabetics has little or no effect

24 LipidSpin was the first occurrence of nonfatal independent of any potential myopathy myocardial infarction, nonfatal stroke, or or rhabdomyolysis. The exact mechanism “Myopathy is a death from cardiovascular causes during remains unclear, but some investigators feared consequence a mean followup of almost five years. have speculated that serum creatinine The annual rate of the primary outcome levels are increased as a result of greater of statin-fibrate was 2.2 percent in the fenofibrate group metabolic production of creatinine rather and 2.4 percent in the placebo group, than decreases in glomerular filtration combination therapy demonstrating no statistical difference rate or renal plasma flow as measured by in outcomes between the two groups.� insulin and para-aminohippuric acid (PAH) and is generally not However, one caveat is that there was a clearance. This has major implications trend toward improvement in patients with for patients with CKD in whom other recommended in dyslipidemia defined as a triglyceride level medications—including those with higher risk patients.” >200mg/dL and an HDL 34 mg/dL or less. beneficial cardiovascular effects such Although our patient’s triglyceride level as ACE inhibitors or ARBs—may be was not this high at the time of fenofibrate changed or discontinued in response to on CV endpoints. In this double 2x2 institution, it certainly had been and his “falsely” elevated creatinine on initiation factorial study, 5,518 patients (men and HDL level was clearly much below this of fenofibrate therapy. Indeed, from our women) with type 2 diabetes who were cutoff. At this, it seems that if there is table, our patient’s creatinine did increase being treated with open-label simvastatin going to be a clinical benefit with a fibrate, after the institution of fenofibrate and, were randomized to receive either masked it is going to be with gemfibrozil, not although other factors may have played a fenofibrate or placebo; all patients in the fenofibrate. role, the timing makes it fairly certain that study were also concurrently randomized at least some of the creatinine rise was to an intensive glycemic control arm A final consideration in this patient secondary to fenofibrate. n versus a standard glycemic control arm. with stage 3 CKD is the rise in serum The primary outcome in the lipid analysis creatinine associated with fenofibrate use, References listed on Page 45.

T cholesterol Triglycerides LDL HDL Non-LDL T chol/HDL Serum Cr (mg/dL) (mg/dL) (mg/dL) (mg/dL) (mg/dL) (mg/dL)

4/15/09* 184 334 89 28 156 6.6 2.2

10/29/09* 158 327 73 20 138 7.9 2.2

2/28/10* 123 143 67 27 96 4.6 2.0

3/16/10+ 94 88 51 25 69 3.8 2.1

3/24/10++ 89 140 46 15 74 5.9 2.0

5/15/10 112 127 61 26 86 4.3 2.9

*Lipid profile while on lovastatin 20mg +Admission fasting lipid panel, simvastatin 40mg then replaced with atorvastatin 80mg ++ Day of discharge, sent home on rosuvastatin 20mg and fenofibrate 67mg

Table 1. Patient’s fasting lipid panels and serum creatinine over the past year.

The Official Publication of the National Lipid Association 25 Case Study No. 2: Creatine Phosphokinase Elevations in African- American Patients

ADELA ROBINSON, RN, MN, NP, CLS Nurse Practitioner California Cardiovascular Institute Fresno, CA

to have other co-morbidities and are more aldolase, is present in . prone to because of the co- Although not as frequently used, morbidities. When lipid-lowering therapy measurement of aldolase may be useful (LLT) is necessary, this raises the potential when myopathy is suspected yet the CK Discuss this article at www.lipid.org for muscle injury secondary to drug-drug is normal.5 These muscle are Go to “Topics” and look for “Case Study No. 2.” interactions. Clinically this is aggravated used to evaluate whether muscle injury because of greater cardiovascular risk exists. Many things can elevate CK, present in African-American patients. including trauma, injections, physical Introduction exertion, seizures, neuromuscular disease, As we evolve in the science of lipidology, psychosis, etc. Medications and drug-drug unique characteristics of specific interactions are frequent causes of muscle populations begin to emerge. One of these injury. Differentiating any given cause of characteristics relates to the safe and muscle injury can present challenges in efficacious treatment of African-Americans clinical practice. This often prompts a risk/ patients with lipid therapy. It is well benefit assessment regarding continuation established that this patient group has of LLT. Table I presents a partial list of baseline elevated creatine phosphokinase medications that can cause myotoxicity (CK) greater than the upper limit of normal when used in conjunction with LLT. (ULN) compared to other ethnic groups.1, This patient group has the greatest overall 2, 7, 9 The reason for this difference is less coronary heart disease (CHD) mortality and An intuitive review of the partial list of clear. the highest out-of-hospital death than any medications in Table I alerts the healthcare other ethnic group in the United States. provider as to possible polypharmacy that Little data exists on this matter, and Proper use of LLT is essential. Much is at can coexist and should alert physicians there is little description as to its clinical stake when LLT is withdrawn because of to potential drug interactions leading to significance. While we do know that elevated CK levels. muscle injury, rhabdomyolysis and even African-Americans have elevated CK values death.11 compared to other ethnic groups,1 the Function of CK exact reason for this difference is not CK is a dimer that exists in serum as Prevalence of Elevated CK clear. three isoforms: MM (skeletal muscle), Brewster, et al. evaluated serum CK levels MB (cardiac and skeletal muscle) and in 1,444 individuals of white European, African-American patients are more likely BB (brain).4, 5 Another muscle , South Asian and African descent. to

26 LipidSpin all ethnicities. By age 85, CK levels were INHIBITORS OF CYPA4 LEADING TO INCREASED LLT CONCENTRATION similar in men and women across the AND TOXICITY board. Erythromycin Management of Elevated CK Once elevated CK levels are found in this population, the healthcare provider is HIV protease inhibitors Rifonavir faced with the decision as to whether to Immunosuppressive drugs Cyclosporine, Tacrolimus withdraw LLT or continue with a different or adjusted regimen. A fundamental tool to Cardiac drugs Verapamil, Amiodarone, Labetalol aid in the decision-making process is the clinical presentation of African-American Anticoagulants Warfarin patients. A challenge to this assessment Psychopharmacologics Fluoxetine, diazapam is a difference in terminology as it relates to muscle discomfort and LLT. An example Others Cimetidine, of this disparity is presented in Table 3, Table 1. Drugs and Toxins Causing Muscle Discomfort/Myopathy. from the viewpoints of the NLA related to Adapted from Klopstock, et.al., Curr Opinion Neurol. 2008. muscle and statin safeties, and are listed by Sathasivam and Lecky in the British determine normal CK reference limits. frequently can be concomitant with Medical Journal.9, 12 Patients with myopathy were excluded. elevated CK levels in African-Americans. They found that “62 percent of ‘healthy None of these hypotheses has been Ultimately, the healthcare provider people’ have CK activity at rest higher validated with scientific study. Finally, must rely on the patient’s description than the reported ULN.” This has led to methodologic and laboratory variations of symptoms (or lack of symptoms), and concept of “hyperCKemia,” which refers contribute to the confusion. reach a decision regarding continuation of to a “normal” baseline CK elevation, yet LLT. Until further research describes the not indicative of muscle changes.7 This Recently, Neal, et al., performed an significance of this elevated CK in African- group documented CK levels up to 4.6-fold analysis of data pooled from the ARIES, Americans receiving LLT, establishing higher in black men compared to the other IRIS and STARSHIP trials, several a threshold of acceptance of CK values ethnic groups.7 of which were “designed to include and/or symptoms can be discussed with ethnic minorities who were previously the patient, enlisting his or her aid in Theories of why this phenomenon occurs underrepresented in statin clinical trials.”2 identifying early changes in symptoms and include, but are not limited to: impaired These investigators found that median CK lab values suggestive of significant muscle activity of CY-P2D6 (which is encoded by levels were higher in African-American injury. an allele that is absent in white and Asian males and females when compared to populations), 6 or to greater expenditure white, Hispanic and South Asian ethnic Differing organizations regard the of energy associated with increased risk groups, even when adjusted for age monitoring of CK in all populations. The of hypertension.2 Skin pigmentation can (Table 2). Differences in CK between American College of Cardiology (ACC)/ also lead to D deficiency, which men and women decreased with age in

Racial/Ethnic Origin Men % Women % African-American 7.84 0.42 White 0.75 0.31 Hispanic 0.79 0.19 South Asian 0.95 0.26

Table 2. Distribution of Baseline Creatine Kinase More Than 3 Times the Upper Limit of Normal. From Neal, et. al., Am J Med (122), 1:2009.

The Official Publication of the National Lipid Association 27 SOURCE TERMINOLOGY DEFINITION Myalgia Muscle pain or weakness without elevated CK.

Myositis Muscle symptoms without elevated CK, typically <10 times ULN.

Rhabomyolysis Muscle symptoms with markedly raised CK , Sathasivam & Lecky typically >10 ULN,

Asymptomatic raised CK Elevated CK without muscle symptoms without muscle symptoms “hyperCKemia”

Myopathy Complaints of myalgia (muscle pain or soreness), weakness, and/or + elevation in McKenney, et al. serum CK >10XULN

Rhabdomyolysis CK >10,000 IU/L or >10X ULN + serum creatinine elevation or medical intervention with IV hydration therapy.

Table 3. Definitions of Muscle Discomfort from Separate Sources. From Sathasivam & Lecky, BMJ, 2008; & McKenney, et. al., JACC, 2006.

American Heart Association (AHA)/National Conclusion 3). When CK elevation is noted in Heart Lung Blood Institute (NHLBI) The treatment of lipid disorders in African- African-Americans on LLT, “reflex” Clinical Advisory recommendations Americans can lead to decision-making not withdrawal of LLT should be judiciously regarding CK surveillance in statin therapy well elucidated by available research. A considered, because of potentially differ from those of McKenney, et al., systematic approach for assessing whether serious cardiovascular consequences. and the NLA.12,13 Furthermore, these to withdraw or continue LLT in the recommendations do not adequately African-American patient has been offered. Further research is needed to validate represent African-Americans, because their this clinical approach towards safest inclusion in clinical statin trials has been Other considerations include: LLT management in African-American underrepresented. Consensus reached patients. Consensus regarding optimum by professional bodies in recommending 1). Remembering that lipid-lowering agents management of muscle discomfort and surveillance of CK in LLT, in the general are not always the cause of muscle injury related to LLT in African-Americans population as well as specific special discomfort; exercise or physical labor, is needed. n populations, will strengthen the clinician’s drugs, toxins and supplements can also ability to more accurately diagnose and induce muscle discomfort and injury. References listed on Page 45. manage this issue. 2). Healthcare providers for African– Until further research guides clinical Americans on polypharmacy should be practice, a proposed approach to decision- alert to the enhanced risk of myalgias making in this patient population is offered or muscle injury due to the potential for the reader’s review. synergistic effects of other medications and lipid-lowering agents.

28 LipidSpin Specialty Corner: Clinical Use of Pedometers in Cardiometabolic Risk Reduction Programs

RALPH LA FORGE, MSc, CLS Physiologist U.S. Indian Health Service – Diabetes Division Durham, NC Duke University Medical Center – Endocrine Division Durham, NC

The story is frequently recounted that There is compelling, comprehensive and Thomas Jefferson—often credited with consistent objective evidence that these are inventing the pedometer, although he proven cost-efficient tools that serve as a didn’t—wrote from Paris in 1786 offering stimulus for walking and an instrument for to buy James Madison one of the devices, individual goal-setting, self-monitoring and Discuss this article at www.lipid.org “Which shall render you an exact account real-time feedback.1 Go to “Topics” and look for “Clinical Use of of the distances you walk.” Two years later Pedometers.” Jefferson sent the pedometer to Madison. It is important to differentiate between According to the Smithsonian Institution, accelerometers, which are significantly blood lipid control and fat weight loss. it was 500 years ago that Leonardo da Vinci more expensive research tools in contrast Reliable and well-engineered step counters are reproducibly accurate and can be used actually designed and constructed the to simple step counters (pedometers). for most physical activities for which there first pedometer. Da Vinci’s notebooks, as Physical activity accelerometers measure is a stepping motion, such as walking or translated by Edward MacCurdy, describe steps but also measure other movement activities that involve movement of the a mechanism showing “how far one goes in forces (i.e., acceleration) usually in at trunk, hips and legs (i.e., stair-climbing, an hour.” least two axes. They also have been dancing, hiking, running, ball sports, etc.). shown to more reliably estimate energy Importantly, pedometers are not designed Circa 2010: There are more than 200 expenditure but are quite comparable to to detect physical activity intensity. manufacturers of pedometers. Most of well-constructed pedometers on recording However, pedometer output correlates the devices are little more than dollar- step counts. Accelerometers, with costs strongly with different accelerometers that store-variety low-durability “toys.” The ranging from $80 to more than $500, do collect time and intensity information in utilization of more reliable, better- are not cost-justified for routine clinical a blinded manner.1 engineered pedometers has gained much use. Well-constructed pedometers are research support in recent years for very reliable for recording step count, and In recent years, higher priced ($50- their ability to incentivize and measure step count is perhaps the most important $90) solid-state pedometers using a less physical activity, especially in preventive outcomes measure for most clinical expensive piezo-electric accelerometer cardiology and endocrinology programs. applications. Each intentional walking step component (i.e., New Lifestyles NL-800- Since 1999, more than 800 published and represents an insulin-sensitizing muscular 2000 series) rather than the standard peer-reviewed studies have demonstrated contraction (similar in mechanism to the spring-levered engine found in most the use of simple pedometers in primary diabetes drug metformin—Figure 1, that pedometers have been shown to be more and secondary prevention settings. contributes to improved insulin sensitivity, accurate in measuring step counts in obese

The Official Publication of the National Lipid Association 29 individuals, especially at slower walking speed threshold would be faster than and least accurate at measuring caloric speeds.2 necessary for shorter individuals, e.g., expenditure.5 Step count itself is the <5’7,” and perhaps slower than optimal primary outcome measure (in contrast to How many steps and how fast? for those taller than 6’2”—so height estimated distance or caloric expenditure) Consistent evidence supports that 30 and gait mechanics should be taken into for health care providers. Each intentional minutes of at least moderate-intensity consideration. walking step is a measure of the number walking is equivalent to ~3,000 steps in of large muscle group contractions, each adults. There is also evidence that a walking The number of daily steps generally of which is an insulin-sensitization process speed equal to 100 steps/min represents required for weight loss is considerably not unlike the of the lower boundary of moderate-intensity higher (>11,000 steps per day for men thiazolidinediones (PPARγ activation) walking for most adults. Indeed, to meet and >9,000 steps per day for women,4 and metformin, as both are AMP kinase current U.S. public health guidelines, than the step count required for overall activators (Figure 1). From a return visit individuals are encouraged to walk a cardiometabolic risk reduction, although clinical perspective—the number of minimum of 3,000 steps in 30 minutes the actual number of steps per day for large muscle group contractions, or the (~3 mph for most adults) five days each weight loss also depends on initial body step count, is the most relevant outcome week.3 Three bouts of 1,000 steps in weight and walking speed. measure. Estimated caloric expenditure and 10 minutes each day can also be used to distance walked are just that—estimates. meet the recommended goal. This walking For Optimum Cardiometabolic Well-engineered step-filtered pedometers speed, when maintained, is sufficient Fitness: do best with recording muscle contractions, to stimulate insulin sensitization among Similar to other forms of endurance which is the insulin-sensitizing PPAR- other cardiometabolic mechanisms that are exercise, insulin sensitization and activating activity we, as clinicians, really important in diabetes and cardiovascular related cardiometabolic benefits of should be measuring. disease prevention. Does this mean that walking are accrued when greater anything slower than 3,000 steps in metabolic loads are placed on the Overall Instructions for Providers: active muscle fibers. You have a choice 1. Clip the pedometer to your belt or (or combination) of two methods for waistband over the midline of one of your improving the insulin sensitization legs or in line over one of your feet. The of each walking step: incorporating a pedometer must fit upright and tightly circuit of hilly terrain and/or increasing to your waist (belt or waistband). For walking (muscle contraction) speed. Of some, when there is no belt or snug pant course, extending your walking time waistband, it may be best to fit it to the to >60 minutes at more moderate waistband of your underwear. speeds and grades can also add to the metabolic load. 2. New Lifestyles, Walk4Life and Accusplit are three companies selling more reliable It is important to note that for pedometers in the $15 to $25 range. patients who are obese or who have Recommended pedometers are ones that metabolic syndrome, prediabetes have been validated to accurately measure or diabetes, the relative increase or steps and have step filters. Step filters are change in daily or weekly step count built into the pedometer’s electronics and above their previous sedentary step reduce the recording of spontaneous and Figure 1. Step Count and Metabolic Benefits. count baseline is the most important fidgety movements. These pedometers 30 minutes is not clinically effective? exercise outcome parameter for are inexpensive, well engineered, and do Absolutely not, but at higher muscle- improving cardiometabolic health. not register most superfluous activities contraction loads and speeds there is going that are unrelated to more meaningful to be greater PPAR and AMPK activations, Step-count = Muscle Contractions = physical activity. Step totals can be used as which are key metabolic mechanisms that Primary Clinical Outcome Measures meaningful behavioral outcomes measures underscore cardiometabolic risk reduction. Pedometers are best at measuring step during 8- to 12-week return visits. It is also important to note that the 3 mph count, less accurate at estimating distance

30 LipidSpin 3. More expensive ($50-$90) solid state 6. Begin a walking program by adding or at least 10,000 steps a day. Several (piezo-electric) pedometers may better from 2,000 to 3,000 step counts (1 to 1.5 recent studies have reported =12,000 reflect step count in obese patients. In the walking miles) to your daily average from steps per day for significant weight loss.4 near future, the first true patient-affordable No. 3 above. For those individuals who have This step count includes all daily activity, clinical pedometer will be available. This been relatively sedentary, begin by adding a not just your walking program. Know also device will be the first affordable steps-only total of 1,000 to 1,500 steps per day (1/2- that the majority of studies indicates that pedometer that features a durable solid- 3/4 mile). significant weight loss requires =2,000 state, step-filtered engine and a long-term kcal per week of physical activity, which memory function that permits only the For example, if you averaged 4,500 step is equivalent to 18 to 20 miles of walking healthcare provider to reset and can display counts per day before you started your (actual caloric expenditure is dependent on total and average daily step count since the walking program, then for the next several body weight). Also understand that, even last clinic visit. weeks add 2,000 step counts to this average if you are not capable of attaining these so you are averaging relatively high weekly step counts, you from 6,500 to 7,500 step can still accrue significant cardiometabolic counts per day. Note that health benefits, including an improved for most people, ~2,000 glucose tolerance, lipoprotein profile and step counts, plus or minus blood pressure reduction. Several large ~200 step counts, equals a diabetes prevention studies demonstrated mile. Make every effort to 40 percent to 60 percent reductions in stay above the “sedentary diabetes risk with only modest weight loss lifestyle index” of <5,000 (Diabetes Prevention Program, DaGing steps (Figure 2).6,7 Diabetes Prevention Program, Finnish and Indian diabetes prevention studies). 7. After two to four weeks add another 2,000 9. Patients should record their daily and/or to 3,000 step counts to weekly step count in a log to be submitted Figure 2. Step Count Cutpoints. Source: Tudor-Locke C et al. 2004. your daily average so you to their cardiometabolic risk reduction are eventually averaging provider. Many pedometer models have 4. Most adults take from 1,800 to 2,200 10,000 or more steps per day on most days long-term memories and have the capacity steps per mile, depending on leg length, of the week. Remember that this 10,000 to store step totals over a 12- to 24-week height and walking style. The average is or more steps includes all daily step count period or longer. ~2,000 steps per mile. If you want to gauge activities, including your walking program. 10. Creative walking programs such as how many steps per mile you take, walk a This total step count should be adjusted to pedometer trekking are most helpful in measured mile (i.e., four laps in the inside each patient’s fitness level, health status instilling longer term use of pedometers. lane of a local quarter-mile track) and record and age. It is important to note that many Pedometer trekking programs are designed the step count. patients who are less ambulatory will have difficulty reaching 10,000 steps per day, in and measured over a series of local foot 5. Assess baseline walking steps. Measure which case the change in daily step count trails or courses that meet the age and and record how many steps taken in a is a more appropriate outcome measure. fitness levels of the community involved. single day and then over the course of a full For example, a patient whose baseline Course distances ranging from 0.5 of a week before starting a program. Start by step count is 3,800 per day and after six mile to 8–10 miles (i.e., 1,000-20,000 putting the pedometer on in the morning, weeks is averaging 7,500 steps per day has steps) are validated by standard pedometer reset to 0, and forget about the pedometer a significantly positive improvement in both measurement. Activities along the trek for the entire day. When retiring for the walking endurance and insulin sensitization. can be added specific to the community or evening, take the pedometer off and record cultural heritage. E-mail [email protected] the number of steps you have accumulated 8. When using pedometers for monitoring for more detailed instructions on pedometry during the course of the day. Repeat this physical activity for weight loss purposes, trekking. n for 5 to 7 days to determine your daily the overall goal is to eventually record from average. 70,000 to 90,000 step counts per week, References listed on Page 45.

The Official Publication of the National Lipid Association 31 PLA Chapter Update: Prescription Fish Oil and Blue Cross of Idaho

J. ANTONIO G. LóPEZ, MD, FACC, FAHA, FACP, FCCP, FNLA Director, Preventive Cardiology and Cardiovascular Rehabilitation Saint Alphonsus Regional Medical Center Boise, ID Director, Telemetry and Heart Failure Saint Luke’s Regional Medical Center Boise ID

MATTHEW K. ITO, PharmD, FCCP, FNLA, CLS Professor of Pharmacy Practice Oregon State University/Oregon Health and Science University Portland, OR

counter fish oil product to treat your high dL) require effective treatment because cholesterol.”1 On June 17, 2009,2 the PLA they are associated with the development immediately retorted and requested that of , diabetes mellitus and Discuss this article at www.lipid.org Blue Cross of Idaho reinstate Lovaza.® cardiovascular disease. Successful Go to “Topics” and look for “Chapter Update.” The PLA affirmed that Lovaza® is the treatment of very high triglycerides only prescription omega-3 oil available in requires a highly concentrated and pure the United States and that there are no product such as Lovaza® with its strong The Pacific Lipid Association (PLA) recently “over-the-counter” omega-3 preparations. concentration of omega-3 fatty acid (900 challenged Blue Cross of Idaho in its The PLA further clarified that dietary mg per 1 g capsule). In contrast, dietary pronouncement to eliminate prescription supplements are the only other source of supplement fish oil contains a high fish oil from its formulary. In a letter dated omega-3 products and are not approved percentage of non-omega-3 material such May 11, 2009, Douglas Dammrose, MD, by the U.S. Food and Drug Administration as saturated fat, cholesterol and possibly senior vice president and chief medical (FDA) to treat, prevent or cure any disease. environmental contaminants including officer for Blue Cross of Idaho, declared Moreover, omega-3 products are indicated pesticides and heavy metals. Furthermore, that, effective July 1, 2009, Blue Cross of for very high triglycerides – not for the there are no head-to-head studies showing Idaho would no longer provide prescription treatment of high cholesterol. Prescription comparability or equivalence of dietary drug benefit coverage for Lovaza® (omega-3 Lovaza® is the only omega-3 product supplement fish oil with prescription acid ethyl esters). Dr. Dammrose stated properly purified, tested and indicated for omega-3. Finally, a full dose of 4 g per day to Blue Cross customers that “… in an the treatment of any lipid disorder. of 90 percent pure prescription omega-3 is attempt to conserve your healthcare required for adequate triglyceride lowering dollars we recommend choosing a more The PLA letter explained that very high while, because of lowered purity, higher cost effective, equally efficacious over-the- triglyceride levels (greater than 500 mg/ doses of dietary supplement fish oil are

32 LipidSpin required to deliver an adequate amount of omega-3 (total DHA and EPA). Thus, in Fish Oil Q & A place of four capsules per day of dietary What is the source of omega-3 fatty acids? supplement fish oil as recommended by Blue Docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), and αlpha-linolenic Cross of Idaho, from six to 16 capsules per acid (ALA) are the most common omega-3 fatty acids. These fatty acids are day would be required as an equivalent dose not synthesized by humans and must be obtained from dietary sources. DHA of omega-3. Such a high dose is not feasible and EPA are obtained from fish oils. Fish do not naturally produce DHA and for long-term use and is likely to reduce EPA. They obtain these omega-3 fatty acids through the ocean food chain the patient’s adherence, which is inversely originating from marine .1 The amount of DHA and EPA per proportional to the number of pills the gram of fish varies by the species, location, and whether the fish is farmed 3 patient must take. Furthermore, the FDA or wild. Fish oils are derived from the tissue of fatty fish and then processed itself has advised that patients not consume in a variety of ways to manufacture dietary supplements or prescription more than 2 g per day of dietary fish oil omega-3 fatty acids. Environmental contaminants that were in the fish to 4 supplements. begin with will remain unless further purification processes are used that also help to concentrate the omega-3 fatty acids. ALA is derived from plant The PLA declared it was medically and sources such as leafy vegetable, nuts, canola and flax seed oils. However, the ethically inappropriate for Blue Cross of effects of ALA on the reduction of triglycerides in humans is minimal, likely Idaho to direct patients to oppose FDA because negligible amounts of ALA are converted to EPA and DHA.2 recommendations and circumvent the only established and approved omega-3 product What are the differences between prescription omega-3 fatty acid ethyl in the treatment of very high plasma or esters and dietary fish oil supplements? serum triglycerides levels. As lipid experts Prescription drugs and dietary supplements are not manufactured and and advocates for our patients, the PLA produced by the same set of FDA regulations. Prescription omega-3 fatty acid strongly urged Blue Cross of Idaho to restore ethyl esters are mandated by the FDA to meet or exceed standards for quality prescription omega-3 to its formulary as a and consistency. The FDA’s current good manufacturing practices (CGMPs) 2 requirement for good medical practice. for human pharmaceuticals assure the identity, strength, quality and purity In response, Dr. Dammrose stated that of pharmaceutical products by requiring that manufacturers of medications the Blue Cross of Idaho Pharmacy and adequately control manufacturing operations.3 The purification process for Therapeutics Committee established its manufacturing prescription omega-3 fatty acid ethyl esters used to meet 5 decision on evidence-based medicine. It the CGMPs nearly eliminates environmental contaminants, cholesterol ® was the committee’s opinion that Lovaza and trans fatty acids.4 Currently, manufacturers of dietary supplements are had insufficient evidence because of lack of regulated under the CGMPs used for food products, which only regulate quality cardiovascular morbidity and mortality the preparation, packing and holding of dietary supplements under safe data. He further argued that there is no conditions. Thus, the quality and quantity of the ingredients varies widely data to support clinical differences between between manufacturers, and there is no guarantee that what’s on the label ® Lovaza and omega-3 fatty acid supplements. is what’s in the bottle. Finally, unlike prescription omega-3 fatty acid ethyl A follow-up letter from PLA on September esters, manufacturers of dietary fish oil supplements do not have to prove 19, 2009, to Blue Cross of Idaho stated that the safety and effectiveness of their products before they are marketed. we are in strong disagreement with excluding 6 Lovaza from the formulary. How can I ensure my patient is getting a higher-quality dietary fish oil supplement in cases where I can’t prescribe prescription omega-3 fatty ® The U.S. FDA has approved Lovaza at a acid ethyl esters? dose of 4 g a day for treatment of very high The United States Pharmacopeia (USP) is a non-governmental, official public ® triglyceride levels. Lovaza is a standardized standards-setting authority for prescription and over-the-counter medicines preparation with FDA-approved safety and and other healthcare products manufactured or sold in the United States. efficacy and the most concentrated source USP sets standards for the quality, purity, strength and consistency of of DHA and EPA available. There is no other these products – standards critical to the public health.5 In 2001, the USP fish oil product approved by the FDA for the PLA Chapter Update (continued on next page) treatment of very high triglycerides levels.

The Official Publication of the National Lipid Association 33 Prescription products are appropriate for treating diseases. Dietary supplements Fish Oil Q & A continued are not FDA-approved to treat, prevent or launched a dietary supplement verification program. The voluntary testing and cure any diseases. There have been many auditing program helps dietary supplement manufacturers ensure the production of reports of adverse events stemming from quality products for consumers. The verification process consists of comprehensive the use of dietary supplement fish oil laboratory testing of dietary supplement products and their ingredients against through the FDA Center for Food Safety and dietary supplement standards found in the USP National Formulary, review of Applied Nutrition (FDA/CFSAN) Adverse manufacturing and quality control documents, an on-site manufacturing facility Event Reporting System (AERS). The PLA audit for compliance with USP standards and FDA CGMPs, and random off-the- feels that it was medically and ethically shelf testing to confirm that USP-verified products continue to meet USP’s strict unsound and, moreover, inappropriate to standards. Products awarded the USP-verified mark help to ensure product purity, let the patient pursue this, contrary to FDA consistency and that what’s on the label is what’s in the bottle.6 However, to date, recommendations and circumventing the very few dietary fish oil supplements have been awarded the USP-verified mark.7 only established and approved omega-3 product for treatment of high triglycerides On June 22, 2007, the FDA announced a final rule establishing dietary supplement levels. Lovaza® continues to remain off the CGMPs requirements, which will require manufacturers to evaluate the identity, formulary of Blue Cross of Idaho. purity, quality, strength and composition of their products. This new rule has been phased in and the mandatory requirements took effect in June 2010.8 These The Question and Answer section reviews requirements will add another level of confidence about the quality of dietary three important questions we feel clinicians supplements. and patients should understand when choosing omega-3 fatty acids. n —Matthew K. Ito, PharmD —J. Antonio G. López, MD References listed on Page 45.

34 LipidSpin In Memoriam: Robert H. Knopp, MD

Dear Colleagues, He was an enthusiastic and influential the American Diabetes Association, the teacher of students, residents, and fellows, Meritorious Service Award of the American I am saddened to announce that Robert as well as mentor for scores of postgraduate Heart Association of Washington, the H. Knopp, MD, the Robert B. McMillen scholars. He was particularly active in Harborview Cares Award, and numerous Endowed Professor in Lipid Research in the nutritional education for medical students other honors. Department of Medicine, died in Seattle on and trainees. Sunday, May 30, of leukemia. He was 72. In 2008, Dr. Knopp was named first Dr. Knopp published more than 350 holder of the Robert B. McMillen Bob Knopp was an scientific papers and chapters and was Professorship in Lipid Research at UW accomplished physician, a prominent investigator of the effects Medicine. Mr. McMillan was a patient a dedicated teacher, of diet, , and lipid-lowering of his and a longtime supporter of UW and a prodigious medications on plasma lipoproteins; the Medicine. A month ago the Society for scholar who made prevention of coronary artery disease and Experimental Biology and Medicine major contributions diabetes; therapy for dyslipidemia and the honored Dr. Knopp with an inaugural in the field of lipid metabolic syndrome; use of ultrasound Distinguished Scientist Award for seminal metabolism and to diagnose atherosclerosis; endocrine research accomplishments and significant related disorders. He was a member of our disorders in pregnancy; and many other contributions to the society. Division of Metabolism, Endocrinology and areas. Nutrition for 36 years and section head at Bob Knopp was indefatigable in his service Harborview for the past 17 years. He was Perhaps his most prominent role was that to his profession, his department, and his also an adjunct professor of obstetrics and of director of the Northwest Lipid Research university and was a beloved friend to his gynecology. Clinic at Harborview, a position he held patients, trainees and colleagues. from 1978 until his death. The clinic A New York native and graduate of Colgate is a leading national center of care and Dr. Knopp is survived by his wife, Judith University and Cornell University in diabetes, lipids, cardiovascular Knopp, and daughters, Elizabeth and College, Dr. Knopp interned at Boston City disease, and related issues of prevention Eleanor. Hospital before completing a residency and and treatment. He also directed the Clinical research fellowship in endocrinology and Research Core of the UW Clinical Nutrition Remembrances can be made to the metabolism at Northwestern University. Research Unit. McMillen Research in Medicine Fund to Following that he served in the Diabetes support the Northwest Lipid Research and Arthritis Field Research Unit of the He was a fellow of the American Clinic, or to St. James Cathedral. U.S. Public Health Service and then joined Association for the Advancement of the faculty of Harvard Medical School. Science and of the American College of With best wishes, He came to the University of Washington Physicians, a past president of the Society William J. Bremner, MD, PhD in 1974 and was an attending physician for Experimental Biology and Medicine, Professor and Chair at Harborview Medical Center for the and a board member of the National Lipid The Robert G. Petersdorf remainder of his life. His many leadership Association, among many other national Endowed Chair in Medicine roles at Harborview included director of and local leadership positions. He received University of Washington Medical Specialties Clinics and of the Lipid the Lester R. Sauvage Hope Heart Award, Seattle, WA Atherosclerosis Prevention Clinic. the Distinguished Service Citation of

The Official Publication of the National Lipid Association 35 News and Notes

NLA Virtual Lipid ClinicTM on XM This year’s update will include sessions NLA Career Corner Radio’s ReachMD Program on sharpening risk prediction using We recently unveiled our new online biomarkers, lipid testing and imaging Career Corner, which features job and modalities, an epidemiology perspective candidate listings. Free postings are on the JUPITER Trial, treating diabetic available for NLA members, who can access dyslipidemia, and lipid management in the Career Corner by going directly to special risk populations. www.lipid.org/about/careers. To submit NLA members can help two virtual patients a Career Corner posting, please e-mail Amy navigate a complex medical world and In addition to the tremendous educational Waller at [email protected]. receive CME credit thanks to a ReachMD opportunities provided, this conference podcast focusing on the Virtual Lipid also offers participants an opportunity to Clinic. Virtual patients Howard and Joseph check out the incredible cultural offerings are discussed by Drs. Alan Brown and of Washington, DC For more information, Peter Jones for the program, “Scenes from check out www.lipid.org/summerCLU. NLA members can access summaries and the Lipid Clinic,” available on XM Radio’s slides with audio from Annual Scientific ReachMD continuing education website at Strategic Recommendations Approved Sessions for the following four programs www.reachmd.com/cme. This program also Recommendations made by the Strategic at www.lipid.org/highlights: is available on the ReachMD MedicalRadio Planning Committee at the March meeting · Keynote Address: Mechanisms of iPhone application. in Austin were approved by the NLA Board Atherogenesis and Plaque Regression of Directors at our annual meeting. To Ira Tabas, MD, PhD CME-certified case management activities learn about future initiatives for the NLA, · Atherosclerosis Imaging Debate: TM also are available in the NLA vClinic please visit our online policy page at CAC vs. CIMT at www.lipid.org/vclinic, where NLA www.lipid.org/policy. Anthony C. DeFranco, MD, and members can work-up and manage virtual Donald Lloyd-Jones, MD patients who present cases similar to those Lipid University™ Launches found in clinical practice. The NLA and the ACCL recently joined · Diet Debate: The Mediterranean Diet forces to launch Lipid University™ vs. Low Carbohydrate Diets 2010 NLA Summer CLU to provide comprehensive, in-depth Penny Kris-Etherton, PhD, RD, and Lipid management professionals will instruction on lipid science for medical Paul Jacques, MD not want to miss this year’s Summer sales professionals to better understand · Controversy: and LDL Clinical Lipid Update, which will feature the pathophysiology of dyslipidemia Lowering expert thought leaders discussing the and atherosclerosis, and also the risk W. Virgil Brown, MD, and “Intermediate Risk Patient” at a joint assessment models that influence clinical Steve Nissen, MD meeting hosted by the Southeast and decision making. After this course, Northeast chapters of the National Lipid representatives will test their clinical Slides for additional programs Association. Come learn the latest lipid competency in a Level II proctored exam presented at Annual Scientific Sessions science and methods for applying it to your administered by the ACCL at testing are available online at www.lipid.org/ clinical practice while earning as many as centers. In August, more than 400 Abbott highlights. 27 continuing education credits through Laboratories employees will attend Lipid pre-conference courses. University™ at one of six U.S. sites.

36 LipidSpin Education and Meeting Update

training in conjunction with the August Screening and Treating Familial 26–27 meeting, held in Washington, DC. Fellows also will be invited to a “mentoring Familial Hypercholesterolemia (FH) took session” with board members and program center stage at Annual Scientific Sessions faculty, and will receive a $500 travel during a special symposium chaired by grant to help offset their expenses. For Drs. Mary McGowan and Paul Hopkins. more information, e-mail Sandra Goode at Opening remarks were made by Katherine [email protected]. Wilemon, an FH patient living in Northeast Florida. Co-sponsored by MEDPED (Make Highlights from the Third Annual Early Diagnosis to Prevent Early Death) Focus on Your Education in the Capital Summit on HDL Therapeutics and the Foundation of the NLA, the Limited space is available to participate in The NLA teamed up with Medscape presentation underscored the importance the ancillary courses that will be offered and theheart.org to produce two online in conjunction with the Summer CLU activities as a continuation of the Third meeting in Washington, DC. Annual Summit on HDL Therapeutics, which took place in May at the Annual These courses are part of the NLA’s Scientific Sessions in Chicago. Contributing Professional Development Pathway for faculty included program chairs Drs. Peter healthcare professionals seeking to advance Toth and Michael Davidson alongside their competency in managing lipid a panel of renowned HDL experts. Stay disorders. tuned for more details and watch out for the Journal of Clinical Lipidology, which will discuss the HDL Summit proceedings in an upcoming issue. Katherine Wilemon, an FH patient, and her daughter, Ella. She talks about her patient experience in a new NLA Goes Global video. Due to the success of our educational of FH as a key public health initiative for Our program consists of five gradual levels programs and the growing need for our organization. To learn more about that address approved core competency lipid education, the NLA was asked to the foundation’s projects related to this areas in both live and online instruction offer our programs internationally. Our disorder, visit us online at formats. For more information about any first partnership with the Australian www.lipidfoundation.org. aspect of the Professional Development Atherosclerosis Society will bring our Pathway, check out www.lipid.org/ Masters in Lipidology™ Course to the In a new video about her patient education/pathway. Asia Pacific Society for Atherosclerosis experience, Ms. Wilemon said that and Vascular Disease this fall. Our second partnering with the NLA provided her with Fellows Invited to Attend the Lipid collaboration will take place in Bangalore a once-in-a-lifetime opportunity to spread Management Training Course and Mumbai for a “Best of the NLA awareness about the challenges of living The NLA will offer complimentary Lipid Conference” in which the NLA will share with FH. Look for highlights from the FH Management Training Course (LMTC) and some of our most popular presentations Symposium at www.lipid.org/highlights in Summer CLU registration to fellows-in- with top cardiologists in India. September.

The Official Publication of the National Lipid Association 37 Annual Scientific Sessions: Highlights Online

Read highlights and slides from Annual resistance, oxidant stress, homocysteine, MerTK cleavage in coronary lesions may Scientific Sessions at www.lipid.org/ oxidized lipids, and saturated fatty acids. be caused by the same NADPH-mediated highlights.The following write-up on the A key effector of macrophage apoptosis oxidative burst in the ER stress/PRR pathway presentation by Ira Tabas, MD, PhD, is an caused by prolonged ER stress is CHOP, that leads to macrophage death. As a result, example of the highlights available. Please a transcription factor involved in a branch cleaved soluble MerTK could potentially be see page 36 for additional highlights which of the UPR. ER stress and CHOP trigger used as a biomarker for CAD. include slides and audio from the meetings. intracellular calcium release and CaMKII activation, which triggers a number of Dr. Tabas hopes that this new research Mechanisms of Atherogenesis and apoptotic pathways including NADPH into the “vulnerable plaque” will result Plaque Regression oxidase. This then increases cell oxidant in development of a “rational, specific, In his keynote address to open this year’s stress, which amplifies, via a positive mechanism-based anti-plaque necrosis NLA conference, Dr. Tabas feedback cycle, the CHOP-ER stress therapy” that will provide ACS patients reviewed current research pathway. However, CHOP is not alone with early protection against future into the reasons why 2–3 triggering apoptosis, Dr. Tabas explained. It events. For example, suppressing ER stress percent of apparently probably combines with other toxic events has been demonstrated with chemical benign atherosclerotic as the first hit in a “multihit” model of cell chaperones, and it might be possible to lesions progress to high-risk death. Tabas and colleagues have identified inhibit oxidant stress more specifically (“vulnerable”) plaques, and reported on the 2 pairs of cell-surface pattern recognition with an NADPH inhibitor, Dr. Tabas latest thinking that plaque necrosis, caused receptors (PRRs)—type A scavenger speculated. On the other hand, blocking by the combination of macrophage apoptosis receptor together with toll-like receptor 4 apoptosis might result in an increased and defective efferocytosis (phagocytic (SRA-TLR4) and CD36-TLR2—that interact number of living macrophages, which could clearance of the apoptotic macrophages), with atherogenic lipoproteins to increase also promote development of vulnerable has been found to be a critical process in oxidant stress and decreases cell survival plaque. Enhancing efferocytosis would not this progression. signaling. only prevent post apoptotic necrosis and inflammation, but also decrease macrophage One cause of macrophage apoptosis in Dr. Tabas also revealed that recent research content. A number of well studied advanced plaques is endoplasmic reticulum by his group suggests that Lp(a), a major molecules and processes have been shown (ER) stress. According to Dr. Tabas, carrier of oxidized lipids in the blood and to enhance efferocytosis, including lipoxins, “This is not the only way macrophages probably a causal risk factor in CHD, may be PPARγ/δ activators, lipoxins, MerTK die in advanced plaques, but we think it the second hit for macrophage apoptosis. cleavage inhibitors, myeloid subsets, and is a very important one.” Normally stress IL-10. “All of these represent ways to boost leads to the induction of proteins that Defective efferocytosis, which is only what is truly defective in these advanced maintain ER homeostasis, through a signal present in advanced atherosclerotic lesions, lesions, which is defective inflammation transduction pathway called the “unfolded is not caused by macrophage death alone, resolution,” Dr. Tabas suggested, but he protein response” (UPR). Under pathologic Dr. Tabas explained. Another mechanism also cautioned that “none of this will work conditions, however, ER stress is not involves MerTK, a transmembrane receptor without lowering apoB lipoprotein as well.” corrected and becomes a prolonged event. that is susceptible to “sheddase”-mediated Many inducers of prolonged ER stress have cleavage under certain conditions, leading —Linda Brookes, MSc been identified in advanced , to failure of efferocytosis. Dr. Tabas’ group including lipoprotein-cholesterol, insulin have recently shown in human tissue that

38 LipidSpin Foundation Update

Our Contributors Foundation Events We greatly appreciate your interest and About the Foundation of the NLA contributions. Because of your support, we The Foundation of the National Lipid are advancing knowledge and awareness of Association is the NLA’s charitable lipidology and have raised nearly $30,000 arm and is charged with serving as an for our grant program. educational and research organization, with an emphasis on serving Our thanks go to the following founding professional, community and public contributors, who made donations of The Foundation hosted a run to remember health interests. $1,000 or more, and we hope you will join at the Annual Scientific Sessions in them in supporting your Foundation. Chicago in May, when more than 25 Since its inception in December participants took part in our inaugural 5K 2008, the Foundation’s primary focus Founding Donors event on a brisk Saturday morning. The has been on generating awareness Thomas Bersot, MD, PhD route from the Sheraton Hotel & Towers of its grant program and identifying Alan Brown, MD to the Navy Pier gave runners and walkers relevant, meaningful public awareness W. Virgil Brown, MD a glimpse of the city and an opportunity to opportunities. Replenishing the grant Mr. and Mrs. Eliot Brinton, MD support a great cause. program is essential to the future Michael Davidson, MD viability and health of our organization, Thomas Dayspring, MD and we need your help to make it Genzyme Corporation happen. Come together with your NLA Anne Goldberg, MD colleagues and support this unique Robert Harner, MD program by making a donation that Linda Hemphill, MD will support professional outreach and Ralph La Forge, MSc education related to lipidology and Mary McGowan, MD critical issues in public health. Carl Orringer, MD Provident Clinical Research Please join with us in our mission of Eli Roth, MD research and awareness in cardiovascular Carl Rubenstein, MD diseases by making a contribution today: Joseph Saseen, PharmD • Log onto www.lipidfoundation.org Neil Stone, MD and click on the “Donate to the Foundation” link; Mr. and Mrs. James Underberg, MD Later that day, NLA members joined forces Kevin Winfield, MD at Carnivale to attend an exceptional • Call (904) 309-6212 and ask G. Russell Warnick, MS evening of dancing and dining to benefit for Katie Smith, Foundation C. Michael Wright, MD the Foundation. The gala fundraiser Coordinator; included more than 125 guests feasting on • Mail your donation to For a full list of all contributors, please visit Nuevo Latino cuisine and getting down to Foundation of the NLA the “Donor Honor Roll” online at the sounds of This End Up, a band led by 6816 Southpoint Pky, Ste. 1000 www.lipidfoundation.org/donors. the NLA’s very own Dr. Alan Brown. Jacksonville, FL 32216.

The Official Publication of the National Lipid Association 39 Honors and Recognition: NLA Young Investigator Award

Seven aspiring researchers participated in NOM risk assessment. The lipid p=0.03) were independent predictors in this year’s NLA Young Investigator measures considered were conventional of NOM. Other significant multivariate competition at Annual Scientific Sessions lipid measures (total cholesterol [TC], predictors were baseline urine albumin in Chicago. LDL-C, HDL-C, triglycerides [TG], non- excretion, anti-hypertensive therapy, age HDL-C) and individual lipid ratios (TC/ and the presence of diabetes mellitus. Palaniappan HDL-C, LDL-C/HDL-C, TG/HDL-C). Cox On evaluating the receiver operation Manickam, MD, proportional hazards model was used to characteristic curves, TG/HDL-C ratio had a from Wayne University adjust for significant risk predictors (Table higher C statistic compared to TC/HDL-C. in Detroit, Mich., took 1). Performance of the predictive model In addition, the performance measures of home an award plaque was assessed using the discrimination and the predictive model with TG/HDL-C were and $500 after capturing calibration statistical measures. superior to the model with TC/HDL-C the Young Investigator ratio. Award for his abstract, Results: Mean age was 65±10 years; 45% Prognostic Utility of Lipid Parameters in were males, 32% were diabetic and 75% Conclusion: In our large population- Prediction of New Onset Microalbuminuria were on anti-hypertensive medication. based cohort, TG/HDL-C ratio is a in Hypertensive Patients. Over a mean follow-up of 4 years, 266 powerful independent predictor of NOM (12%) developed NOM. On multivariate in hypertensive patients. Early aggressive Synopsis: Microalbuminuria has been analysis, TC/HDL-C ratio (HR: 1.74, 95% lipid intervention might delay the onset recognized as a potential marker of CI: 1.09 to 2.77, p=0.02) and TG/HDL-C of microalbuminuria in this subset of future cardiovascular disease (CVD) in Ratio (HR: 1.25, 95% CI: 1.03 to 1.53, population. hypertensive patients. Comparative data P C Likelihood Area under HR (95% CI) † AIC|| Calibration# on the prognostic utility of conventional value Index‡ ratio§ ROC curve** lipid parameters in predicting new Individual Variables onset microalbuminuria (NOM) in TC (mg/dL) 1.02 (0.97 to 1.06) 0.63 0.74 155.3 1392 8.7 0.52 hypertensives is scant. HDL-C (mg/dL) 0.90 (0.81 to 1.01) 0.06 0.74 158.5 1389 8.8 0.57 LDL-C (mg/dL) 1.03 (0.98 to 1.07) 0.25 0.74 155.7 1391 6.6 0.51 Purpose: To identify risk factors in the TG (mg/dL) 1.01 (0.99 to 1.03) 0.21 0.74 156.2 1391 7.0 0.55 lipid profile associated with NOM in Non-HDL-C (mg/dL) 1.03 (0.99 to 1.07) 0.13 0.74 156.3 1391 6.9 0.49 normoalbuminuric hypertensives. Lipid Ratios

TC/HDL-C 1.74 (1.09 to 2.77) 0.02 0.74 159.5 1387 10.2 0.55

Methods: Multi-Ethnic Study LDL-C/HDL-C 1.42 (0.99 to 2.02) 0.06 0.74 157.7 1389 7.2 0.54 of Atherosclerosis (MESA) is a TG/HDL-C 1.25 (1.03 to 1.53) 0.03 0.74 160.0 1387 6.8 0.57 population–based study (n=6,814) Abbreviations: CI, confidence interval. AIC: akaike information criteria; ROC: receiver operating characteristics; HDL-C: high density lipoprotein-cholesterol. of subjects aged 45–84 years, free * All estimates are by Cox proportional hazards analyses adjusted for age, gender, race, systolic and diastolic blood pressure, antihypertensive treatment, fasting glucose levels, diabetes mellitus, use of insulin, oral hypoglycemic use, HbA1c, waist to hip ratio, baseline urinary albumin excretion and baseline from clinical CVD. We did a post-hoc creatinine. †HR values reported are for a 10-unit increase of the individual lipid parameters and per 1 unit increase of the lipid ratios. analysis of the NHLBI limited access ‡C index indicates the power of discrimination (higher values indicate better discrimination). §Likelihood ratio of χ² statistics from the Cox model (higher values indicate a better fit of the predictive model). dataset of MESA subjects including || AIC is a measure of the goodness of fit of the predictive model (lower values indicate a better fit). #Calibration estimates using modified Hosmer-Lemeshowχ ² statistics (lower values < 20 indicate better calibration). normoalbuminuric hypertensive patients ** C statistics determined by ROC curve for individual lipid measure without any additional covariates in predicting new onset microalbuminuria. (n=2,328) to determine the predictive Table 1. Incidence of new onset microalbuminuria according to conventional and novel lipid parameters during value of various lipid parameters follow-up with discrimination and calibration estimates.*

40 LipidSpin New NLA Members Elizabeth Yellen, MD: Brookline, MA Rory Priester, MD: Duluth, GA Frances Zappalla, DO: Wilmington, DE Wade Rankin, DO: Augusta, KY The NLA welcomes the following new Andrew Rhinehart, MD: Bristol, VA members to our organization. Southeast Lipid Association Melvin Ross, MD: Pembroke Pines, FL Lesa Abney, RN: Nashville, TN Luis Ruiz-Rivera, MD: Ponce, Puerto Rico Northeast Lipid Association Anita Airee, DPH: Knoxville, TN Chandra Sajja, MD: Leonardtown, MD Sherley Abraham, MD: Astoria, NY Serge Alexandre: MD, Boca Raton, FL Uchechukwu Sampson, MD: Nashville, TN Sirtaz Adatya, MD: Hartford, CT Jim Arter, MD: Cramerton, NC Sanjay Sarin, MD: Peachtree City, GA Mitchel Alpert, MD: Brick, NJ Geri Aucoin-Behre, NP: Lady Lake, FL Terry Sensing, RN: Madison, MS Bhakti Arondekar, PhD: Philadelphia, PA Phillip Bale, MD: Glasgow, KY Sara Seyal, BSN: Prospect, KY Laurie Beall, NP: Penfield, NY Sridhar Banuru, MD: Henderson, KY Savitha Shama, MD: Johns Creek, GA Michael Bernstein, MD: Slingerlands, NY Walid Barbour, MD: Baltimore, MD Tyson Shelton, PA-C: Hope Mills NC Stephen Bielecki, BS: Maple Glen, PA Dennise Bassetti, MD: Avon Park, FL Mohan Shenoy, MD: Louisville, KY Lana Borno, PharmD: New York, NY Aimee Bert-Moreno, RD: Orlando, FL Marcus St. John, MD: Miami, FL Andrew Bostom, MD: Providence, RI Hetal Bhatt-Chugani, PharmD: Palm Harbor, FL John Starr, MD: Roanoke, VA Craig Brett, MD: Cape Elizabeth, ME Roy Blank, MD: Fort Mill, SC Sallyann Storer, Fayetteville, TN Philippe Brudi, MD: Whitehouse Station, NJ Cindy Bosch, ARNP: Sarasota, FL Anne Sumner, MD: Bethesda, MD Anthony Carlino, MD: Scotch Plains, NJ James Boyd, MD: Leonardtown, MD Susan Taylor, MS: Raleigh, NC Katia Celifie: East Stroudsburg, PA Gregory Brewer, MD: Knoxville, TN Kelli Tidwell, MSN: Knoxville, TN Preston Collier: North Wales, PA Linwood Brown, BA: Olive Branch, MS Regina Wang, MD: Norcross, GA Kacie Cook, RD: Rochester, NY Barbara Cappabianco, ARNP: Altamone Springs, FL Tammy Whitehead, ARNP: Berea, KY Indranil Dasgupta, MD: Philadelphia, PA Karon Champlin: London, KY Carla Yong, MT: Spring Grove, VA Laurie Ann Dicorcia, NP: Midland Park, NJ Sarah Clauss, MD: Bethesda, MD Andres Digenio, MD: Bridgewater, NJ Lucian Cousins, MD: Columbus, GA Midwest Lipid Association Mary DiGiulio, MS: Oradell, NJ Arthur Cromartie, MD: Hattiesburg, MS Gauray Agarwal, MD: Valparaiso, IN Colleen Eannarino: Washington, PA Karen Curzio, PharmD: Atlanta, GA Mahtab Ahmed, MD: Paulding, OH Maureen Franco: Cambridge, MA Paul Daugherty, MD: Hendersonville, TN Hardeep Ahuja, MD: Menomonee Falls, WI Jennifer Fleming, RD: University Park, PA Catherine Dunton, PA-C: Cape Canaveral, FL Imran Ali, MD: Willow Springs, IL Samuel Gidding: Wilmington, DE Steven Dzama: Fayetteville, NC Darcey Amundson, PA-C: Sun Prairie, WI Kathleen Grady, ANP: Hempstead, NY Lisa Funston, NP: Cataula, GA Sameer Ansar, MD: Dundee, IL Evelyn Haberl, APRN: East Amherst, NY La Nora Glaze, RN: Pensacola, FL Issam Asad, MD: West Bloomfield, MI James Harris, ARNP: Derry, NH Avantica Gondi, MD: Lakeland, FL Lillard Ashley, MD: Prairie Village, KS Lisa Hudgins, MD: New York, NY Donald Gordon, MD: Trussville, AL Jane Beato, FNP: St. Louis, MO Rae-Ellen Kavey, MD: Rochester, NY Clarissa Gregory, ARNP: Miami Beach, FL Jean Berry, APNP: Chicago, IL Andrea Kershaw, NP: West Newbury, MA Larry Grogan, PharmD: Greer, SC Nicole Bhave, MD: Chicago, IL Elissa Kim-Adatya, MD: Hartford, CT A-Hamid Hakki, MD: Clearwater, FL Jackie Boucher, RD: Minneapolis, MN Eileen Klein, MD: Berkeley Heights, NJ Ashraf Harahsheh, MD: Washington, DC Melissa Browning, CNP: Marion, OH Lisa Kozlowski, MD: Williamsville, NY Tashia Harmon, ARNP: Pikeville, KY Brian Burke, MD: Dayton, OH Carol Locke, MD: Waltham, MA Philip Henry MD: Johnson City, TN James Bury, MD: Paddock Lake, WI Randall Longley, PharmD: Westfield, MA Hilary Hight MD: Woodstock, GA Dustie Butteiger, BS: Saint Louis, MO Sashi Makam, MD: Newburgh, NY Darlene Hinojosa, MSN: Williamsburg, VA Laura Carey: Westwood Hills, KS Donna Mohan, FNP: Nashua, NH Gregory Hopkins, MD: Senoia, GA Lisa Carter: Olathe, KS Thomas Musliner, MD: North Wales, PA Vanessa Juon: Weston, FL Eva Chomka, MD: Chicago, IL Charlene Naimo, BS: Waltham, MA Ehsanul Karim, MD: Palm Beach Gardens, FL Sharon Cline, MD: Naperville, IL Shah Nawaz, MD: Newbury, NY Melvyn Katzen, MD: Port Charlotte, FL Louie Coulis, MD: Plymouth, WI Gregg Neithardt, MD: Exton, PA Jawaad Khokhar, MD: Columbia, SC Eileen Coverick, RN: Palos Park, IL Prabhjot Nijjar, MD: Philadelphia, PA Jillian King, NP: Rome, GA Anthony DeFranco, MD: Milwaukee, WI Barbara Oberg-Higgins, MD: Portland, ME Leonard Kinland, MD: Brunswick, MD Stephen DePorter, FNP: East Moline, IL Stephen Pandolph, MD: State College, PA Catherine Klein, PhD: Washington, DC Lucy Dey, MD: Chicago Heights, IL Indu Poornima: Pittsburgh, PA Rebecca Kraftick, PA-C: London, KY Abhijeet Dhoble, MD: Rochester, MN Edward Portnay, MD: Staford, CT Ernestina Kyei-Donkor, ARNP: Orlando, FL Thao Doan, MD: Abbott Park, IL Anwer Qureshi, MD: Danville, PA Vincent Laganella, DO: Apollo Beach, FL Michael Doyle, MD: Huntington Woods, MI Tricia Russell: Wilkes-Barre, PA Federico Lenz, MD: Clearwater, FL Angela Feasel, MS: Moscow Mills, MO Magdi Salmon, MD: Cranston, RI Jennifer Li, MD: Durham, NC Christina Fouse, NP: Highland Park, IL Roger Savonen, PhD: Boston, MA Eugene Link, MD: Newport News, VA David Fuhs, PharmD: Woodbury, MN Antoinette Schoenthaler, EdD: Hicksville, NY Antoine Makdissi, MD: Buffalo, NY Mark Goetting, MD: Portage, MI David Shipon, MD: Philadelphia, PA Travis McCoy, MD: Louisville, KY Brook Gram, PA: Alliance, OH Laura Sievering, PA-C: Somers, CT Eduardo Montana, MD: Atlanta, GA Praveen Guntipalli, MD: Detroit, MI Sara Sirna, MD: Philadelphia, PA Edwin Morris, MD: Franklin, NC Abdul Hafeez, MD: Brookfield, WI Tharsan Sivakumar, MD: Lebanon, NH Kanakasabai Narasimhan, MD: Columbia, SC Diala Harb, PharmD: North Royalton, OH Ann Small, RN: East Berlin, PA Wallace Nelms, MD: Wilson, NC Bischan Hassunizadeh, MD: Chelsea, MI Paula Soteropoulos: Cambridge, MA Kim Nuss, PA-C: Kingsport, TN Andrea Hirsch, PharmD: Columbus, OH Joann Stich, NP: Epping, NH Philip O’Donnell, MD: Winchester, VA Amanda Hunt, RN: Naperville, IL Kristy Surprise, NP: Biddeford, ME Jacky Olin, PharmD: Monroe, NC Elizabeth Jackson, MD: Ann Arbor, MI Janet Troski, RN: Manchester, NH Philip Oranburg, MD: Boca Raton, FL Olympia Kalagidis, BA: Chicago, IL Andrei Varnavski, PhD: Brookline, MA Darshika Patel, PharmD: Weston, FL Dionysia Kalogeropoulou, MD: Minneapolis, MN Aungkana Vichiendilokkul, PharmD: Forest Hills, NY Mahesh Patel, MD: Durham, NC Joseph Keenan, MD: Golden Valley, MN Maggie Voughan, PA-C: Saratoga Springs, NY Sandesh Patil, MD: London, KY Kshama Keshava Bhat, MBBS: Pewaukee, WI Vincent Willey, PharmD: Kennett Square, PA Arnoldo Perez-Singh, MD: Sarasota, FL Azariah Kirubakaran, MD: Kearney, NE Bruce Yaffe, MD: New York, NY Curtis Preik, MD: Charlotte, NC David Kovacich, MD: Carmel, IN

The Official Publication of the National Lipid Association 41 Elaine Krul, PhD: Warson Woods, MO Heba Hossenally, PharmD: El Paso, TX Carolyn Lauf, MSN: Altadena, CA Cheryl Kyle, FNP: Montgomery City, MO Rebecca Asaacson, PA: Littleton, CO May Luke, PhD: Alameda, CA Melissa Lamb, FNP: New Sharon, IA Lorretta Jewell-Cousins, PharmD: Tucson, AZ Eric Luria, MD: Gig Harbor, WA Scott Landers, BSN: St. Joseph, MO Andrea Johnson, PharmD: Grand Prairie, TX Susan McBride, FNP: Clovis, CA Aditya Lele, MS: Abbott Park, IL Laura Koepke, ANP: Tucson, AZ Skye McKennon, PharmD: Pullman, WA Robert Lichtenberg, MD: Warrenville, IL JoAnn Linson, PharmD: Tucson, AZ Jeffrey Medland, DO: Eagle River, AK Randy Lieberman, MD: Bloomfield, MI. Eric Luria, MD: Gig Harbor, WA Rick Michel, NP: Ladera Ranch, CA Douglas Logan: Cincinnati, OH Boyd Lyles, MD: Dallas, TX Margo Minissian, MS: Los Angeles, CA Julie Long, APRN: New Ulm, MN Tammy Mattson, PharmD: Glenwood Springs, CO Julie Morris, Laguna Hills, CA Palaniappan Manickam, MD: Troy, MI Lynn Maupin, NP: Tolleson, AZ Joanne Morrison, RN: Long Beach, CA Helen Marinakis, PharmD: Maineville, OH Paul Meggs, MD: Plano, TX Susan Morrow, CNP: Anchorage, AK Carol Marsh, NP: Duluth, MN Nina Menegus, RN: Albuquerque, NM Nancy Munoz, PA-C: Reno, NV Sandra Martens, MD: Sturgeon Bay, WI Gay Meyers, PA-C: Sandy, UT Cesar Ochoa, MD: Panorama City, CA Tracy Martinez, PharmD: Pleasant Ridge, MI Michael Mowdy, DO: Oklahoma City, OK Timothy Polacek, BS: Beaverton, OR Joseph McConnell, PhD: Richmond, VA Radhika Nair, PhD: Round Rock, TX Jamal Rana, PhD: Los Angeles, CA Roland Mesue, PharmD: Hamilton, OH Alexander Nasr, PhD: Plano, TX Jaidesh Reddick, PA-C: San Jose, CA Rudi Mirian, FNP: Macomb, MI Stephen Newman, MD: Weatherford, TX Ian Riddock, MD: Suisun City, CA Sheri Montag, MA: Grand Rapids, MI Betsy Painter, NP: Tucson, AZ Charles Ruggeroli, MD: Las Vegas, NV Susan Nelson, RN: Celina, OH Clevis Parker, MD: Mesa, AZ Lakhjit Sandhu, MD: Fresno, CA Nicole Overbeck-Lynch, PA-C: Cincinnati, OH Mohammed Rais, MD: Thibodaux, LA Mehrnoosh Shakeri, MD: Park City, UT Quinn Pack, MD: Troy, MI Scott Reising, MD: Lubbock, TX Michael Shapiro, DO: Portland, OR Debbra Pantner, BSN: Oscoda, MI Jeanette Roberts, RN: Houston, TX Adam Shaywitz, MD: Thousand Oaks, CA Rodis Paparodis, MD: Chicago, IL Leonard Sanders, MD: Queen Creek, AZ Walter Singleton, MD: Carlsbad, CA Yogin Patel, PharmD: Glendale Heights, IL Kathryn Schmidt, DO: Crowley, TX Santosh Sinha, MD: Pasadena, CA Sara Lynn Peterson, PharmD: Neenah, WI Ryan Schupbach, PharmD: Claremore, OK Emily Smith, PharmD: Shingle Springs, CA Binh An Phan, MD: Glenview, IL Joseph Scott, MD: Denton, TX Bangalore Sury, MD: Long Beach, CA Jennifer Phillips, RD: Clarksville, OH Victor Seghers, MD: Bastrop, TX Chi Tong, PharmD: Modesto, CA Karen Pipes, RN: Ashland, MO Pamela Sifuentes, PA-C: Weslaco, TX Mary Weppler, NP: Anchorage, AK Joseph Poterucha, DO: Omaha, NE Jodi Sparkman, PharmD: Owasso, OK Robert Wolfert, PhD: South San Francisco, CA Maria Pruchnicki, PharmD: Colombus, OH Darryl Steele, MD: Euless, TX Min-Shung Wu, MD: Visalia, CA Ambreen Qureshi, MD: Ottumwa, IA Sue Steele, NP: Euless, TX Song Xue, MD: San Jose, CA Jaiwant Rangi, MD: Detroit, MI Linda Stiles, PhD: Boulder, CO Atanaz Zargar, PharmD: Portland, OR Ramakrishna Reddy, MD: Omaha, NE James Stokes, PharmD: San Antonio, TX Tina Rentmeester, APNP: Bookfield, WI Konstantyn Szwajkun, MD: Murray, UT International Lipid Association Mark Rhyner, MD: Milwaukee, WI Jan Troup, PhD: Houston, TX Maha Al-Mohaissen, MD: British Columbia, Canada Kelley Rodriguez, RN: Kansas City, KS Wesley Tyree, MD: Phoenix, AZ Nafila Al-Riyami, MD: British Columbia, Canada John Rozich, MD: Eau Claire, WI Chuck von Huben, PharmD: Santa Fe, NM Ahmad Al-Sarraf, MD: British Columbia, Canada Debbie Ryan, PhD: Chicago, IL Timothy Walker, MD: Oklahoma City, OK Khalid Al-Wail, MD: Quebec, Canada Rakshak Sarda, MD: Ames, IA Lawrence Wilner, DO: Castle Rock, CO Mohammed Alsheef, MD: Ontario, Canada Thomas Schmeiser, DO: Tallmadge, OH Cory Wilton, BS: Claremore, OK Ragheb Atmeh, PhD: Irbed, Jordan Vijay Shah, MD: Merrillville, IN Maciej Banach, MD, PhD: Lodz, Poland Harpreet Singh, MD: Grand Rapids, MI Pacific Lipid Association Jean Bergeron, MD: Quebec, Canada Saket Sinha, MD: Merrillville, IN Esmeraldo Arada, RN: Clovis, CA Sharmila Dudani, MBBS: New Delhi, India Alexandra Stach-Klysh, PharmD: Elmhurst, IL Suleman Aziz, MD: Federalway, WA Peter George, MBBS: Christchurch, New Zealand Jerzy Sterkowicz, MD: New Albany, OH Lori Bahem, RN: Boise, ID Vanessa G. Covarrubias, PhD: Leiden, Richard Stober, MD: Southfield, MI Christina Begg, RD: Woodinville, WA The Netherlands Lynn Toll, RN: Racine, WI Brian Berelowitz, MD: Las Vegas, NV Brooke Kennedy: Ontario, Canada Satya Toram, MD: Ann Arbor, MI Cameron Byers, PA-C: Fallon, NV Hyun Jin Kim, PhD: Seoul, South Korea Robert C. Turner, MD: Reedsburg, WI Clifton Cahoon, PharmD: Kalama, WA Peter Lansberg, MD: Amsterdam, The Netherlands Karen Vuckovic, RN: Villa Park, IL Courtney Cline, MS: Los Angeles, CA Alfredo Lozada, MD: Buenos Aires, Argentina Linda Wagner, RN: Oak Forest, IL Kenneth Colley, MD: San Francisco, CA Stanislava Macura, MD: Belgrade, Serbia SusanWalthall, NP: Livonia, MI Sonja Connor, RD: Portland, OR Brian McCrindle, MD: Ontario, Canada Kim Weber, MD: Hagerstown, IN Julie Cromer, PharmD: Kirkland, WA Vija Negalur, MD: Dombivli, India Frankie Weinberger, PA-C: Wauwatosa, WI Natalie Davidson, FNP: Redding, CA Yuri Nikitin, MD: Novosibirsk, Russia Laurie Whorley, ANP: Muskego, WI Troy Eden, PA-C: Elko, NV Pascal Pelletier, MD: Quebec, Canada Jacki Wilderman, NP: Evansville, IN Meredith Egger: Palo Alto, CA Lisa Petters: Ontario, Canada Tony Eid, PharmD: Los Angeles, CA Mary Phelan, BSc: Welwyn Garden City, UK Southwest Lipid Association Amy Eubanks, MD: Bremen, GA Nicole Schafer: Ontario, Canada Eric Auerbach, MD: Tulsa, OK Thomas Evans, MD: Tulane, CA Gunter Schrot, MD: Brandenburg, Germany Thomas Bartlett, MD: Colorado Springs, CO Rebecca Farrell, RD: San Francisco, CA Andrey Susekov, MD: Moscow, Russia Robert Bear, DO: Phoenix, AZ James Fretwell, MD: Longmont, CO Nora Vainstein, MD: Buenos Aires, Argentina Ross Brown, MSN: Austin, TX Yohannes Gebreegziabher, MD: Merced, CA Amit Yadav, MD: Rohtak, Haryana Mark Colligan, MD: San Antonio, TX Daniel Ginsberg, MD: Gig Harbour, WA Philippe Yostos, MB.ChB: Ontario, Canada Suzanne Cook, RN: Oklahoma City, OK Henry Huang, MD: Los Angeles, CA Khavar Dar, MD: Odessa, TX Tanvir Hussain, MD: Santa Monica, CA Neal Duhon, MD: Rayne, LA Kevin Ibaraki, PharmD: Yorba Linda, CA Steven Foley, MD: Colorado Springs, CO Joan Jacobs, MA: South San Francisco, CA Shylesh Ganta, MD: Midland, TX Kristen Jadelrab, RN: Palo Alto, CA Elizabeth Glynn, PA-C: Plano, TX Soteria Karahalios, MD: Pebble Beach, CA Ramona Goolsby, NP: Idabel, OK Cindy LaMar, MD: San Jose, CA

42 LipidSpin Meetings and Courses Calendar

Online Activities NLA Professional Available at www.lipid.org/edcuation Development Courses August 26–27 Lipid Insights Virtual Journal Club • Lipid Management Training Course Lipid Insights from AHA 2009: Online Activities Implications for Clinical Practice • Comprehensive Cardiometabolic Risk Available at www.lipid.org/education Sponsored by the NLA Reduction Course–Phase II Moderator: Michael H. Davidson, MD • Masters in Lipidology™ Course Implications of the ARBITER-6 HALTS Trial August 26–28, 2011 Sponsored by the NLA, hosted by SWLA Mayflower Hotel Clinical Lipid Update—Summer Moderator: Kitty Wyne, MD, PhD Washington, DC Hosted by MWLA and SELA www.lipid.org/education Hilton Orlando Bonnet Creek Examination of the ACCORD Trial Orlando, FL Sponsored by the NLA, hosted by PLA Moderator: Matthew Ito, PharmD 2011 NLA Meetings March 11–13, 2011 Clinical Lipid Update—Spring 2010 Meetings & Courses Hosted by SWLA and PLA August 27–29 Hyatt Lost Pines Clinical Lipid Update—Summer Austin, TX Hosted by NELA and SELA 2011 NLA Professional Mayflower Hotel Development Courses Washington, DC March 10–11, 2011 www.lipid.org/summerclu • Lipid Management Training Course Masters in Lipidology™ Course October 2 • 2nd Annual Orange County Symposium Hyatt Lost Pines on Cardiovascular Disease May 19–22, 2011 Austin, TX Prevention through Clinical Lipidology: NLA Annual Scientific Sessions A Focus on Reducing Cardiometabolic Risk Hosted by NELA May 18–19, 2011 Hosted by the NLA and ASPC Sheraton Hotel and Towers • Lipid Management Training Course Grand Californian Hotel New York, NY • Masters in Lipidology™ Course Anaheim, CA www.lipid.org Sheraton Hotel and Towers New York, NY November 13–17 American Heart Association August 25–26, 2011 Sessions 2010 • Lipid Management Training Course Chicago, IL • Masters in Lipidology™ Course scientificsessions.americanheart.org Hilton Orlando Bonnet Creek Orlando, FL

The Official Publication of the National Lipid Association 43 References

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