CONTINUING EDUCATION THIS ACTIVITY IS SUPPORTED BY AN EDUCATIONAL GRANT FROM ESPERION THERAPEUTICS, INC. Lowering LDL Cholesterol With Nonstatin Treatments FACULTY EDUCATIONAL OBJECTIVES Craig J. Beavers, PharmD, FACC, FAHA, At the completion of this activity, the participant will be able to: FCCP, BCCP, BCPS-AQ Cardiology, • Examine the most recent cholesterol guidelines and the ongoing cardiovascular disease burden, CACP particularly with patients on maximally tolerated statins Director, Cardiovascular Services Baptist Health Paducah • Investigate the nonstatin options currently available including emerging therapies Paducah, Kentucky • Identify appropriate patients who may require an additional reduction in LDL cholesterol • Integrate the novel LDL-lowering medications into clinical decision making for at-risk patients Cardiovascular Clinical Pharmacist TARGET AUDIENCE: Retail pharmacists University of Kentucky HealthCare ACTIVITY TYPE: Application Lexington, Kentucky RELEASE DATE: November 16, 2020 Adjunct Assistant Professor EXPIRATION DATE: November 16, 2021 University of Kentucky College of ESTIMATED TIME TO COMPLETE ACTIVITY: 2.0 hours Pharmacy FEE: This lesson is offered for free at www.pharmacytimes.org. Lexington, Kentucky DISCLOSURES The following contributors have no relevant financial relationships with Introduction with a diagnosis of ASCVD.3 Beyond the commercial interests to disclose: Cardiovascular disease (CVD) is the mortality and morbidity associated with FACULTY Craig J. Beavers, PharmD, FACC, FAHA, leading cause of death both worldwide ASCVD, the burden on health care utiliza- FCCP, BCCP, BCPS-AQ Cardiology, and in the United States. Due to concerted tion and cost is excessive. The AHA data CACP public health efforts and therapeutic reveal estimates of annual and direct cost PHARMACY TIMES CONTINUING advances, mortality had declined from of ASCVD to be $351.3 billion. Further- EDUCATION™ PLANNING STAFF the 1990s into the early 2010s; however, more, it is estimated that by the year 2035, Jim Palatine, RPh, MBA; Maryjo Dixon, it appears mortality rates due to CVD are more than 45% of the US population will RPh; Rose Namissa, PharmD, BCPS; Kelly McCormick; Susan Pordon; and increasing again. The most recent American have some form of ASCVD, and total cost Brianna Winters Heart Association (AHA) disease statistics is projected to be $1.1 trillion.1 PHARMACY TIMES® EDITORIAL STAFF approximate 647,000 people in the United Davy James States, or 1 of 4, will die of CVD.1 Athero- CVD and the Role of Blood An anonymous peer reviewer was part of the content validation and conflict sclerotic cardiovascular disease (ASCVD) Cholesterol resolution and has no relevant financial is defined as stroke, transient ischemic There are 5 major modifiable risk factors relationships with commercial interests to disclose. attack (TIA), documented coronary artery for ASCVD, with blood pressure, lipids, disease (CAD) with stable angina, acute diabetes, smoking, and overweight/obesity coronary syndrome (ACS), coronary or responsible for more than half of cardio- other arterial revascularization, peripheral vascular mortality.4 More importantly, 90% vascular disease with or without claudi- of myocardial infarction (MI) events occur cation, and aortic aneurysm.2 Of these, in individuals with at least 1 risk factor.5 CAD is the most common type of CVD In terms of lipids, serum cholesterol and and contributes to half of the deaths each associated lipoproteins (low-density lipo- year. The Centers for Disease Control and protein [LDL], very low-density lipopro- Prevention estimates there are more than tein, high-density lipoprotein [HDL], etc) 18 million adults aged 20 years and older are clearly documented in a variety of data Pharmacy Times Continuing Education™ is accredited by the Accreditation Council for Pharmacy Education (ACPE) as a provider of continuing pharmacy education. This activity is approved for 2.0 contact hours (0.20 CEU) under the ACPE universal activity number 0290-0000-20-317-H01-P. The activity is available for CE credit through November 16, 2021. PHARMACYTIMES.ORG 62 NOVEMBER 2020 www.pharmacytimes.org TABLE 1. STATIN THERAPY INTENSITIES7,a High intensity Moderate intensity Low intensity (lowers LDL, on average, by ≥50%) (lowers LDL, on average, by 30%-50%) (lowers LDL, on average, by <30%) Atorvastatin (Lipitor) 40-80 mg daily Atorvastatin 10-20 mg daily Fluvastatin 20-40 mg daily Rosuvastatin (Crestor) 20-40 mg daily Fluvastatin (Lescol) 40 mg twice daily Lovastatin 20 mg daily Fluvastatin XL 80 mg daily Pitavastatin 1 mg daily Lovastatin (Mevacor) 40 mg daily Pravastatin 10-20 mg daily Pitavastatin (Livalo, Zypitamag) 2-4 mg Simvastatin 10 mg daily daily Pravastatin (Pravachol) 40-80 mg daily Rosuvastatin 5-10 mg daily Simvastatin (Zocor) 20-40 mg daily Adapted from Lloyd-Jones DM, Morris PB, Ballantyne CM, et al. J Am Coll Cardiol. 2017;70(14):1785-1822. aBolded agents and doses indicate statins and doses that were evaluated in randomized, controlled trials included in the guideline decision-making process. sources, from animal studies to randomized controlled trials, approval of the proprotein convertase subtilisin/kexin type 9 as contributing to ASCVD.2 Specifically, LDL plays a key (PCSK9) inhibitors, positive data from the Improved Reduction role in the pathogenesis and perpetuation of ASCVD, and of Outcomes: Vytorin Efficacy International Trial (IMPROVE- elevations of these levels above 100 mg/dL are associated IT) with ezetimibe and consensus that achieving the lowest with this heightened risk; aggressive lowering of these levels threshold of LDL possible would reduce ASCVD risk. This led produces a marked reduction in ASCVD events.2 to the development of the 2018 ACC/AHA blood cholesterol In 2013, the American College of Cardiology (ACC) and AHA guidelines. This version of the guidelines still focuses on the released their first set of cholesterol guidelines, taking over from importance of lifestyle changes and the use of moderate- or high- the National Heart, Lung, and Blood Institute of the National intensity fixed-dose statins, but there were significant departures Institutes of Health.6 In these guidelines, the ACC/AHA focused from the 2013 document, such as endorsements for monitoring on the reduction of ASCVD versus coronary heart disease alone for LDL response to a threshold, additional recommendations to embody entities such as carotid artery disease, peripheral for each of the 4 statin benefit groups, and considerations for vascular disease, and stroke. Based on the available clinical special populations not included in previous guidelines.2,6 In evidence related to ASCVD risk reduction, these guidelines addition, the ACC/AHA used the recommendations of the removed historical LDL treatment targets, focused treatment on guidelines related to non-ASCVD cholesterol management and statin therapy, provided limited recommendations for nonstatin integrated them into the 2019 ACC primary prevention guide- treatment, and devised the 4 major statin treatment groups. lines.8 It should be noted the history of cholesterol guideline These groups are (1) patients with clinical ASCVD; (2) patients development is rich, and other organizations besides ACC/ with LDL 190 mg/dL and greater; (3) patients aged 40 to 75 AHA produce cholesterol management recommendations; a full years with diabetes and with an LDL of 70 mg/dL to 189 mg/ discussion encompassing these documents is beyond the scope dL who were not classified in groups 1 or 2; (4) patients aged 40 of this activity. to 75 years with LDL of 70 mg/dL to 189 mg/dL and a 10-year In addition to the aforementioned new recommendations in ASCVD risk of at least 7.5%. This risk was calculated via the the 2018 guidelines, there are also new recommendations for pooled cohort risk equation (see ADDITIONAL RESOURCES for LDL thresholds at which to consider adding nonstatins as well link to pooled cohort calculator smartphone app). Furthermore, as recommendations for those nonstatin agents. In the most group 4 consists of primary prevention patients. As alluded recent version of the guidelines, the authors acknowledge that above, the recommendations primarily focused on statin some patients experience intolerance, which ranges from 10% to treatment, with preference toward moderate to high intensity 25% and most commonly presents as muscle symptoms. Addi- (TABLE 17), given their robust data in reducing ASCVD events. tionally, patients are concerned about adverse effects (AEs), After the 2013 guideline publication, much changed in the such as development of diabetes or memory impairment.2,9 They field of cholesterol management, including the introduction and also recognized that patients may have variable responses to PHARMACYTIMES.ORG NOVEMBER 2020 63 FIGURE. GUIDELINE RECOMMENDATIONS FOR SECONDARY PREVENTION OF ASCVD2 Clinical ASCVD Healthy Lifestyle ASCVD not at very high-risk* Very high-risk* ASCVD Age <75 y Age >75 y High-intensity or maximal statin (Class I) High-intensity statin (Goal: LDL-C >50% (Class I) If on maximal If PCSK9-I is Dashed statin and considered, arrow LDL-C >70 add ezetimibe indicates mg/dL (>1.8 to maximal RCT- If high- If on maximal Initiation of mmol/L), statin before supported intensity statin therapy Continuation of moderate- or adding adding efficacy, but statin not and LDL-C high-intensity high-intensity ezetimibe is PCSK9-I is less cost tolerated, >70 mg/dL statin is statin is reasonable (Class I) effective use (>1.8 reasonable reasonable