at new options when … · are available via the cpe monitor online system and your participation...

54 DrugTopics | JANUARY 2017 | DrugTopics.com

IntroductionOver the past several years, experts in car-diology and endocrinology have made a major shift in the way that they approach the management of their patients’ lipids. Although statins still rule the initial man-agement of patients with elevated low-den-sity lipoprotein (LDL), the importance of adjunctive therapy is emerging. This arti-cle explores the evolution of major clini-cal guidelines and the literature base that prompted those changes; identifi es the most promising adjunctive antihyperlipid-emic agents; delineates the pharmacologic

and pharmacokinetic advantages and dis-advantages of antihyperlipidemic agents; focuses on PCSK9 inhibitors; and defi nes the role of the pharmacist in the contempo-rary care of patients with hyperlipidemia.

National guidelines for lipid managementLipoproteins are defi ned as very-low-den-sity lipoproteins (VLDL, calculated as 20% of triglyceride concentrations), LDL, and high-density lipoprotein (HDL).1,2 High native HDL concentrations provide some level of car-dioprotection. Total cholesterol (LDL + VLDL

GOAL: Prepare pharmacists with the knowledge they need to have to provide contemporary pharmacologic therapy to patients with hyperlipidemia

After participating in this activity, pharmacists will be able to:> List the benefi ts and limitations of

cholesterol-lowering therapies approved before 2014

> Describe pcsK9 genetic polymorphisms and their contributions to LDL and cardiovascular risk

> Describe pcsK9 inhibitors’ mechanism of action, and their specifi c actions that address previously unaddressed needs

> review clinical trial evidence and assimilate fi nding to understand pcsK9 inhibitors’ safety and effi cacy

> Discuss pcsK9 inhibitors’ place in therapy

> Describe the administration technique for available injectable pcsK9 inhibitors

After participating in this activity, pharmacy technicians will be able to: > recall traditional approaches to cholesterol

management

> identify newer cholesterol-lowering agents, and know their unique uses and dispensing storage requirements

> recognize when to refer patients to the pharmacist for cholesterol counseling

The university of connecticut school of pharmacy is accredited by the Accreditation council for pharmacy Education as a provider of continuing

pharmacy education.

Pharmacists and pharmacy technicians are eligible to participate in the knowledge-based activity, and will receive up to 0.2 CEUs (2 contact hours) for completing the activity, passing the quiz with a grade of 70% or better, and completing an online evaluation. Statements of credit are available via the CPE Monitor online system and your participation will be recorded with CPE Monitor within 72 hours of submission.

ACPE# 0009-9999-17-001-H01-PACPE# 0009-9999-17-001-H01-T

Grant funding: This activity is supported by educational funding from Amgen.

Activity Fee: There is no fee for this activity.

INITIAL RELEASE DATE: JANUARY 11, 2017

EXPIRATION DATE: JANUARY 11, 2019

To obtain CPE credit, visit www.drugtopics.com/cpe and click on the “Take a Quiz” link. This will direct you to the UConn/Drug Topics website, where you will click on the Online CE Center. Use your NABP E-Profi le ID and the session code: 17DT01-JPP48 for pharmacists or the session code: 17DT01-XJK33 for pharmacy technicians to access the online quiz and evaluation. First-time users must pre-register in the Online CE Center. Test results will be displayed immediately and your participation will be recorded with CPE Monitor within 72 hours of completing the requirements.

For questions concerning the online CPE activities, e-mail: [email protected].

EDUCATIONAL OBJECTIVES

FACULTY: C. MICHAEL WHITE, PHARMD, FCP, FCCP Dr. White is professor and chair, University of Connecticut School of Pharmacy, Storrs, Conn, & director, UCONN/Hartford Hospital Health Outcomes, Policy, and Evidence Synthesis Group, Hartford, Conn.

FACULTY DISCLOSURE: Dr. White has no actual or potential confl icts of interest associated with this article.

DISCLOSURE OF DISCUSSIONS OF OFF-LABEL AND INVESTIGATIONAL USES OF DRUGS: This activity may contain discussion of unlabeled/unapproved use of drugs. The content and views presented in this educational program are those of the faculty and do not necessarily represent those of Drug Topics or Uni-versity of Connecticut School of Pharmacy. Please refer to the offi cial prescribing information for each product for discussion of approved indica-tions, contraindications, and warnings.

Abstract Many recent advances in the understanding of lipid management greatly impact the profession of pharmacy and individual pharmacists. Clinical trial evidence has re-established the need to achieve aggressive lipid lowering, including the use of adjunctive therapy when statins are insuf� cient. Ezetimibe and the PCSK9 inhibitors are some of the most promising agents for adjunctive therapy, although many drugs used for lipid management have their advantages and disadvantages. Pharma-cists need to understand why guidelines are evolving and how we can assure that patients reach optimal outcomes.

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DrugTopics.com | JANUARY 2017 | DrugTopics 55

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+ HDL) is not useful clinically, but LDL is very useful and non-HDL cholesterol (LDL + VLDL) might have utility.1

Major national lipid guidelinesNational Cholesterol Education Program (NCEP) adult treatment panel guidelines were published in 2002 and remained in effect through 2013. They recommended achieving an LDL cholesterol level com-mensurate with the patient’s baseline risk of cardiac disease.2 Those with car-diac disease or the highest risk of cardiac disease had to achieve an LDL less than 100 mg/dL, although a level less than 70 mg/dL was acceptable when those with moderate or low cardiac disease risk had to achieve LDL levels less than 130 mg/dL or less than 160 mg/dL, respec-tively. The non-HDL cholesterol goals were 30 mg/dL above the LDL goals for each category of cardiac risk. The guide-lines did not specify a preferred agent for cholesterol management and advo-cated for aggressive multidrug therapy if needed to achieve LDL and non-HDL goals. The authors of the guidelines ini-tially designed the document using epide-miologic data and then assessed clinical trial data to see if it supported their epide-miologic orientation.2

In 2013, the American College of Car-diology and the American Heart Asso-ciation (ACC/AHA) took over the role of hypercholesterolemia guideline creation from NCEP. ACC/AHA guidelines stress the pre-eminence of statin therapy with a dosing intensity dictated by a patient’s cardiovascular risk.3 Patients younger than age 75 years with atherosclerotic cardiovascular disease (ASCVD; historyof acute coronary syndromes [unstable angina, myocardial infarction (MI)], sta-ble angina, stroke or transient ischemic attack, peripheral arterial disease of ath-erosclerotic origin, or arterial revascular-ization [coronary, cerebrovascular, leg artery]), LDL concentration above 190 mg/dL (which includes most patients with heterozygous and homozygous familial hypercholesterolemia [FH]), and those with a 10-year ASCVD risk more than 7.5% (based on ACC/AHA risk calcu-

lator; www.cvriskcalculator.com) should utilize high-intensity statin therapy. Ator-vastatin 40–80 mg or rosuvastatin 20–40 mg are considered high-intensity statin therapy because both reduce an average patient’s LDL more than 50%.

Patients with diabetes mellitus who do not meet the criteria for high-intensity therapy, patients with a 10-year risk of ASCVD between 5% and 7.4%, and those not tolerating higher-intensity statin ther-apy can consider a moderate-inten-sity statin therapy. Atorvastatin 10–20 mg, rosuvastatin 5–10 mg, simvastatin 20–40 mg, pravastatin 40–80 mg, lov-astatin 40 mg, fl uvastatin 80 mg, or pitavastatin 2–4 mg are moderate-inten-sity statins because these reduce LDL by 30% to 49%. If patients do not tolerate or are likely to not tolerate high-intensity statin therapy, moderate-intensity statin therapy should be employed. In persons older than age 75 years, the guideline does not insist on treating it with phar-macotherapy or on any intensity of statin therapy. For all patients, once the maxi-mum tolerated statin dose is achieved, the ACC/AHA 2013 guidelines state that a nonstatin drug may be considered to further reduce LDL, but the benefi ts and risks, drug interactions, and patient preference should be considered, and the ACC/AHA had no preference about whether or not it should be used.3

In August 2016, the European Soci-ety of Cardiology (ESC) along with the European Atherosclerosis Society (EAS)

developed their guideline. Its recommen-dations are a hybrid of the NCEP and the ACC/AHA 2013 approaches.4 Patients with ASCVD, diabetes mellitus, or chronic kidney disease are considered high or very high risk. For all other patients, they recommend using the Systematic COr-

onary Risk Evaluation (SCORE) system, which estimates the 10-year cumulative risk of a fi rst fatal ASCVD event (scoring criteria given in ESC/EAS 2016 guide-lines), unlike the ACC/AHA CV risk cal-culator, which estimates fatal and non-fatal event risk. Low and moderate ASCVD death risk have a 10-year risk of less than 1% and 1% to 5%, while those with risks of 5% to less than 10% and 10% or greater are classifi ed as high or very high risk, respectively. All patients with ASCVD are considered very high risk, as are those with diabetes melli-tus who have target organ damage such as retinopathy or nephropathy. Patients with a marked elevation in total choles-terol (>310 mg/dL) or blood pressure (>180/110 mm Hg) would be considered high risk even if the SCORE risk was less than 5%, as would all other patients with diabetes mellitus. In patients at very high ASCVD risk, an LDL goal of less than 70 mg/dL or a 50% or greater reduc-tion from baseline if the LDL is 70 to 135 mg/dL is recommended. In patients at high ASCVD risk, an LDL goal of less than 100 mg/dL or a 50% or greater reduc-tion from baseline if the LDL is 100 to 200 mg/dL is recommended. In sub-jects at low or moderate risk, a target LDL of less than 115 mg/dL is recom-mended. Statins are considered the pre-ferred baseline therapy in all patients not achieving their goal, and the dose should be maximized to achieve the LDL goal or to the maximum tolerated dose. Unlike

the ACC/AHA guideline, the ESC/EAS 2016 guideline specifi cally recommends adjunctive therapy if the LDL goals are not achieved and recommends that ezet-imibe be the preferred second-line ther-apy for resistant patients.4

C O N T I N U E D O N P A G E xx >

What will the new ACC/AHA guidelines say about LDL goals and the best way to risk stratify patients

when they come out?

pAUse ANd poNdeR



Pharmacologic and safety comparison of different lipid-lowering medications

MECHANISM OF ACTION

USE IN UNEXPLAINED ELEVATED LFTS

MUSCLE TOXICITY POTENTIAL

USE IN RENAL DYSFUNCTION

PREGNANCY/ BREASTFEEDING DRUG INTERACTIONS GI ADR

POTENTIAL NOTES

PCSK9 inhibitors

® Blocks PCSK9, extends life of LDL receptors that take LDL out of the circulation

Yes +/- Yes ® Pregnancy No human data, animal data show no risk® Breastfeeding Possible use

® No known interactions, eliminated by saturable binding to PCSK9 and nonsaturable proteolysis

+ ® Skin ADRs Injection pain, bruising, rash, eczema, erythema, urticaria® Neurocognitive Events Confusion, memory impairmentSQ dosing only

Statins ® Block HMG CoA, a critical step in cholesterol synthesis

No Lova, Simva ++++ Prava, Atorva, Rosuva, Fluva, Pitava ++

Yes (Rosuva can cause increased urine protein, not pathogenic)

® Pregnancy Category X® Breastfeeding Contraindicated

® All statins: avoid use/caution with cyclosporine® Simva, Lova, Atorva: caution or contraindication with CYP3A4 inhibitors® Pitava: avoid use with potent UGT inhibitors® Space statins from BAS® Statins+daptomycin or colchicine =increased myopathy risk

+ ® Best initial therapy for high cholesterol, most evidence for benefi t

Fibrates ® Activates lipoprotein lipase® Converts VLDL into LDL and breaks down LDL

No ++ Gem: Yes, but monitorFeno: Contra-indicated in severe renal dysfunction, dose altered in impaired renal function

® Pregnancy: Category C® Breastfeeding Contraindicated

® Fibrates+warfarin=increased INR® Space fi brates from BAS® Gem increases repaglinide conc greatly, contraindicated® Gem increases statin conc more than Feno (both increase risk of myopathy when combined with statins)® Feno+colchicine=increased myopathy risk® Feno+Ezet=increased gallbladder risk

Gem +++ (dyspepsia, diarrhea, � atulence)Feno +

® No use in gallbladder dx pts

Niacin ® Hepatocyte diacylglycerol acyltransferase–2 inhibitor, leads to breakdown of VLDL and LDL particles

No ++ Use with caution

® Pregnancy Category C® Breastfeeding Possible use

® Niacin increases risk of myopathy with statins® Niacin increases liver risk with statins® Space niacin from BAS® ASA+niacin=less niacin fl ushing, premedicate 30 min before

+++ Dyspepsia, nausea (take with food)Contraindicated with active peptic ulcer

® Increase serum uric acid conc, transiently increase serum glucose® False positive for catecholamines, glucose in urine

Ezetimibe ® NPC1L1 protein inhibitor, leads to less dietary and biliary cholesterol absorption

Not recommended but not contra-indicated

+/- Yes ® Pregnancy Category C® Breastfeeding Possible use

® Ezet+Feno=increased gallbladder risk (avoid use with all � brates)® Ezet+cyclosporine=higher cyclosporin conc® Space Ezet from BAS

+Diarrhea

® Only 1 dose (10 mg)

Lomitapide ® Microsomal triglyceride transfer protein inhibition, necessary for VLDL assembly and secretion in the liver

No ?? Yes ® Pregnancy Category X ® Breastfeeding Don’t use

® Contraindicated with CYP3A4 inhibitors® Lomit+warfarin=increased INRSpace Lomit from BAS® Lomit may block CYP3A4 (Simva conc increase) and block PgP (possible digoxin, dabigatran interactions)

++++Diarrhea, nausea, dyspepsia, fl atulence

® Supplement with fat-soluble vitamins, omega-3 FAs. Avoid in malabsorption patients

Mipomersen ® Antisense oligo nucleotide to apo B-100 mRNA, needed to create LDL and VLDL

No ?? Not recommended with severe renal impairment, proteinuria, or dialysis

® Pregnancy Category B (use only if clearly indicated)® Breastfeeding Possible use (use caution)

® No kinetic interactions with statins, ezetimibe, warfarin (can be used safely together)

_ ® SQ dosing only® No use in fatty liver disease

BAS ® Binds cholesterol–rich bile acids, prevents entrohepatic recycling of cholesterol

Yes – Yes ® Pregnancy Category B® BreastfeedingSafe to use

® Attenuates absorption of lipid and diabetes medications, levothyroxine, oral contraceptives, olmesartan, digoxin, warfarin, fat-soluble vitamins

+++ Constipation bloating

® Colesevelam has less-severe drug interactions than older BAS

+ Little to no effect; ++++ Major effect; – No effect; ?? Unknown effect. Note: Pregnancy category A is safest, followed by B, C, and D, with X being the least safe. Abbreviations: ADRs, adverse drug reactions; ASA, aspirin; Atorva, atorvastatin; BAS, bile acid sequestrant; Conc, concentration; Ezet, ezetimibe; Feno, fenofibrate; Gem, gemfibrozil; GI, gastrointestinal; INR, international normalized ratio; LDL, low-density lipoprotein; LFTs, liver function tests; Lova, lovastatin; NPC1L1, Niemann-Pick C1 Like 1; Pitava, pitavastatin; Prava, pravastatin; Rosuva, rosuvastatin; Simva, simvastatin; SQ, subcutaneous; VLDL, very-low-density lipoproteins. Source: Refs 5,7,10,11

TABLE 1



NEW OPTIONS WHEN STATINS ARE NOT ENOUGH

Clinical trials driving differences in the guidelinesAlthough the NCEP guidelines were driven by epidemiologic associations, the ACC/AHA and the ESC/EAS 2016 guidelines are driven primarily by ran-domized, controlled trials.2–4 The results of major placebo-controlled trials in patients with ASCVD (CARE, LIPID, HPS, GREACE) show that set doses of statins reduce the occurrence of subsequent coronary events and mortality versus placebo.3–5 In patients with elevated LDL levels but no ASCVD, major placebo-con-trolled trials (WOSCOPS, AFCAPS/ Tex-CAPS, ASCOT-LLA) show that set doses of statins reduce ASCVD events and may also reduce mortality versus placebo. In 2 clinical trials of patients with ASCVD and 1 trial of patients without ASCVD, using higher-intensity statin therapy (sec-ondary prevention: PROVE-IT, TNT; pri-mary prevention: JUPITER) was associ-ated with better outcomes than those seen with the use of moderate-inten-sity statin therapy.3–5 At the time that the ACC/AHA 2013 guidelines were being constructed, however, major clinical tri-als demonstrated no additional benefi ts when fenofi brate, niacin, or the experi-mental cholesteryl ester transfer protein inhibitors were used with statins versus statins alone (AIM-HIGH, HPS2-THRIVE, ACCORD, ILLUMINATE).3–5 This lack of literature support for achieving better results when such adjunctive therapy was added to a statin was the reason the ACC/AHA guidelines abandoned the specifi c target LDL goals of the NCEP, which had advocated for multidrug ther-apy if needed to achieve them.

Until June 2015, we lacked data from randomized, controlled trials suggest-ing that adding a drug to a statin for fur-ther lowering of LDL reduced the occur-rence of ASCVD events more than using a statin alone.3 This changed with the publication of the Improved Reduction of Outcomes: Vytorin Effi cacy International Trial (IMPROVE-IT).6 Patients (n=18,144; median follow-up, 6 years) within 10 days

of a recent MI or unstable angina event were randomized to receive ezetimibe 10 mg daily plus simvastatin 40 mg or sim-vastatin 40 mg alone. The primary end-point was a composite of cardiovascu-lar death, nonfatal MI, unstable angina requiring rehospitalization, coronary revascularization, or nonfatal stroke. Those receiving ezetimibe plus simvas-tatin had a lower on-treatment LDL (53.7 mg/dL vs 69.5 mg/dL, P<.001) and fewer ASCVD events (32.7% vs 34.7%, P=.016) than those receiving simvas-tatin alone. Rates of muscle, gallbladder, and hepatic adverse effects and cancer were similar between the groups, making the balance of benefi t to harm very favor-able. Although this is the fi rst and most compelling data that lowering LDL lev-els with adjunctive therapy is better than using a statin alone, there are some lim-itations. First, the group was very high risk for recurrent ASCVD events, having just experienced one within the past 10 days, and they compared adjunctive ther-apy with ezetimibe on top of moderate- rather than high-intensity statin therapy.6

None of the PCSK9 inhibitor trials completed to date assessed mortality or cardiovascular events as a prespec-ifi ed primary outcome.7 In a meta-anal-ysis, however, PCSK9 monoclonal anti-bodies reduced the odds of experiencing all-cause mortality by 55% (P=.015) and MI by 51% (P=.03).8 It should be noted that the researchers used a fi xed-effect model to pool these studies, while a ran-dom-effects model might have been more prudent given the clinical and meth-odologic heterogeneity in the constitu-ent studies.8 The ODYSSEY LONG TERM trial had 49% and 84% of the weight for the all-cause mortality and MI outcomes, respectively, and warrants separate dis-cussion.9 Patients (n=2341) at high risk for cardiovascular events with LDL con-centrations 70 mg/dL or higher despite

maximum tolerated statins received ali-rocumab 150 mg or placebo subcuta-neous injection every other week. The patient’s LDL was reduced from 123 mg/dL to 48 mg/dL in the alirocumab group. In a post-hoc analysis, the alirocumab group had a lower occurrence of major adverse cardiac events (MACE; death from coro-nary disease, nonfatal MI, nonfatal isch-emic stroke, or unstable angina requir-ing hospitalization) than placebo (1.7% vs 3.3%; P=.02) but was driven primarily by reductions in nonfatal MI (0.9% vs 2.3%; P=.01).9

When the data from adjunctive ezet-imibe and PCSK9 inhibitor therapy ver-sus statin alone trials are viewed along with the higher- versus lower-inten-sity statin therapy trials, the most likely assumption is that lowering LDL to a greater extent further reduces ASCVD events, a conclusion built into the ESC/EAS 2016 guidelines but not able to be incorporated in the ACC/AHA 2013 guidelines.3-5,7

Comparing pharmacologic agents that lower LDLTable 1 compares and contrasts the pharmacologic and safety features of the main antihyperlipidemic agents being used in the United States.5,7,10,11 Some agents have advantages in patients with liver or renal disease, in pregnancy or lactation, and in terms of gastrointestinal tolerability, muscle symptomatology, and drug interactions. The agents also differ in terms of the expected range of LDL reductions that can be expected as denoted in Figure 1.5,7,10,11 Lipid apheresis (in which a dial-ysis-like machine is used to extract lipo-proteins from the bloodstream), PCSK9 inhibitors, and high-intensity statin ther-apy have the greatest ability to reduce LDL, with the fi rst 2 options being mark-edly expensive.5,7,10,11 Lipid apheresis is also inconvenient, however, because a patient has to go to a health system and be hooked up to the machine. Lomi-tapide and mipomersen are options in patients with homozygous FH, but are

C ON T INUE D ON PAGE xx >

Pharmacologic and safety comparison of different lipid-lowering medications

MECHANISM OF ACTION

USE IN UNEXPLAINED ELEVATED LFTS

MUSCLE TOXICITY POTENTIAL

USE IN RENAL DYSFUNCTION

PREGNANCY/ BREASTFEEDING DRUG INTERACTIONS GI ADR

POTENTIAL NOTES

PCSK9 inhibitors

® Blocks PCSK9, extends life of LDL receptors that take LDL out of the circulation

Yes +/- Yes ® Pregnancy No human data, animal data show no risk® Breastfeeding Possible use

® No known interactions, eliminated by saturable binding to PCSK9 and nonsaturable proteolysis

+ ® Skin ADRs Injection pain, bruising, rash, eczema, erythema, urticaria® Neurocognitive Events Confusion, memory impairmentSQ dosing only

Statins ® Block HMG CoA, a critical step in cholesterol synthesis

No Lova, Simva ++++ Prava, Atorva, Rosuva, Fluva, Pitava ++

Yes (Rosuva can cause increased urine protein, not pathogenic)

® Pregnancy Category X® Breastfeeding Contraindicated

® All statins: avoid use/caution with cyclosporine® Simva, Lova, Atorva: caution or contraindication with CYP3A4 inhibitors® Pitava: avoid use with potent UGT inhibitors® Space statins from BAS® Statins+daptomycin or colchicine =increased myopathy risk

+ ® Best initial therapy for high cholesterol, most evidence for benefi t

Fibrates ® Activates lipoprotein lipase® Converts VLDL into LDL and breaks down LDL

No ++ Gem: Yes, but monitorFeno: Contra-indicated in severe renal dysfunction, dose altered in impaired renal function

® Pregnancy: Category C® Breastfeeding Contraindicated

® Fibrates+warfarin=increased INR® Space fi brates from BAS® Gem increases repaglinide conc greatly, contraindicated® Gem increases statin conc more than Feno (both increase risk of myopathy when combined with statins)® Feno+colchicine=increased myopathy risk® Feno+Ezet=increased gallbladder risk

Gem +++ (dyspepsia, diarrhea, � atulence)Feno +

® No use in gallbladder dx pts

Niacin ® Hepatocyte diacylglycerol acyltransferase–2 inhibitor, leads to breakdown of VLDL and LDL particles

No ++ Use with caution

® Pregnancy Category C® Breastfeeding Possible use

® Niacin increases risk of myopathy with statins® Niacin increases liver risk with statins® Space niacin from BAS® ASA+niacin=less niacin fl ushing, premedicate 30 min before

+++ Dyspepsia, nausea (take with food)Contraindicated with active peptic ulcer

® Increase serum uric acid conc, transiently increase serum glucose® False positive for catecholamines, glucose in urine

Ezetimibe ® NPC1L1 protein inhibitor, leads to less dietary and biliary cholesterol absorption

Not recommended but not contra-indicated

+/- Yes ® Pregnancy Category C® Breastfeeding Possible use

® Ezet+Feno=increased gallbladder risk (avoid use with all � brates)® Ezet+cyclosporine=higher cyclosporin conc® Space Ezet from BAS

+Diarrhea

® Only 1 dose (10 mg)

Lomitapide ® Microsomal triglyceride transfer protein inhibition, necessary for VLDL assembly and secretion in the liver

No ?? Yes ® Pregnancy Category X ® Breastfeeding Don’t use

® Contraindicated with CYP3A4 inhibitors® Lomit+warfarin=increased INRSpace Lomit from BAS® Lomit may block CYP3A4 (Simva conc increase) and block PgP (possible digoxin, dabigatran interactions)

++++Diarrhea, nausea, dyspepsia, fl atulence

® Supplement with fat-soluble vitamins, omega-3 FAs. Avoid in malabsorption patients

Mipomersen ® Antisense oligo nucleotide to apo B-100 mRNA, needed to create LDL and VLDL

No ?? Not recommended with severe renal impairment, proteinuria, or dialysis

® Pregnancy Category B (use only if clearly indicated)® Breastfeeding Possible use (use caution)

® No kinetic interactions with statins, ezetimibe, warfarin (can be used safely together)

_ ® SQ dosing only® No use in fatty liver disease

BAS ® Binds cholesterol–rich bile acids, prevents entrohepatic recycling of cholesterol

Yes – Yes ® Pregnancy Category B® BreastfeedingSafe to use

® Attenuates absorption of lipid and diabetes medications, levothyroxine, oral contraceptives, olmesartan, digoxin, warfarin, fat-soluble vitamins

+++ Constipation bloating

® Colesevelam has less-severe drug interactions than older BAS

+ Little to no effect; ++++ Major effect; – No effect; ?? Unknown effect. Note: Pregnancy category A is safest, followed by B, C, and D, with X being the least safe. Abbreviations: ADRs, adverse drug reactions; ASA, aspirin; Atorva, atorvastatin; BAS, bile acid sequestrant; Conc, concentration; Ezet, ezetimibe; Feno, fenofibrate; Gem, gemfibrozil; GI, gastrointestinal; INR, international normalized ratio; LDL, low-density lipoprotein; LFTs, liver function tests; Lova, lovastatin; NPC1L1, Niemann-Pick C1 Like 1; Pitava, pitavastatin; Prava, pravastatin; Rosuva, rosuvastatin; Simva, simvastatin; SQ, subcutaneous; VLDL, very-low-density lipoproteins. Source: Refs 5,7,10,11

< C ON T INUE D F ROM PAGE xx Lowering LDL to a greater extent further reduces AscVD events.




expensive options with important safety and tolerability drawbacks.5 As identi-fi ed in the ESC/EAS 2016 lipid guide-lines, statins are fi rst-line agents fol-lowed by adjunctive ezetimibe.4 A case could be made for several options to be the second adjunctive agent added to a patient’s regimen, but the PCSK9 inhib-itors have the most potent LDL lowering in general patients, patients with hetero- and homozygous hypercholesterolemia, and the strongest evidence of reducing ASCVD events.7,10,11

Spotlight on PCSK9 inhibitorsLDL receptors are expressed on the surface of hepatocytes. The recep-tor binds LDL and is internalized, the

LDL detaches, and the LDL receptor re-emerges on the cell surface while the LDL is broken down.7 The normal LDL recep-tor is recycled approximately 150 times before being broken down itself. PCSK9, however, binds to the LDL receptor and prevents it from releasing its bound LDL once internalized. This leads to prema-ture LDL degradation and increases circu-lating LDL concentrations. PCSK9 inhibi-tors are monoclonal antibodies that pre-vent PCSK9 from binding LDL recep-tors and therefore prolong the receptors’ effective life. People with dysfunctional PCSK9 have lower circulating LDL and lower risk of ASCVD events.7

Evolocumab and alirocumab are both indicated as adjunctive to diet and max-imally tolerated statin therapy for the treatment of adults with heterozygous FH or clinical ASCVD who require addi-tional lowering of LDL.10,11 Evolocumab is also indicated for patients with homo-zygous FH receiving other LDL-lowering

therapies such as statins, ezetimibe, or LDL apheresis who require additional lowering of LDL.10

The impact of these agents on effi -cacy, safety, and tolerability endpoints in patients without homozygous FH is dis-played in Table 1 and Figure 1.5,7,10,11 This data was derived from numerous well-conducted trials in patients with hetero-zygous FH or a high risk of cardiovas-cular disease. In patients with homo-zygous FH, only evolocumab has been assessed. In the TESLA-B trial, the use of adjunctive injectable evolocumab reduced LDL by 31% (P<.001) versus pla-cebo, which is in line with that seen with other drugs approved for homozygous FH such as lomitapide and mipomersen.5,12 At the European Atherosclerosis Society meeting in June 2016, researchers pre-

sented the results of the open-label and single-blinded TAUSSIG trial.13 In patients with homozygous FH, adjunctive evoloc-umab reduced LDL by 23%, and over 1.7 years of follow-up, there were no deaths and the annualized cardiac event rate was 2.1%. This is less than the 3.5% esti-mated annual event rate in other trials conducted in homozygous FH patients receiving statin plus ezetimibe.13

Role of pharmacists in contemporary practiceChanging back from a statin-driven guide-line to an LDL goal-derived guideline is very important for the practicing phar-macist. Technicians could refer patients with known genetic predilection to hyper-cholesterolemia, those complaining of a family history of premature MI or isch-emic strokes, or patients with cardiac dis-ease currently to the pharmacist for a more in-depth assessment of the ade-quacy of their lipid-lowering therapy. Phar-

macist-directed or -supported lipid and cardiovascular disease clinics have been shown to move more patients to their LDL goals than standard practices.14 This is because achieving health targets, like an LDL goal, blood-pressure goal, or INR level, takes a time-intensive dynamic pro-cess. Engaging a drug expert with the time and expertise to deal with issues of adherence, intolerance, concomitant dis-eases, drug interactions, and resistance is critical to long-term results.14

Patients with ASCVD or those at the highest risk for ASCVD events should achieve an LDL level of less than 70 mg/dL, whereas those with a high risk should achieve an LDL level less than 100 mg/dL.4

Even those with a low-to-moderate risk should achieve an LDL goal of less than 115 mg/dL.4 These LDL goals from the ESC/EAS 2016 guidelines are much more stringent than the NCEP goals of yesteryear and make pharmacist involve-ment central to success.2–4

Pharmacists should start with statins and try to maximize the dose before seeking adjunctive therapy.3–5 Ezeti-mibe has stronger outcome data than the PCSK9 inhibitors, with a lower drug acquisition cost and more-convenient oral dosing making it the fi rst adjunctive treatment of choice. Data show that nia-cin and fi bric acid derivatives lack addi-tional fi nal health outcome benefi ts when added to statins and have a less favorable safety profi le than the PCSK9 inhibitors. This makes the PCSK9 inhib-itors the preferable second-line adjunc-tive therapy.3–5 This is also true in patients with homozygous FH who are on statins and ezetimibe where PCSK9 inhibitors have distinct liver safety advantages over mipomersen and lomi-tapide with similar lipid benefi ts.5,7

Although these are evidence-based standard recommendations for the aver-age patient, many patients have coexist-ing diseases and disorders, drug intoler-ances, and adverse events and use con-comitant drugs, making standard recom-mendations implausible. For example, patients resisting self-injection or the high drug acquisition cost could lead the phar-

< C ON T INUE D F ROM PAGE xx

If having natively higher HDLs is cardioprotective, why doesn’t raising HDL with drug therapy protect against

ASCVD events?

pAUse ANd poNdeR




macist to recommend a bile acid seques-trant for the second adjunctive therapy instead of a PCSK9 inhibitor.4,5,10,11 Bile acid sequestrants reduce LDL well and do not have serious overlapping toxici-ties with statins and ezetimibe, but their impact on ASCVD events is unknown and they are not as well tolerated.5 Some patients cannot use statins at all. Ezeti-mibe monotherapy, with its 18% average reduction in LDL, is unlikely to get them to goal. PCSK9 inhibitors with or without adjunctive ezetimibe can be an accept-able alternative combination regimen that can provide acceptable lipid effects with a strong safety profi le.5,7,10,11

Drug counseling on signs and symp-toms of adverse effects, expected ben-efi ts when the patients are compli-ant, and proper administration times and approaches are critical. Spacing bile acid sequestrants from drugs like statins (giving the bile acid sequestrant 3–4 hours apart from statins, levothyrox-ine, warfarin, and digoxin), using pravas-tatin and fl uvastatin at bedtime, and taking niacin with food to avoid stom-ach upset are all useful tips.5 Patients starting on PCSK9 inhibitors will need to understand how to administer a subcu-taneous injection, and pharmacists, with their certifi cations for immunizations,

are increasingly prepared to counsel them on safe use.10,11 PCSK9 inhibitors are refrigerated and must be warmed to room temperature for 30 to 40 min-utes before use, but discarded if at room temperature for 24 hours or longer. The drug product should be inspected visu-ally and if the solution is discolored or contains visible particulate matter, it should not be used. Standard aseptic injection technique is required for every injection. Subcutaneous injections into the thigh, abdomen, or upper arm area are advisable but not if those areas are burned, infl amed, infected, or if a rash is noted. Patients should rotate injection sites, and PCSK9 inhibitors should not be injected into the same site as other injectable medication. Some fi ne tun-ing of this counseling based on whether the injections come in a syringe, pen, or autoinjector will be needed.10,11

ConclusionThere is a new shift in the paradigm of lipid management. The resumption of LDL goals provides great opportunities for pharmacists to have an important impact on the healthcare team and in patients’ lives, but it requires knowledge of the guidelines themselves, the clinical trials that underlie them, and unique pharma-cologic and pharmacokinetic properties of the drugs that are available for use. •

Dark black lines represent minimum and maximum LDL-reducing effects (in %) that can be achieved through use of that modality. Abbreviations: BAS, bile acid sequestrants; HI, high intensity; Is; inhibitors; LI, low intensity. Source: Refs 5,7,10,11

percent LdL cholesterol reductions with commonly used drugs FIGURE 1

0

Aphe

resis

PCSK

9 Is

HI Sta

tins

LI St

atins

Lom

itapid

e

Mipom

erse

n

Niacin

Ezet

imibe

Fibra

tes

BAS

10

20

30

40

50

60

70

80

1. cui Y, Blumenthal rs, Flaws JA, et al. Non–high-density lipoprotein choles-terol level as a predictor of cardiovascu-lar disease mortality. Arch Intern Med. 2001;161(11):1413–1419.

2. National cholesterol Education program (NcEp) Expert panel on Detection, Evalua-tion, and Treatment of High Blood choles-terol in Adults (Adult Treatment panel iii). Third report of the National cholesterol Education program (NcEp) Expert panel on Detection, Evaluation, and Treatment of High Blood cholesterol in Adults (Adult Treatment panel iii) fi nal report. Circula-tion. 2002;106(25):3143–3421.

3. stone NJ, robinson Jg, Lichtenstein AH, et al; American college of cardiology/Ameri-can Heart Association Task Force on prac-tice guidelines. 2013 Acc/AHA guideline

on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults. Circulation. 2014;129(25 suppl 2):s1–s45.

4. catapano AL, graham i, De Backer g, et al. 2016 Esc/EAs guidelines for the manage-ment of dyslipidaemias: The Task Force for the management of Dyslipidaemias of the European society of cardiology (Esc) and European Atherosclerosis society (EAs) developed with the special contribution of the European Association for cardiovascu-lar prevention & rehabilitation (EAcpr). Eur Heart J. 2016. Epub ahead of print.

5. White cm. mTm essentials for cholesterol management. Drug Topics. 2014;2:64–73.

6. cannon cp, Blazing mA, giugliano rp, et al; improVE-iT investigators. Ezeti-mibe added to statin therapy after acute coronary syndromes. N Engl J Med.

2015;372(25):2387–2397.

7. White cm. Therapeutic potential and criti-cal analysis of the pcsK9 monoclonal anti-bodies evolocumab and alirocumab. Ann Pharmacother. 2015;49(12):1327–1335.

8. Navarese Ep, Kolodziejczak m, schulze V, et al. Effects of proprotein convertase subtilisin/kexin type 9 antibodies in adults with hypercholesterolemia: a systematic review and meta-analysis. Ann Intern Med. 2015;163(1):40–51.

9. robinson Jg, Farnier m, Krempf m, et al; oDYssEY LoNg TErm investigators. Effi -cacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med. 2015;372(16):1489–1499.

10. Amgen inc. repatha package insert. Thousand oaks, cA: Amgen inc.; revised July 2016.

11. sanofi -Aventis u.s. LLc. praluent pack-age insert. Bridgewater, NJ: sanofi -Aventis u.s. LLc; revised July 2015.

12. raal FJ, Honarpour N, Blom DJ, et al; TEsLA investigators. inhibition of pcsK9 with evolocumab in homozy-gous familial hypercholesterolaemia (TEsLA part B): a randomised, double-blind, placebo-controlled trial. Lancet. 2015;385(9965):341–350.

13. stiles s. TAussig hints at fewer cV events with add-on evolocumab in homozygous familial hypercholes-terolemia. Available at http://www.medscape.com/viewarticle/864207. Accessed october 13, 2016.

14. White cm. pharmacists need rec-ognition as providers to enhance patient care. Ann Pharmacother. 2014;48(2):268–273.

REFERENCES

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1. What type of data did NCEP guidelines primarily use when defi ning the LDL goals of individual patients?

a. randomized controlled trialsb. uncontrolled clinical trialsc. Epidemiologic studiesd. case reports

2. Why did ACC/AHA 2013 guidelines not recommend LDL goals like the NCEP guidelines and instead strongly advocate for different intensities of statin therapy with no position on use of adjunctive therapy?

a. Because clinical trials conducted to that point assessed set doses of statins of different intensities to reduce AscVD risk, not statin therapy linked to specifi c target LDL goals, and found no additional benefi ts from using adjunctive therapy

b. Because no studies were conducted adding another lipid-altering drug to statins versus a statin alone

c. Because the Acc/AHA as a rule does not publish guidelines with target goals for diseases

d. Because statins were so widely used it would make it easier for clinicians to adopt their guidelines

3. According to ACC/AHA 2013 guidelines, what type of statin therapy is recommended for use in those >75 years with or without ASCVD?

a. High intensityb. Low intensityc. moderate intensityd. They do not insist on the use of statins or a

statin dose intensity.

4. What is the major difference between the ACC/AHA 2013 CV risk calculator and the ESC/EAS 2016 SCORE risk system?

a. Acc/AHA 2013 calculator uses risk over 20 years instead of 10 years.

b. Acc/AHA 2013 calculator uses risk over 10 years instead of 20 years.

c. Acc/AHA 2013 calculator determines risk of all AscVD events, while Esc/EAs 2016 scorE only determines fatal AscVD events.

d. There is no difference, they calculate the same type of risk over the same time period.

5. What LDL goals are recommended by ESC/EAS 2016 guidelines?

a. Very high risk = LDL <90 mg/dL; high risk = LDL <110 mg/dL; low-to-moderate risk = LDL <130 mg/dL

b. Very high risk = LDL <70 mg/dL; high risk = LDL <100 mg/dL; low-to-moderate risk = LDL <115 mg/dL

c. Very high risk = LDL <40 mg/dL; high risk = LDL <70 mg/dL; low-to-moderate risk = LDL <100 mg/dL

d. Very high risk = LDL <100 mg/dL; high risk = LDL <130 mg/dL; low-to-moderate risk = LDL <160 mg/dL

6. According to ESC/EAS 2016 guidelines, which adjunctive agent is preferred when statins are insuffi cient to achieve LDL goals?

a. Ezetimibeb. Niacinc. Fenofi brated. Evolocumab

7. What did the PROVE-IT, TNT, and JUPITER trials show?

a. That higher-intensity statin therapy was not better than moderate-intensity statin therapy at reducing AscVD events

b. That higher-intensity statin therapy was the same as moderate-intensity statin therapy at reducing AscVD events

c. That higher-intensity statin therapy was better than moderate-intensity statin therapy at reducing AscVD events

d. That statins were better than other lipid-lowering drugs at reducing AscVD events

8. Why was the IMPROVE-IT trial so impactful on the ESC/EAS 2016 guidelines and clinical care?

a. it showed for the fi rst time that bile acid sequestrants provided the same AscVD event reductions as statins.

b. it showed for the fi rst time that bile acid sequestrants provided better AscVD event reductions than statins.

c. it showed for the fi rst time that bile acid sequestrants provided inferior AscVD event reductions than statins.

d. it showed for the fi rst time that adding ezetimibe to a statin was better at reducing AscVD events than using a statin alone.

9. Which of the following drugs are known to be harmful to the developing fetus as designated by a Category X status?

a. statins, lomitapideb. Lomitapide, mipomersenc. Fibrates, ezetimibe d. statins, fi brates

10. Which of the following statins would have the lowest risk of drug interactions when combined with CYP3A4 inhibitors?

a. simvastatin b. Lovastatinc. rosuvastatin d. Atorvastatin

11. Which of the following drugs do not have a high risk of GI effects such as nausea or diarrhea?

a. pcsK9 inhibitors b. Niacinc. Lomitapide d. Fibrates

12. Which of the following drugs can raise serum uric acid concentrations making it riskier in patients with gout?

a. Fibratesb. Bile acid sequestrantsc. mipomersend. Niacin

13. Which of the following can decrease absorption of fat-soluble vitamins?

a. Bile acid sequestrants, lomitapideb. Ezetimibe, statinsc. statins, mipomersend. mipomersen, lomitapide

14. Which of the following drugs have the greatest ability to reduce LDL cholesterol?

a. Low-intensity statins b. pcsK9 inhibitorsc. Niacind. Fibrates

15. How does blocking PCSK9 help reduce LDL cholesterol from the circulation?

a. it reduces LDL receptor manufacture.b. it enhances LDL receptor manufacture.c. it reduces LDL receptor destruction.d. it enhances LDL receptor destruction.

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FOR PHARMACISTS

TEST QUESTIONS




16. Which of the following drugs is linked appropriately with an important potential drawback?

a. Ezetimibe = subcutaneous dosing onlyb. Fibrates = contraindicated in gallbladder

diseasec. pcsK9 inhibitors = serious drug interactionsd. mipomersen = contraindicated with active

peptic ulcer disease

17. If there is a patient who cannot use a statin, what is a limitation of ezetimibe monotherapy?

a. it only reduces LDL by an average of 18% and patients are unlikely to achieve their Esc/EAs 2016 LDL goal.

b. it reduces LDL by an average of 60% and patients are likely to have an LDL that is too low and require discontinuation of therapy.

c. Ezetimibe only reduces cholesterol in patients with high pcsK9 concentrations.

d. Ezetimibe does not reduce LDL cholesterol unless it is combined with another lipid-lowering drug.

18. When counseling a patient on alirocumab administration, what of the following points should be stressed?

a. swallow the tablet and stay upright for 30 minutes.

b. premedicate with aspirin to prevent the fl ushing response.

c. inject into the thigh, abdomen, or upper arm and rotate the site.

d. inject into the buttocks or thigh and rotate the site.

19. Why should a patient look at their PCSK9 injection before injecting it?

a. To be sure it contains the right volumeb. To be sure it is free of particulate matterc. To be sure it is not discoloredd. B and c are both correct

20. How long should evolocumab be left out of the refrigerator before injecting?

a. 10 min b. 20 minc. 30 min d. 24 hr

1. Which of the following drugs is a PCSK9 inhibitor?

a. Evolocumabb. Ezetimibec. Niacind. Lovastatin

2. If you see someone buying over-the-counter niacin, which of the following is a reason to have the patient consult the pharmacist before letting them purchase it?

a. it can raise uric acid levels.b. should not be used in people with active

peptic ulcer diseasec. it can have drug interactions with other

medications like statins and bile acid sequestrants.

d. All of the above

3. PCSK9 inhibitors can only be injected into the following type of skin:

a. infl amedb. Freckledc. skin with a rashd. Burned

4. Which of the following 2 lipoproteins are both associated with ASCVD when their concentrations are too high?

a. HDL, LDLb. VLDL, HDLc. LDL, VLDLd. pBL, HDL

5. Why should statins be avoided in patients receiving colchicine or daptomycin?

a. increased risk of liver diseaseb. increased risk of kidney diseasec. increased risk of myopathyd. Decreased ability to lower LDL

6. What drug should be used fi rst for most patients with elevated LDL cholesterol?

a. Fibratesb. statinsc. Bile acid sequestrantsd. Lomitapide

7. Which of the following drugs is the least expensive?

a. Lomitapideb. mipomersenc. pcsK9 inhibitord. Ezetimibe

8. How many times is an LDL receptor usually recycled before it is broken down by the body?

a. 10b. 15c. 100d. 150

9. According to the ESC/EAS 2016 guidelines, what is the LDL goal for someone with the highest risk of ASCVD?

a. <30 mg/dLb. <70 mg/dLc. <90 mg/dLd. <120 mg/dL

10. Which statin can increase the risk of spilling a protein in the urine?

a. Lovastatinb. simvastatinc. pitavastatind. rosuvastatin

FOR PHARMACY TECHNICIANS


Overset page

pcsK9 inhibitors are monoclonal antibodies that prevent pcsK9 from binding LDL receptors and therefore prolong their effective life.

Do you feel that bile acid sequestrants will reduce ASCVD events as well as ezetimibe given that these reduce LDL to

the same extent?

pAUse ANd poNdeR

changing back from a statin-driven guideline to an LDL goal-derived guideline is very important for the practicing pharmacist.

at new options when … · are available via the cpe monitor online system and your participation...

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