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New Therapeutic Alternatives for the Management of Dyslipidemia Manouchkathe Cassagnol, Danielle Ezzo and Priti N. Patel Journal of Pharmacy Practice published online 18 October 2013 DOI: 10.1177/0897190013507582 The online version of this article can be found at: http://jpp.sagepub.com/content/early/2013/10/18/0897190013507582

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New York State Council of Health-system Pharmacists

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Review

New Therapeutic Alternatives for the Management of Dyslipidemia

Journal of Pharmacy Practice 00(0) 1-13 ª The Author(s) 2013 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0897190013507582 jpp.sagepub.com

Manouchkathe Cassagnol, PharmD, CGP, BCPS1, Danielle Ezzo, PharmD, BCPS, CGP1, and Priti N. Patel, PharmD, BCPS1

Abstract Hypercholesterolemia affects over 34 million adults in the United States and is a major cause of coronary heart disease (CHD). Conventional therapies, such as statins, have demonstrated their ability to improve clinical end points and decrease morbidity and mortality in patients with CHD. Lomitapide (Juxtapid1), mipomersen (Kynamro1), and icosapent (Vascepa1) are 3 novel agents approved by the US Food and Drug Administration in the past 2 years, which offer new lipid-lowering treatment options with unique pharmacology. Keywords hypercholesterolemia, ezetimibe/atorvastatin, icosapent, lomitapide, mipomersen

Continuing Education Learning Objectives By the end of the article, the reader should be able to: 1. 2. 3. 4. 5. 6.

Describe the epidemiology, presentation, and causes of hypercholesterolemia. Describe the use of lomitapide, mipomersen, and icosapent; 3 drugs in the treatment of hypercholesterolemia. Discuss the clinical pharmacology of lomitapide, mipomersen, and icosapent. Discuss the monitoring parameters for efficacy and toxicity of lomitapide, mipomersen, and icosapent. Compare the pharmacoeconomic data of lomitapide, mipomersen, and icosapent to currently available therapies. Describe the role of the pharmacist for the safe and effective use of lomitapide, mipomersen, and icosapent.

Introduction Hypercholesterolemia is characterized by a total cholesterol (TC) 240 mg/dL, affecting just over 13% of the adult population.1,2 Hypercholesterolemia is considered one of the major risk factors for coronary heart disease (CHD).1 The lifetime risk of CHD in the United States is *50% and 32% in men and women, respectively.3 Hypercholesterolemia is generally caused by a combination of genetic lipid disorders and poor diet or lifestyle choices4 (Table 1). Lipophilic particles including cholesterol, triglycerides (TG), and phospholipids are found within carrier proteins called lipoproteins. Lipoproteins facilitate the transportation of these particles in the blood. Apolipoproteins (apo) are required for lipoprotein assembly, secretion, and lipid metabolism.4 An overview of the various lipoproteins are included in Table 2. Alterations in lipid metabolism cause dyslipidemia and result in a number of complications including corneal arcus of the eye, xanthomas, and atherosclerosis.4 The National Cholesterol Education Program-Adult Treatment Panel III (NCEP-ATP3) guidelines identify low-density

lipoprotein cholesterol (LDL-C) as the primary target for cholesterol-lowering therapy, because it is considered to be the most atherogenic lipoprotein.1,5-8 They have also established LDL-C as an independent risk factor for CHD events.5-8 In populations that maintain LDL-C 125mg/dL LDL-C 300-600 mg/dL TG 400-800 mg/dL

Familial hypertriglyceridemia Type IV Type V Hypoalphalipoproteinemia

Unknown Unknown Defect in HDL catabolism

TG 200-500 mg/dL TG > 1000 mg/dL HDL < 35 mg/dL

Abbreviations: apo, apolipoprotein; HDL, high-density lipoprotein; LDL-C, low-density lipoprotein cholesterol; TG, triglyceride; VLDL, very low-density lipoprotein. a Adapted from Ross et al.4

Table 2. Characteristics of Lipoproteins.a Lipoprotein

Composition

Apolipoprotein

Chylomicrons VLDL IDL LDL HDL

Cholesterol: Cholesterol: Cholesterol: Cholesterol: Cholesterol:

A-I, -II, -IV; B-48; C-I, -II; E B-100; C-I, -II, -III; E B-100, E B-100 A-I, -II; C-I, -II-, -III; E

7%; triglycerides: 85%-95% 20%-30%; triglycerides: 50%-65% 40%; triglycerides: 20% 51%-58%; triglycerides: 4%-8% 18%-25%; triglycerides: 2%-7%

Abbreviations: HDL, high-density lipoprotein; IDL, intermediate-density lipoprotein; LDL, low-density lipoprotein; VLDL, very low-density lipoprotein a Adapted from Ross et al.4

lipoprotein has emerged as an independent risk factor for CHD events in more recent trials, and therefore, some TG-rich lipoproteins are thought to be atherogenic.19-21 The TG-rich remnant lipoprotein, very LDL-C (VLDL-C), has been shown to carry many of the characteristics of atherogenic LDL-C.22-28 Hence, hypertriglyceridemia can be considered a surrogate marker for atherogenic VLDL-C. There are many causes of elevated TG concentrations including, excess weight, physical inactivity, cigarette smoking, excess alcohol intake, metabolic disease (ie, diabetes), very high carbohydrate diet (>60% of total energy), and medications (ie, b-blockers, estrogens, protease inhibitors, and corticosteroids).29,30 Therefore, it becomes imperative to control these conditions to minimize the risk of increasing TG.31 A TG concentration 200 mg/dL, there is an increased association of atherogenicity, therefore, making TGs an appropriate target for cholesterollowering therapy.1,32-34 HDL-C is considered atherogenic when it is 55% LDL-C reduction is ezetimibe/atorvastatin 10/40 mg.44 In comparison to atorvastatin 80 mg alone, the combination drug at its highest dose provides an additional 7% LDL-C reduction— resulting in an LDL-C-lowering capacity of >60%.44 There are no additional contraindications, precautions, or adverse events (AEs) than would be expected with the individual agents in this combination tablet. Fibric acid derivatives, fish oils, and niacin are generally reserved for managing the secondary targets (TG, HDL-C), as they have limited effects on LDL-C lowering.1

Cassagnol et al

3

In fact, prescription of omega-3 acid ethyl esters (Lovaza1) can significantly increase LDL-C up to 46%.45-48 These agents are effective at lowering TG up to 50% and moderately increasing HDL-C up to *14%.45-48 Recently, 3 newer agents with unique pharmacology have been approved by the FDA including lomitapide (Juxtapid1), mipomersen (Kynamro1), and icosapent (Vascepa1)49-51 (Table 3). Both lomitapide and mipomersen are indicated for the treatment of HoFH, a genetically rare disease. Despite advances in treatment, patients with HoFH are challenging to treat, and many do not live beyond the age of 30 without the use of nonpharmacologic methods including LDL apheresis (process of filtering the blood through venous access to remove excess LDL-C particles).52-55 Icosapent, used to manage hypertriglyceridemia, provides an alternative prescription fish oil product with improved lipid effects. The purpose of this article is to review these new agents and their role in the management of dyslipidemias.

(CYP3A4).49 Therefore, significant drug interactions with other CYP3A4 substrates, inducers, and inhibitors can be expected. In fact, coadministration of lomitapide 60 mg with ketoconazole 200 mg twice daily, a strong CYP3A4 inhibitor, resulted in a 27-fold increase in the area under the curve (AUC) and a 15-fold increase in the maximum concentration (Cmax) of lomitapide.49 Lomitapide also displays a dose-dependent inhibition of the CYP3A4. When coadministered with simvastatin 40 mg, lomitapide 60 mg increased the AUC and Cmax of simvastatin by 99% and 102%, respectively.49 When coadministered with warfarin 10 mg, lomitapide 60 mg increased the international normalized ratio (INR), AUC, and Cmax of both enantiomers (Rþ warfarin " AUC 28%, " Cmax 14%; S-warfarin " AUC 30%, " Cmax 15%; and INR " AUC 7%, " Cmax 22%).49 Lomitapide is a P-glycoprotein (P-gp) inhibitor and thus may require a dose adjustment of concomitant P-gp substrates.49 Lomitapide has a mean terminal half-life of *40 hours, with *60% and *30% of the dose being excreted in the urine and feces, respectively.49

Search Strategy

Dosing and Administration. Prior to the initiation of lomitapide, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase, and total bilirubin should be measured.49 A negative pregnancy test should also be obtained in women of childbearing age, and a low-fat diet (3 times upper limit of normal (ULN).49 Lomitapide is available as 5-, 10-, and 20-mg capsules that should be swallowed whole with water and without food at least 2 hours after the evening meal.49 Taking the drug with food may cause gastrointestinal (GI) AEs.49 Due to its effect on chylomicron and VLDL-C synthesis, patients should also take supplemental vitamin E (400 units daily), linoleic acid (200 mg daily), a-linolenic acid (210 mg daily), eicosapentaenoic acid (EPA, 110 mg daily), and docosahexaenoic acid (DHA, 80 mg daily) in order to prevent fat-soluble nutrient deficiency.49,57

A text word search for ‘‘lomitapide,’’ ‘‘mipomersen,’’ and ‘‘icosapent’’ was performed using PubMed to include articles indexed for MEDLINE. To be as thorough as possible, no limitations were used. A second search using International Pharmaceutical Abstracts was also performed with the predetermined search terms. The bibliographies of all relevant articles retrieved were scanned to identify any other pertinent articles that may have been missed by the previous searches. We included select phase 2 and 3 trials for our discussion.

Lomitapide Indication. Lomitapide (Aegerion Pharmaceuticals, Cambridge, Massachusetts; Figure 1) is indicated as an adjunct to diet and other lipid-lowering treatments, including LDL apheresis, for patients with HoFH to reduce LDL-C, TC, apoB, and nonHDL-C (the sum of LDL-C and VLDL-C).49 It underwent the standard FDA review process. In addition, it has an orphan drug designation—meaning it was developed to treat a disorder affecting 1 L and is 99% protein bound.49 It undergoes extensive liver metabolism, predominantly through the cytochrome P-450 isoenzyme 3A4

Warnings and AEs. Lomitapide carries a boxed warning regarding elevations in serum transaminases and hepatic steatosis with or without increases in AST/ALT.49 In clinical trials, 34% of the patients had an AST or ALT increase >3 times ULN and 14% had an increase >5 times ULN.49 Liver transaminases should be monitored at baseline, then monthly for the first year, then every 3 months, thereafter.49 Due to these

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Table 3. Summary of Lipid-Lowering Therapies.a Lomitapide

Mipomersen

Icosapent

Indication

Reduce LDL, TC, apoB, and non-HDL cholesterol in patients with homozygous familial hypercholesterolemia as an adjunct to low-fat diet and other lipid-lowering treatments

Dose

Prior to initiation, measure ALT, AST, alkaline phosphatase, and total bilirubin; obtain negative pregnancy test from women of childbearing potential; and initiate low-fat diet with 3 ULN (with further adjustments for AST or ALT >5 ULN) Weak CYP3A4 inhibitors Dialysis Mild hepatic impairment (Child-Pugh A) Oral bioavailability: 7% Distribution: 99.8% Plasma protein bound Metabolism: liver Excretion: urine and feces

Reduce LDL, apoB, TC, and nonHDL cholesterol in patient with homozygous familial hypercholesterolemia as an adjunct to low-fat diet and other lipid-lowering treatments 200 mg weekly

Treatment for adults with severe hypertriglyceridemia (500 mg/dL); adjunct to lipid-lowering lifestyle modifications 4 g daily; 2 (1 g) capsules twice daily

Dose adjustments

Pharmacokinetics

Route of administration Contraindications

Black box warnings Warnings

Drug interactions

ADRs Cost Pregnancy category REMS

Oral capsules Pregnancy Concomitant moderate or strong CYP3A4 inhibitors Moderate or severe hepatic impairment (Child-Pugh B or C), active liver disease, or unexplained persistent elevations in serum transaminases Elevations in serum transaminases Risk of hepatic steatosis Hepatotoxicity Embryo-fetal toxicity Reduces absorption of fat soluble nutrients GI adverse reactions Interaction with CYP3A4 inhibitors Risk of myopathy with concomitant simvastatin or lovastatin Changes in INR during warfarin therapy Risk of malabsorption in patients with hereditary disorders of galactose intolerance CYP3A4 inhibitors Warfarin Simvastatin and lovastatin P-glycoprotein substrates Bile acid sequestrants Gastrointestinal (diarrhea, nausea, vomiting, dyspepsia, and abdominal pain) US$27 156 per 28 tablets X May only be prescribed and dispensed by certified prescribers and pharmacies

ALT or AST  3 ULN

Bioavailability 54%-78% Distribution: 90% plasma protein bound Metabolism: tissue by endonucleases Excretion: urine Subcutaneous injection Moderate or severe hepatic impairment, active liver disease, or unexplained persistent elevations in serum transaminases Elevations in serum transaminases Risk of hepatic steatosis Hepatotoxicity Elevation in transaminases Hepatic steatosis

Caution with other drugs that may cause hepatotoxicity

Hepatotoxicity, injection site reactions, and flu-like symptoms US$16 269.31 per 4 injections B May only be prescribed and dispensed by certified prescribers and pharmacies

US$220.80 per 120 (1 g) capsules C None

Abbreviations: ADR, adverse drug reaction; ALT, alanine aminotransferase; ALA, a-linolenic acid; apo, apolipoprotein; AST, aspartate aminotransferase; CYP3A4, cytochrome P-450 isoenzyme 3A4; DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; GI, gastrointestinal; HDL, high-density lipoprotein; INR, international normalized ratio; LDL, low-density lipoprotein; REMS, Risk Evaluation and Mitigation Strategy; TC, total cholesterol; ULN, upper limit of normal. a Adapted from Pownall et al.,47 Koski,48 and Juxtapid.49

Cassagnol et al

Figure 1. Lomitapide (Juxtapid).49

risks, lomitapide is available only through a Risk Evaluation and Mitigation Strategy (REMS) program, requiring prescribers to enroll in the Juxtapid REMS Program to obtain training and certification.49,58 Additionally, the drug may only be dispensed through certified pharmacies.49,58 Lomitapide is contraindicated in patients who are taking concomitant medications that are moderate or strong CYP3A4 inhibitors (ie, ketoconazole, itraconazole, clarithromycin, ritonavir, and indinavir), that have moderate or severe hepatic impairment (Child-Pugh B and C), and with active liver disease or unexplained persistent elevations in AST/ALT.49 Animal studies demonstrated severe fetal malformations, making it a pregnancy category X drug; therefore, women of childbearing potential must use contraception during treatment.49 If an oral contraceptive is used, a maximum dose of lomitapide 30 mg/d is recommended.49 Women who become pregnant while receiving lomitapide must stop taking the drug immediately.49 The most common AEs reported in clinical trials were GI reactions including diarrhea (79%), nausea (65%), dyspepsia (38%), and vomiting (34%).49 These GI AEs are due to its mechanism of action; however, this may be minimized by adhering to a low-fat diet.49 As mentioned previously, concomitant administration of lomitapide and simvastatin increases exposure to simvastatin.49 Due to the risk of myopathy and rhabdomyolysis when this occurs, the dose of simvastatin should be reduced by 50% when used with lomitapide. Since the metabolism of lovastatin is similar to that of simvastatin, the same dosage adjustment is recommended when lomitapide and lovastatin are used concomitantly. Dose adjustments for concomitant use of other lipid-lowering therapies (ie, atorvastatin, rosuvastatin, micronized fenofibrate, ezetimibe, and extended release niacin) are not required. Concentrations of warfarin may be increased by lomitapide; therefore, INR should be monitored regularly with warfarin dose adjustments made accordingly. As mentioned earlier, lomitapide is a P-gp inhibitor; therefore, dose reduction in P-gp substrates (ie, aliskiren, ambrisentan, colchicine, ranolazine, sitagliptan, dabigatran, and digoxin) may be required with concomitant use. Administration of a bile acid sequestrant should be separated from lomitapide administration by at least 4 hours to avoid changes in drug absorption.49

5 Clinical Data. A phase 2, multicenter, double-blind, 12-week study examined the use of lomitapide in conjunction with ezetimibe in 84 patients with hypercholesterolemia.59 Patients were included if they were 18 to 70 years of age, they had 0 to 1 risk factors for CHD (ie, smoking, hypertension, and family history) with an LDL-C of 160 to 250 mg/dL, and they had >2 risk factors with an LDL-C of 130 to 250 mg/dL. Exclusion criteria included uncontrolled hypertension, serum creatinine >2.5 mg/dL, liver disease, AST/ALT >1.5 times ULN, symptomatic heart failure, diabetes, TG >400 mg/dL, or an acute cardiovascular event in the preceding 6 months. Lipid-lowering therapies had to be discontinued 4 weeks before screening. Patients were randomly assigned to one of the following groups: group 1: ezetimibe 10 mg daily plus placebo; group 2: lomitapide 5 mg daily for the first 4 weeks, 7.5 mg for the next 4 weeks, 10 mg for the following 4 weeks, and placebo for the entire 12 weeks; and group 3: lomitapide with the same dosing schedule as group 2 plus ezetimibe 10 mg daily for 12 weeks. The primary outcome was percentage change in LDLC. A total of 85 patients were randomized to the 3 treatment arms (29 group 1, 28 group 2, and 28 group 3). At baseline, mean age was approximately 55 years with LDL-C levels ranging from 162 to 169 mg/dL among the 3 groups. After 12 weeks of treatment, LDL-C decreased to 127 mg/dL (20%), 120 mg/ dL (30%), and 88.8 mg/dL (46%) in groups 1, 2, and 3, respectively. During the study, 18 (20%) patients stopped or were taken off the study medication, with elevated liver enzymes being the most common reason for discontinuation. The authors concluded that the combination of lomitapide and ezetimibe could be an effective treatment option for patients with hypercholesterolemia.59 Lomitapide was studied in a small, phase 3, open-label, multicenter, multinational study.60 Patients were included if they had HoFH diagnosed based on either clinical criteria or documented genetic mutations. Exclusion criteria included major surgery in the previous 3 months, heart failure, history of liver disease, AST or ALT > 2 times ULN, serum creatinine > 2.5 mg/dL, recent malignancy, alcohol or drug abuse, bowel disease or malabsorption, or chronic lung disease. Eligible patients started with a minimum 6week run-in phase during which their previous lipidlowering therapies were continued and stabilized. This was followed by a 26-week efficacy phase during which lomitapide was initiated at 5 mg daily dose and titrated at 4-week intervals to a maximum of 60 mg daily or highest tolerated dose. At the end of the 26-week efficacy phase, patients entered a 52-week safety phase during which their dose of lomitapide was continued. The primary efficacy end point was percentage change in LDL-C from baseline after 26 weeks of treatment. A total of 29 patients were enrolled, with 23 completing the efficacy and safety phases. In all, 100% of the patients had a genetic diagnosis of HoFH, 93.1% were on statin therapy, 75.9% were receiving ezetimibe, and 62.1% had undergone LDL apheresis. At the end of 26 weeks, LDL-C decreased from baseline by 50% (336-166 mg/dL, P < .0001). In addition, significant decreases (P values

6

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Figure 2. Mipomersen (Kynmaro).50

ranging from 90% protein bound at clinically relevant concentrations.50 It does not undergo metabolism via the CYP isoenzyme system; therefore, no significant drug interactions can be expected. Endonucleases metabolize mipomersen to form

Cassagnol et al shorter oligonucleatides.50 Mipomersen is primarily excreted in the urine with a terminal elimination half-life of *1 to 2 months.50 Dosing and Administration. Mipomersen is currently available as a subcutaneous injection.50 The recommended dose is 200 mg once a week. It is recommended for the dose to be administered on the same day each week. In the event that a dose is missed, it should not be given within 3 days of the next dose. Lipid levels should be monitored every 3 months for the first year in order to assess efficacy. Mipomersen’s time to steady state is estimated to be 6 months; and therefore, maximal reduction in LDL-C may not be seen until then. The level of reduction in LDL-C should be assessed to determine whether the benefits of LDL-C reduction outweigh the potential risk of liver toxicity with mipomersen. Mipomersen should be discontinued if the ALT or AST rises to 3 times the ULN and for clinically significant liver toxicity.50 Mipomersen is available in single-used 2 mL vials or 1 mL prefilled syringes containing 200 mg/mL.50 The drug should be stored in the refrigerator at 36 F to 46 F. It is also stable at 86 F, away from extreme heat for up to 14 days. When refrigerated, the dose of mipomersen should be allowed to reach room temperature before administration. Mipomersen should be administered into the abdomen, thigh, or outer area of the upper arm.50 Warnings and AEs. Mipomersen also carries a boxed warning for the risk of hepatotoxicity.50 In pooled data from clinical trials, elevations in transaminases were reported in 30% of the patients receiving the treatment drug versus 15% in placebo.50 It is recommended to draw a baseline ALT, AST, alkaline phosphatase, and total bilirubin prior to initiating treatment.50 Monthly monitoring of these liver enzyme tests is recommended for the first year of treatment and every 3 months, thereafter.50 Mipomersen increases the risk of hepatic steatosis, with or without an increase in transaminases.50 Consequently, extreme caution should be exercised when using mipomersen with other hepatotoxins. Alcohol should be limited to no more than 1 drink/d.50 Animal studies showed no evidence of fetal harm or impaired fertility, making it a pregnancy category B drug.50 However, mipomersen use during pregnancy should only be initiated when the potential benefit is clear. Mipomersen is excreted in human milk and consideration of discontinuing the drug or nursing is recommended.50 Due to the risk associated with mipomersen use, the drug is available only through a REMS program.50,63 Providers and pharmacies must be enrolled in the Kynamro REMS Program to obtain training and certification before prescribing and dispensing the drug.50,63 In all, 84% of the patients treated with mipomersen (vs 33% in placebo group) experienced injection site reactions including erythema, pain, tenderness, pruritus, and local swelling.50 Proper technique should be ensured to reduce the potential for such reactions, such as alternating injection sites.50 Flu-like symptoms were also reported in 30% of the patients and occurred within approximately 2 days of initiation.50

7 Clinical Data. Mipomersen was studied in a randomized, doubleblind, placebo-controlled, phase 3 trial assessing efficacy and safety as add-on therapy in patients with heterozygous familial hypercholesterolemia (HeFH) and coronary artery disease (CAD).62 The inclusion criteria were as follows: patients who had LDL-C 100 mg/dL, TG 200 mg/dL, and receiving stable maximally tolerated statin, with or without other lipidlowering therapies. The exclusion criteria were as follows: apharesis in the previous 8 weeks, unstable angina, New York Heart Association class III or IV heart failure, diabetes mellitus, any condition known to cause hyperlipidemia, AST or ALT 1.5 times ULN, and significant renal or hepatic disease. There were 124 patients randomized to the treatment group (n ¼ 83) of mipomersen 200 mg weekly or placebo (n ¼ 41) for 26 weeks. There were a total of 114 patients who completed the study (placebo: n ¼ 41; treatment: n ¼ 73). The primary end point was percentage change in LDL-C, and secondary end points included percentage change in apoB, TC, and non-HDLC. In the treatment arm, mean percentage reduction in LDL-C was 28%, whereas a small increase in LDL-C was observed in the placebo arm (þ5.2%; P < .001). LDL-C reduction was seen by week 5, with maximal reduction noted at week 21. A greater mean percentage change in apoB was also observed in the mipomersen-treated group when compared to placebo (26.3% vs þ7%, P < .001). A significant reduction in TC (19.4%, P < .001), non-HDL-C (25%, P < .001), VLDLC (14.3%, P ¼ .023), and TG (13.8%, P ¼ .042) was also seen in the treatment group. Serious AEs reported were not related to study medication (placebo 4.9%, treatment group 7.2%). These events included CAD and supraventricular tachycardia in the placebo-treated group and basal cell carcinoma, angina pectoris, acute myocardial infarction, chest pain, pulmonary embolism, and noncardiac chest pain in the mipomersen-treated group. The AEs that were reported due to the study drug primarily included injection site reaction (41.5% placebo, 92.8% mipomersen) and flu-like symptoms (31.7% placebo, 49.4% mipomersen). There were ALT elevations 3 times ULN that occurred in 2.4% of placebo group and 14.5% of mipomersen group with confirmation 1 week later in 6% in the treatment group versus 0% in the placebo.62 The efficacy and safety of mipomersen was also studied in a randomized, double-blind, placebo-controlled, multicentered phase 3 study.64 Patients included in this study were 12 years with genetic confirmation or a clinical diagnosis of HoFH. Diagnosis was based on an untreated LDL-C >500 mg/dL with either a xanthoma at 3 kg during the lead-in period), A1C >9.5%, ALT/AST >3 times ULN, evidence of muscle injury, and recent blood or plasma donation. Certain medications, such as those for weight loss, protease inhibitors, corticosteroids, and isotretinoin, were prohibited during the study. Lipid-modifying drugs, other than statins and ezetimibe for patients at high risk of acute coronary syndrome, were discontinued during screening. After the initial screening visit, patients started a 4- to 6-week stabilization period in which diet, lifestyle, and medications were maintained. If subsequent fasting TG levels were between 500 and 2000 mg/dL, patients were eligible to enter the 12-week double-blind treatment period. During the treatment period,

9 patients were randomized to 1 of the 3 arms, icosapent (called AMR101 in the study) 4 g/d, icosapent 2 g/d, or placebo. The primary end point was placebo-corrected median percentage change in TG from baseline to 12 weeks. Other end points included percentage change from baseline to week 12 in VLDL-C, apoB, lipoprotein-associated phospholipase A2, TC, LDL-C, HDL-C, VLDL-TG, and non-HDL-C. A total of 229 patients were randomized to the treatment as follows: 77 patients to icosapent 4 g/d, 76 patients to icosapent 2 g/d, and 76 patients to placebo. At baseline, patients were on average overweight (BMI 30.8 kg/m2), with severe hypertriglyceridemia (median TG level of 679.5 mg/dL). Nearly 25% remained on statin therapy with 55% at high risk of CHD, and 27% had diabetes. Icosapent 4 g/d demonstrated a 33.1% placebo-corrected TG decrease (P < .0001), while icosapent 2 g/d was associated with a 19.7% decrease (P ¼ .0051). Both 4 and 2 g/d demonstrated significant decreases in TG in patients whose baseline TG was >750 mg/dL (45.4%, P ¼ .001 and 32.9%, P ¼ .0016, respectively). Significant decreases were seen in the 4 g/d group in non-HDL-C (17.7%, P < .0001), lipoprotein-associated phospholipase A2 (13.6%, P ¼ .0003), VLDL-TG (25.8%, P ¼ .0023), and apoB (8.5%, P ¼ .0019) concentrations. LDL-C was not significantly changed in either icosapent group. Treatment-related AEs included diarrhea (1%-5% in the 3 groups), nausea (1%-5%), and eructation (0%-4%).66 The second trial was a phase 3, multicenter, placebo controlled, randomized, double-blinded study conducted in the United States.67 The overall study design was similar to that of the previous study in that a 4- to 6-week stabilization phase was followed by a 12-week double-blind treatment period. After the stabilization period, if TG levels were 200 to 500 mg/dL and LDL-C was 40 to 100 mg/dL, patients were randomized to receive icosapent 4 g/d, icosapent 2 g/d, or placebo for 12 weeks. The inclusion and exclusion criteria, however, were different from the study mentioned earlier. Patients were included if they were over 18 years of age, at high risk of cardiovascular disease (according to NCEP-ATP3), willing to maintain stable diet and lifestyle during the study, and had been receiving at least 4 weeks of stable statin therapy (atorvastatin, simvastatin, or rosuvastatin, with or without ezetimibe) at doses likely to achieve LDL 40 to 100 mg/dL. Exclusion criteria were BMI >45 kg/m2, significant weight change, nonHDL-C 3 g/d proteinuria, malignancy, bariatric surgery, on long-term use of antihypertensives or antidiabetics, thyroid-stimulating hormone >1.5 times ULN, ALT or AST >3 times ULN, and unexplained creatinine kinase >3 times ULN. The primary end point in this study was median placeboadjusted percentage change in TG levels from baseline to week 12. Other end points included changes in non-HDL-C, LDL-C, apoB, VLDL-C, lipoprotein-associated phospholipase A2, TC, HDL-C, VLDL-TG, and C-reactive protein. A total of 226, 234, and 227 patients were included in the primary analysis for the icosapent 4 g/d, icosapent 2 g/d, and placebo groups, respectively. Most patients were caucasian (96%), male (61%), and diabetic (73%) with moderate hypertriglyceridemia (median

10 baseline TG level 259 mg/dL). Other baseline values were as follows: median LDL-C 83 mg/dL and mean baseline hemoglobin A1C 6.6%. At the end of 12 weeks of treatment, the median placebo-adjusted change in TG level was 21.5% (P < .0001) and 10.1% (P ¼ .0005) in the icosapent 4 and 2 g/d groups, respectively. Significant decreases were also seen in the 4 g/d group for LDL-C (6.2%, P ¼ .0062), non-HDL-C (13.5%, P < .0001), VLDL-C (24.4%, P < .0001), and apoB (9.3%, P < .0001). The 2 g/d dose significantly lowered non-HDL-C, VLDL-C, and apoB. Treatment-emergent AEs occurring in >3% of the patients included diarrhea, nausea, nasopharyngitis, and arthralgia.67 The studies of icosapent showed similar reduction in TG, VLDL, and VLDL-TG. The decrease in TG was higher in the first study when compared to the second (33.1% in the 4 g/d group vs 21.5%). This was possibly due to the fact that baseline TG was much higher in the first study when compared to the second (679.5 vs 259 mg/dL). They also demonstrated similar smaller reductions in non-HDL-C and VLDL-C, in contrast to current available prescription therapies.45 However, LDL-C was not changed in the first study, while the second study found a small change. These studies demonstrate that icosapent has promising benefits in reduction in patients with hypertriglyceridemia. However, icosapent has not been evaluated on its effects on cardiovascular morbidity and mortality outcomes. Patients with a history of hepatic impairment and patients on antiplatelet/anticoagulant therapy due to the increased risk of hepatotoxicity and bleeding should be monitored during therapy. An advantage of icosapent is that it does not increase LDL-C in patients, whereas other omega-3 products can increase LDL-C up to 44%.45 In fact, one of the studies found a small decrease in LDL-C. Although no adequate studies in pregnant women have been conducted, icosapent is deemed a pregnancy category C.

Pharmacoeconomic Considerations The costs of the new products for the treatment of HoFH are quite impressive. The cost of lomitapide and mipomersen is *US$325 000 and US$200 000, respectively, per year.68,69 These therapies are novel and may provide benefit in further lowering patient’s LDL-C, with or without other therapies, in difficult to treat patients and potentially reducing LDL-C apheresis sessions. Apheresis costs are considerably high (*US$4 000/treatment) and require twice monthly sessions as well as additional costs involved for travel to one of the 35 apheresis sites available nationally.70 Quality of life for patients may be improved with the introduction of these agents while still preserving LDL reduction. More studies are needed to truly show the economic value. The yearly out-of-pocket cost of both prescription fish oil therapies is approximately US$2400.71,72 This cost may exceed the cost of many overthe-counter fish oil preparations; however, over-the-counter fish oil products offer variable clinical lipid effects—as their formulations are not standardized and are not regulated by the FDA.

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Place in Therapy Given the cost and serious AEs associated with both lomitapide and mipomersen, they are not agents that should be used in the broader patient population. They should be reserved for difficult to treat, most severe HoFH patient population. Additionally, icosapent is a reasonable alternative to other fish oils, because of its minimal effects on LDL-C and comparable cost. Table 3 provides a summary of the new treatment options.

Pharmacist’s Role Pharmacists have a major role to play in ensuring adequate education of patients and allied health professionals on the appropriate use, potential adverse effects, and the proper monitoring of lomitapide, mipomersen, and icosapent. For example, mipomersen is an injectable agent used once weekly; therefore, patients should be educated on how to monitor and treat local injection site reactions. Evaluation of patients’ medication regimen for potential drug interactions and contraindications to therapy will assist in optimizing safe and effective use of these medications. The key monitoring parameters include liver transaminases for lopitamide and mipomersen and bleeding for icosapent. Pharmacists should also ensure that the proper steps are taken to obtain certification and enrollment to be recognized as authorized dispensers of lomitapide and mipomersen as required by the FDA’s REMS program. In considering the cost of these newer agents, underinsured/uninsured patients may have difficulty obtaining some of these costly agents. There are patient assistance programs for all new agents, which include reimbursement services for out-ofpocket costs or other savings and discounts.73-75 The pharmacist can play a vital role in informing patients of the availability of various patient support programs and providing them with guidance on how to obtain more information on this program, which is available on the manufacturer’s Web site.73-75

Conclusion Clinical trials have highlighted the efficacy and role of lomitapide and mipomersen in the management of HoFH and icosapent in the management of hypertriglyceridemia. Lomitapide and mipomersen are agents that should be used to provide further decreases in LDL-C than conventional therapy. Lomitapide may also be used in conjunction with apheresis in cases of very high levels of LDL-C. Mipomersen may be an option for patients who require additional therapy, but its injectable formulation may become a barrier to treatment initiation. Icosapent provides an alternative to other omega-3 products in that it will not increase LDL-C. Dosing precautions, drug interactions, and AEs can pose serious safety concerns with these new agents. However, use of these agents should be initiated in appropriate patients and with close attention to the prescribing information to ensure the safe and optimal use of these new lipid-lowering drugs.

Cassagnol et al Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.

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Continuing Education Credit The New York State Council of Health-system Pharmacists (NYSCHP) is pleased to provide you with the opportunity to obtain continuing education credit for this article online at HealthSystemCE.org (http://www.healthsystemce.org); login using your email address and HSCE password; then click the ‘‘Journal CE’’ tab. There is no charge to NYSCHP members. If you are not a member of NYSCHP, call 1-518-456-8819 to pay the $15 fee to access the quiz and obtain the password necessary to access the Journal’s CE article. In lieu of this fee, a completed membership application with your dues may be submitted. A grade of 70% or above is required to earn the CE credit. Repeat examinations will be permitted once for a grade below 70%. The NYSCHP is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. This program provides 1.6 contact hours (0.16 CEUs) of continuing education. Universal Activity Number is 0134-0000-13-171-H01-P. Submission of exam for CE credit expires December 15, 2016.