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 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 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 , 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.

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TABLE 1. 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 10-20 mg daily 20-40 mg daily (Crestor) 20-40 mg daily Fluvastatin (Lescol) 40 mg twice daily 20 mg daily Fluvastatin XL 80 mg daily 1 mg daily Lovastatin (Mevacor) 40 mg daily 10-20 mg daily Pitavastatin (Livalo, Zypitamag) 2-4 mg 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 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 (Class IIa) moderate- mmol/L), (Class IIa) (Class IIa) intensity adding statin ezetimibe (Class I) may be If on clinically judged maximal LDL-C lowering reasonable therapy and LDL-C >70 mg/dL (>1.8 mmol/L), or (Class IIb) non-HDL-C >100 mg/dL (>2.6 mmol/L), adding PCSK9-I is reasonable (Class IIa)

Reprinted with permission. Circulation. 2018;139:e1046-e1081 © 2018 American Heart Association, Inc. ACS, acute coronary syndrome; ASCVD, atherosclerotic cardiovascular disease; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; MI, myocardial infarction; PCSK9-I, PCSK9 inhibitor. Clinical ASCVD consists of ACS, those with history of MI, stable or unstable angina or coronary other arterial revascularization, stroke, transient ischemic attack (TIA), or peripheral artery disease (PAD) including aortic aneurysm, all of atherosclerotic origin. Very-high risk includes a history of multiple major ASCVD events or 1 major ASCVD event and multiple high-risk conditions. high-intensity statin therapy. For example, a post hoc analysis of classes of .2 These factors, in conjunction with the the Justification for the Use of Statins In Prevention: An Inter- collective evidence, have brought the need to understand and vention Trial Evaluating Rosuvastatin (JUPITER) trial, which utilize nonstatin therapy for LDL reduction to the forefront. A randomized primary prevention patients to high-intensity rosu- detailed discussion of the strengths and limitations of compo- vastatin 20 mg daily or placebo, demonstrated 46.3% receiving nents of the guidelines, such as the pooled cohort risk equation, rosuvastatin had an LDL-C reduction of greater than 50% from is beyond the scope of this activity. baseline.10 It should be noted, outside of clinical trials, reasons for less-than-anticipated response could be due to nonadherence STAR* to statin therapy and/or lifestyle recommendations and must What patient history should be collected and evaluated also be addressed in context. Lastly, the authors acknowledged to make a treatment decision about nonstatin therapy? patients experience dyslipidemias beyond LDL abnormalities *S = Stop; T = Think; A = Assess; R = Review that are more effectively treated with additional or alternative

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Moving Beyond Statin Therapy reduction and the secondary prevention data; there are no current As outlined earlier in this article, the 2018 guidelines began randomized, controlled data demonstrating reduced ASCVD to address the situations in which it may be prudent to events with either agent in the primary prevention population.2,8 consider the addition of nonstatin therapy when the ability It should be noted, however, the recommendations for statin to achieve appropriate LDL reduction does not occur after therapy and intensity for diabetes is driven by age and risk assurance of adherence to lifestyle modification and statin factors. Noting ASCVD risk is increased with age and other risk therapy. The emergence of evidence for both ezetimibe and factors in diabetes, the 2018 guidelines depart from the absolute PCSK9 inhibitors provided the foundation for these revised 10-year risk of ASCVD estimate via the pooled cohort equation recommendations. A discussion of the evidence is found later alone. Thus, high-intensity statin therapy is now recommended in the review, but an overview of the updated recommenda- in patients with diabetes with diabetes-specific enhancers, such tions on the matter is warranted to understand the role of as longevity of diabetes (≥10 years with type 2 and ≥20 years nonstatin therapy. with type 1), microvascular complications, peripheral vascular In patients with ASCVD (ie, a secondary prevention popu- disease, or increased age (notably, men older than 50 years and lation), the guidelines outline several strategies (FIGURE2). women older than 60 years). Although no LDL threshold is Guiding the strategies is the reintroduction of an LDL threshold recommended when considering nonstatin therapy, achieving a at which to consider nonstatin therapy based on random- 50% or greater reduction in LDL is advised. In these patients ized, controlled trial data. In patients with ASCVD receiving or younger patients with a 10-year ASCVD risk (≥20%) in maximally tolerated statin therapy, an LDL goal of 70 mg/dL whom use of moderate- or high-intensity statin therapy failed or higher is recommended as a threshold for the addition of to achieve a 50% reduction, addition of ezetimibe should be nonstatin therapy.2 It should be noted if a patient is intolerant considered. Also new to the 2018 guidelines are recommenda- to a high-intensity statin, consideration of a moderate-intensity tions for patients outside of the traditionally considered age statin with a goal 30% to 49% reduction should occur before range of 40 to 75 years with diabetes. Shared decision making using nonstatin therapy alone. The guideline specifically should occur regarding initiation and continuation of statin outlines the use of ezetimibe or a PCSK9 inhibitor as agent of therapy in diabetes populations outside of the 40 to 75 years age choice, with ezetimibe being preferred over PCSK9 inhibitors range. Patients who are younger than 40 years or older than 75 due to generic availability and documented safety and toler- years with the formerly mentioned risk-enhancing factors and ability. Furthermore, PCSK9 inhibitors are reserved for patients who are open to therapy should be considered for moderate- who are considered to be very-high risk due to multiple major intensity statin therapy.2,8 ASCVD events or high-risk conditions (eg, diabetes, smoking) with still elevated LDL and/or non-HDL cholesterol levels on Evidence for Advanced Treatment Options maximum tolerated statin therapy. for Lowering LDL In terms of primary prevention populations, the addition of Ezetimibe a nonstatin to maximally tolerated statin therapy is also recom- Ezetimibe works by inhibition of the Niemann-Pick C1-like mended in select cases, notably patients with a baseline LDL 1 protein, which leads to decreased cholesterol absorption of 190 mg/dL or greater, those with defining severe hypercho- in the small intestine.11 Surrogate-based LDL reduction data lesterolemia, those who are unable to reach LDL threshold or with ezetimibe have demonstrated, when added to statins, tolerate statins, and patients with diabetes. Likewise, in the an improvement of 15% to 25% in LDL (TABLE 27,11-18).2 secondary prevention population, the maximally tolerated statin The IMPROVE-IT trial is the first, and currently only, study should be attempted and then consideration of nonstatins may demonstrating an ASCVD risk reduction when ezetimibe be warranted for those whose percent LDL reduction is less than 10 mg was added to moderate-intensity statin monotherapy. 50% or whose LDL is greater than 70 mg/dL, as opposed to 100 In this trial, more than 18,000 patients hospitalized with an mg/dL in the secondary population. In the primary prevention ACS event within the previous 10 days were randomized to category, the guidelines favor ezetimibe initially over a PCSK9 receive simvastatin 40 mg and placebo daily or simvastatin 40 inhibitor, despite large LDL efficacy with the latter, due to similar mg and ezetimibe 10 mg daily. The mean LDL in both study reasons cited previously; a PCSK9 inhibitor can be prioritized groups was 93.8 mg/dL at baseline, with more than one-third if a 50% reduction is needed. Evidence supporting the use of of patients in each group receiving statin therapy before the ezetimibe and PCSK9 inhibitors is based on surrogate LDL ACS index event. After a median follow-up of 6 years, the

PHARMACYTIMES.ORG NOVEMBER 2020 65 TABLE 2. FDA-APPROVED NONSTATIN AGENTS CONSIDERED PRIMARILY FOR LDL REDUCTION7,11-18 Drug/drug Mechanism Dosing Mean % Adverse effects Select drug−drug Considerations class of action reduction in LDL (AEs) interactions in use Ezetimibe Inhibits 10 mg orally daily, 18% with Upper Cyclosporine, Generic (Zetia) Niemann- with or without monotherapy; respiratory , bile acid available, Pick C1-like food 25% with statin tract infection, sequestrants oral use, well 1 protein; , tolerated reduces arthralgia cholesterol absorption in small intestine PCSK9 Binds to ≈50%-60% Alirocumab: No known Cost, SC inhibitors PCSK9 and (Praluent): monotherapy Nasopharyngitis, clinically administration, increases 75 mg or 150 SC injection-site significant drug− robust LDL the number every 2 weeks or reactions, drug interactions reduction, of LDL 300 mg SC every influenza. need for receptors 4 weeks No early signs of specialty to clear neurocognitive pharmacy, circulating events prior LDL (Repatha): authorization 140 mg SC every Evolocumab: issues 2 weeks or 420 mg Nasopharyngitis, SC every 4 weeks upper respiratory tract infection, influenza, back pain, injection- site reactions. No evidence of increase in neurocognitive AEs

A1C, glycated hemoglobin; ASCVD, atherosclerotic cardiovascular disease; GI, gastrointestinal; LDL, low-density lipoprotein; PCSK9, proprotein convertase subtilisin/kexin type 9; SC, subcutaneous. median time-weighted average LDL fell to 53.7 mg/dL in the could not secure a labeled indication for ASCVD risk reduc- simvastatin/ezetimibe group versus 69.5 mg/dL in the sim- tion, likely due to the relative risk reduction of 6% over a 7-year vastatin/placebo group. The primary composite end point of treatment window as well as the fact that all patients were on cardiovascular death, nonfatal MI or stroke, hospitalization moderate-intensity statin therapy.19 As noted in the 2018 guide- for unstable angina, or coronary revascularization was signif- lines, ezetimibe is a reasonable choice for patients who do not icantly reduced by year 7 in patients enrolled in the treatment achieve desired LDL reduction defined by intensity of statin (simvastatin/ezetimibe) arm compared with the simvastatin or with ASCVD and LDL greater than 70 mg/dL or when the monotherapy arm, with a hazard ratio (HR) of 0.936 (95% CI, cost of other nonstatin therapy may be problematic.2 0.89-0.99; P = .016). Among the individual cardiovascular end points of the primary outcomes, significant reductions in STAR nonfatal MI (HR, 0.87; 95% CI, 0.80-0.95; P = .002), with a How would you educate your patients about the risk and benefits of each nonstatin therapy? number needed to treat of 50, and ischemic stroke (HR, 0.79; 95% CI, 0.67-0.94; P = .008) were reported. Subgroup anal- ysis identified 2 populations, those with diabetes (HR, 0.86; 95% CI, 0.78-0.94; P = .023) and those 75 years and older Bile Acid Sequestrants (HR, 0.80; 95 CI, 0.70-0.90; P = .005), in which treatment The other means of reducing dietary cholesterol, similar had the greatest benefit. Despite the modest benefit, ezetimibe to ezetimibe, is using bile acid sequestrants (BAS). BAS,

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TABLE 2. FDA-APPROVED NONSTATIN AGENTS CONSIDERED PRIMARILY FOR LDL REDUCTION7,11-18 (continued) Drug/drug Mechanism Dosing Mean % Adverse effects Select drug−drug Considerations class of action reduction in LDL (AEs) interactions in use Bile acid Binds bile Hcl ≈15%-30% Constipation, Phenytoin, Pill burden, sequestrants acids in (Welchol): dyspepsia, and warfarin, inconvenience intestine 6 tablets orally nausea levothyroxine in preparation, and limits once daily with a GI AEs, lack reabsorption meal or liquid OR 3 of ASCVD risk tablets orally twice reduction data, daily OR one 3.75- colesevelam gram suspension lowers A1C by packet orally daily 0.5%, safe in OR 1.875-gram pregnancy packet orally twice daily; mix powder with 4-8 oz of water, fruit juice, or soft drink; take with meal; 3.75 grams are equal to 6 tablets

Cholestyramine (Questran): 8-16 grams per day orally divided in 2 doses

Colestipol (Colestid): 2-16 grams per day orally given once or in divided doses

Bempedoic Inhibits ≈18% with statin; Uric acid Inhibits No ASCVD acid adenosine (Nexletol): ≈24% without increase/gout, OATP1B1/1B3; outcomes triphosphate- 180 mg orally daily statin tendon rupture, avoid simvastatin currently, gout citrate (ATP) muscle spasm doses >20 mg or risk, history lyase (ACL) Bempedoic ≈38% with statin pravastatin doses of tendon leading to acid/ezetimibe >40 mg rupture, limited inhibition of (Nexlizet): myopathy cholesterol 180 mg bempedoic risk due to synthesis and acid/10 mg mechanism upregulation ezetimibe orally of LDL daily receptors

A1C, glycated hemoglobin; ASCVD, atherosclerotic cardiovascular disease; GI, gastrointestinal; LDL, low-density lipoprotein; PCSK9, proprotein convertase subtilisin/kexin type 9; SC, subcutaneous. which include colesevelam, , and cholestyr- taken daily and cholestyramine exists in powder form, which amine, are nonabsorbed, lipid-lowering polymers that bind is unfavorable. In addition, these agents can pose issues bile acid in the intestinal tract and prevent its reabsorption related to absorption-based drug–drug interactions, such as (TABLE 27,11-18). These agents are effective at lowering LDL, observed with warfarin or phenytoin. Thus, these agents have with a 15% to 27% reduction, depending on agent.7 However, been relegated to an alternative for patients intolerant to ezet- they are limited in use due to the lack of ASCVD data in imibe who require less than 25% reduction to reach desired conjunction with statins as well as the burden associated with LDL and/or non-HDL cholesterol goal and have triglycerides each agent. For example, colesevelam requires 6 tablets to be below 300 mg/dL, given their limited effect on this marker.

PHARMACYTIMES.ORG NOVEMBER 2020 67 The one subgroup that BAS still play a key role in LDL with placebo. After a median follow-up of 2.8 years, treatment with reduction for ASCVD risk is women who are pregnant, as alirocumab was associated with a 15% reduction of the primary they are considered safe in this population.7 composite end point of cardiovascular death, nonfatal MI, fatal or nonfatal ischemic stroke, or unstable angina requiring hospi- PCSK9 Inhibitors talization compared with placebo (HR, 0.85; 95% CI, 0.78-0.93; As discussed previously, the 2018 ACC/AHA guidelines P <.001). Likewise to FOURIER, there were similar results provided endorsement for both ezetimibe and PCSK9 inhibi- with the secondary cardiovascular end points of nonfatal MI, tors for the reduction of both LDL and ASCVD risk. The ischemic stroke, and unstable angina requiring hospitalization; PCSK9 inhibitors bind to the target PCSK9, an enzyme that however, in this trial, there was a 15% reduced risk of all-cause helps regulate LDL receptors, and increase the number of mortality compared with placebo (HR, 0.85; 95% CI, 0.73-0.98; LDL receptors for clearing circulating LDL (TABLE 27,11-18). In P = .026). It should be noted, though, this was not a primary end the United States, alirocumab and evolocumab are currently point of the trial and could have been influenced by the almost approved agents. Both agents have demonstrated efficacy 1-year longer follow-up compared with FOURIER.21 in LDL surrogate-based studies, with a reduction of up to The LDL reduction and the newer mechanism of action of 45% to 64% when added to statin therapy in a variety of the PCSK9 inhibitors has been met with some hesitancy given populations.7 However, the 2018 guideline recommendations the lack of data on the long-term safety of these agents. For followed 2 large hard outcomes trials. both agents, there are concerns regarding injection-site reac- The first trial, Further Cardiovascular Outcomes Research with tions, which can occur in anywhere from 4% to 17% of patients, PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER), depending on the agent. Beyond injection-site reactions, much enrolled more than 27,000 patients with clinical ASCVD and attention has been focused around neurocognitive function, an LDL of 70 mg/dL or greater (or a non-HDL cholesterol of given these similar reported effects associated with statins and ≥100 mg/dL) while taking moderate- to high-intensity statin their LDL reduction. To address concerns regarding cognitive therapy (with or without ezetimibe). Patients were randomized dysfunction related to evolocumab and/or achieving a lower to receive subcutaneous injections of evolocumab either 140 mg LDL level, a subgroup of 1204 FOURIER patients also partici- every 2 weeks or 420 mg monthly or matching placebo. The pated in the concurrent Evaluating PCSK9 Binding Antibody median LDL at baseline was 92 mg/dL among both study Influence on Cognitive Health in High Cardiovascular Risk groups. After 48 weeks of treatment, LDL in the treatment group Subjects (EBBINGHUS) trial. This trial prospectively evaluated was significantly reduced to a median value of 30 mg/dL, with participants’ cognitive function with the Cambridge Neuropsy- the lowest being 19 mg/dL. This demonstrated a mean absolute chological Test Automated Battery (CANTAB), specifically its reduction of 56 mg/dL. After a median follow-up of 26 months, spatial working memory strategy index of executive function event rates for the primary composite end point of cardiovas- component. Scores of this component were 4 to 28, with lower cular death, nonfatal MI, stroke, coronary revascularization, scores indicating more efficient use of strategy and planning. In or hospitalization for unstable angina was 9.8% with treatment the trial, subjects were scored with the CANTAB at baseline, at compared with 11.3% with placebo (HR, 0.85; 95% CI, 0.79- week 24, yearly, and at the end of the trial. At baseline and over 0.92; P <.001). In addition, the treatment group had significantly a median 19-month follow-up, each group had a mean score reduced risk of key secondary end points, including MI, total of 17.8; no significant changes were noted between the groups stroke, and coronary revascularization; however, the rates of for spatial working memory strategy index of executive func- cardiovascular death were similar between the groups.20 tion. There was also no difference in any secondary end points The next trial, Evaluation of Long-Term, Cardiovascular looking at other metrics measuring working memory, episodic Outcomes After Acute Coronary Syndrome During Treatment with memory, or psychomotor speed scores. The data support lower Alirocumab (ODYSSEY-OUTCOMES), examined alirocumab LDL and/or use of PCSK9 inhibitors do not lead to neurocogni- or placebo in more than 18,000 patients at 1 to 12 months after tive changes in the short or intermediate term.22 an ACS event with an LDL of 70 mg/dL or higher or a non-HDL Given the positive outcomes with PCSK9 inhibitors with cholesterol of 100 mg/dL and higher while receiving a high- minimal safety concerns, this class of nonstatin therapy can be intensity statin or a maximally tolerated statin. In both study added to reduce both LDL and ASCVD risk in patients who are groups, baseline median LDL concentration was 87 mg/dL and unable to reach goals with maximally tolerated statins. Further- was lowered by 54.7% after 48 months with treatment compared more, evolocumab is indicated for use in homozygous familial

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hypercholesterolemia. The agents are self-administered via period. The primary end point was percent change in LDL from subcutaneous injection once or twice a month, which could be baseline to 12 weeks. Patients were considered to be at high a barrier given the administration route. However, one of the cardiovascular risk if they had clinical ASCVD, including cere- largest hindrances to therapy has been the large cost of treatment.2 brovascular disease, symptomatic peripheral arterial disease, or HeFH. All patients had baseline LDL of 70 mg/dL or higher while Bempedoic Acid receiving maximally tolerated statin with or without additional Recently, the FDA approved bempedoic acid 180 mg and bempe- lipid therapy, consistent with guideline recommendations for doic acid 180 mg/ezetimibe 10 mg combination. They are indicated additional therapy. Most patients were taking maximally tolerated for treatment of established ASCVD or heterozygous familial statin therapy alone (79.7%), and 10.3% in treatment and 12.5% in hypercholesterolemia (HeFH) as an adjunct to diet and maximally placebo were taking additional lipid-lowering agents in conjunc- tolerated statin therapy in adult patients who require additional tion with a statin. A majority of the patients were taking high- LDL lowering. Bempedoic acid is a once-daily, oral small molecule intensity statin therapy (53.3%) or moderate-intensity (31.8%). that inhibits cholesterol synthesis and leads to LDL reduction At baseline, approximate LDL levels were 120 mg/dL in both (TABLE 27,11-18).12,18,23 The therapy is a prodrug that requires groups. By week 12, the primary end point was greater in the activation to bempedoyl-CoA by very long-chain acyl- bempedoic group versus placebo (–15.1% vs 2.4%; P <.001).26 CoA synthetase 1 (ASCVL1), an enzyme located in the . The CLEAR Harmony trial was the largest, with a total of 2230 Bempedoyl-CoA acts as a competitive inhibitor to the patients with ASCVD and/or HeFH and an LDL of 70 mg/dL or enzyme ATP-citrate lyase (ACL) that cleaves citrate into greater while receiving maximally tolerated statin therapy either oxaloacetate and acetyl-CoA. This prevents the substrates alone or in combination with other lipid-lowering therapies for required for HMG-CoA reductase to synthesize cholesterol, at least 4 weeks before screening. Patients received bempedoic resulting in lowering of LDL through inhibition of choles- acid 180 mg orally daily or placebo over a 52-week period. The terol synthesis and upregulation of hepatic LDL receptors to primary end point was overall safety, assessed by incidence of clear circulating LDL.23,24 AEs; secondary efficacy end points assessed percent change in Several large phase 3 trials, denoted by Cholesterol Lowering LDL from baseline to 12 weeks. The vast majority of patients via Bempedoic acid, an ACL-Inhibiting Regimen (CLEAR), had ASCVD (97.6%) and nearly all were receiving statin have established the LDL-lowering effect of bempedoic acid in therapy, with 49.9% at high intensity and 43.5% at moderate patients with high cardiovascular risk as well as in those with intensity. Baseline LDL value was approximately 103 mg/dL previous statin intolerance. Consistent with each CLEAR trial, and at 12 weeks was decreased by an overall –18.1% reduction bempedoic acid 180 mg orally daily was added to baseline lipid versus placebo (P <.001); this reduction remained consistent at drugs, including maximally tolerated statin and/or ezetimibe, 52 weeks. The incidence of any AE (78.5% vs 78.7%; P = .91) over a 12-week period.25,26 The CLEAR Serenity trial included or serious AE (14.5% vs 14%; P = .80) did not differ between 345 patients with previous statin intolerance and elevated LDL treatment and placebo (see examples of AEs in TABLE 27,11-18). receiving either nonlipid-lowering therapy, nonstatin therapy, There was a difference in AEs leading to discontinuation at a rate or low-intensity statin therapy. Patients with ASCVD or HeFH of 10.9% in treatment versus 7.1% in placebo (P = .005). The were required to have a baseline LDL of 100 mg/dL or higher; most common AEs in both arms were myalgia (6.0% vs 6.1%; primary prevention patients were required to have an LDL of at least P = .92), gout (1.2% vs 0.3%; P = .03), and new-onset or wors- 130 mg/dL. The primary end point was the change in LDL from ening diabetes (3.3% vs 5.4%; P = .02). As noted, diabetes baseline to 12 weeks. The majority of the patients were in the occurred more frequently in the placebo arm, and this may have primary prevention category (>60%) or had ASCVD; fewer than been due to potential positive effects of bempedoic acid on 3% had HeFH. At entry, the median LDL was 157.6 mg/dL, glucose; however, the numbers of events were low, and more with more than half the patients not on background therapy at base- research is needed to confirm this conclusion. There were low line. After 12 weeks, LDL was significantly reduced with bempe- rates of neurocognitive events, and they did not differ between doic acid compared with placebo (–23.6% vs –1.3%; P <.001).27 groups. Adjudicated major cardiovascular events during the CLEAR Wisdom was a multicenter trial in which 779 patients 52-week study period were reported at 4.6% and 5.7% but did at high cardiovascular risk were randomized to bempedoic acid not reach significance (P = .3). Of note, there is a large-scale 180 mg daily or placebo in addition to maximally tolerated extension phase of this trial underway to better understand if statin therapy.26 Patients were followed for a 52-week study there is a long-term cardiovascular benefit.25

PHARMACYTIMES.ORG NOVEMBER 2020 69 Bempedoic Acid With Ezetimibe analysis for approval. The FDA noted the elevations typically The efficacy of bempedoic acid in conjunction with ezeti- occur in the first 4 weeks of treatment and persisted. Thus, the mibe was established in two phase 3 trials. The first explored product labeling recommends periodic assessment of uric acid the benefits of bempedoic acid 180 mg plus ezetimibe 10 mg levels and monitoring for signs and symptoms during treatment. orally daily, bempedoic acid 180 mg alone, ezetimibe alone, Patients were also found to be at an increased risk of tendon or placebo in addition to maximally tolerated statin therapy rupture compared with placebo (0.5% vs 0%). The FDA review in 301 patients with elevated ASCVD risk. The patients had found the risk factors associated with this phenomenon included to have either ASCVD or HeFH and a baseline LDL of at age older than 60 years, use of fluoroquinolones, administra- least 100 mg/dL or multiple cardiovascular risk factors and tion of intra-articular steroids, or a previous history of rotator an LDL of at least 130 mg/dL. The study assessed a primary cuff syndrome.12,30 The prescribing information recommends end point of change in LDL from baseline to week 12, with avoiding in patients with history of tendon disorders and stop- a mean baseline close to 150 mg/dL in both groups. Collec- ping therapy if joint pain, swelling, inflammation, or tendon tively, 34.6% of patients were receiving high-intensity statin rupture occurs.12 Results of pooled safety data from the 4 clinical therapy, 30.2% were receiving other low-moderate inten- trials evaluating bempedoic acid showed similar rates of AEs sity, and 35.2% were on no statin therapy. By week 12, LDL when compared with placebo but did have a 3.2-fold greater reduction was significantly greater in the combined bempo- incidence of increased uric acid (2.1% vs 0.5%) and 2.5-fold doic acid/ezetimibe arm (–36.2%) compared with bempedoic greater likelihood of gout (1.4% vs 0.4%). The overall incidence acid alone (–17.2%), ezetimibe monotherapy (–23.2%), or of tendon rupture with bempedoic acid when compared with placebo (1.8%) (P <.001 for all comparisons).28 placebo was 0.2% versus 0.31 The second trial, CLEAR Tranquility, assessed the primary As denoted earlier in this activity, an important piece of end point of percent change in LDL at 12 weeks with bempedoic clinical evidence needed for bempedoic acid is ASCVD risk acid or placebo added to daily ezetimibe 10 mg. A total of 269 reduction, which is being investigated in the CLEAR Outcomes patients with statin intolerance taking either low-dose statin, trial that is currently recruiting and underway with results to be fibrates, , BAS, or fish oil with an LDL of at least 100 mg/dL expected in 2022. Bempedoic acid’s place in therapy will likely were randomized to either arm after a 4-week run-in period depend on the results of this trial.32 At the moment, the agent can with ezetimibe. The mean LDL at baseline was 127.6 mg/dL. play a role in patients who are statin intolerant and/or those who It should be noted 45% of patients were taking lipid-lowering require additional LDL lowering. It might also be an option to therapy (other than ezetimibe) prior to randomization, with a use in addition to ezetimibe when the cost of PCSK9 inhibitors higher proportion of patients taking concomitant lipid-lowering limits their use. therapy (47.5%) compared with placebo (39.1%). From baseline to week 12, mean LDL was reduced by 23.5% in the bempedoic Other Lipid-lowering Agents acid plus ezetimibe arm and increased by 5% in the placebo Beyond statins, ezetimibe, PCSK9 inhibitors, and bempe- group, making a mean change of –28.5% (P <.001).29 doic acid, there are other lipid-lowering agents used in the All these trials had similar types and rates of AEs as outlined management of dyslipidemia, such as fibrates, niacin, fish in the CLEAR Harmony trial previously discussed. Myalgias oils, , and .2 However, many are not and other muscle-related AEs occurred at low rates and were given priority recommendation for use in ASCVD risk reduc- not different from the placebo group. The novel mechanism of tion in either the guidelines or expert consensus documents.2,7 action of bempedoic acid combined with its principal activity The reasoning behind this is multifactorial and can be attrib- site occurring in the liver versus the muscle tissue limit muscle- uted to a lack of data around hard ASCVD outcomes, such related AEs and make this agent ideal for patients who are as fibrates; negative data in terms of ASCVD risk reduction, intolerant to statins.25 Furthermore, bempedoic acid was not such as niacin via the Heart Protection Study 2−Treatment associated with concerns for new or onset-worsening diabetes of HDL to Reduce the Incidence of Vascular Events (HPS2- or neurocognitive events as observed with statins. Bempedoic THRIVE) trial, or no ASCVD data; and indication for very acid was consistently found to increase uric acid levels, which limited patient populations, such as mipomersen or lomi- did translate into gout flares and was highlighted in the FDA tapide.7,33 The recent Reduction of Cardiovascular Events

PHARMACYTIMES.ORG 70 NOVEMBER 2020 www.pharmacytimes.org

With Icosapent Ethyl−Intervention Trial (REDUCE-IT) the guidelines mention the impact pharmacist intervention demonstrated a reduction in ASCVD events in patients with can have on patient adherence to lipid-lowering therapy as established ASCVD or diabetes with risk factors on statin with supported through a 2016 Cochrane systematic review.2,39 residual hypertriglyceridemia; however, the LDL and triglyc- This has been confirmed in a 2018 meta-analysis of 26 eride effects were mixed and not robust, which may indicate randomized-controlled trials, which demonstrated that when a different mechanism of benefit beyond lipid effects or that LDL was the sole outcome, a reduction of 13.73 mg/dL in results may be limited to the population studied.34 Thus, at LDL occurred.40 the time of publication, these classes cannot be prioritized Pharmacists play key roles in optimizing the patient’s phar- for LDL reduction in order to receive ASCVD risk reduction. macotherapy, managing AEs, identifying and resolving adher- ence issues, educating patients, and implementing cost-saving Emerging Therapy measures. These activities can be done in a variety of practice is a chemically synthesized, small interfering settings in which pharmacists deliver care (eg, community, ribonucleic acid (siRNA) molecule that is designed to ambulatory, health system). Observation that a patient has not produce sustained hepatocyte-specific, PCSK9-specific RNA been routinely filling their statin therapy can allow for a conver- silencing. Using the siRNA molecules, the translation of their sation as to why this is occurring. The pharmacist should be complementary target messenger RNA can be selectively and able to recommend LDL testing to achieve appropriate goals catalytically silenced, which, in this case, is PCSK9. The and work to optimize the therapy plan if the patient is not at downstream result is an LDL reduction similar to PCSK9 target. Should the patient describe issues related to intolerance inhibitors.35 The benefit is the agent can be given subcutane- (ie, patient complaining of statin-associated muscle toxicity), ously every 6 months, which has the potential to improve the pharmacist can recommend switching the statin, lowering adherence. Three double-blind phase 3 (ORION-9, -10, -11) the dose, or alternate-day regimens. Should cost of therapy be a trials exploring populations with ASCVD or ASCVD risk barrier, the pharmacist could recommend a generic for a name and HeFH have been presented and published. In all trials, brand and can work through patient assistance and/or other inclisiran was administered as 300 mg (equivalent to 284 mg programs to ensure coverage. No matter the barrier, the pharma- of inclisiran free acid) subcutaneously every 6 months or cist can work with the patient and prescribing clinician to devise placebo and change in LDL at 510 days was recorded. Among a solution. Furthermore, the pharmacist can educate the patient all 3 trials, 90% of patients were on maximally tolerated statin, on the benefits and risks of therapy, and the alternative of not and each trial saw roughly 50% reduction in LDL from base- taking therapy as prescribed. Also, all pharmacists can prevent line (mean of 153 mg/dL in ORION-9; mean of 105 mg/dL critical drug–drug interactions with lipid-lowering therapy, in ORION-10 and ORION-11). The significant major AEs such as certain statins and CYP3A4 inhibitors and those listed were mild injection-site reactions, upper respiratory tract in TABLE 2.7,11-18 Finally, pharmacists should be familiar with infections, dyspnea, and bronchitis.36,37 Inclisiran is currently means to perform point-of-care and/or order laboratory tests, being evaluated by the FDA, with a decision expected by the calculate an ASCVD risk (including cholesterol values, family end of 2020; a large outcomes trial is underway.38 history, blood pressure, age, diabetes history, and smoking history; see ADDITIONAL RESOURCES), and interpret cholesterol STAR data in conjunction with additional risk factors to be able to help What questions would you ask a patient in order to guide therapy recommendations beyond statin therapy. optimize their lipid management regimen? Conclusion Patients with dyslipidemia who meet criteria for lipid- The Pharmacist’s Role in Optimizing lowering therapy should initially be started on appropriate Cholesterol Management intensity statin therapy to reduce LDL and non-HDL choles- An important recommendation in the 2018 ACC/AHA terol as well as ASCVD risk. Due to a variety of factors, not Cholesterol Guidelines is use of team-based care as an effec- all patients will achieve desired LDL goals or tolerate statin tive means of improving patient outcomes. Specifically, therapy. Given the available data demonstrating ASCVD risk

PHARMACYTIMES.ORG NOVEMBER 2020 71 reduction, as well as in the concurrent nature of the 2018 study): case-control study. Lancet. 2004;364(9438):937-952. doi: 10.1016/S0140-6736(04)17018-9 guidelines, ezetimibe and PCSK9 inhibitors should be 6. Stone NJ, Robinson JG, Lichtenstein AH, et al; American College of Cardiology/American Heart utilized as the next line of therapy to reach targets. The Association Task Force on Practice Guidelines. 2013 ACC/AHA guideline on the treatment of nonstatin agents currently approved and under develop- blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American ment add to the armamentarium of treatment options avail- College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll able to reduce LDL cholesterol and manage patients with Cardiol. 2014;63(25 Pt B):2889-2934. doi: 10.1016/j.jacc.2013.11.002 cardiovascular risk. However, until additional outcomes 7. Lloyd-Jones DM, Morris PB, Ballantyne CM, et al. 2017 Focused update of the 2016 ACC data related to ASCVD risk reduction are presented, other expert consensus decision pathway on the role of non-statin therapies for LDL-cholesterol lowering agents that reduce LDL should be used in conjunction with in the management of atherosclerotic cardiovascular disease risk: a report of the American ezetimibe and PCSK9 inhibitors either with statin therapy College of Cardiology Task Force on Expert Consensus Decision Pathways. J Am Coll Cardiol. or when statins cannot be tolerated. Pharmacists have 2017;70(14):1785-1822. doi: 10.1016/j.jacc.2017.07.745 an essential role in ensuring patients can optimize their 8. Arnett DK, Blumenthal RS, Albert MA, et al. 2019 ACC/AHA guideline on the primary preven- lipid-lowering regimen. tion of cardiovascular disease: a report of the American College of Cardiology/American Heart

Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol. 2019;74(10):e177-

ADDITIONAL RESOURCES e232. doi: 10.1016/j.jacc.2019.03.010 9. Thompson PD, Panza G, Zaleski A, Taylor B. Statin-associated side effects. J Am Coll Cardiol. 2018 American College of www.acc.org/guidelines/ Cardiology/American Heart hubs/blood-cholesterol 2016;67(20):2395-2410. doi: 10.1016/j.jacc.2016.02.071 Association 2018 Blood 10. Ridker PM, Mora S, Rose L; JUPITER Trial Study Group. Percent reduction in LDL cholesterol Cholesterol Guideline Hub following high-intensity statin therapy: potential implications for guidelines and for the prescrip-

American College of www.acc.org/tools-and- tion of emerging lipid-lowering agents. Eur Heart J. 2016;37(17):1373-1379. doi: 10.1093/ Cardiology ASCVD Risk practice-support/mobile- eurheartj/ehw046 Estimator Plus Smartphone resources/features/2013- App 11. Zetia. Prescribing information. Merck & Co., Inc; 2013. Accessed October 2, 2020. merck.com/ prevention-guidelines- product/usa/pi_circulars/z/zetia/zetia_pi.pdf ascvd-risk-estimator 12. Nexletol. Prescribing information. Esperion Therapeutics, Inc; 2020. Accessed October 2, European Society of www.escardio.org/ 2020. pi.esperion.com/nexletol/nexletol-pi.pdf Cardiology 2019 Guidelines on Guidelines/Clinical- 13. Repatha. Prescribing information. Amgen Inc; 2019. Accessed October 2, 2020. pi.amgen. Dyslipidaemias Practice-Guidelines/ Dyslipidaemias- com/~/media/amgen/repositorysites/pi-amgen-com/repatha/repatha_pi_hcp_english.pdf Management-of 14. Praluent. Prescribing information. Regeneron Pharmaceuticals, Inc; 2020. Accessed October 2, 2020. regeneron.com/sites/default/files/Praluent_PI.pdf

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1. Virani SS, Alonso A, Benjamin EJ, et al; American Heart Association Council on Epidemi- accessdata.fda.gov/drugsatfda_docs/label/2011/022362s007lbl.pdf ology and Prevention Statistics Committee and Stroke Statistics Subcommittee. Heart disease 16. Cholestyramine. Prescribing information. Par Pharmaceutical, Inc; 2019. DailyMed, US and stroke statistics-2020 update: a report from the American Heart Association. Circulation. National Library of Medicine. Updated November 1, 2019. Accessed September 8, 2020. dailymed.

2020;141(9):e139-e596. doi: 10.1161/CIR.0000000000000757 nlm.nih.gov/dailymed/drugInfo.cfm?setid=b0c65058-22c3-4f57-9b61-9bc6fcd6e240

2. Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/ 17. Colestid. Prescribing information. Pfizer Inc; 2017. Accessed October 2, 2020. labeling.pfizer.

AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: a report of com/ShowLabeling.aspx?id=593 the American College of Cardiology/American Heart Association Task Force on Clinical Practice 18. Nexlizet. Prescribing information. Esperion Therapeutics, Inc; 2020. Accessed October 2,

Guidelines. J Am Coll Cardiol. 2019;73(24):e285-e350. doi: 10.1016/j.jacc.2018.11.003 2020. pi.esperion.com/nexlizet/nexlizet-pi.pdf

3. Centers for Disease Control and Prevention. Heart disease facts. Reviewed September 8, 2020. 19. Cannon CP, Blazing MA, Giugliano RP, et al; IMPROVE-IT Investigators. Ezetimibe added

Accessed October 2, 2020. cdc.gov/heartdisease/facts.htm to statin therapy after acute coronary syndromes. N Engl J Med. 2015;372(25):2387-2397. doi:

4. Patel SA, Winkel M, Ali MK, Narayan KM, Mehta NK. Cardiovascular mortality associated with 10.1056/NEJMoa1410489

5 leading risk factors: national and state preventable fractions estimated from survey data. Ann 20. Sabatine M, Giugliano RP, Keech AC, et al; FOURIER Steering Committee and Investiga-

Intern Med. 2015;163(4):245-253. doi: 10.7326/M14-1753 tors. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med.

5. Yusuf S, Hawken S, Ounpuu S, et al; INTERHEART Study Investigators. Effect of potentially 2017;376(18):1713-1722. doi: 10.1056/NEJMoa1615664 modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART 21. Schwartz GG, Streg PG, Szarek M, et al; ODYSSEY OUTCOMES Committees and Investi-

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gators. Alirocumab and cardiovascular outcomes after acute coronary syndrome. N Engl J Med. 31. Banach M, Duell PB, Gotto AM Jr, et al. Association of bempedoic acid administration with

2018;379(22):2097-2107. doi: 10.1056/NEJMoa1801174 atherogenic lipid levels in phase 3 randomized clinical trials of patients with hypercholesterolemia.

22. Giugliano RP, Mach F, Zavitz K, et al; EBBINGHAUS Investigators. Cognitive func- JAMA Cardiol. Published online July 1, 2020. doi: 10.1001/jamacardio.2020.2314 tion in a randomized trial of evolocumab. N Engl J Med. 2017;377(7):633-643. doi: 10.1056/ 32. Evaluation of Major Cardiovascular Events in Patients With, or at High Risk for, Cardiovas-

NEJMoa1701131 cular Disease Who Are Statin Intolerant Treated With Bempedoic Acid (ETC-1002) or Placebo

23. Zagelbaum NK, Yandrapalli S, Nabors C, Frishman WH. Bempedoic acid (ETC-1002): ATP (CLEAR Outcomes). ClinicalTrials.gov identifier: NCT02993406. Updated August 4, 2020. citrate lyase inhibitor: review of a first-in-class medication with potential benefit in statin-refrac- Accessed August 28, 2020. clinicaltrials.gov/ct2/show/NCT02993406 tory cases. Cardio Rev. 2019;27(1):49-56. doi: 10.1097/CRD.0000000000000218 33. Landray MJ, Haynes R, Hopewell JC, et al; HPS2-THRIVE Collaborative Group. Effects of

24. Pinkosky SL, Filippov S, Srivastave RA, et al. AMP-activation protein kinase and ATP-citrate extended-release niacin with in high-risk patients. N Engl J Med. 2014;371(3):201-212. lyase are two distinct molecular targets for ETC-1002, a novel small molecule regulator of lipid and doi: 10.1056/NEJMoa1300955 carbohydrate metabolism. J Lipid Res. 2013;54(1):134-151. doi: 10.1194/jlr.M030528 34. Bhatt DL, Sterg PG, Miller M, et al; REDUCE-IT Investigators. Cardiovascular risk reduction

25. Ray KK, Bays HE, Catapano AL, et al; CLEAR Harmony Trial. Safety and efficacy of bempe- with icosapent ethyl for hypertriglyceridemia. N Engl J Med. 2019;380(1):11-22. doi: 10.1056/ doic acid to reduce LDL cholesterol. N Engl J Med. 2019;380(11):1022-1032. doi: 10.1056/ NEJMoa1812792

NEJMoa1803917 35. Ray KK, Landmesser U, Leiter LA, et al. Inclisiran in patients at high cardiovascular risk with

26. Goldberg AC, Leiter LA, Stroes ES, et al. Effect of bempedoic acid vs placebo added to maxi- elevated LDL cholesterol. N Engl J Med. 2017;376(15):1430-1440. doi: 10.1056/NEJMoa1615758 mally tolerated statins on low-density lipoprotein cholesterol in patients at high risk for cardiovas- 36. Raal FJ, Kallend D, Ray KK, et al; ORION-9 Investigators. Inclisiran for the treatment of cular disease: the CLEAR Wisdom randomized . JAMA. 2019;322(18):1780-1788. doi: heterozygous familial hypercholesterolemia. N Engl J Med. 2020;382(16):1520-1530. doi:

10.1001/jama.2019.16585 10.1056/NEJMoa1913805

27. Laufs U, Banach M, Mancini JG, et al. Efficacy and safety of bempedoic acid in patients with 37. Ray KK, Wright RS, Kallend D, et al; ORION-10 and ORION-11 Investigators. Two phase 3 hypercholesterolemia and statin intolerance. J Am Heart Assoc. 2019;8(7):e011662. doi: 10.1161/ trials of inclisiran in patients with elevated LDL cholesterol. N Engl J Med. 2020;382(16):1507-

JAHA.118.011662 1519. doi: 10.1056/NEJMoa1912387

28. Ballantyne CM, Laufs U, Ray KK, et al. Bempedoic acid plus ezetimibe fixed-dose combination 38. A Randomized Trial Assessing the Effects of Inclisiran on Clinical Outcomes Among People in patients with hypercholesterolemia and high CVD risk treated with maximally tolerated statin With Cardiovascular Disease (ORION-4). ClinicalTrials.gov identifier: NCT03705234. Updated therapy. Eur J Prev Cardiol. 2020;27(6):593-603. doi: 10.1177/2047487319864671 November 29, 2019. Accessed October 5, 2020. clinicaltrials.gov/ct2/show/NCT03705234

29. Ballantyne CM, Banach M, Mancini GB, et al. Efficacy and safety of bempedoic acid added to 39. Van Driel ML, Morledge MD, Ulep R, Shaffer JP, Davies P, Deichmann R. Interven- ezetimibe in statin-intolerant patients with hypercholesterolemia: a randomized, placebo-controlled tions to improve adherence to lipid-lowering medication. Cochrane Database Syst Rev. study. Atherosclerosis. 2018;277:195-203. doi: 10.1016/j.atherosclerosis.2018.06.002 2016;12(12):CD004371. doi: 10.1002/14651858.CD004371.pub4

30. FDA. Center for Drug Evaluation and Research. Integrated Review Executive Summary Inter- 40. Dixon DL, Khaddage S, Bhagat S, Koenig RA, Salgado TM, Baker WL. Effect of pharmacist disciplinary Assessment Appendices. Published June 14, 2019. Accessed August 1, 2020. www. interventions on reducing low-density lipoprotein cholesterol (LDL-C) levels: a systematic review accessdata.fda.gov/drugsatfda_docs/nda/2020/211616Orig1s000IntegratedR.pdf and meta-analysis. J Clin Lipidol. 2020;14(3):282-292.e4. doi: 10.1016/j.jacl.2020.04.004

PHARMACYTIMES.ORG NOVEMBER 2020 73 POSTTEST QUESTIONS

Please use the following case to answer questions 1-3. 5. GG is a 65-year-old man who is on atorvastatin 20 mg daily, as he was not able to tolerate 80 mg daily, and JJ is a 64-year-old White man with a medical history of ezetimibe 10 mg daily due to his past medical history hypertension, dyslipidemia, type 2 diabetes, myocardial of a stroke, atrial fibrillation, and myocardial infarction infarction (18 months ago), and obesity. He presented within the past year. He is adherent to therapy, and to your pharmacy’s medication therapy management his LDL today is 130 mg/dL. His medication list also program. You collected a lipid panel with a point-of- includes aspirin 81 mg daily, colchicine 0.6 mg as care machine and obtained the following results: total needed, nitroglycerin 0.4 mg sublingual as needed, cholesterol, 214 mg/dL; triglycerides, 186 mg/dL; HDL, 41 warfarin goal INR 2-3, and lisinopril 10 mg daily. Which treatment would be the most ideal to recommend for mg/dL; LDL, 106 mg/dL. His home medications include GG? metformin 500 mg twice daily, dapagliflozin 10 mg daily, lisinopril 40 mg daily, atorvastatin 80 mg daily, carvedilol A. Bempedoic acid 180 mg orally daily 25 mg twice daily, and aspirin 81 mg daily. B. Colesevelam 1.875 grams orally twice daily C. Evolocumab 140 mg subcutaneously every 2 weeks 1. According to the 2018 American College of Cardiology/ D. Icosapent ethyl 2 grams twice daily American Heart Association (ACC/AHA) cholesterol guidelines, which of the following patient factors, in 6. Which statement best describes the potential benefit addition to history of atherosclerotic cardiovascular of inclisiran as compared with PCSK9 inhibitors if disease (ASCVD), places JJ at very-high risk? approved by the FDA? A. Age A. Improved adherence B. Race B. More robust LDL reduction C. Type 2 diabetes C. No injection-site reactions D. LDL >80 mg/dL on high-intensity statin D. Oral administration

2. JJ has been adherent to his current statin therapy. 7. Which patient would be the most ideal candidate to Which would be the best threshold to consider receive bempedoic acid? additional lipid-lowering agents for JJ? A. A 42-year-old woman with diabetes and ASCVD A. LDL ≥70 mg/dL pooled risk score of 15% who is on atorvastatin 80 mg B. LDL ≥100 mg/dL daily with an LDL of 55 mg/dL C. Achieving a 50% reduction in LDL from baseline B. A 65-year-old man with HeFH on rosuvastatin 20 mg D. LDL threshold not needed daily, ezetimibe 10 mg daily, and alirocumab 75 mg subcutaneously every 2 weeks with an LDL of 3. According to the 2018 ACC/AHA cholesterol guidelines, 68 mg/dL which nonstatin agent is the best to recommend adding C. A 50-year-old woman with an ST-segment myocardial to JJ’s current therapy? infarction 3 months ago on maximally tolerated A. Alirocumab 75 mg subcutaneously every 2 weeks atorvastatin 20 mg daily, ezetimibe 10 mg daily, and B. Bempedoic acid 180 mg orally daily LDL of 100 mg/dL C. Colesevelam 1.875 mg orally daily D. A 20-year-old patient with diabetes on atorvastatin 20 D. Ezetimibe 10 mg orally daily mg daily with an LDL of 100 mg/dL

4. Which of the following is a prodrug that lowers LDL-C 8. Which of the following criteria places a patient at very- by inhibition of ATP-citrate lyase (ACL) in the liver with high risk, per the 2018 ACC/AHA guidelines, and should no action in the skeletal muscle? lead to the patient being evaluated for additional A. Alirocumab ASCVD risk reduction if LDL is ≥70 mg/dL after B. Bempedoic acid maximally tolerated statin? C. Inclisiran A. Symptomatic asthma D. Ezetimibe B. Symptomatic osteoarthritis C. Symptomatic atrial fibrillation D. Symptomatic peripheral vascular disease

PHARMACYTIMES.ORG 74 NOVEMBER 2020 www.pharmacytimes.org

POSTTEST QUESTIONS (continued)

9. Which of the following adverse effects is associated 10. Which statement best describes the neurocognitive with bempedoic acid? effect of the PCSK9 inhibitors compared with placebo? A. Rhabdomyolysis A. There have been no randomized, placebo-controlled B. Dyspepsia trial data to explore this question. C. Upper respiratory infections B. Data suggest a slight decrease in neurocognitive D. Tendon rupture function. C. Data suggest there is no difference in neurocognitive function. D. Data suggest there is increased neurocognitive function.

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