Official Publication of the National Lipid Association LipidSpin

Inflammation and Cardiometabolic Risk

Also in this issue: Clinical Trial Evidence for the Role of Reducing Inflammation for Cardiovascular Disease Prevention Identifying and Managing the Patient with High Inflammatory Burden Dietary Patterns and Systemic Inflammation: Examining the Connection

This issue is sponsored by the Pacific Lipid Association.

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Editors DANIEL E. SOFFER, MD, FNLA* 2 From the NLA President 18 Practical Pearls Clinical Associate Professor of Medicine New Clinical Guidelines: Paving the Top 10 Ways to Reduce Inflammation University of Pennsylvania — Cezary Wójcik, MD, PhD, DSc, FNLA* Internal Medicine and Preventive Cardiology Road Ahead University of Pennsylvania Health System — Alan S. Brown, MD, FNLA* Philadelphia, PA — Daniel E. Soffer MD, FNLA* — Kaye-Eileen Willard MD, FNLA* KAYE-EILEEN WILLARD, MD, FNLA* 20 Case Study Medical Director, Lipid Clinic and Physician Advisor Identifying and Managing the Patient Ascension Wisconsin All Saints Racine, WI 4 From the PLA President with High Inflammatory Burden President’s Views — Michelle Taylor, CCRN, ANP Associate Editors — Nathan D. Wong, PhD, FNLA — Rob Greenfield, MD, FNLA* Lori A. Alexander, MSHS, RD, CCRC, CLS, FNLA; Christie M. Ballantyne, MD, FNLA*; Thomas A. Barringer, MD, FNLA*; Carolyn Burns, MD*; Ashley D. Davila, RN, MSN, Chapter Update CNS, CLS; Daniel A. Duprez, MD, PhD, FNLA; Debra A. 5 Editor’s Corner 23 Friedrich, DNP, ARNP, FNP, BC, CLS, FNLA; Raymond A. Sparking the Conversation on Focus on Member Engagement Gaskins, MD*; Douglas S. Jacoby, MD, FNLA*; Laney K. Inflammatory Disease Management — Nathan D. Wong, PhD, FNLA Jones, PharmD, MPH; Matthew D. Kostoff, PharmD, CLS; — Eric K. Gupta, PharmD, CLS, FNLA Spencer D. Kroll, MD, PhD, FNLA*; Merle Myerson, MD, — Daniel E. Soffer MD, FNLA* EdD, FNLA*; Hal Roseman, MD, FNLA*; Khalid H. Sheikh, — Michael D. Shapiro, DO, FNLA* MD, FNLA*; Mark Sherman, MD, FNLA; Leandro Slipczuk, — Carol Kirkpatrick, PhD, MPH, RDN, CLS, FNLA MD, PhD; and Nathan D. Wong, PhD, FNLA 7 Clinical Feature — Yehuda Handelsman, MD, FNLA Executive Director Clinical Trial Evidence for the BRIAN HART, JD Role of Reducing Inflammation for 25 Specialty Corner National Lipid Association Cardiovascular Disease Prevention Dietary Patterns and Systemic LipidSpin is published five times a year by the — Bruce A. Warden, PharmD, BCPS-AQ Inflammation: Examining the National Lipid Association — Cezary Wójcik, MD, PhD, DSc, FNLA* 6816 Southpoint Parkway, Suite 1000 — Michael D. Shapiro, DO, FNLA* Connection Jacksonville, FL 32216 — Alyssa Lynott, RDN, LD Phone: 904-998-0854 | Fax: 904-998-0855 — Carol Kirkpatrick, PhD, MPH, RDN, CLS, FNLA Copyright ©2019 by the NLA. All rights reserved. 11 Guest Editorial — Geeta Sikand, MA, RDN, CDE, CLS, FNLA Visit us on the web at lipid.org. High-sensitivity C-reactive Protein Versus Coronary Artery Calcium 29 Member Spotlight The National Lipid Association makes every effort to provide accurate information in the LipidSpin at the Scoring: Dissecting a Biological Wenjun Fan, MS time of publication; however, circumstances may alter Target from a Cardiovascular Risk certain details, such as dates or locations of events. Any changes will be denoted as soon as possible. The NLA Assessment Tool 30 Education, News and Notes invites members and guest authors to provide scientific — Anurag Mehta, MD and medical opinion, which do not necessarily reflect the — Amit Khera, MD, MSc policy of the Association. 31 Events Calendar

Join the conversation on NLA social media! EBM Tools for Practice 14 Foundation Update Best Biomarkers for Inflammation 32 — Anne C. Goldberg, MD, FNLA facebook.com/nationallipid — Terrance J. Moran, MD, FNLA*

twitter.com/nationallipid References Let’s Get Social facebook.com/nationallipid 16 Lipid Luminations 33 linkedin.com/company/national- Medications that Reduce twitter.com/nationallipidlipid-association Inflammation Also May Reduce 36 NLA Tear Sheet Cardiovascular Disease instagram.com/nationallipidinstagram.com/nationallipid — Eric K. Gupta, PharmD, CLS, FNLA

linkedin.com/company/ lipid.org *indicatesnational-lipid-association ABCL Diplomate status

Official Publication of the National Lipid Association 1 From the NLA President and Editors of LipidSpin: New Clinical Guidelines: Paving the Road Ahead

ALAN S. BROWN, MD, FNLA DANIEL E. SOFFER, MD, FNLA President, National Lipid Association Editor, LipidSpin Director, Division of Cardiology Clinical Associate Professor of Medicine Advocate Lutheran General Hospital University of Pennsylvania Co-Director, Cardiology Service Line Internal Medicine and Preventive Cardiology Advocate Medical Group University of Pennsylvania Health System Clinical Associate Professor Philadelphia, PA Loyola Stritch School of Medicine Diplomate, American Board of Clinical Lipidology Park Ridge, IL Diplomate, American Board of Clinical Lipidology

KAYE-EILEEN WILLARD, MD, FNLA Editor, LipidSpin Medical Director, Lipid Clinic and Physician Advisor Ascension Wisconsin All Saints Racine, WI Diplomate, American Board of Clinical Lipidology

one-size-fits-all. The guidelines would on their merits (and shortcomings). have to be concise, clear, evidence-based, Based upon the response to retention flexible, universal, simple. They would hypothesis of atherosclerosis, observational, Discuss this article at have to provide the best advice for the genetic and clinical trial evidence, www.lipid.org/lipidspin greatest number of patients without therapeutic lipid and lipoprotein compromising advice to individuals. We management of ASCVD risk should think the 2018 Cholesterol Clinical Practice emphasize the following: Guidelines (CPGs)(1) accomplished that, “Knowing is not enough; we must apply. and we applaud the effort of the Writing • A healthy lifestyle is the foundation of Willing is not enough; we must do.” Committee. care for all individuals. This remark by Goethe introduces readers • One should reduce apolipoprotein B to the rationale for the Institute of Medicine As you know, the American Heart (apoB) containing lipoprotein levels of the National Academies Committee Association (AHA) and American College (primarily represented by the low- on Standards for Developing Trustworthy of Cardiology (ACC) enlisted the assistance density lipoprotein cholesterol (LDL- Clinical Practice Guidelines: Guidelines We of 10 other stakeholder organizations, C)) as much as possible by enhancing Can Trust 2011. including the National Lipid Association peripheral clearance of atherogenic (NLA), to ensure best practices, consensus lipoproteins, using statin drugs as the If you were asked to compose a set of and distribution of their recommendations foundation of pharmacotherapy. guidelines to advise clinicians on the best making up the 2018 Guidelines on the • The statin dose should be one used approach to cholesterol management, how Management of Blood Cholesterol, released in randomized placebo controlled would you write them? What if that same at AHA Scientific Sessions in November clinical trials (RPCTs), higher intensity set of guidelines was meant to inform 2018. Look for an upcoming LipidSpin issue preferred over moderate, and the goals health systems? Insurers? Other national dedicated exclusively to the Guidelines, for intensity of response should be health systems? They would have to be where NLA member authors will weigh in matched to ASCVD risk.

2 LipidSpin • Volume 17, Issue 1 • January 2019 • Since clinicians and patients do not 10-year risk of 7.5%-19.9% (intermediate Individual clinicians and patients can always know their pre-treatment lipid risk), risk-enhancing factors favor treat “beyond the Guidelines,” but should levels, there should also be thresholds initiation of statin therapy. recognize they do so with less evidence over which intensification of therapy 9. In adults 40-75 years without DM supporting care. In fact, there are many should be considered. and with LDL-C ≥70-189 mg/dL, at a examples where this makes sense, but • Since there is a high rate of attrition 10-year ASCVD risk of ≥7.5%-19.9%, it is not difficult to come up with a list with statin therapy, regular monitoring if a decision about statin therapy is of examples where this backfired (using to ensure medication tolerability, uncertain, consider measuring CAC. extended release niacin in our patients response to therapy and adherence to 10. Assess adherence and percentage achieving low LDL-C with moderate care is recommended. This begins with response to LDL-C–lowering intensity statin? Alpha-blockers as education and a shared discussion, and medications and lifestyle changes monotherapy for hypertension? Lidocaine the relationship has to be maintained with repeat lipid measurement 4-12 for ventricular ectopy during myocardial and reinforced over time. weeks after statin initiation or dose infarction?). As such, these approaches are adjustment, repeated every 3-12 months not endorsed, and clinicians are cautioned Since national CPGs are written for as needed. to proceed with care when adding therapy general use by clinicians, health systems, for which the evidence is not based upon governing bodies and insurers, simple, clear The 2018 Guidelines outline the critical randomized placebo control trials (RPCTs). messaging with distinct recommendations role of lifestyle intervention (message No. are necessary. This approach will invariably 1), and reminds clinicians that treatment We advise patience and support rigorous leave debate at the margins where nuance is not bestowed upon patients, but rather clinical scientific investigation going and experience are critical, and we look is an agreed-upon conclusion that takes forward. Many clinical questions remain in forward to those discussions in LipidSpin into consideration the above concerns our field, and while we have to apologize and upcoming NLA meetings. This iteration (message No. 6). They also reinforce the for our shortcomings to our patients when of the Cholesterol Guidelines emphasizes critical aspect of assessment of response they jump to reasonable conclusions about the messaging, establishing the 10 and adherence to therapy (message potential benefit (e.g. PCSK9i for primary “takeaway messages:” No. 10), which informs outcomes and prevention instead of statins, niacin or recommendations of care. PCSK9i for high Lp(a)), clinical care is 1. In all individuals, emphasize a heart- about helping our patients make the best healthy lifestyle across the life course. The remainder of the messages are specific, decisions in the present world, helping 2. In patients with clinical ASCVD, reduce content-driven recommendations with a them access best available care, providing LDL-C with high-intensity statin therapy review of supporting evidence. The four support and managing expectations. or maximally tolerated statin therapy. main categories of risk are identified 3. In very high-risk ASCVD, use LDL-C (clinical ASCVD, LDL-C >190 mg/dL, DM For now, let’s thank our NLA of 70 mg/dL to consider addition of and primary prevention with moderate representatives to the Guidelines writing nonstatins to statin therapy. ASCVD risk). They introduced opportunity team, Carl E. Orringer, MD, FNLA; Joseph 4. In patients with severe to integrate advanced-risk evaluation by J. Saseen, PharmD, FNLA; and Lynne T. hypercholesterolemia (LDL-C ≥190 mg/ acknowledging there is a range of ASCVD Braun, PhD, CNP, CLS, FNLA, and our dL), begin high-intensity statin therapy amongst patients in those risk categories colleagues from all 12 organizations. We without calculating 10-year ASCVD risk. and suggested evidence-based criteria appreciate your hard work and excellence. 5. In patients 40-75 years with diabetes for enhanced stratification. In particular, In particular, we thank you for reminding mellitus (DM) and LDL-C ≥70 mg/dL, apolipoprotein B, lipoprotein (a) and us of the critical importance of the healthy start moderate-intensity statin therapy coronary artery calcium scoring (CACS) lifestyle, the emphasis on communication without calculating 10-year ASCVD risk. are tools that lipidologists use regularly with our patients and the need for long- 6. In adults 40-75 years evaluated for but have largely remained a “hidden term support for long-term therapy. n primary ASCVD prevention, have a secret.” Hopefully, the new Guidelines clinician–patient risk discussion before will lead to greater utilization of these Disclosure statement: Dr. Brown has served as Consultant for Akcea, Amgen, Kowa, Regeneron and starting statin therapy. important risk markers. They also reinforce Sanofi. Dr. Soffer has served as Consultant for Amgen 7. In adults 40-75 years without DM and the importance of treatment thresholds, Inc, Akcea Therapeutics, Medicure, Regeneron, and with LDL-C ≥70 mg/dL, at a 10-year giving clinicians (patients and payers) has been a disease management Speaker on disease ASCVD risk of 7.5%, start a moderate- clear recommendations for when there states (FCS and FH respectively) for Amgen Inc ≥ and Sanofi. Dr. Willard has received honoraria from intensity statin if a discussion of is strong enough evidence to intensify Regeneron, Sanofi, Amgen and Akcea. treatment options favors statin therapy. pharmacotherapy. References are listed on page 33. 8. In adults 40-75 years without DM and

Official Publication of the National Lipid Association 3 Sparking the Conversation on Inflammatory Disease Management

From the PLA President: President’s Views

NATHAN D. WONG, PhD, FNLA President, Pacific Lipid Association Professor and Director, Heart Disease Prevention Program Division of Cardiology, University of California Irvine, CA

ranges from contributions dealing with perspectives of where we have been and are going with the field of inflammation Discuss this article at as a contributor of cardiovascular disease www.lipid.org/lipidspin risk, to the best ways to measure and reduce inflammation — both lifestyle and pharmacologic — to case study examples of the high inflammatory risk patient and their evaluation and management. I am honored to have the opportunity to work with you all in promoting education, My key priority is to improve member service and quality improvement efforts in communication and to improve clinical lipidology and preventive cardiology membership participation in PLA and as this year’s President of the Pacific Lipid National Lipid Association activities. and featuring member accomplishments Association. Having great passion in this I know our talented NLA Marketing and other news via a quarterly newsletter. field over the 30-year span of my career, I and Communications team is working enthusiastically hope to further promote on both traditional and novel ways of In an effort to encourage your involvement, involvement of our membership in local, communicating with NLA membership as I also am inviting you to each contact me regional and national efforts focused on a whole, including through newer social at [email protected] should you have any better management of lipids and related media methods. My plan is to reach our suggestions or needs I can personally help risk factors to help combat cardiovascular members with new initiatives (see also the you with (and most of you who know me disease as America’s leading cause of PLA Chapter Update section of LipidSpin), well know I am quite responsive) to better morbidity and mortality. including cholesterol control quality involve you in PLA and NLA activities. I improvement partnerships such as with also hope we can get more involvement of The Pacific Lipid Association is proud to the American Heart Association’s Check. PLA members on NLA national committees, present our issue of LipidSpin focusing on Change. Control. (CCC) Cholesterol.™ certainly another valuable opportunity to inflammation and cardiovascular disease, a quality improvement program, hosting make your voice known. n topic of timely importance given the recent of local dinner and regional educational release of the CANTOS trial. Our issue programs, partnership in local health fairs Disclosure statement: Dr. Wong has no financial disclosures to report.

4 LipidSpin • Volume 17, Issue 1 • January 2019 Sparking the Conversation on Inflammatory Disease Management

From the LipidSpin Editor: Sparking the Conversation on Inflammatory Disease Management

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

The “response to retention” model of It seems almost quaint to read a atherosclerosis holds up as the present and centuries-old argument that it is lipid, not best narrative explanation for the initiation inflammation and vice versa that causes and propagation of atherosclerotic atherosclerosis. The public disagreement Discuss this article at cardiovascular disease (ASCVD).(1) As between Virchow and Rokitansky (2) is www.lipid.org/lipidspin you know, this model posits that the right up there with “you got chocolate in passage of apolipoprotein B (apoB)- my peanut butter ... no, you got peanut containing lipoproteins (LP) triggers the butter on my chocolate” or “tastes great ... initiation of the atheroma. Low density less filling.” However, their disagreement lipoproteins (LDL) and triglyceride rich spawned 100 years of science to bring of statins and other therapies (ezetimibe, lipoprotein remnants (TRLr) are retained us this far, and we are indebted to their PCSK9 monoclonal antibodies and now by proteoglycans in the subendothelial passion in pursuit of the truth. We have high dose eicosapentaenoic acid), and space where they undergo modification come so far in that 100 years, so it is reiteration of the value of comprehensive (mostly oxidation). The oxidation of LDL surprising that right after I introduce risk reduction in the care of our patients. is an inflammatory trigger for resident myself as a Clinical Lipidologist, I often monocytes phagocytosis and conversion to hear some version of the following This issue of LipidSpin is dedicated to the “foam cell.” It is thus, the formation of question: “Doc, does cholesterol matter? recent advances in the clinical anti- the foam cell that represents the necessary It’s all about inflammation, right?” I am inflammatory approach to ASCVD care. common pathway of atherosclerosis. The sure I am not the only one who has had How important are inflammatory markers lipids carried by lipoproteins are thus this experience. Invariably, this is followed and the recognition of inflammatory the fuel for the fire (foam cell release of by “Did you ever read the Cholesterol diseases in risk stratification? Can we affect cytokines, subsequent recruitment of and Myth?” and “Are eggs ok to eat?” ASCVD risk by targeting inflammation? targeting of monocytes, T-lymphocytes, What aspects of inflammation are better neutrophils and the remodeling of the The last 40-plus years have seen large targets than others? normal arterial morphology by expression scale clinical trials confirm the role of of proteases, smooth muscle cell and LDL-cholesterol (LDL-c) reduction, value Some of these questions are addressed fibroblast recruitment) that can burn down of statin drugs, role of non-high density by ongoing excellent science. Others just the entire house (myocardial infarction, lipoprotein-cholesterol (nonHDL-c) and spawn new questions. The articles in this cerebrovascular event). apoB-lowering, confirming the critical role LipidSpin have shed light on this subject,

Official Publication of the National Lipid Association 5 but I still have many other questions, including: Is it possible to customize diets that target inflammation and lipid- “This issue of lowering? How does the microbiome LipidSpin is dedicated contribute to the inflammasome? If a drug lowers LDL-c effectively, but does to recent advances not reduce inflammatory markers, how do we explain its benefit and vice versa? in the clinical anti- Should we go back to thinking about the pleiotropic effects of medicines (statins, inflammatory approach eicoapentaenoic acid)? How good is the evidence that we should be treating to ASCVD care.” individuals with inflammatory diseases as an indication of need for intensification “To keep a lamp burning, we have to keep of therapy? Should we expect anti- putting oil in it.” Mother Theresa n inflammatory pharmacotherapy to be another tool in our belt in the future? Disclosure statement: Dr. Soffer has served as Consultant for Amgen Inc, Akcea Therapeutics, I hope you enjoy this issue of LipidSpin as Medicure, Regeneron, and has been a disease management Speaker on disease states (FCS and FH our first foray into inflammatory disease respectively) for Amgen Inc and Sanofi. management. I expect this conversation to References are listed on page 33. continue for many years to come, possibly another 100 years.

6 LipidSpin • Volume 17, Issue 1 • January 2019 Clinical Feature: Clinical Trial Evidence for the Role of Reducing Inflammation for Cardiovascular Disease Prevention

BRUCE A. WARDEN, PharmD, BCPS-AQ CEZARY WOJCIK, MD, PhD, DsC, FNLA Center for Preventive Cardiology Department of Family Medicine Knight Cardiovascular Institute Oregon Health and Science University Oregon Health and Science University Portland, OR Portland, OR Diplomate, American Board of Clinical Lipidology

MICHAEL D. SHAPIRO, DO, FNLA Center for Preventive Cardiology Knight Cardiovascular Institute Oregon Health and Science University Portland, OR Diplomate, American Board of Clinical Lipidology

Introduction CVD.”(4) Despite statins’ remarkable Despite significant advances in detection benefits, approximately 60% to 70% of and treatment, cardiovascular disease ASCVD events continue to occur in statin- (CVD) is the leading cause of death and treated patients, an observation referred disability worldwide.(1,2) The 3-hydroxy- to as residual cardiovascular risk.(5,6) Discuss this article at www.lipid.org/lipidspin methylglutaryl coenzyme A (HMG- Recent studies involving the cholesterol CoA) reductase inhibitors (aka statins) absorption inhibitor ezetimibe and the ushered in a new era for prevention of proprotein convertase subtilisin-like/kexin cardiovascular disease. The first statin, type 9 (PCSK9) inhibitors evolocumab lovastatin, became commercially available and alirocumab have confirmed that lower Inflammatory markers linked to ASCVD in 1987. This was followed in 1994 by LDL-C is associated with reduced ASCVD Several lines of evidence — ranging from the landmark Scandinavian Simvastatin events, regardless of the agent used and epidemiologic to genetic, experimental and Survival Study (4S), which demonstrated proportional to the degree of LDL-C clinical trials — have linked inflammation that lowering low-density lipoprotein lowering.(7-10) Yet, even with aggressive to all phases of atherosclerosis.(11,12) cholesterol (LDL-C) led to significant LDL-C reduction, vascular events continue Broadly, the inflammatory mediators can reductions in major atherosclerotic CVD to occur at an alarming rate, suggesting be classified into those involving a central and atherosclerotic cardiovascular disease that there are additional important pathway or an alternative pathway. The (ASCVD) events.(2,3) Since then, statin factors at play. This review will focus on central inflammatory pathway involves therapy has remained the cornerstone of inflammation as a risk factor for — and activation of the nucleotide-binding ASCVD prevention and has been coined therapeutic target of — ASCVD residual oligomerization domain (NOD)-like “the single most important advance in risk reduction. receptor family pyrin domain containing the therapeutic armamentarium against 3 (NLRP3) inflammasome, resulting in

Official Publication of the National Lipid Association 7 the production of interleukin-1 (IL-1), ezetimibe appears to share at least some Thus, the JUPITER trial did not prove the which binds to its specific interleukin-1 anti-inflammatory effects with statins, inflammatory hypothesis for reduction of (IL-1) receptor, initiating the production of PCSK9 inhibitors do not reduce hsCRP ASCVD risk. Nevertheless, American and interleukin-6 (IL-6) and other downstream or other inflammatory markers, despite European guidelines both endorse hsCRP mediators, including the non-specific liver- dramatic LDL-C lowering.(19) as a biomarker to refine risk estimates in derived acute-phase reactant C-reactive select patients.(22, 23) protein (CRP)(see Fig. 1). Interestingly, Ten years ago, the landmark Justification cholesterol crystals within atherosclerotic for the Use of Statins in Prevention: an On the heels of JUPITER, the Canakinumab plaque activate the NLRP3 inflammasome Intervention Trial Evaluating Rosuvastatin Anti-inflammatory Thrombosis Outcome to initiate this cascade of events, (JUPITER) trial went beyond evaluation Study (CANTOS) was the first trial to providing a mechanistic link between of the incremental prognostic value of prospectively test the inflammatory hypercholesterolemia and vascular hsCRP. JUPITER was a randomized, double- hypothesis of ASCVD.(24) CANTOS inflammation. The alternative inflammatory blind, placebo-controlled, multicenter enrolled 10,061 subjects with a past pathway involves lipoprotein-associated trial that enrolled 17,802 apparently history of MI and hsCRP ≥2 mg/L on phospholipase A2 (Lp-PLA2), secretory healthy (primary prevention) subjects stable background medical therapy and PLA2 (sPLA2), P-selectin, 5-lipoxygenase (age ≥50 years for men and ≥60 years for randomized them to placebo or one (5-LO) and other mediators.(13) women, LDL-C <130 mg/dl and hsCRP of three doses of canakinumab, a fully ≥2 mg/L), who would not otherwise human monoclonal antibody that inhibits Clinical Trial Evidence qualify for guideline-directed statin IL-1β, every 3 months. Median LDL-C Agents targeting the central immune therapy.(6) Subjects were randomized and hsCRP at baseline were 82 mg/dl signaling pathway to rosuvastatin 20 mg or placebo. The and 4.2 mg/L, respectively. As compared The CRP molecule is now well trial was terminated prematurely after a to placebo, hsCRP was reduced by 26%, established as a downstream biomarker median follow-up of 1.9 years because of 37% and 41% in the canakinumab 50 mg, of inflammation, associated with risk of significant cardiovascular event reduction 150 mg and 300 mg groups, respectively. ASCVD and independent of traditional among rosuvastatin recipients. At the Similar trends were seen for reductions in risk factors. High-sensitivity CRP (hsCRP) time of study termination, those in the IL-6 levels without significant reduction levels <1, 1-3 and >3 mg/L confer rosuvastatin group experienced a 49% in LDL-C. Over a median follow-up of low, moderate and high vascular risk, LDL-C reduction (to 55 mg/dl) and a 48% 3.7 years, the primary efficacy endpoint respectively (12). Statins lower CRP reduction in hsCRP (to 2.2 mg/L). The (non-fatal MI, non-fatal stroke, CV death) independently of LDL-C reduction. In fact, primary endpoint (non-fatal myocardial was 4.5%, 4.11%, 3.86% and 3.9% among in the Cholesterol and Recurrent Events infarction [MI], non-fatal stroke, the placebo, canakinumab 50 mg, 150 (CARE) trial, greater ASCVD reduction hospitalization for unstable angina [UA], mg and 300 mg groups. Canakinumab, was noted in those subjects with higher arterial revascularization or cardiovascular 150 mg subcutaneously every 3 months, baseline hsCRP levels.(14) This observation [CV] death) occurred in 0.77% vs. 1.36% met the primary endpoint with a 15% was recapitulated in several other statin [hazard ratio (HR) 0.56; 95% confidence reduction of non-fatal MI, nonfatal stroke trials.(15-18) The consistency of this interval (CI) (0.46-0.69), number needed or cardiovascular death, an effect size finding gave birth to the notion of dual to treat (NNT) of 95] in the rosuvastatin strikingly similar to what was seen in targets — greatest ASCVD risk reduction vs. placebo groups, respectively. All-cause the cardiovascular outcomes trials with realized with a combination of reduced mortality also was reduced 20%, relative the PCSK9 inhibitors.(8-10) Additionally, LDL-C (<70 mg/dl) and hsCRP (<2 mg/L). to placebo. As previously discussed in the subjects randomized to canakinumab 150 (15-18) Moreover, the concept of dual context of other clinical trials, the greatest mg every 3 months achieved significant targets has been extended in trials of non- absolute risk reduction with rosuvastatin reductions in MI, hospitalization for UA statin therapies, including ezetimibe in the occurred in those with the highest levels of leading to urgent revascularization and Improved Reduction of Outcomes: Vytorin hsCRP.(21) Importantly, the lowest event any coronary revascularization. There Efficacy International Trial (IMPROVE-IT) rates were observed in those who achieved was no impact on CV or all-cause death. and evolocumab in the Further both an LDL-C <70 mg/dl and hs-CRP <2 Remarkably, fatal cancers (especially Cardiovascular Outcomes Research with mg/L. Whether the benefit seen in JUPITER lung), arthritis and gout were reduced PCSK9 Inhibition in Subjects with Elevated was because of LDL-C lowering, reduction with canakinumab. The most important Risk (FOURIER ) trials.(19, 20) While in inflammation or both was not clear. adverse event observed with canakinumab

8 LipidSpin • Volume 17, Issue 1 • January 2019 was a higher rate of fatal infection or sepsis, 0.18% vs. 0.28-0.34% placebo vs. canakinumab, respectively. A post- hoc subanalysis evaluated outcomes stratified by achieved hsCRP.(25) Subjects randomized to canakinumab who achieved hsCRP <2 mg/L vs ≥2 mg/L demonstrated a statistically significant relative risk reduction (RRR) of 25% in the primary efficacy endpoint of CANTOS vs. a non- significant RRR of 10%, respectively. All- cause and CV death also were significantly reduced in those with on-treatment hsCRP < 2 mg/L. Thus, on-treatment hsCRP value may prove to be a useful tool to determine continued treatment with canakinumab. However, the U.S. Food and Drug Administration (FDA) recently decided not to approve canakinumab for a new indication of CV risk reduction. The FDA Figure 1. Overview of the role of inflammation in the development of atherosclerotic plaque. Circulating is seeking additional data in the responder monocytes penetrate the arterial wall and enter the subendothelial space through diapedesis to become population. For the first time, CANTOS macrophages. As these arterial wall macrophages engulf low-density lipoprotein particles, they transform provides proof of concept that targeting into foam cells, which elaborate several inflammatory mediators, acting both locally and systemically. Lipid- laden foam cells undergo cell death, contributing to the necrotic core of the growing plaque, while smooth inflammation — without impacting muscle cells proliferate and migrate from the media toward the intima. Different stages of the inflammatory lipoprotein levels — can further reduce process involve specific mediators, which are targets (orange boxes) of different categories of drugs (white ASCVD events, and it opens the door for boxes) discussed in the article. Graphic created by Dr. Thomas Dayspring has been modified and used with his permission. future investigation into the therapeutic modulation of inflammation for CV risk reduction. has been validated as a risk marker (STABILITY) trial and in 13,026 subjects In this regard, the medical community (28), Lp-PLA2 inhibitors have failed to presenting with an ACS over 2.5 years waits with interest for the results of the demonstrate benefit in three Phase III in the Stabilization of Plaque Using Cardiovascular Inflammation Reduction cardiovascular outcome trials.(29-31) The Darapladib — Thrombolysis in Myocardial Trial (CIRT). CIRT enrolled 4,786 subjects Vascular Inflammation Suppression to Infarction-52 (SOLID-TIMI 52) trial (30, with prior MI, diabetes mellitus or Treat Acute Coronary Syndrome for 16 31). The STABILITY trial did reduce the metabolic syndrome and randomized them Weeks (VISTA-16) trial enrolled 5,145 ACS secondary endpoints of major and total to oral low-dose methotrexate (target patients who were randomly allocated to coronary events (p=0.0045 and 0.02, dose of 15-20 mg per week) vs. placebo placebo or varespladib, an oral secretory respectively). However, the significance of (26). The CIRT trial was terminated PLA2 (sPLA2) inhibitor. Active therapy these findings remains unclear given the prematurely on March 13,, 2018. The was associated with modest reductions lack of effect on the primary cardiovascular results were presented at the American in LDL-C and CRP compared to placebo, endpoint. Moreover, in both STABILITY Heart Association meeting in November but the study was prematurely terminated and SOLID-TIMI 52, more patients 2018.(27) because of futility and possible harm discontinued therapy because of adverse (excess MI rates, 3.4% vs. 2.2%, HR 1.66 events. Agents targeting alternative immune ; 95% CI 1.16-2.39) (29). The second signaling pathways agent, darapladib, which is an oral Lp-PLA2 Inclacumab, a monoclonal antibody Modulation of non-central inflammatory inhibitor, failed to demonstrate benefit in targeting P-selectin, a cell adhesion pathways has yet to produce promising 15,828 subjects with stable CAD over 3.7 molecule expressed on endothelial cells clinical results. While lipoprotein- years in the Stabilization of Atherosclerotic and platelets that promotes leukocyte associated phospholipase A2 (Lp-PLA2) plaque by Initiation of Darapladib Therapy recruitment and thrombus growth and

Official Publication of the National Lipid Association 9 stabilization, revealed promising results 60). Losmapimod did not reduce the new coronary calcification, it failed to in a small Phase II trial, Effects of the primary cardiovascular outcome in the demonstrate a difference in inflammatory P-Selectin Antagonist Inclacumab on smaller exploratory efficacy analysis and, cell infiltration in subjects undergoing Myocardial Damage After Percutaneous thus, the investigators did not proceed carotid endarterectomy.(11) Coronary Intervention for Non-ST-Segment with a larger efficacy analysis.(35) Elevation Myocardial Infarction (SELECT- Finally, salsalate, an anti-inflammatory ACS) by reducing troponin and creatine Emerging Therapies derivative of aspirin that does not inhibit kinase-myocardial band.(32) However, There are numerous other anti- cyclooxygenase (and, thus, has no effect on inclacumab failed to reduce vein graft inflammatory therapies that are in bleeding or platelet aggregation), reduces disease progression in a Phase II trial various stages of evaluation for ASCVD leukocyte counts, likely as a result of its involving patients undergoing coronary risk reduction. Colchicine, an oral effect on NF-κB.(11) Earlier studies with artery bypass, Effects of P-Selectin anti-inflammatory agent that inhibits salsalate demonstrated reductions in Antagonist Inclacumab in Patients neutrophil function through inhibition hsCRP. Salsalate is now being evaluated Undergoing Coronary Artery Bypass Graft of tubulin polymerization, significantly in the Phase II/III Targeting Inflammation Surgery (SELECT-CABG).(33) No Phase III reduced CV events in a small unblinded Using Salsalate in Cardiovascular Disease trials of inclacumab have been conducted trial — Low-Dose Colchicine (LoDoCo). (TINSAL-CVD) trial in subjects with to date. Two additional Phase III studies testing established CAD to determine if this colchicine in this context include the therapy can promote plaque regression. Succinobucol, a derivative of probucol, is Colchicine Cardiovascular Outcome Trial The anticipated study completion date is an orally active antioxidant without the (COLCOT) and the Low-Dose Colchicine winter 2019.(36) QT-prolonging effect. Succinobucol was for Secondary Prevention of Cardiovascular evaluated in a Phase III trial, Aggressive Disease (LoDoCO2) trial.(11) COLCOT Summary Reduction of Inflammation Stops Events will evaluate subjects with ACS with an Despite remarkable achievements (ARISE), of 6,144 subjects presenting anticipated completion date of fall 2019. in therapeutic LDL-C lowering with with ACS. (34) The trial did not meet The interleukin-1 receptor antagonists (IL- concomitant decline in atherosclerotic its primary endpoint but demonstrated 1RA), anakinra and rilonacept, are events, residual cardiovascular risk statistically significant reductions in subcutaneously administered and currently remains unacceptably high. In the wake some of the secondary and tertiary are being evaluated in Phase II trials in of the CANTOS trial, there is renewed outcomes. However, several safety ACS and chronic kidney disease patients, enthusiasm for orthogonal approaches concerns were noted, including increases respectively.(36) These agents currently to ASCVD risk reduction, particularly in hospitalizations for heart failure, new- have no Phase III studies under way. with respect to targeting inflammation. onset atrial fibrillation, bleeding, anemia, Numerous trials now are under way, diarrhea and increases in LDL-C and An early Phase I/II trial, Controlled Level testing a variety of other anti-inflammatory hsCRP. Everolimus in Acute Coronary Syndromes agents to determine if this will be an (CLEVER-ACS) will examine the oral effective means by which to further erode The p38 Mitogen-activated protein mammalian target of rapamycin (mTOR) residual CV risk. n kinase (MAPK) is an enzyme expressed inhibitor everolimus in ACS patients to in endothelial cells, myocytes and determine its ability to reduce infarct size, Disclosure statement: Dr. Warden has no financial disclosures to report. Dr. Wojcik has no financial macrophages that magnifies the myocardial function and inflammation.(36) disclosures to report. Dr. Shapiro has received inflammatory cascade through Estimated study completion date is winter honoraria from Kastle, Novartis and Regeneron. overproduction of various cytokines, 2019. Of note, mTOR inhibitor use in References are listed on page 33. and it may be linked to atherogenesis solid organ transplant recipients has been development and plaque destabilization. associated with profound dyslipidemias, Losmapimod, an oral p38 MAPK inhibitor, potentially limiting its role in ASCVD was evaluated in 3,503 ACS patients in management. the Phase III trial Losmapimod to Inhibit The 5-LO inhibitor (Atreleuton,VIA-2291) p38 MAP Kinase as a Therapeutic Target was evaluated in three Phase II studies. and Modify Outcomes After an Acute While therapy was associated with a Coronary Syndrome (LATITUDE–TIMI reduction in inflammatory markers and

10 LipidSpin • Volume 17, Issue 1 • January 2019 Guest Editorial: High-sensitivity C-reactive Protein Versus Coronary Artery Calcium Scoring: Dissecting a Biological Target from a Cardiovascular Risk Assessment Tool

ANURAG MEHTA, MD Katz Preventive Cardiology Fellow Division of Cardiology Department of Medicine Emory University School of Medicine Atlanta, GA

AMIT KHERA, MD, MSc Professor Division of Cardiology Department of Internal Medicine University of Texas Southwestern Medical Center Dallas, TX

Differentiating Biological Targets for pathophysiology. Unfortunately, these Cardiovascular Risk Reduction from two concepts often are conflated — the Risk Assessment Tools value of a marker for serving as a biological Cardiovascular disease (CVD) remains the target can be very different from its utility leading cause of mortality across the globe. as a risk assessment tool. Discuss this article at www.lipid.org/lipidspin The cornerstones of CVD prevention and treatment are accurate risk assessment High-sensitivity C-reactive protein (hsCRP) — such that the intensity of preventive and coronary artery calcium (CAC) score treatment matches the magnitude of are two such biological markers. In this absolute risk — and targeting biological editorial, we aim to disentangle the utility available. markers that are known to mediate CV of hsCRP as a biological target for CV HsCRP as a cardiovascular risk assessment risk, respectively. risk reduction and of CAC as an aid to tool: improving CV risk assessment. Systemic inflammation has long been Biological markers are informed by regarded as a CV risk factor, and pathophysiologic disease mechanisms and C-reactive Protein multiple studies have demonstrated the often are used as a titratable target during CRP is an acute-phase protein produced independent association of elevated hsCRP treatment, such as low-density lipoprotein predominantly by the liver and is with CV events. (1,2) Hence, hsCRP has cholesterol (LDL-C) levels. On the other a nonspecific marker of systemic been evaluated as a CV risk assessment hand, risk assessment tools are markers inflammation. Plasma CRP levels can be tool in several epidemiologic studies. that improve on actuarial CV risk and are readily measured using standardized high- (3-7) However, its widespread utility has at times agnostic to underlying disease sensitivity assays that are commercially been limited by significant gender and

Official Publication of the National Lipid Association 11 ethnic variations in levels, as well as its effect of statin therapy, thereby refuting (22) Interestingly, a post-hoc analysis of association with smoking, diabetes, and the paradigm of statins preferentially CANTOS examined 3-month on-treatment visceral obesity — established risk factors benefiting those with elevated hsCRP.(19) hsCRP levels to determine response that portend accelerated atherosclerosis. Similarly, recent analyses from the Further to canakinumab.(23) The subgroup of (8,9) The incremental value of hsCRP for Cardiovascular Outcomes Research with patients who achieved an hsCRP level CV risk prediction was evaluated by the PCSK9 Inhibition in Subjects with Elevated <2mg/L had a significant reduction in Emerging Risk Factor Collaboration in Risk (FOURIER) and Studies of PCSK9 the primary composite endpoint as well more than 160,000 asymptomatic people Inhibition and the Reduction of Vascular as CV death and all-cause mortality, with from 38 cohorts.(10) HsCRP yielded a Events (SPIRE) trials did not demonstrate no significant reduction in any of these net reclassification improvement (1.52%), enhanced relative risk reduction with endpoints in those whose on-treatment and the addition of hsCRP to a model proprotein convertase subtilisin/kexin hsCRP remained ≥2mg/L.(23) The direct containing traditional risk factors led to a type 9 (PCSK9) inhibitors among patients clinical relevance of this analysis is the minimal but significant improvement in with higher hsCRP.(20,21) However, in potential to measure hsCRP after one dose risk discrimination (change in C-statistic the SPIRE trial, on-treatment hsCRP levels of canakinumab to determine who most 0.0039), an effect that was limited to men. were independently predictive of CV would benefit from ongoing treatment (10) Lastly, using an hsCRP level of >2 events while on-treatment LDL-C no longer with this expensive agent. mg/L as the cut point for defining elevated was associated with outcomes, spotlighting CV risk has performed poorly in some the concept of residual inflammatory risk. Coronary Artery Calcium Score studies and may be inadequate to inform (21) CAC is a marker of subclinical coronary risk assessment.(11,12) atherosclerosis burden, and CAC scores are measured using non-contrast computed HsCRP as a biological target for reducing tomography of the chest.(24) cardiovascular risk: “CAC is a powerful Despite a number of presumed CAC as a cardiovascular risk assessment mechanistic links, genetic studies have risk marker and an tool: confirmed that CRP largely is not causally effective adjunct to CAC score is a well-established related to CVD.(13-15) Rather, it is a independent predictor of CVD events. barometer of vascular inflammation and TRF in identifying (11) The significant advantage of using atherosclerotic risk factors — including CAC for CV risk assessment is a consistent obesity — that result in CRP release those at highest improvement in risk discrimination and from the liver in response to cytokines, risk reclassification in asymptomatic principally interleukin-6.(16,17) Thus, CV risk who would individuals. These findings stem from CRP is not a direct biological target, per numerous prospective, population-based se, but it could be used as an indicator most benefit from cohorts of adults without overt CVD. to determine who would most benefit preventive therapies.” (25-30) The degree of improvement in from anti-inflammatory therapies.(17) risk discrimination and reclassification This hypothesis was assessed in the afforded by CAC is much higher than with Justification for the Use of Statins in other non-traditional risk factors (TRF), Primary Prevention: An Intervention Trial The Canakinumab Anti-inflammatory including hsCRP.(31,32) For example, in Evaluating Rosuvastatin (JUPITER) trial, Thrombosis Outcome Study (CANTOS) the Rotterdam Study, the hazard ratio for which randomized asymptomatic patients trial recently provided evidence to incident coronary heart disease (CHD) with LDL-C <130 mg/dL and hsCRP support the hypothesis of targeting was greater than sixfold in those with >/= 2 mg/L to rosuvastatin or placebo inflammation without lowering LDL-C for the highest versus lowest CAC quartile, and demonstrated a robust reduction in CV risk reduction.(22) Here, canakinumab while it was only 1.6 for the same adverse CV events with rosuvastatin along (monoclonal antibody targeting quartile comparison for hsCRP.(31) The with a concomitant reduction in LDL-C interleukin-1 beta) was shown to reduce powerful CV risk information conferred and hsCRP levels.(18) However, a post-hoc recurrent CV events independent of by CAC testing has the potential to guide analysis demonstrated that elevated hsCRP LDL-C in patients with previous myocardial appropriate preventive therapy.(33-35) did not independently predict an enhanced infarction (MI) and hsCRP >2 mg/L. In an analysis of a JUPITER trial-eligible

12 LipidSpin • Volume 17, Issue 1 • January 2019 population of the Multi-Ethnic Study of than 50% lowering of LDL-C in the arm inflammation, has led to the re-emergence Atherosclerosis (MESA) study, applying randomized to atorvastatin with baseline of hsCRP assessment. HsCRP may serve CAC scores markedly splayed CVD risk and CAC of ~ 200, the increase in CAC over as a trackable biologic indicator of those utility of rosuvastatin, such that the 5-year two years was similar to that in the placebo who are deriving the greatest benefit from number needed to treat for preventing arm.(40) If one serially reassessed CAC in emerging anti-inflammatory therapy. n CVD events was 124 with a CAC of 0 patients similar to these trial populations, versus only 19 with a CAC >100.(36) one erroneously would assume they Disclosure statement: Dr. Mehta has no financial disclosures to report. Dr. Khera has no financial MESA investigators also demonstrated “failed” statin therapy. disclosures to report. that, among those with statin indication One potential explanation for these References are listed on page 33. per the 2013 ACC/AHA Guideline on observations is that statins can promote the Treatment of Blood Cholesterol to coronary atheroma calcification Reduce Atherosclerotic Cardiovascular independent of their beneficial plaque- Risk in Adults, approximately one-half regressive effects.(41,42) Also, the have a CAC score of 0, placing them in a baseline CAC score dominates the risk risk group where statins generally would estimate, and progression or change over not be warranted.(33) Additional studies time adds little to risk estimation for most have extended this paradigm to aspirin use patients.(43) Lastly, CAC progression has and blood pressure management whereby been shown to be an inevitable process CAC testing can enhance the efficiency that happens in a predictable manner.(44) of these treatments.(37,38) In all of These observations cast serious doubts these scenarios, CAC testing is agnostic on the benefit of serial CAC scanning to to the underlying biology contributing monitor response to preventive therapies to CVD risk, but it identifies those with and discredit its value as a titratable target the highest absolute risk and provides an for CV risk reduction.(45,46) opportunity to accrue the greatest absolute risk reduction with primary preventive Conclusion therapies. CAC is a powerful risk marker and an effective adjunct to TRF in identifying CAC as a biological target for reducing those at highest CV risk who would cardiovascular risk: most benefit from preventive therapies. Given the strong independent association The 2018 AHA/ACC Guideline on the of CAC with CV risk, it is tempting to Management of Blood Cholesterol track the effectiveness of preventive recommends that CAC scanning may interventions with serial CAC scanning. be considered in guiding primary However, several lines of evidence point prevention decisions among individuals to the fallacy of this approach. In the at intermediate 10-year risk (7.5% to placebo-controlled, randomized Saint 20%) of developing an atherosclerotic Francis Heart Study, patients with elevated cardiovascular disease (ASCVD) CAC (≥ 80th percentile for sex and race) event (class of recommendation IIa). randomized to atorvastatin had significant (47) However, it reflects CV risk by reductions in LDL-C and trended toward approximating the total burden of a 30% reduction in CV events compared atherosclerosis and not by elucidating to those randomized to placebo, but there specific biologic pathways that can be was no difference in the progression of targeted. In contrast, hsCRP is a modest CAC over time in these two groups.(39) predictor of CV risk and its elevated levels Similarly, a sub-analysis from the Scottish are considered an ASCVD risk-enhancer Aortic Stenosis and Lipid Lowering in the current cholesterol guidelines. Trial, Impact on Regression (SALTIRE) (47) The landmark CANTOS trial, which trial demonstrated that, despite greater offers the potential to specifically target

Official Publication of the National Lipid Association 13 EBM Tools for Practice: Best Biomarkers for Inflammation

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

with promising results. High-Sensitivity C-Reactive ProteinPrimary risk prediction: Multiple Interleukin-6 (IL-6) studies have shown that elevated levels Discuss this article at Primary risk prediction: In a meta- of hs-CRP among healthy individuals is a www.lipid.org/lipidspin analysis of patients without known strong predictor of future cardiovascular coronary artery disease (CAD), IL-6 events, with a two to four-fold increase elevation showed a relative risk of 1.25 in risk comparing top versus bottom for non-fatal myocardial infarction (MI) tertile, independently of age, gender or coronary heart disease (CHD) death and cholesterol levels.(6) The addition Atherosclerosis is widely recognized as a (p=0.001).(2) Matrix metalloproteinase-9 of hs-CRP to the Reynolds Risk Score chronic inflammatory disorder. Therapies (MMP-9), soluble CD40-ligand (sCD40L), has shown improved ability to estimate with anti-inflammatory effects in patients and tumor necrosis factor alpha (TNF-α) — 10-year cardiovascular risk.(7) In a direct with an increased inflammatory status all upstream markers — had no significant comparison of a panel of inflammatory can reduce cardiovascular events, as the association. markers — including serum amyloid A, CANTOS study showed.(1) Inflammatory In the Physicians’ Health Study, IL-6 and IL-6 and soluble intercellular adhesion markers are an essential tool for evaluating high-sensitivity C-reactive protein (hs- molecule type 1 (sICAM-1) — and various a patient’s inflammatory state. The CRP) had similar predictive risk for future lipid markers, hs-CRP surpassed all of question is: which biomarker is best? myocardial infarction.(3) them as a predictor of cardiovascular events.(8) In the Physicians’ Health Study, A significant body of evidence involves Secondary risk prediction: In the those in the highest quartile of CRP the interleukin-Iβ/interleukin-6 (IL-Iβ/ Stabilization of Atherosclerotic Plaque had three times the risk of an MI, and IL-6) axis, with epidemiologic studies by Initiation of Darapladib Therapy Trial twice the risk of an ischemic stroke.(9) mainly focusing on downstream markers of (STABILITY) and the Stabilization of A cohort study of patients with chronic inflammation (e.g. C-reactive protein [CRP] Plaques using Darapladib — Thrombosis inflammatory conditions revealed that and fibrinogen). Upstream markers of in Myocardial Infarction 52 (SOLID- the incidence of developing diabetes or inflammation, such as IL-6, have had less TIMI 52) trial, IL-6 was significantly and coronary heart disease was greatest in focus.(Figure 1) independently associated with incident those with the highest tertile of CRP. cardiovascular (CV) events, including CV (10) A study of diabetics demonstrated In addition, other biomarkers that involve death, MI and heart failure.(4,5) that baseline and second-year CRP levels different pathways, such as lipoprotein- There are no studies showing IL-6 as provided cardiovascular risk prediction associated phospholipase A2 (Lp-PLA2) and a predictive marker of the success of independently of standard risk factors myeloperoxidase (MPO) have been studied therapy. and glycemic control.(11) In the Anglo-

14 LipidSpin • Volume 17, Issue 1 • January 2019 Scandinavian Cardiac Outcomes Trial Patients (SPIRES) Trial showed that Myeloperoxidase (MPO) (ASCOT), baseline levels of CRP and low- persistent elevation of hs-CRP at 14 Myeloperoxidase (MPO), released from density lipoprotein cholesterol (LDL-C) weeks was associated with increased activated neutrophils, produces reactive were comparable in identifying subsets future CV events even after low levels oxygen species that can cause endothelial at risk of future events.(12) The 2013 of LDL-C were achieved.(20) dysfunction, high-density lipoprotein (HDL) ACC/AHA guidelines include hs-CRP as a 7. Canakinumab Anti-inflammatory dysfunction and plaque instability. recommended marker for measurement Thrombosis Outcome Trial (CANTOS). when the treatment decision is uncertain Despite no change in LDL-C, lowering Prospective studies of healthy individuals based on global risk scoring. hs-CRP below 2 mg/L resulted in and patients with stable and unstable a 25% reduction in major adverse CAD have shown an association between Secondary risk prediction: The cardiovascular events (p<0.001) elevated MPO levels and future CV event baseline level of hs-CRP in the Further and 31% reduction in cardiovascular risk, although other studies were less Cardiovascular Outcomes Research with mortality (p<0.0001).(21) predictive.(28,29) PCSK9 Inhibition in Subjects with Elevated Risk Trial (FOURIER) predicted those at Lipoprotein-Associated Phospholipase In a study of patients with CAD, hs-CRP greatest risk for cardiovascular events.(13) A2 (Lp-PLA2 activity) and MPO each was predictive for CV Lp-PLA2 is an enzyme produced by mortality with additive value and a 4.33- On-treatment risk prediction: Achieved lymphocytes and activated macrophages fold increase in risk when both were level of hs-CRP on treatment is a strong that binds primarily to low-density elevated.(30) There are no studies showing predictor of subsequent outcomes(14) as lipoprotein (LDL) in the serum. Reductions MPO as a predictive marker of success of several trials have shown: in LDL cause a decline in Lp-PLA2 activity, therapy. 1. Aggrastat-to-Zocor Trial (A to Z). The limiting some of its predictive value in achieved levels of hs-CRP at 30 days patients on lipid-lowering therapy.(22,23) Conclusions: and four months were independently 1. Hs-CRP has the most data regarding associated with long-term survival and Multiple studies have shown that prediction of CV risk and is the only risk of MI.(15) elevated Lp-PLA2 levels are predictive inflammatory marker able to predict 2. Reversing Atherosclerosis with for cardiovascular events in primary therapeutic success. It appears to be Aggressive Lipid Lowering Trial prevention and are associated with roughly the biomarker of choice at this time (REVERSAL) reported that regression a doubling of risk(24), however, since and the only one recommended for of vascular disease occurred only in pharmacologic inhibition of Lp-PLA2 does measurement by the 2013 ACC/AHA the group of patients who achieved not reduce event rates(4,5), it is neither a guidelines. low levels of both LDL-C and hs-CRP. goal of therapy nor a U.S. Food and Drug 2. IL-6 has potential, but in head-to-head (16) Administration (FDA)-approved or health comparison with hs-CRP, it was not as 3. Improved Reduction of Outcomes: insurance-reimbursed test.(25) predictive. It also is not as accessible Vytorin Efficacy International Trial as hs-CRP for the practicing clinician. (IMPROVE-IT) and Pravastatin or Lp-PLA2 has shown an additive effect 3. Lp-PLA2 can be used to evaluate Atorvastatin Evaluation and Infection with CRP on CAD risk prediction.(26) risk in primary prevention in statin- Therapy Trial (PROVE-IT) showed Compared with high CRP/low Lp-PLA2 naïve patients. It may be helpful as a that patients that met both targets levels, high CRP/high Lp-PLA2 levels complementary marker of risk with — LDL-C <70 mg/dL and hs-CRP predict a significant risk increase for CAD hs-CRP. It is not designed as a goal of <2 mg/L — had the best outcomes. death (p=0.048).(27) therapy nor to be predictive of risk in (17,18) secondary prevention. 4. Justification for the Use of Statins Importantly, there are two available 4. MPO could be helpful as a in Prevention: An Intervention Trial assays to measure Lp-PLA2 protein with complementary marker of risk with hs- Evaluating Rosuvastatin (JUPITER) equally predictive value. However, direct CRP, but it is less effective as a single patients had the least CV events when measurement of protein concentration can marker. n achieving both an LDL-C <70 mg/dL be dramatically affected by pre-analytic and an hs-CRP <2 mg/L.(19) handling conditions. Therefore, most Disclosure statement: Dr. Moran has received honoraria from Sanofi/Regeneron and Amgen. 5. In ASCOT, on-treatment hs-CRP instead favor measuring the protein’s following statin treatment predicted enzymatic activity, which possesses much References are listed on page 34. subsequent risk reductions.(12) less variability. 6. The Safety and Cardiovascular Event Efficacy of Bococizumab in High-Risk

Official Publication of the National Lipid Association 15 Lipid Luminations: Medications that Reduce Inflammation Also May Reduce Cardiovascular Disease

ERIC K. GUPTA, PharmD, CLS, FNLA Associate Professor, Pharmacy Practice and Administration Western University of Health Sciences, College of Pharmacy Pomona, CA

by decreasing mevalonate, downstream formation of thromboxane A2, leading products such as FPP and GGPP are to decreased platelet aggregation and decreased and their inflammatory potential decreased ASCVD events.(4) In secondary Discuss this article at reduced. Given that reducing inflammation prevention, low-dose aspirin (50-325 www.lipid.org/lipidspin may reduce ASCVD, let us review mg/d) is associated with a 21% decrease medications known to reduce inflammation in nonfatal myocardial infarction (MI), and their potential effects in reducing nonfatal stroke and cardiovascular death. ASCVD. There is an increased risk of bleeding, Along with lipid accumulation, but aspirin for secondary prevention is inflammation plays a key role in the NSAIDs/COX-2 Inhibitors recommended for all patients.(5) However, development of atherosclerosis.(1) Perhaps Non-steroidal anti-inflammatory drugs the risks and benefits are not as universal 3-hydroxy-3-methylglutaryl coenzyme A (NSAIDs) and cyclooxygenase-2 (COX- in primary prevention. The United States reductase (HMG CoA reductase) inhibitors 2) inhibitors are widely used in the Preventive Services Task Force reviewed (statins) are effective in the prevention treatment of inflammatory diseases such the use of aspirin in primary prevention of of atherosclerotic cardiovascular disease as rheumatoid arthritis and psoriasis cardiovascular disease and recommends (ASCVD) because they significantly among others. However, they have been use only in patients from 50 to 69 years decrease low-density lipoprotein (LDL) associated with increased risks for ASCVD, of age with a 10-year risk ≥10% who do particles and inflammation. In the possibly because of their effects on not have an increased risk for bleeding cholesterol synthetic pathway, statins increasing blood pressure or decreasing and are willing to take aspirin for at least block the formation of mevalonate renal function.(3) A recent meta-analysis 10 years.(6) Aspirin is a mainstay of through the inhibition of HMG CoA demonstrated that increased risk was ASCVD prevention and should be used in reductase. However, there are multiple greatest during short-term use (8-30 days) all patients in secondary prevention and downstream products before the formation and with a higher daily dose.(3) Therefore, in the appropriate patients for primary of cholesterol, and some of those — such NSAIDs and COX-2 inhibitors do not have prevention. as farnesyl pyrophosphate (FPP) and a role in reducing ASCVD. geranylgernayl pyrophosphate (GGPP) — Canakinumab may play essential roles in immune cell Aspirin Canakinumab is a fully human activation, cytokine production and other Aspirin irreversibly binds to monoclonal antibody that binds to human aspects of inflammation.(2) Therefore, cyclooxygenase-1, which reduces the interleukin-1β (IL-1β) and prevents it from

16 LipidSpin • Volume 17, Issue 1 • January 2019 interacting with the interleukin-1 receptor, which will decrease the production of which leads to anti-inflammatory effects. urate crystals. A study of allopurinol in (7) It is approved for the treatment of “Not all medications chronic kidney disease demonstrated rare disorders, but a recent prospective, a lower risk of cardiovascular events in randomized trial — Canakinumab used to treat allopurinol versus the control group (HR Antiinflammatory Thrombosis Outcomes inflammation are 0.43; p=0.02; 95% CI 0.21-0.88).(17) This Study (CANTOS) — assessed its effects benefit may be because of a decrease in hs- in reducing ASCVD.(8) The CANTOS beneficial to reduce CRP.(18) Further prospective, randomized study demonstrated in patients with controlled trials need to be conducted to a history of MI and a high-sensitivity ASCVD morbidity and validate this effect. C-reactive protein (hs-CRP) >2.0 mg/L that canakinumab had no effect on lipid mortality.” In summary, not all medications used to levels, significantly reduced inflammatory treat inflammation are beneficial to reduce biomarkers (hs-CRP by approximately ASCVD morbidity and mortality. Aspirin 40% and IL-6 by approximately 35%), disease and either type 2 diabetes or and canakinumab are the only entities and significantly reduced the primary metabolic syndrome has been completed proven effective through randomized, endpoint (nonfatal MI, nonfatal stroke or to determine the effects on a primary controlled clinical trials. Aspirin already is cardiovascular death) by 15% (p=0.021, endpoint of nonfatal MI, nonfatal stroke, widely recommended, and it remains to be 95% CI 0.74-0.98) for the 150 mg dose cardiovascular death, and hospitalization seen if canakinumab will be widely used given subcutaneously every three months. for unstable angina leading to urgent for ASCVD. Some therapies, like NSAIDs However, there was an increased risk revascularization.(14). In this trial, and COX-2 inhibitors, have been proven of death from infection or sepsis in the methotrexate did not reduce IL-1β, IL-6, to be harmful and should not be used. canakinumab arm versus placebo (0.31 or hs-CRP versus placebo and did not Lastly, there are older anti-inflammatory events vs 0.18, p=0.02).(8) Also the price significantly reduce the primary endpoint agents that are in various stages of large of one dose is estimated to be around (hazard ratio 0.96, CI 0.79-1.16, p=0.67). prospective clinical trials. It remains to $16,000, which may be cost-prohibitive.(9) Methotrexate was associated with an be seen if they will be effective. If so, increased risk of infection (p=0.02), they may provide us with cost-effective Methotrexate leukopenia (p<0.001), gastrointestinal alternatives to reduce inflammation toward Methotrexate inhibits dihydrofolate disorders (p=0.006), mouth sores the greater goal of reducing ASCVD. n reductase, which interferes with DNA (p=0.001), and elevated liver function synthesis and cellular replication and, in tests (p=0.03).(14) Methotrexate did not Disclosure statement: Dr. Gupta has received honoraria from Amgen. turn, leads to a decrease in inflammation. demonstrate a benefit in ASCVD in this References are listed on page 35. It is approved for the treatment of some trial, however it may be due to the lower forms of cancer, rheumatoid arthritis baseline hs-CRP levels of the participants and psoriasis.(10) Methotrexate use (1.6 mg/L vs 4.2 mg/L in CANTOS).(14) is associated with decreased amounts Perhaps, a future study enrolling patients of IL-1β and IL-6.(11) A six-year study with more elevated levels of inflammation of 1,240 patients with rheumatoid may produce different results. arthritis taking a mean dose of 13 mg/ week of methotrexate demonstrated a Other Agents 70% reduction in cardiovascular disease Colchicine inhibits microtubule formation mortality.(12) A subsequent meta- and may interfere with inflammasome, analysis demonstrated a 21% lower leading to decreased production of risk for cardiovascular disease with an interleukin-1 beta (IL-1β).(15) A recent average methotrexate dose between meta-analysis found that colchicine can 13-15 mg/week.(13) A large, prospective, reduce composite cardiovascular outcomes randomized trial comparing methotrexate by 60%.(16) There are prospective trials 15-20 mg/week versus placebo in patients under way to further evaluate this concept. with previous MI or multivessel coronary Allopurinol inhibits xanthine oxidase,

Official Publication of the National Lipid Association 17 Practical Pearls: Top 10 Ways to Reduce Inflammation

CEZARY WÓJCIK, MD, PhD, DSc, FNLA Department of Family Medicine Oregon Health and Sciences University Portland, OR Diplomate, American Board of Clinical Lipidology

for CV risk reduction in the foreseeable physical activity are at least partially future. The following are top 10 practical caused by the release of several anti- approaches to lower systemic inflammation inflammatory cytokines from skeletal — approaches that either reduce or may muscles. Moreover, even without Discuss this article at www.lipid.org/lipidspin reduce CV risk. It needs to be kept in mind weight loss, physical activity leads to that, while those strategies are or may be a decrease in the size of visceral fat, beneficial, it is unclear how much of that which is a known producer of pro- benefit depends on the anti-inflammatory inflammatory cytokines. Numerous effect versus other mechanisms of action. studies have associated increased Inflammation is a dynamic process with physical activity with longevity and many interconnected signaling pathways 1. Diet — Western dietary pattern decreased risk of cardiometabolic involving multiple classes of cells by which (high in red meat, full-fat dairy disorders.(6) the human body responds to pathogen and refined carbohydrates) is 3. Probiotics — Emerging evidence exposure and/or tissue damage, playing a pro-inflammatory, while healthy links changes in gut microbiome central role in all stages of atherosclerosis. patterns such as low-fat, plant-based with increased CV risk, possibly (1) Cholesterol crystals directly activate and Mediterranean diets are anti- through the increased risk of obesity nucleotide-binding oligomerization inflammatory. There is a proven CV and systemic inflammation, raising domain-like receptor protein 3 (NLRP3) benefit to following a Mediterranean the hypothesis that probiotics inflammasome and interleukin 1 beta (IL- diet, which is associated with high- may decrease inflammation and 1β) production. Therefore, cholesterol sensitivity C-reactive protein (hs- thus, decrease CV risk.(7) Several lowering, per se, has an anti-inflammatory CRP) lowering in patients at risk probiotic strains, most notably effect.(2) The Canakinumab Anti- for heart disease.(4,5) Moreover, L. reuteri NCIMB 30242, reduce hs- inflammatory Thrombosis Outcome Study weight loss associated with reduced CRP and fibrinogen and directly lower (CANTOS) has proven that blocking energy intake leads to a reduction of low-density lipoprotein-cholesterol IL-1β signaling with canakinumab inflammatory markers.(6) (LDL-C) and total cholesterol levels. decreases cardiovascular (CV) events by 2. Physical activity — Sedentary (8) More trials are needed to fully ~15% without impacting lipid levels.(3) lifestyle is pro-inflammatory, while determine anti-inflammatory effects However, because of its very high cost, increased physical activity reduces of probiotics and their potential canakinumab is unlikely to be approved inflammatory markers. Benefits of impact on CV outcomes

18 LipidSpin • Volume 17, Issue 1 • January 2019 4. Curcumin — Supplementation with effects, statins have demonstrated be treated by many agents, among this natural product derived from “pleiotropic effects” that include them the renin–angiotensin– turmeric is associated with variably effects on multiple pathways aldosterone axis blockade. While decreased levels of circulating associated with the lowering of angiotensin-converting enzyme (ACE) hs-CRP and other inflammatory inflammatory markers.(1,2) inhibitors do not affect inflammation, markers. This variability depends despite their known CV benefits, 7. Aspirin and other antiplatelet on the preparations used and ARBs appear to lower circulating agents — While the benefits of the duration of supplementation. inflammatory markers by blocking the aspirin mostly are attributed to Its exact mechanism of action is angiotensin 1 receptor and, thus, may the anti-platelet — and, thus, anti- unknown. More trials are needed to provide additional benefits.(18) thrombotic activity — the highest fully determine its anti-inflammatory reduction in CV risk is achieved 1. Metformin, sodium-glucose effects and any potential impact on in patients with high hs-CRP cotransporter-2 inhibitors CV outcomes.(9) levels, regardless of the degree (SGLT2i) and glucagon-like 5. Omega-3-polyunsaturated fatty of anti-platelet effects, indicating peptide-1 receptor agonists acids (PUFAs) — While both its potential value in patients (GLP1-RAs) — Type 2 diabetes eicosapentaenoic acid (EPA) and with evidence of inflammation. is considered a coronary artery docosahexaenoic acid (DHA) decrease (13) However, other nonsteroidal disease equivalent and is associated triglycerides, DHA may increase anti-inflammatory drugs (NSAIDs) with inflammation. Emerging LDL-C levels. However, they both increase cardiovascular risk despite evidence indicates that the choice of decrease systemic inflammation. efficiently decreasing inflammation. antidiabetic agent matters, especially A recent meta-analysis of available On the other hand, antiplatelet in patients at high CV risk. Among trials suggests a modest 8% reduction agents clopidogrel and prasugrel its many effects, metformin lowers in cardiac death associated with are able to lower hs-CRP and other hs-CRP and other inflammatory omega-3 supplementation.(10) In inflammatory markers without markers, having beneficial effects on the Reduction of Cardiovascular affecting cyclooxygenase activity.(1,2) the CV system.(19) GLP1-RAs and Events with EPA-Intervention SGLT2i lower different inflammatory Trial (REDUCE-IT), administration 8. Non-Statins — Effects of ezetimibe markers, which may, at least in of ~4 g daily of pure EPA over on inflammation, either alone or in part, account for their surprising CV a median of 4.9 years to both combination with statins, are modest benefits.(20) n primary and secondary prevention and likely directly stem from the patients with LDL-C < 100 mg/dL degree of LDL-C lowering.(14) There Disclosure Statement: Dr. Wojcik has no financial disclosures to report. and triglycerides 135 to 499 mg/ also appears to be a beneficial effect References are listed on page 35. dL lead to a 25% reduction in major of fibrates on inflammatory markers, adverse cardiovascular events.(11) especially in diabetic patients, Those beneficial effects can be at possibly mediated downstream of least partially accounted for by the peroxisome proliferator-activated anti-inflammatory effects of omega-3 receptor (PPAR).(15) Similarly, PUFAs. niacin appears to decrease hs-CRP levels in patients after a recent non- 6. Statins — As demonstrated in ST-elevation myocardial infarction Justification for the Use of Statins (NSTEMI).(16) Surprisingly, in Prevention: an Intervention Trial proprotein convertase subtilisin/kexin Evaluating Rosuvastatin (JUPITER), type 9 (PCSK9) inhibitors do not statins decrease CV events and all- lower hs-CRP levels based on meta- cause mortality, even in patients with analysis of published trials.(17) low levels of LDL-C, when they have high levels of hs-CRP indicative of 9. Angiotensin II receptor blockers systemic inflammation.(12) On top (ARB) — Hypertension is a well- of their well-known LDL-lowering established CV risk factor. It can

Official Publication of the National Lipid Association 19 Case Study: Identifying and Managing the Patient with High Inflammatory Burden

ROB GREENFIELD, MD, FNLA MICHELLE TAYLOR, CCRN, CLS, ANP University of California-Irvine Medical Center Acute Care NP - Cardiology California Heart Associates MemorialCare Heart and Vascular Institute Fountain Valley, CA Orange Coast Medical Center Diplomate, American Board of Clinical Lipidology Fountain Valley, CA

after suffering an ST-segment elevation placement of two drug-eluting stents. The myocardial infarction (STEMI) that was following morning, as we approached her successfully stented. Aside from being an bedside, she asked us, “Why did I have Discuss this article at ex-smoker who quit 35 years ago, there another heart attack?” www.lipid.org/lipidspin is no history of diabetes or hypertension and no family history for premature heart MS. TAYLOR: A significant percentage disease. At the time of her MI, she was of residual ASCVD risk exists in patients placed on atorvastatin 80 mg daily. Six treated with high-intensity statin, months later, the dose was reduced to especially if inflammation still may CASE STUDY 40 mg daily because of complaints of be present.(1) While Ms. C was not This case has unanswered questions myalgias. Other medications included ASA obese, remained a non-smoker and was but shows how a cardiologist and nurse 81 mg daily, metoprolol XL 25 mg daily normotensive with a normal fasting blood practitioner who became certified lipid and losartan 25 mg daily. A lipid profile glucose, her elevated hs-CRP suggests the specialists create a team approach for their one month ago demonstrated these results presence of an inflammatory component in patient. (Table 1). her ongoing cardiovascular risk. In 2008, the Justification for the Use of MS. TAYLOR AND DR. GREENFIELD: One month after her initial appointment, Statins in Prevention: an Intervention Ms. C is a 59-year-old woman relocating she was admitted through the emergency Trial Evaluating Rosuvastatin (JUPITER) from another state and seeking a department (ED) with an acute anterior (2) took patients free of atherosclerotic cardiology follow-up evaluation two years wall myocardial infarction treated with cardiovascular disease (ASCVD) with

Total cholesterol (TC) 146 mg/dl High-sensitivity C-reactive protein (hs-CRP) 3.5 mg/L (repeated 2 weeks later at 3.2 mg/L) Triglycerides (TG) 130 mg/dl Lipoprotein (a) [Lp(a)]= 10 nmol/L High-density lipoprotein cholesterol (HDL-C) 58 mg/dl Fasting glucose 96 mg/dl, Low-density lipoprotein cholesterol (LDL-C) 62 mg/dl. Hemoglobin A1C (HbA1C) 5.6%. Blood pressure (BP) was 110/70 Pulse 64 Body mass index (BMI) 28 kg/m2 Physical exam otherwise unremarkable Table 1.

20 LipidSpin • Volume 17, Issue 1 • January 2019 our patient has suffered a cardiovascular event. She is very well treated with a high-intensity statin and has a low LDL-C, but she still suffered recurrent MI. Her persistent elevated hs-CRP suggested a marker of residual cardiovascular risk. I took this time to review the medical literature with our patient. I wanted to show her that there is clinical trial evidence demonstrating that residual ASCVD risk is associated with elevated hsCRP, even in patients on maximal medical therapy and who have achieved high-intensity LDL-C reduction.

More Evidence of Residual Risk: FOURIER, GLAGOV and CANTOS: More recent literature sheds additional

Figure 1. light on this conundrum of inflammation. The Global Assessment of Plaque hs-CRP > 2 mg/L and relatively normal controlled blood pressure and glucose, as is Regression With a PCSK9 Antibody as LDL levels <130mg/dl. Treatment with the case on our patient. Investigators from Measured by Intravascular Ultrasound rosuvastatin resulted in a 44% reduction the Cleveland Clinic also have identified (GLAGOV) (figure 1) (6) illustrated that, in the primary endpoint of nonfatal MI, the gut microbiome as playing a role in even when the LDL-C level had been stroke or death. In addition, the lowest inflammation and cardiovascular disease.(3) reduced to below 50 mg/dl by using event rates in JUPITER were shown in Consumption of red meat, egg yolks and a high-intensity statin in combination those with both an LDL-C < 70 mg/dl and energy drinks and substances that contain with the PCSK-9 inhibitor evolocumab, an hs-CRP < 2 mg/L. choline, L-carnitine and betaine can result atherosclerosis still continued to progress in production of trimethylamine (TMA) in more than one-third of these patients, The National Lipid Association (NLA) that when oxidized in the liver is converted demonstrating that the disease was not Recommendations for Patient-Centered to trimethylamine oxide (TMAO), a halted in these high-risk patients despite Management of Dyslipidemia: Part 2 substance that is pro-inflammatory. Higher such aggressive therapy. comprehensively outlines therapeutic levels of TMAO are predictive of increased lifestyle changes and the appropriateness risk of major cardiovascular events.(4) Moreover, in the landmark FOURIER of discussing it as initial management. Vegans and vegetarians have much lower cardiovascular outcomes trial(7) of (1) While our patient often consumed TMA levels than omnivores, which may evolocumab, the modest 15% relative risk red meat and bakery products, the in part explain their lower risk for major reduction indicates many ASCVD events NLA recommendations suggest a diet adverse cardiovascular events. Increased still occur despite aggressive therapy. emphasizing fish consumption — physical activity with 150 minutes/week of When these results were stratified by preferably high in omega-3 fatty acids moderate exercise such as brisk walking, baseline levels of hs-CRP in those with — poultry, nuts, seeds, grains, fruits as recommended by the ACC/AHA Lifestyle higher levels of hs-CRP, risk reduction and vegetables, and limited saturated Management Guidelines(5), also can help was attenuated despite aggressive LDL-C fats found in red meat and whole milk promote normal levels of lipids and blood reduction down to 20 mg/dL.(8) (Figure 2) products, as well as processed meats and pressure, addressing residual ASCVD risk sugar. in our patients. Finally, Canakinumab Anti-inflammatory Thrombosis Study (CANTOS) evaluated Residual risk often remains in patients DR. GREENFIELD: As healthcare the response to interleukin 1-beta (IL-1β) treated with statins, especially if hs-CRP providers, we become distressed when we monoclonal antibody in stable ASCVD remains elevated(2) and despite well- can’t find a plausible explanation as to why (prior MI) patients with hs-CRP levels

Official Publication of the National Lipid Association 21 >/= 2 mg/L and mean LDL-C 82 mg/ dl.(9) From canakinumab injected at a dose of 150 mg or 300 mg every three months, there was no change in LDL-C, but there was a 41% decrease in hs-CRP and a 15% relative risk reduction for the composite primary endpoint of nonfatal MI, stroke and CV death over 3.7 years of follow-up. There was a higher rate of fatal infections in the canakinumab compared to placebo group, however. This medicine recently was rejected by the United States Food and Drug Administration (FDA) as directed therapy for cardiovascular risk reduction, but the results of CANTOS support the concept that anti-inflammatory pharmacotherapy may have a future role in care.

MS. TAYLOR AND DR. GREENFIELD: Figure 2. What does the future hold? The future development of targets for looking at promoting natural inhibitors “Optimism is the faith that leads to inflammation remains an active area of interleuken 1 (IL-1) (IL-receptor achievement. Nothing can be done without of investigation.(10) Recent research antagonists). hope and confidence.” — Helen Keller n reveals other potential anti-inflammatory candidates, including colchicine, a drug Take-home messages Disclosure Statement: Dr. Greenfield has received honoraria from Sanofi, Regeneron and Amgen. used in treatment of gout(11), a crystal- Ms. C has residual ASCVD risk suggested Dr. Taylor has no financial disclosures to report. induced disease that may share a similar by elevated hs-CRP despite optimal References are listed on page 35. mechanism of action as cholesterol crystals medical therapy and LDL-C reduction. do in coronary plaques. The Cardiovascular Presently, the only available therapy Inflammation Reduction Trial (CIRT) of for this is intensification of therapies, low-dose methotrexate in individuals at especially therapeutic lifestyle changes and high risk for cardiovascular disease who possibly specific diets shown to reduce have diabetes or the metabolic syndrome inflammation. Moreover, addressing was stopped early because of futility.(12) residual risk needs to be a team approach. Observers of this study point out that While many cardiologists often are most the mean hs-CRP level in study subjects concerned about the immediate result of was normal and failure to demonstrate the success of a percutaneous intervention, improved outcome may be because of spending time and collaborating with other selection of the wrong patient type. providers and the greater healthcare team They noted that observational data of — including nurses, nurse practitioners methotrexate benefits in rheumatoid and and lifestyle “interventionalists” such psoriatic arthritis patients provides hope as registered dietitian nutritionists and for benefit in others. There also are animal exercise physiologists who best can work studies of investigational agents looking out a long-term plan to reduce risk over at other inflammatory cytokines, such as a lifetime — is crucial. Optimism also interleukin 18 (IL-18), tumor necrosis remains for the future development of factor (TNF-alpha), and even studies newer therapies to target inflammation.

22 LipidSpin • Volume 17, Issue 1 • January 2019 Chapter Update: Focus on Member Engagement

ERIC K. GUPTA, PHARMD, CLS, FNLA NATHAN D. WONG, PhD, FNLA President-Elect, Pacific Lipid Association President, Pacific Lipid Association Associate Professor, Professor and Director, Heart Disease Pharmacy Practice and Administration Prevention Program Western University of Health Sciences, Division of Cardiology, University of California College of Pharmacy Irvine, CA Pomona, CA

MICHAEL D. SHAPIRO, DO, FACC, FNLA CAROL KIRKPATRICK, PhD, MPH, RDN, Treasurer, Pacific Lipid Association CLS, FNLA Center for Preventive Cardiology Secretary, Pacific Lipid Association Knight Cardiovascular Institute Clinical Associate Professor/Director Oregon Health and Science University Wellness Center, Kasiska Division of Health Sciences Portland, OR Idaho State University Diplomate, American Board of Clinical Lipidology Pocatello, ID

Yehuda Handelsman, MD, FACP, FACE, FNLA Past President, Pacific Lipid Association Private Practice: Endocrinology, Diabetes, Metabolism, Internal Medicine Medical Director and Principal Investigator Metabolic Institute of America Tarzana, CA

This year promises to be an important newer and younger members (and forgive turning point for the Pacific Lipid us if we have not mentioned all who have Association (PLA). Our goal is to made recent valuable contributions). reinvigorate our membership through One key example is PLA member Geeta Discuss this article at www.lipid.org/lipidspin greater opportunities to serve the PLA Sikand, MS, RDN, CLS, FAND, FNLA, and National Lipid Association (NLA). Director of Nutrition for UC Irvine’s This can only be done by improving Preventive Cardiology Program, a long- member communication and engaging time NLA member. Geeta recently led a our membership in activities that are both large writing group of nutrition experts continues to serve as an advocate for personally rewarding and promote the on completing the paper, “Clinical and patients and professionals who would mission and goals of the PLA/NLA. cost benefit of medical nutrition therapy benefit from access to registered dietitian by registered dietitian nutritionists nutritionists. First, it is worthwhile to applaud some for management of dyslipidemia: a accomplishments of a few of our PLA systematic review and meta-analysis,” Moreover, PLA Immediate Past President, members who have contributed greatly which was published in the Journal of Yehuda Handelsman, MD, FNLA, head to the mission of the PLA/NLA and serve Clinical Lipidology online (tinyurl.com/ of the Metabolic Institute of America, as an inspiration for the involvement of jclmedicalnutritiontherapy). Geeta is legendary in his creation of the

Official Publication of the National Lipid Association 23 highly successful Diabetes in the Heart risk assessment and gold-level recognition recent accomplishments (publications, Conferences (the second annual meeting for demonstrating 70% of eligible high- promotions, awards) that we might just completed) and, of course, the World risk patients are on statin therapy, as part highlight in this new forum. Congresses on Insulin Resistance, Diabetes of a nationwide effort to improve lipid and Cardiovascular Disease successfully control among our higher risk patients. Most importantly, we hope through the held annually in Los Angeles for the past We especially encourage our members to activities highlighted above, and other 15 years. be part of this effort. More details can be means, we will empower our members to found at tinyurl.com/ahaccc. be more active contributors to the mission In addition, the Orange County (California) of the PLA/NLA. We encourage members Symposium for Cardiovascular Disease to be leaders in their community by Prevention, which has had as an important promoting lipid education and other goals focus educating local clinicians about “We encourage of the PLA/NLA among their colleagues. clinical lipidology, endorsed by the PLA We especially encourage you to advocate and organized by PLA Past Presidents members to be for healthcare providers and scientists Paul Rosenblit, MD, PhD, FNLA, Rob of tomorrow to join in the great mission Greenfield, MD, FNLA, and Nathan Wong, leaders in their to help prevent cardiovascular disease PhD, FNLA, is now in its 10th year. through improved education, clinical care, community by and research around clinical lipidology. n Finally, cardiologist, clinical lipidologist promoting lipid and PLA Past President John R. Nelson, Disclosure statement: Dr. Gupta has received honoraria from Amgen. Dr. Wong has no financial MD, FNLA, organized a satellite program education and other disclosures to report. Dr. Shapiro has received at the 2018 NLA Scientific Sessions, “The honoraria from Kastle, Novartis and Regeneron. Dr. Kirkpatrick has no financial disclosures to report. Emerging Role of Eicosapentaenoic Acid goals of the PLA/ (EPA) and Docosahexanoic Acid (DHA) in Atherosclerosis,” that was an extremely NLA among their popular event. Additionally, because of his passion for community service, Dr. colleagues.” Nelson, along with PLA members, Wayne True, MD, MPH, FNLA, and Nathan Wong, PhD, FNLA, provided participant consultation on cardiovascular risk factor Second, the PLA is making a concerted management at the Native Health Center effort to better promote education in at the February 2017 Spring Clinical Lipid lipids and related cardiovascular risk Update in Phoenix. We have provided factors by encouraging its members to this service at such health fairs because host local dinner programs, as well as of the collaboration we have had over the regional symposia. A document is being past few years with the American Heart made available to all PLA members about Association (AHA). specific non-branded CME and non-CME opportunities available by a variety of The PLA has several important initiatives sponsors in the lipid and cardiometabolic for this year. One key effort is a space. collaboration between the AHA and the NLA, initiated by the PLA, that will Third, we hope to further improve establish the first jointly marketed program member communication and highlight between a NLA chapter and the AHA. The member accomplishments through a Check. Change. Control. Cholesterol.™ quarterly newsletter being produced program offers practices and organizations by all NLA chapters. It is my hope that opportunities to receive participant-level PLA members will reach out to the NLA recognition for initiating cardiovascular communications staff to inform us of any

24 LipidSpin • Volume 17, Issue 1 • January 2019 Specialty Corner: Dietary Patterns and Systemic Inflammation: Examining the Connection

ALYSSA LYNOTT, RDN, LD CAROL KIRKPATRICK, PHD, Nutrition/Wellness Coach, Wellness Center MPH, RDN, CLS, FNLA Idaho State University Director, Wellness Center Kasiska Division of Health Sciences Idaho State University Pocatello, ID Kasiska Division of Health Sciences Pocatello, ID

GEETA SIKAND, MA, RDN, CDE,CLS, FNLA Director of Nutrition Preventive Cardiology Program Associate Clinical Professor of Medicine (Cardiology) University of California Irvine Irivine, CA

Introduction Mediterranean-style dietary patterns, Chronic systemic inflammation is can promote anti-inflammatory effects. associated with the development of many (3,4) Studies using evidence-based chronic diseases, including metabolic cardioprotective dietary patterns — or Discuss this article at syndrome, obesity, type 2 diabetes components of these dietary patterns — www.lipid.org/lipidspin mellitus, and atherosclerotic cardiovascular found an association with reductions in disease (ASCVD). Because of this, an inflammatory biomarkers.(2,5,6) The anti- increasing number of clinicians are inflammatory properties of these dietary measuring inflammatory biomarkers in patterns are attributed to the indirect independent of weight loss.(2,6) patients. The inflammatory biomarkers consequences of metabolic improvements most commonly measured in clinical (i.e., weight reduction, triglyceride (TG)- Polyunsaturated Fatty Acids and practice are C-reactive protein (CRP), lowering, non-high-density lipoprotein Inflammation which is an acute-phase protein, and cholesterol/apolipoprotein B (non HDL-c/ The authors feel strongly that the evidence interleukin-6 (IL-6) and tumor necrosis apoB)-lowering, glycemic improvements) does not show an inflammatory reaction to factor-alpha (TNF-α), which are pro- and directly from the greater than 8,000 high intake of n-6 PUFA’s as is commonly inflammatory cytokines.(1,2) phytochemicals found in vegetables, fruits, claimed. In a prospective cohort study, Nutrition is one of the most important beans, lentils, nuts, seeds and whole an increase in n-6 PUFAs intake did lifestyle factors and it has the potential grains.(7) The DASH and Mediterranean- not lead humans to have increased pro- to have a significant impact on the style dietary patterns are rich in low- inflammatory cytokines such as CRP, IL-6 inflammatory process. Strong evidence glycemic-index foods. Studies suggest and soluble TNF receptors 1 and 2, and supports that cardioprotective dietary low-glycemic foods and specific nutrients a high intake of both n-3 and n-6 PUFAs patterns, including the Dietary Approaches in these dietary patterns have the potential was associated with the lowest levels of to Stop Hypertension (DASH) and to reduce inflammatory biomarkers inflammatory biomarkers.(8) Additionally,

Official Publication of the National Lipid Association 25 examined a “healthy” dietary pattern or a Mediterranean-style dietary pattern compared to Western-style or meat- based dietary patterns. The “healthy” and Mediterranean-style dietary patterns are similar in that they both have a high intake of fruits, vegetables, low-fat dairy products, whole grains, fish and lean poultry; however, the Mediterranean-style dietary pattern also is high in olive oil, lentils, legumes, and nuts. A Western-style dietary pattern has a high intake of red meats, processed meats, refined grains, high-fat dairy and other high-fat foods. Figure 1. Forest plot of the association between the dietary inflammatory index and the risk of cardiovascular Results of systematic reviews and meta- diseases.17 analyses suggested that the Western-style dietary patterns were associated with plasma n-6 PUFA concentration was increase in inflammatory biomarkers.(12) higher levels of inflammatory markers, inversely associated with the level of while “healthy” and Mediterranean- pro-inflammatory interleukin-1Ra and Nuts have been shown to reduce high style dietary patterns were associated positively associated with the level of sensitivity CRP (hs-CRP), IL-6 and with lower levels of CRP, IL-6 and TNF- anti-inflammatory transforming growth fibrinogen and increase adiponectin. α(2,5,6,13) Lower CRP was consistently factor-β.(9) Strong evidence supports that Dietary patterns high in nuts are associated and significantly associated with dietary replacing saturated fatty acids (SFAs) with with lower inflammatory biomarkers, patterns, especially the Mediterranean- PUFAs is associated with a decreased risk such as intercellular adhesion molecule-1 style dietary pattern.(2,5,6) One systematic of ASCVD(10) and is recommended as (ICAM-1) and vascular cell adhesion review (5) examined the association part of an overall cardioprotective dietary molecules (VCAM). Nuts are also a good between dietary indices or scores vs. pattern.(3,4) Clinicians can feel confident source of L-arginine content, a precursor dietary patterns and found that, among when they educate patients on consuming of nitric oxide production.(7) Turmeric, 18 cross-sectional studies, 17 found foods rich in n-6 PUFAs in place of foods cinnamon, red wine, and dark chocolate statistically significant associations with rich in SFAs. Plant-based foods rich in n-6 also have been found to exhibit anti- the dietary scores (10 studies used the PUFAs include nuts, seeds and oils (e.g., inflammatory effects.(7) Clinicians should Mediterranean Diet Score or the Healthy safflower, soybean and sunflower) and educate patients that dark chocolate, Eating Index score) and inflammatory can be part of a cardioprotective dietary particularly some less pure forms, is biomarkers. pattern. high in calories and sugar, but can be included in small portions within an Additionally, a small randomized crossover Fatty Fish, Fruits, Vegetables, Nuts, overall cardioprotective dietary pattern. In study of post-pubescent females with Turmeric and Cinnamon addition clinicians should always exercise metabolic syndrome (n=60) found that Fatty fish (e.g., salmon, cod, halibut, extreme caution when discussing health following the DASH dietary pattern for 6 tuna, anchovies, mackerel, and sardines) benefits of any alcohol, since there is a weeks resulted in a significant decrease are good sources of n-3 fatty acids and very high prevalence of alcoholism and in CRP.(14) Although there was not a are effective in lowering inflammatory it should not be promoted for its health significant interventional effect on serum biomarkers.(7) Fruits and vegetables benefits. TNF-α, IL-2, IL-6 or adiponectin, there are rich in many phytochemicals (e.g., was a trend to significant level of a group anthocyanins, carotenoids, lycopene Cardioprotective Dietary Patterns and time interactions for IL-6. Strong evidence and lutein) and have been shown to Inflammation supports the cardioprotective and potential reduce inflammatory biomarkers.(7,11) Systematic reviews(2,5) and meta- anti-inflammatory benefits of following a Conversely, a higher intake of red meat analyses(6) on dietary patterns and their Mediterranean-style dietary pattern and and processed meat was associated with an effect on inflammatory biomarkers have DASH has the components of the “healthy”

26 LipidSpin • Volume 17, Issue 1 • January 2019 dietary pattern examined in multiple studies. These results also support the use of a dietary assessment tool to determine the potential for a patient’s dietary pattern to increase inflammatory biomarkers.

The Dietary Inflammatory Index and ASCVD Risk The Dietary Inflammatory Index (DII) was developed to provide a tool that could assess the overall inflammatory potential of an individual’s dietary patterns.(15) Several studies have determined a direct association between the DII score and a high risk of ASCVD.(16-19) The DII assesses the impact of 45 food parameters Figure 2. Forest plot of summary relative risks (RRs) of CVD occurrence and CVD mortality for the highest vs. on six inflammatory biomarkers (CRP, lowest (reference) category of DII. The Iowa Women’s Health Study (IWHS); National Health and Nutrition Examination Survey (NHANES); Swedish Mammography Study (SMC).18 IL-4, IL-6, IL-10, IL-1β and TNF-α). Each dietary parameter was assigned a positive score (+1) if its effect was pro- legumes, nuts, seeds, whole grains, non- the Dietary Inflammatory Index is not inflammatory (significantly increased IL-1β, tropical plant-based oils and fatty fish — considered an evidence-based assessment IL-6, TNF-α or CRP, or decreased IL-4 or have the potential to reduce inflammatory tool for the relationship between dietary IL-10), a negative score (-1) if its effect markers in individuals. intake and inflammation in clinical was anti-inflammatory, and 0 if it did not practice. Clinicians are encouraged to significantly change the biomarkers.(16) Conclusion assess patients’ dietary intake compared Thus, a higher DII score represents a pro- A cardioprotective dietary pattern such to evidence-based cardioprotective dietary inflammatory diet and a lower DII score as DASH or the Mediterranean-style diet patterns and provide education and/ represents an anti-inflammatory diet. Two is an evidence-based intervention for or referral to a RDN for individualized meta-analyses that examined using the DII ASCVD prevention and management. medical nutrition therapy for following a to assess the risk of CVD determined that Recent research results have indicated cardioprotective dietary pattern. n individuals consuming a pro-inflammatory that dietary patterns can beneficially diet had a 35%(17) to 36%(18) higher affect inflammatory biomarkers. Clinicians Disclosure Statement: Dr. Lynott has no financial disclosures to report. Dr. Kirkpatrick has no financial risk for CVD than those following an can have a “teaching moment” if they disclosures to report. Dr. Sikand has no financial anti-inflammatory diet (Figures 1 and 2). identify whether a patient is consuming a disclosures to report. Similarly, a meta-analysis by Zhong, et pro- vs. anti-inflammatory dietary pattern. References are listed on page 35. al.,(19) determined that pro-inflammatory Knowing this information would allow diets — indicated by a higher DII — are referral to a registered dietitian nutritionist independently associated with an increased (RDN) for medical nutrition therapy on risk of CVD and CVD mortality. Results following a personalized “healthy,” DASH from these studies suggest the DII may be or Mediterranean-style dietary pattern. A a valuable tool in determining CVD risk. cardioprotective dietary pattern will benefit patients’ health as research continues to Summary clarify the role of lifestyle therapies on Strong evidence suggests that diet plays an systemic inflammation and ASCVD risk. important role in inflammatory response, as reported by the impacts of DII on ACVD Authors’ note: The Dietary Inflammatory risk and mortality. Dietary patterns, such Index has been validated for use in a as DASH and the Mediterranean-style diet variety of populations and has been — with a high intake of fruit, vegetables, used in research. However, at this time,

Official Publication of the National Lipid Association 27 Member Spotlight

WENJUN FAN, MS PhD Candidate University of California-Irvine Irvine, CA

Could you explain the correlation Q. What are your plans after earning between Public Health and your your PhD? interest in lipid management? Discuss this article at A: My ultimate goal is to be a physician www.lipid.org/lipidspin A: In ancient days, public health was more as well as an academic researcher. focused on the management of infectious From my master’s degree in Biomedical disease such as measles, smallpox, and Translational Science, I’ve learned chickenpox, etc. With the development of that we are experiencing a significant Q: Could you tell us about what drew medical techniques, most of the infectious gap between academic research and you to preventive cardiology? diseases were under control through clinical practice. The conflict between vaccines or other preventive procedures, individualized treatment and general A: I was very interested in cardiology especially in developed countries. guidelines is controversial and always during medical school. However, after Therefore, a research trend towards debated between academic researchers witnessing my two grandpas pass away chronic disease management emerged and clinical practitioners. I am fortunate from a serious heart attack and ischemic in public health. Lipid management is to have received an education from both stroke, I realized the importance of significantly important as it is related medical school and graduate school in cardiovascular disease prevention before to various chronic conditions including public health. I’m willing to apply my limited treatments could be applied for its dyslipidemia, diabetes mellitus, metabolic interdisciplinary knowledge to benefit both irreversible consequences. I believe there syndrome and cardiovascular disease. sides and more importantly, to benefit are millions of individuals and families Moreover, lipid levels are modifiable patients. living with regret for not taking appropriate through lifestyle management as well preventive cardiology strategies for their as pharmaceutical therapy. As public Q. You have published a number loved ones before it is too late. I was health researchers, our role is to improve of papers, presented at the NLA’s drawn to this specialty so that I could save outcomes of numerous chronic conditions abstract competition, and presented more lives by providing treatments for through constructing strategies to at the American Diabetes Association. these diseases. optimize lipid profiles on a population What advice do you have for other level while physicians are responsible for young members who are interested Q. I understand that you are currently individualized regimens. in increasing their involvement in the studying for your PhD in Public Health. field?

28 LipidSpin • Volume 17, Issue 1 • January 2019 A: I was very excited to present my work associations in lipidology worldwide, the My two friends and I spent a whole day at the 2018 NLA Scientific Sessions in NLA provides great opportunities for young climbing a giant snowy mountain on our Las Vegas, and it gave me a chance to researchers to advance their careers in this own. The climbing was exhausting, and interact with experts from multiple fields field. My mentor, Nathan D. Wong, PhD, the frigidity made me think of giving up of lipid study. I was inspired by their FNLA, introduced me to lipidology, and I somewhere in the middle. “Make choices, comments and thoughts for my work was proud to present my very first work on stick to it and don’t look back,” I said to and most importantly, it exposed me to hypertriglyceridemia at Scientific Sessions. myself and shared this encouragement additional research topics and connected I also got a chance to meet with world- with my friends. me with other research groups for famous experts in lipidology at the meeting possible cooperation in the future. My and exchanged comments on each other’s By the end of the day, we finally made to suggestions for other young members is work. After becoming a new member, I the top, and the moment we lay on the to accumulate your knowledge at school gained access to various online education ground outside the resort, we observed much as possible, including reading papers, resources as well as the Journal of Clinical the “glowing green ripples forming arcs becoming involved with multiple research Lipidology and LipidSpin, which keeps me that constantly transform their shape into projects and gaining research experience updated with the latest news in lipidology. new glowing diaphanous forms” as NASA from your colleagues. These things are all astronaut Don Pettit once so eloquently helpful and an essential part of preparing Q. Could you tell us a bit about your described it. It was the most beautiful view to attend a scientific conference. other interests or hobbies? I will keep in my mind forever. I love the feeling of big rewards after conquering Q. How do you feel that the NLA A: In my spare time, my favorite hobby is challenges. has helped to advance your career or to travel and explore the world’s enormous knowledge of lipidology? natural wonders. My most memorable trip was to Alaska, for the unique and A: As one of the most prestigious mysterious scenery of the Aurora Borealis.

The National Lipid Association is thankful for a productive 2018. We couldn’t achieve success without the support of our members, communities and industry partners.

We would like to acknowledge and extend gratitude to the following members of our 2018 Industry Council:

2018 AKCEA THERAPEUTICS ESPERION Industry AMARIN REGENERON Council AMGEN SANOFI

Official Publication of the National Lipid Association 29 Education and Meeting News and Notes

Register Now for the Spring Clinical authored and peer-reviewed by Clinical Lipidology or Accreditation Council Lipid Update in Portland members of the NLA for Clinical Lipidology? The deadline Register now for the National Lipid to apply to apply for the Spring Testing Association’s Spring Clinical Lipid For more information or questions about Window is March 8, 2019. Applications Update (CLU), hosted by the Pacific dues, contact [email protected]. must be postmarked by those dates. Lipid Association and Southwest Lipid For more information, visit lipid.org/ Association, in Portland, Ore. Feb. 22-24, Board Nominations Now Being Accepted education/certification or contact Nicole 2019, at the Hilton Portland Downtown. Nominations for NLA Board and Chapter of- Woodsmall at [email protected]. Hear from the top minds in clinical ficer positions are now being accepted. You lipidology, engage with NLA leadership, can nominate a colleague for NLA Board and NLA Mentoring Program participate in riveting discussions on Chapter officer positions by writing a letter The NLA is accepting applications to breakthrough treatments and more! of recommendation that states the nomi- become mentors for our early career nee’s service and contribution as well as members. The mentoring program was Don’t miss one of clinical lipidology’s vouch for the nominee’s character. Letters established to help develop the next premier events. Visit lipid.org/springclu to from existing leadership are beneficial and generation of clinical, academic, and complete your registration today. letters from Chapter Presidents are advised administrative leaders in lipidology. for seeking a national position. A nominee For more information, visit lipid.org/ Submit Your Abstract for 2019 Scientific will also need to submit a letter stating the education/trainees/mentoring. Sessions by February 4 nominee’s interest in the position, suit- Submit your abstract now through Feb. ability for leadership and acceptance of the Women in Lipidology Section 4, 2019, for the 2019 NLA Scientific responsibilities of the position. Nominations Joyce Ross, MSN, CRNP, FNLA, Anne Sessions in Miami May 16-19. Accepted are open and can be submitted at lipid.org/ Goldberg, MD, FNLA, Carol Kirkpatrick, abstracts will be published in the 2019 nominate. PhD, RD, MPH, FNLA, and Roda Scientific Sessions edition of the Journal of Plakogiannis, PharmD, FNLA are co-chairing Clinical Lipidology. For more information The nomination period closes at 5 p.m. EST the Women in Lipidology section of the on awards and travel grants, and to submit on February 4, 2019. For questions, contact NLA. The primary goal of the group is to your abstract and poster through the Vivian Grifantini at [email protected]. increase the involvement of the female online submission system, visit lipid.org/ membership of the NLA in speaking roles, abstracts. Online Courses Now Available leadership roles, writing groups, and for Purchase: Updated Masters committees. For more information, contact Remember to Pay Your 2019 NLA in Lipidology and Foundations of Allison Fellers at [email protected]. Member Dues Lipidology Don’t miss out on all of the great benefits The new and improved Online Foundations Genetics Work Group that come with being a member of the of Lipidology and Masters in Lipidology The Genetics Work Group is co-chaired National Lipid Association! Pay your 2019 courses are now available. Take an in- Amy Sturm, MS, LGC and Nathan Stitzel, dues by visiting lipid.org/dues. depth virtual training whether you want MD, PhD. This work group has recently to dive into basic concepts or take your been established and will focus on providing Your NLA membership provides you with basic knowledge to the next level with this resources and tools to NLA members on access to numerous resources including: valuable content. For more information, ways to use genetic testing and provide • Special member rate to attend CE/ visit lipideducation.com. the latest information in genetic lipid CME-accredited educational programs disorders. For more information, contact offered by the NLA Certification in Lipidology [email protected]. • Annual subscription to the Journal of Preparing to become certified in lipidology Clinical Lipidology and LipidSpin— through either the American Board of

30 LipidSpin • Volume 17, Issue 1 • January 2019 NLA Events Calendar

2019 National Lipid Association Clinical Lipid Update—Spring Hosted by the Pacific and Southwest Chpaters FOUNDATIONS February 22-24, 2019 of Lipidology FEBRUARY 22-24 Hilton Portland Downtown Portland, OR Course lipid.org/springclu 2019 Foundations of Lipidology PORTLAND February 21-22, 2019 Portland, OR

May 15-16, 2019 Aventura, FL 2019 National Lipid Association NATIONAL LIPID ASSOCIATION Scientific Sessions September 12-13, 2019 Hosted by the Southeast Chapter Minneapolis, MN 9 SCIENTIFIC May 16-19, 2019 SESSIONS 1 Turnberry Isle Miami

0 Aventura, FL lipid.org/sessions MIAMI 2 MASTERS in Lipidology Course 2019 National Lipid Association Clinical Lipid Update—Fall Hosted by the Midwest and Northeast Chapters Masters in Lipidology February 21-22, 2019 September 13-15, 2019 Portland, OR Renaissance Minneapolis Hotel, the Depot

Minneapolis, MN May 15-16, 2019 SEPTEMBER 13-15 lipid.org/fallclu Aventura, FL

September 12-13, 2019 2019 Minneapolis, MN MINNEAPOLIS

Official Publication of the National Lipid Association 31 Foundation Update

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

“As you consider Discuss this article at www.lipid.org/lipidspin your charitable giving throughout the year, please keep the I would like to thank everyone who supported the Foundation of the National Foundation in mind.” Lipid Association in 2018 by volunteering to work on our patient resource initiatives or awareness campaigns, attending a problems by providing resources to both fundraiser, purchasing a Lipids Are My Life patients and healthcare providers. shirt at an NLA conference, speaking with your colleagues and patients about the With your help, we are able to expand Foundation or making a donation. and improve our efforts and help more patients, families and caregivers. n As you consider your charitable giving throughout the year, please keep the Foundation in mind. You can donate online at LearnYourLipids.com, in-person at an NLA conference or by shopping at the NLA’s online store at NLAstore. logosoftwear.com. The NLA donates all sale proceeds to the Foundation in an effort to support our mission to improve the welfare of patients and families affected by cholesterol and triglyceride

32 LipidSpin • Volume 17, Issue 1 • January 2019 References

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Pradham AD, Aday AW, Rose LM, et al. Residual risk on treatment 2014;7(10):1054-1056. Cardiovasc Imaging. 2015;8(6):743-744. with PCSK9 inhibition and statin therapy. Circulation. 2018;137:00- 25. Polonsky TS, McClelland RL, Jorgensen NW, et al. Coronary artery 46. Khera A, Greenland P. Coronary Artery Calcium: If Measuring Once 00. doi.org/10.1161/CIRCULATIONAHA.118:034645. calcium score and risk classification for coronary heart disease Is Good, Is Twice Better? Circulation. 2018;137(7):680-683. 21. Ridker PM, MacFadyen JG, Everett BM, et al. Relationship of prediction. JAMA. 2010;303(16):1610-1616. 47. Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/ C-reactive protein reduction to cardiovascular event reduction 26. Erbel R, Mohlenkamp S, Moebus S, et al. Coronary risk AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on following treatment with canakinumab: a secondary analysis from the stratification, discrimination, and reclassification improvement the Management of Blood Cholesterol. J Am Coll Cardiol. 2018 Nov CANTOS randomized controlled trial. Lancet. 2108;391:319-328. based on quantification of subclinical coronary atherosclerosis: the 8. doi: 10.1016/j.jacc.2018.11.003 22. Ridker PM, MacFadyen JG, Walfert RL, et al. Relationship of Heinz Nixdorf Recall study. J Am Coll Cardiol. 2010;56(17):1397- lipoprotein-associated phospholipase A2 mass and activity with 1406. EBM Tools for Practice vascular events among primary prevention patients allocated to 27. Elias-Smale SE, Proenca RV, Koller MT, et al. Coronary calcium 1. Ridker PM, Thuren ET, MacFadyen JG, et al. Anti-inflammatory placebo or statin therapy: an analysis from the JUPITER trial. 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DOI: 10.1161/JAHA.116.005077. risk for incident heart disease in middle-aged man and women in predictive value of detecting subclinical coronary and carotid 5. Fanola CL, Morrow DA, Cannon CP, et al. Interleukin-6 and the risk the Atherosclerosis Risk in Communities (ARIC) study. Circulation. atherosclerosis in asymptomatic adults: the BioImage study. J Am of adverse outcomes in patients after an acute coronary syndrome: 2004;109:837-842. Coll Cardiol. 2015;65(11):1065-1074. observations from the SOLID-TIMI 52 trial. J Am Heart Assoc. 27. May HT, Horne BD, Anderson JL, et al. Lipoprotein-associated 31. Kavousi M, Elias-Smale S, Rutten JH, et al. Evaluation of newer 2017;6:e005637. DOI: 10. 1161/JAHA.117.005637. phospholipase A2 independently predicts the angiographic risk markers for coronary heart disease risk classification: a cohort 6. Ridker PM. High-sensitivity C-reactive protein. Potential adjunct for diagnosis of coronary artery disease and coronary death. Am Heart J. study. Ann Intern Med. 2012;156(6):438-444. global risk assessment in the primary prevention of cardiovascular 2006;152:997-1003. 32. Yeboah J, Young R, McClelland RL, et al. Utility of Nontraditional disease. Circulation. 2001;103:1813-1818. 28. Meusese MC, Stroes ES, Hazen SL, et al. Serum myeloperoxidase Risk Markers in Atherosclerotic Cardiovascular Disease Risk 7. Ridker PM, Buring JE, Rifai N, et al. Development and validation of levels are associated with the future risk of coronary artery disease Assessment. J Am Coll Cardiol. 2016;67(2):139-147. improved algorithms for the assessment of global cardiovascular risk in apparently healthy individuals. The EPIC-Norfolk Prospective 33. Nasir K, Bittencourt MS, Blaha MJ, et al. Implications of Coronary in women: the Reynolds Risk Score. JAMA. 2007;97:611-619. Population Study. J Am Coll Cardiol. 2007;50:159-165. Artery Calcium Testing Among Statin Candidates According to 8. Ridker PM, Hennekens CH, Buring IE, et al. 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34 LipidSpin • Volume 17, Issue 1 • January 2019 30. Heslop CL, Frohlich JJ, Hill JS. Myeloperoxidase and C-reactive 6. Pedersen BK. Anti-inflammatory effects of exercise: role in diabetes 2018:4-10. protein have combined utility for long-term prediction of and cardiovascular disease. Eur J Clin Invest. 2017;47:600-611. 11. Micha R, Imamura F, Wyler von Ballmoos M, et al. Systematic review cardiovascular mortality after coronary angiography. J Am Coll 7. Kobyliak N, Conte C, Cammarota G, et al. Probiotics in prevention and meta-analysis of methotrexate use and risk of cardiovascular dis- Cardiol. 2010;55:1102-1109k. and treatment of obesity: a critical view. Nutr Metab (Lond). ease. Am J Cardiol. 2011 Nov. 1;108(9):1362-70. 2016;13:14. 12. Ridker PM, Everett BM, Pradhan A, et al.; CIRT Investigators. Low- Lipid Luminations 8. DiRienzo DB. Effect of probiotics on biomarkers of cardiovascular Dose Methotrexate for the Prevention of Atherosclerotic Events. N 1. Geovanini GR, Libby P. Atherosclerosis and inflammation: overview disease: implications for heart-healthy diets. Nutr Rev. 2014;72:18- Engl J Med. 2018 Nov 10. doi: 10.1056/NEJMoa1809798. [Epub and updates. Clin Sci (Lond). 2018;132:1243-1252. 29. ahead of print.] 2. Zeiser R. Immune modulatory effects of statins. Immunology. 9. Sahebkar A. Are curcuminoids effective C-reactive protein-lowering 2018;154:69-75. agents in clinical practice? Evidence from a meta-analysis. Phytother Specialty Corner 3. Bally M, Dendukuri N, Rich B, et al. Risk of acute myocardial Res. 2014;28:633-642. 1. Smidowicz A, Regula J. Effect of nutritional status and dietary infarction with NSAIDs in real-world use: Bayesian meta-analysis 10. Maki KC, Palacios OM, Bell M, Toth PP. Use of supplemental patterns on human serum C-reactive protein and interleukin-6 of individual patient data. BMJ. 2017;357:j1909.doi:10.1136/bmj. long-chain omega-3 fatty acids and risk for cardiac death: An concentrations. Adv Nutr. 2015 Nov 13;6(6):738-47. j1909. updated meta-analysis and review of research gaps. J Clin Lipidol. 2. Schwingshackl L, Hoffmann G. Mediterranean dietary pattern, 4. Tantry US, Navarese EP, Myat A, et al. Combination oral 2017;11:1152-1160 e1152. inflammation and endothelial function: a systematic review and antithrombotic therapy for the treatment of myocardial infarction: 11. Bhatt DL, Steg PG, Miller M, et al. Cardiovascular Risk Reduction meta-analysis of intervention trials. Nutr Metab Cardiovasc Dis. recent developments. Expert Opin Pharmacother. 2018;19:653-65. with Icosapent Ethyl for Hypertriglyceridemia. N Engl J Med. 2014 Sep;24(9):929-39. 5. Berger JS, Brown DL, Becker RC. Low-dose aspirin in patients 2018; doi: 10.1056/NEJMoa1812792. [Epub ahead of print] 3. Eckel RH, Jakicic JM, Ard JD, et al. 2013 AHA/ACC guideline on with stable cardiovascular disease: a meta-analysis. Am J Med. 12. Ridker PM, Danielson E, Fonseca FA, et al. Rosuvastatin to prevent lifestyle management to reduce cardiovascular risk: a report of the 2008;121:43-9. vascular events in men and women with elevated C-reactive American College of Cardiology/American Heart Association Task 6. Bibbins-Domingo K on behalf of the U.S. Preventive Services Task protein. N Engl J Med. 2008;359:2195-2207. Force on Practice Guidelines. J Am Coll Cardiol. 2014;63(25 Pt Force. Aspirin use for the primary prevention of cardiovascular 13. Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Hennekens CH. B):2960-84. disease and colorectal cancer: U.S. Preventive Services Task Force Inflammation, aspirin, and the risk of cardiovascular disease in 4. Jacobson TA, Maki KC, Orringer CE, et al. National Lipid recommendation statement. Ann Intern Med. 2016;164:836-45. apparently healthy men. N Engl J Med. 1997;336:973-979. Association Recommendations for Patient-Centered Management 7. ILARIS® [package insert]. East Hanover, NJ: Novartis 14. Ishibashi T, Takeishi Y. Ezetimibe and vascular inflammation. Curr of Dyslipidemia: Part 2. J Clin Lipidol. 2015 Nov-Dec;9(6 Pharmaceuticals Corp.; 2012. Vasc Pharmacol. 2011;9:99-108. Suppl):S1-122.e1. 8. Ridker PM, Everett BM, Thuren T, et al. Anti-inflammatory therapy 15. Wagner AM, Sanchez-Quesada JL, Benitez S, Bancells C, Ordonez- 5. Barbaresko J, Koch M, Schulz MB, et al. Dietary pattern analysis with canakinumab for atherosclerotic disease. N Engl J Med. Llanos J, Perez A. Effect of statin and fibrate treatment on and biomarkers of low-grade inflammation — a systematic literature 2017;377:1119-31. inflammation in type 2 diabetes. A randomized, cross-over study. review. Nutr Rev. 2013;71(8):511-27. 9. Roland D. The price dilemma over a $16,000 drug. Fox Business. Diabetes Res Clin Pract. 2011;93:e25-28. 6. Neale EP, Batterham MJ, Tapsell LC. Consumption of a healthy https://www.foxbusiness.com/features/the-price-dilemma-over-a- 16. Karacaglar E, Atar I, Altin C, et al. The Effects of Niacin on dietary pattern results in significant reductions in C-reactive protein 16000-drug. Published July 12, 2017. Accessed Aug. 1, 2018. Inflammation in Patients with Non-ST Elevated Acute Coronary levels in adults: a meta-analysis. Nutr Res. 2016 May;36(5):391- 10. Methotrexate [package insert]. Huntsville, AL: DAVA Syndrome. Acta Cardiol Sin. 2015;31:120-126. 401. Pharmaceuticals Inc.; 2016. 17. Sahebkar A, Di Giosia P, Stamerra CA, et al. Effect of monoclonal 7. Sikand G, Kris-Etherton PM, Boulos NM. Impact of functional 11. Kremer JM, Lawrence DA, Hamilton R, et al. Long-term study of antibodies to PCSK9 on high-sensitivity C-reactive protein levels: a foods on diabetes and cardiovascular disease prevention. Curr the impact of methotrexate on serum cytokines and lymphocyte meta-analysis of 16 randomized controlled treatment arms. 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Recent controversies and advances. Annual Rev Nutr. 2017;37:423- 13. Micha R, Imamura F, Wyler von Ballmoos M, et al. Systematic Nutr Metab Cardiovasc Dis. 2017;27:657-669. 46. review and meta-analysis of methotrexate use and risk of 20. Verges B, Charbonnel B. After the LEADER trial and SUSTAIN-6, 10. Sacks FM, Lichtenstein AH, Wu JHY, et al. Dietary Fats and cardiovascular disease. Am J Cardiol. 2011;108:1362-70. how do we explain the cardiovascular benefits of some GLP-1 Cardiovascular Disease: A Presidential Advisory From the American 14. N Engl J Med. 2018 Nov 10. doi: 10.1056/NEJMoa1809798. [Epub receptor agonists? Diabetes Metab. 2017;43 Suppl 1:2S3-2S12. Heart Association. Circulation. 2017 Jul 18;136(3):e1-e23. ahead of print] 11. Almeida-de-Souza J, Santos R, Lopes L, et al. Associations 15. Colcrys® [package insert]. Deerfield, IL: Takeda Pharmaceuticals Case Studies between fruit and vegetable variety and low-grade inflammation in America Inc.; 2012. 1. 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Official Publication of the National Lipid Association 35

2018 Guideline on the Treatment of High Blood Cholesterol 2018 Guideline on the Treatment of High Blood Cholesterol Education for Clinicians from the National Lipid Association Education for Clinicians from the National Lipid Association

Monitoring Primary Prevention Recommendations – Page 2 Guideline Summary and Secondary Prevention Once patients Recommendations begin a – treatment Page plan, 1 providers oUcs^LnNAooNooArŒrc‰ŠyNN]oyVrUASAorVaTcn §. In Primary Prevention, personalized risk assessment and risk reduction are recommended – See Algorithm The 2018 AHA/ACC Cholesterol Treatment Guideline was nonfasting endorsed by the NLA and lipid nine test and check other for statin societies intoler who - • In Adults with primary LDL-­‐C >190 mg/dl, a high-­‐intensity statin is recommended to -­‐ lower LDL C by > 50%. made key contributions. Overall, it offers an evidence-­‐based and patient-­‐centered ance, and retest approach every 3 to 12 months to if the needed. assessment 4oVaT rUN kNnJNarATN nNLsJrVca Va  ®  ¨nArUNn If LDL-­‐C remains >100 mg/dl after maximizing the statin , dose addition of ezetimibe is reasonable. If LDL-­‐C is and treatment of ASCVD risk: It recommends intensive rUAarcrA^JUc^NorNnc^©VaSc^^cy®sk`caVrcnVaTcS LDL lowering for ‘very high risk’ ASCVD patients, supports kArVNaroJAaUN^k{csNorV`ArNUcyyN^^rUNorArVa still > 100 mg/dl and criteria for FH are present, addition of a PCSK9 inhibitor may be considered. statin therapy in primary prevention when 10-­‐Year ASCVD Risk is `NLVJArVcaVoycn]VaT™ 5% to <7.5% if LDL-­‐C is -­‐ 160 189 mg/dl and ‘risk enhancing factors’ are present, and endorses the use of cyNnVaT CAC  ®  scoring ^NxN^o I{ ‰Û TNaNnA^^{ for NmsA^o reclassifying risk when indecision exists. • In Adults with DM and Age 40-­‐75, a moderate-­‐intensity statin is recommended regardless of risk, and a about 1% reduction in heart disease and stroke Key points and algorithms with color-­‐coded Classes of Recommendation nVo]š Isr rUN are NSSNJr JAa shown IN NxNa TnNArNn below and on Page 2. yUNa high-­‐intensity statin is reasonable for those with multiple ASCVD risk factors. orAnrVaTyVrUUVTUNnIAoN^VaN^NxN^ocS  ® ™%a • In Children-­‐Adolescents Age 0-­‐19 years with a clinical diagnosis a of FH, statin can be safely started at age 10. §. Diet and lifestyle remain the foundation of risk reduction – Patients should the basis of several be large counseled studies, it's estimated to follow an rUArnNLsJVaT  ® ^NxN^oyVrUorArVaoI{AIcsr • In Adults Age -­‐ 20 39, estimate lifetime risk via the ASCVD Plus Risk , Estimator and consider a statin -­‐ if LDL C is anti-­‐atherogenic diet of fruits and vegetables, whole ‹™`T¦L grains, JAanNLsJNUNAnrLVoNAoNAaLornc]N legumes, nuts, lean proteins, and liquid risk by about 21%, based on the results of several persistently >160-­‐189 mg/dl with elevated lifetime risk, family history of early ASCVD, or risk enhancing factors. vegetable oils, that is low in added sugars and sodium, large and studies. to avoid tobacco and engage in regular exercise. • In Adults Age -­‐ 40 75 + LDL -­‐ 70 189 mg/dl, calculate 10-­‐year ASCVD isk R via the ASCVD Plus Risk Estimator §. In Secondary prevention, very high risk ASCVD patients Implementing are treated intensively -­‐ See Algorithm the 2018 + Table -­‐ If 10-­‐Year ASCVD Risk is 5% to <7.5%, consider a statin if ‘risk enhancing’ factors are present [=LDL-­‐C 160-­‐189 -­‐ In ASCVD With Very High Risk [when >1 Major ASCVD Event OR 1 MajoGuideliner ASCVD RecommendationsEvent + Multiple High Risk mg/dl, South Asian ancestry, inflammatory diseases like HIV or RA, CKD, metabolic syndrome, history of early When initiating treatment plans and before pre- Conditions are present, as per , Table] a high -­‐intensity statin to scribing lower LDL-­‐C therapy, by > 50% providers is should recommended. If menopause or pre-­‐eclampsia, FHx of early > CAD, TGs 175 mg/dl, or elevated Apo-­‐B, hsCRP or Lipoprotein-­‐A. LDL remains > 70 mg/dl, ezetimibe and, if needed, a PCSK9 , inhibitor x should ^^cykArVNarorcAo]msNorVcaoAaLNzknNoo be considered. -­‐ If 10-­‐Year ASCVD Risk is 7.5% to <20%, a moderate intensity statin is recommended after a clinician-­‐patient Figure 1. Primary Prevention. concerns and preferences about their ability -­‐ In ASCVD Without High Risk features, recommendations are for a high AaL^V]N^VUccLrcSc^^cyAaLorVJ]rcrUN intensity statin to lower LDL-­‐C by risk discussion to reduce LDL-­‐C by 30%-­‐49%. If the decision about statin use remains uncertain, consider a CAC Akc VaLVJArNoAkc^VkckncrNVa œ1 9šArUNncoJ^NncrVJJAnLVcxAoJs^AnLVoNAoNœ  šJcncaAn{AnrNn{JA^JVs`œUo 0-š lifestyle and medication plan UVTU®oNaoVrVxVr{ ®nNAJrVxNkncrNVaœ  ® š^cy®LNaoVr{^VkckncrNVaJUc^NorNnc^œAaL k¨A©š^VkckncrNVa¨A©™ >50% in those < 75 years , and for either a high or moderate intensity x `kUAoV~NrUNkcrNarVA^Scn^cyNnVaTrUN statin in those over age 75. score. If score is 0, a statin can be deferred unless the patient is a smoker or has DM FHx ASCVD. A statin is patient’s cardiovascular disease risk reasonable if CAC score is 1 to 99 AU, and recommended if CAC score is >100 AU. Dex finition VoJsooAa{kcooVI^NLnsTVarNnAJrVcaoAaL of Very High Risk ASCVD adverse >1 Major effects ASCVD Event -­‐ If 10-­‐Year risk is >20%, a high intensity statin is recommended to lower LDL-­‐C by > 50%. x Address issues that factor into, or may -­‐ Always engage patients in a discussion of benefits and risks before prescribing a statin for primary prevention. Recent become ACS a barrier (within to, a shared-decision past ) 12 months plan, History such as of costs MI and the (other patient’s overall than health recent ACS above) Monitoring The 2018 guideline recommends offering History of ischemic stroke Once patients begin a treatment plan, providers options such as phone and calendar reminders, oUcs^LnNAooNooArŒrc‰ŠyNN]oyVrUASAorVaTcn Symptomatic NLsJArVcaA^AJrVxVrVNošAaLoV`k^V€NL`NLVJArVca PAD (claudication with ABI nonfasting lipid test and check for statin intoler- 1 + High Risk Conditions `NLVJArVcaVoycn]VaT™downloadable Age x >Women 65 years (Section 4.5.3) cyNnVaT  ®  ^NxN^o I{ ‰Û TNaNnA^^{ NmsA^o x -Nck^NyVrULVAINrNo¨1NJrVcaŒ™‹© about ASCVD 1% reduction Risk in heart Estimator disease and stroke Familial x -Nck^NyVrUJUncaVJ]VLaN{LVoNAoN hypercholesterolemia nVo]š Isr rUN NSSNJr JAa IN NxNa TnNArNn yUNa Prior (Section CABG 4.5.4) or PCI outside of the major orAnrVaTyVrUUVTUNnIAoN^VaN^NxN^ocS  ® ™%a the basisSee of Table several of large studies, it's estimated x -Nck^NyVrUJUncaVJVaA``Arcn{ ASCVD event rUArnNLsJVaT  ® ^NxN^oyVrUorArVaoI{AIcsr conditions/HIV (Section 4.5.5) ASCVD Risk Enhancers Diabetes mellitus ‹™`T¦L JAanNLsJNUNAnrLVoNAoNAaLornc]N x Older adults (Section 4.4.4.1) Hypertension risk byin about the 21%, left based on the lower results of algorithm several x -Nck^NyVrUU{kNnrnVT^{JNnVLN`VA large studies. CKD (Section (eGFR 34.5.2)0-­‐59 ml/min/1.73 ) m2 Current smoking Implementing the 2018 FigureFigu re 2. Secondary 1. Secondary prevention. Prevention Persistently elevated LDL-­‐C >100 mg/dl Guideline Recommendations (>2.6 mmol/L) despite maximally tolerated Graphic When initiating reprinted treatment with plans permission and before from pre-  1VaLVJArNoAJsrNJcncaAn{o{aLnc`Nœ1 9šArUNncoJ^NncrVJJAnLVcxAoJs^AnLVoNAoNœ ® šUVTU®LNaoVr{^VkckncrNVaJUc^NorNnc^œ Check, Change, Control Cholesterol.  ® š^cy®LNaoVr{^VkckncrNVaJUc^NorNnc^œ"š`{cJAnLVA^VaSAnJrVcaœAaL- 1 ‘Vš- 1 ‘VaUVIVrcn™¤9Nn{UVTUnVo]VaJ^sLNoAUVorcn{cS statin therapy and ezetimibe scribing therapy, providers should Cholesterol Management Guide for Healthcare `s^rVk^N`A\cn1 9NxNarocn‰`A\cn1 9NxNarAaL`s^rVk^NUVTU®nVo]JcaLVrVcao™ History of congestive HF x ^^cykArVNarorcAo]msNorVcaoAaLNzknNoo FigureFigure 1. Primary 2. Primary Prevention. Prevention Practitioners: concerns and Highlights preferences of about the their ability 2018 Guideline Graphic reprinted with permission from Check, Change, Control Cholesterol. Cholesterol Management tioners: Guide for Healthcare Practi on the AaL^V]N^VUccLrcSc^^cyAaLorVJ]rcrUN Management of Blood Cholesterol. Akc VaLVJArNoAkc^VkckncrNVa œ1 9šArUNncoJ^NncrVJJAnLVcxAoJs^AnLVoNAoNœ  šJcncaAn{AnrNn{JA^JVs`œUo 0-š lifestyle and medication plan 3cLcya^cALrUNSs^^xNnoVcacSrUNŠˆ‰ Uc^NorNnc^sVLN^VaNšk^NAoNxVoVrHighlights of the 2018 Guideline on the Management of Blood Cholesterol. © 2018 American Heart Association, Inc. UVTU®oNaoVrVxVr{ ®nNAJrVxNkncrNVaœ  ® š^cy®LNaoVr{^VkckncrNVaJUc^NorNnc^œAaL k¨A©š^VkckncrNVa¨A©™ © 2018 American Heart Association, Inc. 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Figure 2. Secondary prevention.

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Primary Prevention Recommendations – Page 2 §. In Primary Prevention, personalized risk assessment and risk reduction are recommended – See Algorithm • In Adults with primary LDL-­‐C >190 mg/dl, a high-­‐intensity statin is recommended to -­‐ lower LDL C by > 50%. If LDL-­‐C remains >100 mg/dl after maximizing the statin , dose addition of ezetimibe is reasonable. If LDL-­‐C is still > 100 mg/dl and criteria for FH are present, addition of a PCSK9 inhibitor may be considered. • In Adults with DM and Age 40-­‐75, a moderate-­‐intensity statin is recommended regardless of risk, and a high-­‐intensity statin is reasonable for those with multiple ASCVD risk factors. • In Children-­‐Adolescents Age 0-­‐19 years with a clinical diagnosis a of FH, statin can be safely started at age 10. • In Adults Age -­‐ 20 39, estimate lifetime risk via the ASCVD Plus Risk , Estimator and consider a statin -­‐ if LDL C is persistently >160-­‐189 mg/dl with elevated lifetime risk, family history of early ASCVD, or risk enhancing factors. • In Adults Age -­‐ 40 75 + LDL -­‐ 70 189 mg/dl, calculate 10-­‐year ASCVD isk R via the ASCVD Plus Risk Estimator -­‐ If 10-­‐Year ASCVD Risk is 5% to <7.5%, consider a statin if ‘risk enhancing’ factors are present [=LDL-­‐C 160-­‐189 mg/dl, South Asian ancestry, inflammatory diseases like HIV or RA, CKD, metabolic syndrome, history of early menopause or pre-­‐eclampsia, FHx of early > CAD, TGs 175 mg/dl, or elevated Apo-­‐B, hsCRP or Lipoprotein-­‐A. -­‐ If 10-­‐Year ASCVD Risk is 7.5% to <20%, a moderate intensity statin is recommended after a clinician-­‐patient risk discussion to reduce LDL-­‐C by 30%-­‐49%. If the decision about statin use remains uncertain, consider a CAC score. If score is 0, a statin can be deferred unless the patient is a smoker or has DM FHx ASCVD. A statin is reasonable if CAC score is 1 to 99 AU, and recommended if CAC score is >100 AU. -­‐ If 10-­‐Year risk is >20%, a high intensity statin is recommended to lower LDL-­‐C by > 50%. -­‐ Always engage patients in a discussion of benefits and risks before prescribing a statin for primary prevention. Monitoring Once patients begin a treatment plan, providers oUcs^LnNAooNooArŒrc‰ŠyNN]oyVrUASAorVaTcn nonfasting lipid test and check for statin intoler- ance, and retest every 3 to 12 months if needed. 4oVaTPerform rUN kNnJNarATN Risk nNLsJrVca Assessment Va  ®  ¨nArUNn rUAarcrA^JUc^NorNnc^©VaSc^^cy®sk`caVrcnVaTcS kArVNaroJAaUN^k{csNorV`ArNUcyyN^^rUNorArVain all adults via the free, `NLVJArVcaVoycn]VaT™downloadable cyNnVaT  ®  ^NxN^o I{ ‰Û TNaNnA^^{ NmsA^o about ASCVD 1% reduction Risk in heart Estimator disease and stroke nVo]š Isr rUN NSSNJr JAa IN NxNa TnNArNn yUNa orAnrVaTyVrUUVTUNnIAoN^VaN^NxN^ocS  ® ™%a the basisSee of Table several of large studies, it's estimated rUArnNLsJVaTASCVD  ® ^NxN^oyVrUorArVaoI{AIcsr Risk Enhancers ‹™`T¦L JAanNLsJNUNAnrLVoNAoNAaLornc]N risk byin about the 21%, left based on the lower results of algorithm several large studies. Implementing the 2018 Guideline Recommendations Graphic When initiating reprinted treatment with plans permission and before from pre- Check, scribing Change, therapy, providers Control should Cholesterol. Cholesterol x ^^cykArVNarorcAo]msNorVcaoAaLNzknNoo Management Guide for Healthcare FigureFigure 1. Primary 2. Primary Prevention. Prevention Practitioners: concerns and Highlights preferences of about the their ability 2018 Guideline on the AaL^V]N^VUccLrcSc^^cyAaLorVJ]rcrUN Management of Blood Cholesterol. Akc VaLVJArNoAkc^VkckncrNVa œ1 9šArUNncoJ^NncrVJJAnLVcxAoJs^AnLVoNAoNœ  šJcncaAn{AnrNn{JA^JVs`œUo 0-š lifestyle and medication plan UVTU®oNaoVrVxVr{ ®nNAJrVxNkncrNVaœ  ® š^cy®LNaoVr{^VkckncrNVaJUc^NorNnc^œAaL k¨A©š^VkckncrNVa¨A©™ © 2018 American Heart Association, Inc. x `kUAoV~NrUNkcrNarVA^Scn^cyNnVaTrUN Provided Courtesy of the National Lipid Association© 2018 . For more patient’s information cardiovascular: www.lipid.org disease risk x VoJsooAa{kcooVI^NLnsTVarNnAJrVcaoAaL adverse effects x Address issues that factor into, or may become a barrier to, a shared-decision plan, such as costs and the patient’s overall health The 2018 guideline recommends offering options such as phone and calendar reminders, NLsJArVcaA^AJrVxVrVNošAaLoV`k^V€NL`NLVJArVca doses to help patients stick to their treatment plans. The 2018 guideline also includes considerations for special populations in the United States: x 0AJVA^¦NrUaVJTncsko¨1NJrVcaŒ™™‰© x Women (Section 4.5.3) x -Nck^NyVrULVAINrNo¨1NJrVcaŒ™‹© x -Nck^NyVrUJUncaVJ]VLaN{LVoNAoN (Section 4.5.4) x -Nck^NyVrUJUncaVJVaA``Arcn{ conditions/HIV (Section 4.5.5) x Older adults (Section 4.4.4.1) x -Nck^NyVrUU{kNnrnVT^{JNnVLN`VA (Section 4.5.2)

Figure 2. Secondary prevention.

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