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research-article2013
AOPXXX10.1177/1060028013504079Annals of PharmacotherapyNelson and Munger
Review Article
Icosapent Ethyl for Treatment of Elevated Triglyceride Levels
Annals of Pharmacotherapy 47(11) 1517–1523 © The Author(s) 2013 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1060028013504079 aop.sagepub.com
Scott D. Nelson, PharmD1, and Mark A. Munger, PharmD, FCCP, FACC1
Abstract Objectives: To review the pharmacology, pharmacokinetics, clinical trial data, adverse effects, and formulary considerations of icosapent ethyl for the treatment of high triglyceride (TG) levels. Data Sources: A literature search with keywords Vascepa, icosapent ethyl, AMR101, and eicosapentaenoic acid of articles up to July 2013, along with the package insert for Vascepa and current guidelines for hypertriglyceridemia. Study Selection/Data Extraction: Two phase-III, placebocontrolled, randomized, double-blind, 12-week clinical trials were included in this review: the MARINE trial and ANCHOR study. The MARINE trial consisted of mainly overweight Caucasian men with fasting TG ≥500 and ≤2000 mg/dL taking 4 g/day icosapent ethyl, 2 g/day, or placebo. The ANCHOR study consisted of mainly overweight Caucasians with type2 diabetes mellitus on statin therapy, with fasting TG ≥200 and 500 mg/dL). The pharmacology, pharmacokinetics, clinical trial outcomes, adverse effects, and formulary decisions of this new agent are presented to assist providers in making clinical decisions on the use of this new agent in the treatment of significantly elevated TG levels.
Pathophysiology, Causes, and Treatment of Hypertriglyceridemia A TG is a naturally occurring hydrophobic blood lipid consisting of 3 molecules of fatty acid combined with glycerol.1
TGs are impermeable to transport across the duodenum and must be broken down by pancreatic lipase, which hydrolyzes the ester bond releasing the free fatty acids (FFAs) and glycerol for absorption across enterocyte cells. The fatty acid and glycerol components are subsequently combined with cholesterol and proteins to form chylomicrons. Chylomicrons which are 80% to 95% TG rich are then secreted from the enterocyte cells into the lymph system, where they are transported to the blood stream through the internal jugularsubclavian vein junction, as shown in Figure 1.2,3 In the capillary systems of muscle and adipose tissue, binding of TGs to glycosylphosphati-dylinositol-anchored high-density 1
University of Utah College of Pharmacy, Salt Lake City, UT, USA
Corresponding Author: Mark A. Munger, PharmD, FCCP, FACC, University of Utah, 30 South, 2000 East, Rm #105M, Salt Lake City, UT 84112-5820, USA. Email: [email protected]
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Figure 1. Overview of triglyceride metabolism.a
Abbreviations: Apo A-V, apolipoprotein A-V; CMR, chylomicron remnant; FFAs, free fatty acids; HTGL, hepatic triglyceride lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, low-density lipoprotein receptor; LPL, lipoprotein lipase; LRP, LDL receptor–related protein; VLDL, very-low-density lipoprotein; VLDL-R, very low-density lipoprotein receptor. a Reprinted with permission from figure 3 in Circulation, 2011;123:2292-2333. doi:10.1161/CIR.0b013e3182160726.
lipoprotein (HDL)-binding protein occurs, resulting in core TG hydrolysis by lipoprotein lipase to lipolytic products and FFAs. Muscle or fat tissue then uptake the lipolytic products and FFAs, reforming TG to be used for energy. Thereby, TGs act as very important blood lipids for the body’s metabolism. Elevated TG levels are associated with atherosclerosis even in the absence of hypercholesterolemia, predisposing the individual to cardiovascular disease.4,5 Diagnosis is by laboratory monitoring of TG levels because elevated levels are asymptomatic, although xanthoma skin lesions may be manifested but lack high sensitivity and specificity. The incidence of high TG (>500 mg/dL) in the United States is approximately 1.1% and is more common in patients with type-2 diabetes mellitus (T2DM) or coronary heart disease.2 TG measurements are relatively imprecise because of interactions with other lipids and interindividual variability.6 However, persistent very high levels of TG are associated with eruptive xanthomas, lipemia retinalis, hepatospelomegaly, and an increased risk of acute pancreatitis, which accounts for approximately 1% to 4% of all acute pancreatitis cases.7 Hypertriglyceridemia can be associated with inborn errors of lipid metabolism requiring effective treatment.8
Treatment for mild-moderate hypertriglyceridemia consists of lifestyle changes.8 Reduction in carbohydrates and saturated fat in the diet combined with 30 to 60 minutes of moderate-intensity aerobic activity, such as brisk walking, at least 5 days, preferably 7 days, per week, supplemented by an increase in daily lifestyle activities (eg, walking breaks at work, gardening, and household work) to improve cardiorespiratory fitness and move patients out of the leastfit, least-active high-risk cohort (bottom 20%).9 Medications are recommended in patients where lifestyle changes are inadequate and in combination therapy with high TG levels.
Icosapent Ethyl Icosapent ethyl (Vascepa) is an ethyl ester prodrug of eicosapentaenoic acid (EPA) used for reduction of TG levels and is in the same class as omega-3 fatty acids. Icosapent ethyl was approved in 2012 by the Food and Drug Administration (FDA) for the treatment of patients with TG levels >500 mg/dL along with lifestyle changes, such as diet.
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Pharmacology Icosapent ethyl works as a prodrug that is de-esterified during absorption in the small intestine to the active metabolite EPA. The mechanism of action of EPA in reducing TG levels is not completely understood. One proposed mechanism suggests that EPA inhibits acyl CoA:1,2-diacylglycerol acyltransferase, thereby decreasing hepatic production of TG.10 Additionally, omega-3 fatty acids have a high affinity for peroxisome proliferator–activated receptors, which then increase hepatic peroxisomal β-oxidation of fatty acids.10 Other proposed mechanisms include decreased production/ release of very-low-density lipoproteins (VLDL) and decreased plasma lipoprotein lipase activity.10
Pharmacokinetics11 Icosapent ethyl is absorbed in the small intestine and deesterified to the active metabolite EPA. Circulation is mainly through the thoracic duct lymphatic system. Icosapent ethyl was given in clinical trials with or following a meal, and peak plasma concentrations of EPA were reached approximately 5 hours after administration. The volume of distribution is about 88 L, with more than 99% of EPA bound to plasma proteins. EPA undergoes hepatic β-oxidation to acetyl CoA, which is then converted into energy via the Krebs cycle. Total plasma clearance is 684 mL/h with a half-life of about 89 hours. There appears to be no renal excretion and no drug-drug interactions via cytochrome P450–mediated metabolism. There is potential for drug-drug interactions with highly protein bound drugs (ie, valproate), but this is unlikely and has not been directly studied. One small study using omega-3 fatty acids in patients taking valproate did not show a difference in valproate concentrations.12
Clinical Trials A literature search was completed using PubMed, Google Scholar, and ClinicalTrials.gov with MESH terms and keywords Vascepa, icosapent ethyl, AMR101, and eicosapentaenoic acid of all articles up to July 2013. Two clinical trials were found: the Multicenter, Placebo-Controlled, Randomized, Double-Blind, 12-Week Study With an OpenLabel Extension (MARINE) Trial (ClinicalTrials.gov no. NCT01047683) and the Acid Ethyl Ester Therapy in StatinTreated Patients With Persistent High Triglycerides (ANCHOR) study (ClinicalTrials.gov no. NCT01047501).13,14 The MARINE trial was a phase III, multicenter, international, placebo-controlled, randomized, double-blind study consisting of 77 patients taking 4 g/d icosapent ethyl, 76 taking 2 g/d icosapent ethyl, and 76 taking placebo.13 The majority of patients were overweight Caucasian men on a stable diet with fasting TG between 500 and 2000 mg/dL.
About 25% used a statin and 30% had T2DM. The median baseline fasting TG was 710 mg/dL, and median low-density lipoprotein cholesterol (LDL-C) was 90 mg/dL in the treatment group. After 12 weeks of therapy, the treatment group had a placebo-corrected median decrease for fasting TG of 33.1% (P < .0001) for patients receiving 4 g/d of icosapent ethyl and 45.5% (P < .0001) in the TG >750 mg/ dL subgroup. There was a nonsignificant decrease in the LDL-C levels between the treatment and placebo groups. Patients taking 2 g/d saw a 19.7% (P < .01) decrease in fasting TG, with a nonsignificant increase in LDL-C. Subgroup analysis showed that there was no significant change in LDL particle size.15 In the subgroup of patients receiving statin therapy, there was a 65% decrease in fasting TG levels (P < .0001), suggesting possible synergy. Additionally, there were statistically significant decreases in non-HDL-C (−17.7%), VLDL-C (−28.6%), VLDL-TG (−25.8%), and apolipoprotein B (−8.5%). The only treatment-related adverse events reported in >3% of patients were gastrointestinal intolerances, which were more common with placebo than icosapent ethyl. The ANCHOR study was a phase III, multicenter, placebo-controlled, randomized, double-blind study conducted in the United States, involving 233 patients taking 4 g/d icosapent ethyl, 236 taking 2 g/d icosapent ethyl, and 233 taking placebo.14 The patients were mainly overweight Caucasians with T2DM on a stable diet with fasting TG levels between 200 and 500 mg/dL. About 93% used a statin, and 73% had T2DM. The patients enrolled had well-controlled LDL-C levels (40-99 mg/dL), and the patients with T2DM had well-controlled blood glucose levels with a mean hemoglobin A1c 1000 mg/dL32 and limited to 1 to 3 drinks a day for men and 1 to 2 drinks for women.2,33,34 TG levels are increased by certain disorders of metabolism and diseases such as poorly controlled T2DM, metabolic syndrome, hypothyroidism, and genetic disorders of lipid metabolism. A positive correlation has been established between hemoglobin A1c and TG levels,35 and therefore, successfully treating T2DM may help treat high TG levels. Drugs that can increase TG levels include HIV antiretrovirals, cyclosporine, tacrolimus, everolimus, estrogen, thiazide diuretics, tamoxifen, and second-generation antipsychotics, among others. Although there are many causes for high TG levels, obesity and physical inactivity are the most common.36 Therefore, lifestyle changes are recommended and play a central role in the treatment of high TG levels, such as improving diet and exercise, improving blood glucose control, and avoiding or limiting alcohol. A link between high TG levels and acute pancreatitis has been established,37-40 but controversy remains as to when treatment should start for primary prevention of acute pancreatitis. The Adult Treatment Panel III (ATP-III) guidelines recommend medication treatment if TG >500 mg/dL to prevent the risk of acute pancreatitis36; however, more recent studies suggest a much higher TG threshold of >1000 mg/dL.2 Elevated TG levels are also associated with an increased coronary risk41; however, statin therapy has the most data supporting its use for the prevention of cardiac risk or events/mortality. Therefore, statins are the recommended first-line therapy in treating dyslipidemias. Even in those with high TG (200-499 mg/dL), lowering LDL-C remains the goal, often with statin therapy along with lifestyle modifications.36 Some patients may require additional therapy if they have TG levels too high for statin monotherapy or if lifestyle changes are not enough to reduce their TG levels.
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Nelson and Munger Table 1. Overview of TG-Lowering Medications.2,8,11,32,33,36,50 Drug
Serum TG (Percentage Change)
Serum LDL-C (Percentage Change)
Serum HDL (Percentage Change)
Statins
↓ 10-30
↓ 20-60
↑ 5-10
Nicotinic acid
↓ 30-50
↓ 10-25
↑ 15-35
Fibrates
↓ 30-50
↑ 5-30
↑ 10-25
Ezetimibe Icosapent ethyl P-OM3
↓ 5-10 ↓ 30-50 ↓ 20-50
↓ 20 ↓ 0-5 ↑ 5-40
NS NS ↑ 5-10
Approximate AWP (dollars/month) Crestor = 161 Atorvastatin = 58 Simvastatin = 2 Niaspan = 206 Niacin IR = 12 Gemfibrozil = 20 Fenofibrate = 59 Zetia = 187 Vascepa = 221 Lovaza = 236
Abbreviations: TG, triglycerides; LDL-C, low-density lipoprotein cholesterol; HDL, high-density lipoprotein; AWP, average wholesale price; P-OM3, prescription omega-3 fatty acid ethyl esters; NS, nonsignificant.
Additional therapies for reducing TG levels include nicotinic acid, fibric acid derivatives, ezetimibe, and P-OM3. These medications have been shown to reduce TG levels up to 50%, as shown in Table 1. Nicotinic acid is an effective therapy for reducing TG levels by 30% to 50% without an increase in LDL-C. Immediate-release nicotinic acid is associated with flushing/pruritus and increases in blood glucose, and the extended-release formulation has been associated with hepatotoxicity. Fibric acid derivatives can decrease TG levels by approximately 50% but when used alone can increase LDL-C by 15% to 25% by forming larger LDL-C particles and are typically given with a statin.36 Caution must be used when giving a statin with a fibrate because of the increased risk of myopathy. Ezetimibe can cause a modest decrease of 5% to 10% in TG levels, which for most patients would not be enough alone. P-OM3 can decrease TG by up to 50% with no drug interactions with statins. Although P-OMG and icosapent ethyl are very similar in their TG-lowering ability (perhaps because of the EPA component), P-OM3 is a mixture of EPA and docosahexaenoic acid, the latter of which can increase LDL-C by 31% in some instances.42,43 Therefore, one advantage of icosapent ethyl over P-OM3 is the ability to lower TG without increasing LDL-C. Despite their ability to lower TG levels, the clinical benefit of decreasing cardiovascular events with these agents remains unclear. In a meta-analysis of 14 randomized controlled trials of nicotinic acid alone or in combination with other lipid-lowering drugs, nicotinic acid was able to reduce the relative odds ratio by 25% for major cardiac events.44 Despite the reduction in major cardiac events, the metaanalysis was unable to determine mortality benefit. A recent meta-analysis of 18 randomized controlled trials assessing the effects of fibrates on cardiovascular outcomes compared with placebo showed that fibrate therapy can reduce the relative risk of major cardiovascular events by 10% but had no effect on mortality.45 In the ENHANCE trial, Ezetimibe
failed to show a difference in carotid artery intima-media thickness (a surrogate measure to assess the progression of atherosclerosis) in patients with familial hypercholesterolemia, despite reductions in TG and LDL-C.46 Likewise, a meta-analysis of 48 randomized controlled trials of P-OM3 failed to show a mortality benefit47; however, 1 study did show a slight reduction in mortality in patients with heart failure taking omega-3 fatty acids.48 Icosapent ethyl can decrease surrogate markers similar to other therapies, but the question remains: is there a difference in clinical outcomes, such as a reduction in major cardiovascular events or mortality? One study of 18 645 patients in Japan taking EPA in combination with pravastatin or simvastatin (the JELIS study) showed a 19% (P = .011) reduction in major coronary events in the treatment group.49 This reduction in major coronary events remained statistically significant in the subset of patients with a prior history of coronary events, whereas those without a prior history had a nonsignificant 18% reduction. Additionally, participants in the treatment arm had a reduction in LDL-C of 25% and no significant difference in mortality. It still remains to be seen if icosapent ethyl can duplicate those findings with the currently ongoing REDUCE-IT study. Common side effects of P-OM3 are eructation (belching) (4%), taste perversion (4%), and dyspepsia (3%). The primary side effect of icosapent ethyl is joint pain (2%), suggesting that icosapent ethyl may have fewer side effects. Both icosapent ethyl (Vascepa) and P-OM3 (Lovaza) are priced similarly, with an average wholesale price per month of $220.80 and $236.39,50 respectively. Pharmacoeconomic analyses of omega-3 fatty acids are lacking, and none are currently available for icosapent ethyl.
Conclusions Icosapent ethyl is effective in reducing TG levels without increasing LDL-C within 4 weeks of therapy. Icosapent
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ethyl seems to have efficacy similar to other TG-lowering therapies. The clinical significance for reducing major cardiovascular events or mortality remains in question and is currently under study. In comparison to P-OM3, icosapent ethyl shows similar TG-lowering ability and costs about the same but may be better tolerated and does not increase LDLC. Although icosapent ethyl is costly, it has few side effects and can easily be used as an add-on to statin therapy without an apparent increase in interactions or myopathy. Because statins are a recommended first-line therapy, icosapent ethyl should be added for those patients whose TG levels remain elevated (>200 mg/dL) despite adequate lifestyle modifications or for those patients who have TG >500 mg/dL and contraindications to statin therapy or other TG-lowering agents. 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.
References 1. Genest J, Libby P, Gotto A. Lipoprotein disorders and cardiovascular disease. In: Zipes D, Libby P, Bronow R, Braunwald E, eds. Braunwald’s Heart Disease: A Textbook of Cardiovascular Medicine. 7th ed. New York, NY: Elsevier Saunders; 2005:1013-1034. 2. Miller M, Stone NJ, Ballantyne C, et al. Triglycerides and cardiovascular disease: a scientific statement from the American Heart Association. Circulation. 2011;123:2292-2333. doi:10.1161/CIR.0b013e3182160726. 3. Ginsberg HN. Lipoprotein physiology. Endocrinol Metab Clin North Am. 1998;27:503-519. 4. Austin MA, Hokanson JE, Edwards KL. Hypertriglyceridemia as a cardiovascular risk factor. Am J Cardiol. 1998;81:7B-12B. 5. Ballantyne CM, Olsson AG, Cook TJ, Mercuri MF, Pedersen TR, Kjekshus J. Influence of low high-density lipoprotein cholesterol and elevated triglyceride on coronary heart disease events and response to simvastatin therapy in 4S. Circulation. 2001;104:3046-3051. 6. Beckman J, Libby P, Creager M. Diabetes mellitus, the metabolic syndrome, and atherosclerotic vascular disease. In: Zipes D, Libby P, Bronow R, Braunwald E, eds. Braunwald’s Heart Disease: A Textbook of Cardiovascular Medicine. 7th ed. New York, NY: Elsevier Saunders; 2005:1035-1046. 7. Leaf DA. Chylomicronemia and the chylomicronemia syndrome: a practical approach to management. Am J Med. 2008;121:10-12. doi:10.1016/j.amjmed.2007.10.004. 8. Yuan G, Al-Shali KZ, Hegele RA. Hypertriglyceridemia: its etiology, effects and treatment. CMAJ. 2007;176:1113-1120. doi:10.1503/cmaj.060963. 9. Fihn SD, Gardin JM, Abrams J, et al. 2012 ACCF/AHA/ACP/ AATS/PCNA/SCAI/STS guideline for the diagnosis and
management of patients with stable ischemic heart disease: a report of the American College of Cardiology Foundation/ American Heart Association Task Force on Practice Guidelines, and the American College of Physicians, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. J Am Coll Cardiol. 2012;60:e44-e164. doi:10.1016/j.jacc.2012.07.013. 10. Hoy SM, Keating GM. Omega-3 ethylester concentrate: a review of its use in secondary prevention post-myocardial infarction and the treatment of hypertriglyceridaemia. Drugs. 2009;69:10771105. doi:10.2165/00003495-200969080-00008. 11. Vascepa (icosapent ethyl) [product information]. Dublin, Ireland: Amarin; 2012. 12. Brandt HM, Popish SJ, Lott RS. Effect of omega-3 fatty acids on valproate plasma protein binding. Ann Clin Psychiatry. 2010;22:280-282. 13. Bays HE, Ballantyne CM, Kastelein JJ, Isaacsohn JL, Braeckman RA, Soni PN. Eicosapentaenoic acid ethyl ester (AMR101) therapy in patients with very high triglyceride levels (from the Multi-center, plAcebo-controlled, Randomized, double-blINd, 12-week study with an open-label Extension [MARINE] trial). Am J Cardiol. 2011;108:682-690. doi:10.1016/j.amjcard.2011.04.015. 14. Ballantyne CM, Bays HE, Kastelein JJ, et al. Efficacy and safety of eicosapentaenoic acid ethyl ester (AMR101) therapy in statin-treated patients with persistent high triglycerides (from the ANCHOR study). Am J Cardiol. 2012;110:984992. doi:10.1016/j.amjcard.2012.05.031. 15. Bays HE, Braeckman RA, Ballantyne CM, et al. Icosapent ethyl, a pure EPA omega-3 fatty acid: effects on lipoprotein particle concentration and size in patients with very high triglyceride levels (the MARINE study). J Clin Lipidol. 2012;6:565-572. doi:10.1016/j.jacl.2012.07.001. 16. Davidson MH, Stein EA, Bays HE, et al. Efficacy and tolerability of adding prescription omega-3 fatty acids 4 g/d to simvastatin 40 mg/d in hypertriglyceridemic patients: an 8-week, randomized, double-blind, placebo-controlled study. Clin Ther. 2007;29:1354-1367. doi:10.1016/j.clinthera.2007.07.018. 17. Makrides M, Neumann MA, Gibson RA. Effect of maternal docosahexaenoic acid (DHA) supplementation on breast milk composition. Eur J Clin Nutr. 1996;50:352-357. doi:http:// www.ncbi.nlm.nih.gov/pubmed/87934. 18. Ando M, Sanaka T, Nihei H. Eicosapentanoic acid reduces plasma levels of remnant lipoproteins and prevents in vivo peroxidation of LDL in dialysis patients. J Am Soc Nephrol. 1999;10:2177-2184. 19. Micromedex Healthcare Series [Internet database]. Updated periodically. Thomson Reuters (healthcare) Inc http://www. micromedexsolutions.com/micromed/ 20. Kim DN, Eastman A, Baker JE, et al. Fish oil, atherogenesis, and thrombogenesis. Ann N Y Acad Sci. 1995;748:474-480; Discussion 480-481. 21. Agren JJ, Vaisanen S, Hanninen O, Muller AD, Hornstra G. Hemostatic factors and platelet aggregation after a fish-enriched diet or fish oil or docosahexaenoic acid supplementation. Prostaglandins Leukot Essent Fatty Acids. 1997;57:419-421. 22. Mori TA, Beilin LJ, Burke V, Morris J, Ritchie J. Interactions between dietary fat, fish, and fish oils and their effects on
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Nelson and Munger platelet function in men at risk of cardiovascular disease. Arterioscler Thromb Vasc Biol. 1997;17:279-286. 23. Lee KW, Blann AD, Lip GY. Effects of omega-3 polyunsaturated fatty acids on plasma indices of thrombogenesis and inflammation in patients post-myocardial infarction. Thromb Res. 2006;118:305-312. doi:10.1016/j.thromres.2005.07.018. 24. Nordoy A, Bonaa KH, Sandset PM, Hansen JB, Nilsen H. Effect of omega-3 fatty acids and simvastatin on hemostatic risk factors and postprandial hyperlipemia in patients with combined hyperlipemia. Arterioscler Thromb Vasc Biol. 2000;20:259-265. 25. Nilsen DW, Dalaker K, Nordoy A, et al. Influence of a concentrated ethylester compound of n-3 fatty acids on lipids, platelets and coagulation in patients undergoing coronary bypass surgery. Thromb Haemost. 1991;66:195-201. 26. Hansen JB, Olsen JO, Wilsgard L, Lyngmo V, Svensson B. Comparative effects of prolonged intake of highly purified fish oils as ethyl ester or triglyceride on lipids, haemostasis and platelet function in normolipaemic men. Eur J Clin Nutr. 1993;47:497-507. 27. Russo C, Olivieri O, Girelli D, et al. Omega-3 polyunsaturated fatty acid supplements and ambulatory blood pressure monitoring parameters in patients with mild essential hypertension. J Hypertens. 1995;13:1823-1826. 28. Bays HE. Safety considerations with omega-3 fatty acid therapy. Am J Cardiol. 2007;99:35C-43C. doi:10.1016/j.amjcard.2006.11.020. 29. Harris WS. Expert opinion: omega-3 fatty acids and bleeding—cause for concern? Am J Cardiol. 2007;99:44C-6C. doi:10.1016/j.amjcard.2006.11.021. 30. Stone NJ. Secondary causes of hyperlipidemia. Med Clin North Am. 1994;78:117-141. 31. Chait A, Brunzell JD. Acquired hyperlipidemia (secondary dyslipoproteinemias). Endocrinol Metab Clin North Am. 1990;19:259-278. 32. Pejic RN, Lee DT. Hypertriglyceridemia. J Am Board Fam Med. 2006;19:310-316. 33. Brunzell JD. Clinical practice: hypertriglyceridemia. N Engl J Med. 2007;357:1009-1017. 34. Van de Wiel A. The effect of alcohol on postprandial and fasting triglycerides. Int J Vasc Med. 2012;2012:862504. doi:10.1155/2012/862504. 35. Khan HA, Sobki SH, Khan SA. Association between glycaemic control and serum lipids profile in type 2 diabetic patients: HbA1c predicts dyslipidaemia. Clin Exp Med. 2007;7:24-29. doi:10.1007/s10238-007-0121-3. 36. 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) final report. Circulation. 2002;106:3143-3421. 37. Chait A, Brunzell JD. Chylomicronemia syndrome. Adv Intern Med. 1992;37:249-273. 38. Athyros VG, Giouleme OI, Nikolaidis NL, et al. Long term follow-up of patients with acute hypertriglyceridemiainduced pancreatitis. J Clin Gastroenterol. 2002;34:472-475. 39. Dominguez-Munoz JE, Malfertheiner P, Ditschuneit HH, et al. Hyperlipidemia in acute pancreatitis: relationship with etiology, onset, and severity of the disease. Int J Pancreatol. 1991;10:261-267. 40. Toskes PP. Hyperlipidemic pancreatitis. Gastroenterol Clin North Am. 1990;19:783-791. 41. Cullen P. Evidence that triglycerides are an independent coronary heart disease risk factor. Am J Cardiol. 2000;86:943-949. 42. Ford ES, Li C, Zhao G, Pearson WS, Mokdad AH. Hypertriglyceridemia and its pharmacologic treatment among US adults. Arch Intern Med. 2009;169:572-578. doi:10.1001/ archinternmed.2008.599. 43. Harris WS, Ginsberg HN, Arunakul N, et al. Safety and efficacy of Omacor in severe hypertriglyceridemia. J Cardiovasc Risk. 1997;4:385-391. 44. Bruckert E, Labreuche J, Amarenco P. Meta-analysis of the effect of nicotinic acid alone or in combination on cardiovascular events and atherosclerosis. Atherosclerosis. 2010;210:353361. doi:10.1016/j.atherosclerosis.2009.12.023. 45. Jun M, Foote C, Lv J, et al. Effects of fibrates on cardiovascular outcomes: a systematic review and meta-analysis. Lancet. 2010;375:1875-1884. doi:10.1016/S0140-6736(10)60656-3. 46. Kastelein JJ, Akdim F, Stroes ES, et al. Simvastatin with or without ezetimibe in familial hypercholesterolemia. N Engl J Med. 2008;358:1431-1443. doi:10.1056/NEJMoa0800742. 47. Hooper L, Thompson RL, Harrison RA, et al. Risks and benefits of omega 3 fats for mortality, cardiovascular disease, and cancer: systematic review. BMJ. 2006;332:752-760. doi:10.1136/bmj.38755.366331.2F. 48. Tavazzi L, Maggioni AP, Marchioli R, et al. Effect of n-3 polyunsaturated fatty acids in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebocontrolled trial. Lancet. 2008;372:1223-1230. doi:10.1016/ S0140-6736(08)61239-8. 49. Yokoyama M, Origasa H, Matsuzaki M, et al. Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis. Lancet. 2007;369:1090-1098. doi:10.1016/ S0140-6736(07)60527-3. 50. Drug Topics Red Book Online. Greenwood Village, CO: Truven Health Analytics; 2013.
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research-article2013
AOPXXX10.1177/1060028013504079Annals of PharmacotherapyNelson and Munger
Review Article
Icosapent Ethyl for Treatment of Elevated Triglyceride Levels
Annals of Pharmacotherapy 47(11) 1517–1523 © The Author(s) 2013 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1060028013504079 aop.sagepub.com
Scott D. Nelson, PharmD1, and Mark A. Munger, PharmD, FCCP, FACC1
Abstract Objectives: To review the pharmacology, pharmacokinetics, clinical trial data, adverse effects, and formulary considerations of icosapent ethyl for the treatment of high triglyceride (TG) levels. Data Sources: A literature search with keywords Vascepa, icosapent ethyl, AMR101, and eicosapentaenoic acid of articles up to July 2013, along with the package insert for Vascepa and current guidelines for hypertriglyceridemia. Study Selection/Data Extraction: Two phase-III, placebocontrolled, randomized, double-blind, 12-week clinical trials were included in this review: the MARINE trial and ANCHOR study. The MARINE trial consisted of mainly overweight Caucasian men with fasting TG ≥500 and ≤2000 mg/dL taking 4 g/day icosapent ethyl, 2 g/day, or placebo. The ANCHOR study consisted of mainly overweight Caucasians with type2 diabetes mellitus on statin therapy, with fasting TG ≥200 and 500 mg/dL). The pharmacology, pharmacokinetics, clinical trial outcomes, adverse effects, and formulary decisions of this new agent are presented to assist providers in making clinical decisions on the use of this new agent in the treatment of significantly elevated TG levels.
Pathophysiology, Causes, and Treatment of Hypertriglyceridemia A TG is a naturally occurring hydrophobic blood lipid consisting of 3 molecules of fatty acid combined with glycerol.1
TGs are impermeable to transport across the duodenum and must be broken down by pancreatic lipase, which hydrolyzes the ester bond releasing the free fatty acids (FFAs) and glycerol for absorption across enterocyte cells. The fatty acid and glycerol components are subsequently combined with cholesterol and proteins to form chylomicrons. Chylomicrons which are 80% to 95% TG rich are then secreted from the enterocyte cells into the lymph system, where they are transported to the blood stream through the internal jugularsubclavian vein junction, as shown in Figure 1.2,3 In the capillary systems of muscle and adipose tissue, binding of TGs to glycosylphosphati-dylinositol-anchored high-density 1
University of Utah College of Pharmacy, Salt Lake City, UT, USA
Corresponding Author: Mark A. Munger, PharmD, FCCP, FACC, University of Utah, 30 South, 2000 East, Rm #105M, Salt Lake City, UT 84112-5820, USA. Email: [email protected]
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Figure 1. Overview of triglyceride metabolism.a
Abbreviations: Apo A-V, apolipoprotein A-V; CMR, chylomicron remnant; FFAs, free fatty acids; HTGL, hepatic triglyceride lipase; IDL, intermediatedensity lipoprotein; LDL, low-density lipoprotein; LDL-R, low-density lipoprotein receptor; LPL, lipoprotein lipase; LRP, LDL receptor–related protein; VLDL, very-low-density lipoprotein; VLDL-R, very low-density lipoprotein receptor. a Reprinted with permission from figure 3 in Circulation, 2011;123:2292-2333. doi:10.1161/CIR.0b013e3182160726.
lipoprotein (HDL)-binding protein occurs, resulting in core TG hydrolysis by lipoprotein lipase to lipolytic products and FFAs. Muscle or fat tissue then uptake the lipolytic products and FFAs, reforming TG to be used for energy. Thereby, TGs act as very important blood lipids for the body’s metabolism. Elevated TG levels are associated with atherosclerosis even in the absence of hypercholesterolemia, predisposing the individual to cardiovascular disease.4,5 Diagnosis is by laboratory monitoring of TG levels because elevated levels are asymptomatic, although xanthoma skin lesions may be manifested but lack high sensitivity and specificity. The incidence of high TG (>500 mg/dL) in the United States is approximately 1.1% and is more common in patients with type-2 diabetes mellitus (T2DM) or coronary heart disease.2 TG measurements are relatively imprecise because of interactions with other lipids and interindividual variability.6 However, persistent very high levels of TG are associated with eruptive xanthomas, lipemia retinalis, hepatospelomegaly, and an increased risk of acute pancreatitis, which accounts for approximately 1% to 4% of all acute pancreatitis cases.7 Hypertriglyceridemia can be associated with inborn errors of lipid metabolism requiring effective treatment.8
Treatment for mild-moderate hypertriglyceridemia consists of lifestyle changes.8 Reduction in carbohydrates and saturated fat in the diet combined with 30 to 60 minutes of moderate-intensity aerobic activity, such as brisk walking, at least 5 days, preferably 7 days, per week, supplemented by an increase in daily lifestyle activities (eg, walking breaks at work, gardening, and household work) to improve cardiorespiratory fitness and move patients out of the leastfit, least-active high-risk cohort (bottom 20%).9 Medications are recommended in patients where lifestyle changes are inadequate and in combination therapy with high TG levels.
Icosapent Ethyl Icosapent ethyl (Vascepa) is an ethyl ester prodrug of eicosapentaenoic acid (EPA) used for reduction of TG levels and is in the same class as omega-3 fatty acids. Icosapent ethyl was approved in 2012 by the Food and Drug Administration (FDA) for the treatment of patients with TG levels >500 mg/dL along with lifestyle changes, such as diet.
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Pharmacology Icosapent ethyl works as a prodrug that is de-esterified during absorption in the small intestine to the active metabolite EPA. The mechanism of action of EPA in reducing TG levels is not completely understood. One proposed mechanism suggests that EPA inhibits acyl CoA:1,2-diacylglycerol acyltransferase, thereby decreasing hepatic production of TG.10 Additionally, omega-3 fatty acids have a high affinity for peroxisome proliferator–activated receptors, which then increase hepatic peroxisomal β-oxidation of fatty acids.10 Other proposed mechanisms include decreased production/ release of very-low-density lipoproteins (VLDL) and decreased plasma lipoprotein lipase activity.10
Pharmacokinetics11 Icosapent ethyl is absorbed in the small intestine and deesterified to the active metabolite EPA. Circulation is mainly through the thoracic duct lymphatic system. Icosapent ethyl was given in clinical trials with or following a meal, and peak plasma concentrations of EPA were reached approximately 5 hours after administration. The volume of distribution is about 88 L, with more than 99% of EPA bound to plasma proteins. EPA undergoes hepatic β-oxidation to acetyl CoA, which is then converted into energy via the Krebs cycle. Total plasma clearance is 684 mL/h with a half-life of about 89 hours. There appears to be no renal excretion and no drug-drug interactions via cytochrome P450–mediated metabolism. There is potential for drug-drug interactions with highly protein bound drugs (ie, valproate), but this is unlikely and has not been directly studied. One small study using omega-3 fatty acids in patients taking valproate did not show a difference in valproate concentrations.12
Clinical Trials A literature search was completed using PubMed, Google Scholar, and ClinicalTrials.gov with MESH terms and keywords Vascepa, icosapent ethyl, AMR101, and eicosapentaenoic acid of all articles up to July 2013. Two clinical trials were found: the Multicenter, Placebo-Controlled, Randomized, Double-Blind, 12-Week Study With an OpenLabel Extension (MARINE) Trial (ClinicalTrials.gov no. NCT01047683) and the Acid Ethyl Ester Therapy in StatinTreated Patients With Persistent High Triglycerides (ANCHOR) study (ClinicalTrials.gov no. NCT01047501).13,14 The MARINE trial was a phase III, multicenter, international, placebo-controlled, randomized, double-blind study consisting of 77 patients taking 4 g/d icosapent ethyl, 76 taking 2 g/d icosapent ethyl, and 76 taking placebo.13 The majority of patients were overweight Caucasian men on a stable diet with fasting TG between 500 and 2000 mg/dL.
About 25% used a statin and 30% had T2DM. The median baseline fasting TG was 710 mg/dL, and median low-density lipoprotein cholesterol (LDL-C) was 90 mg/dL in the treatment group. After 12 weeks of therapy, the treatment group had a placebo-corrected median decrease for fasting TG of 33.1% (P < .0001) for patients receiving 4 g/d of icosapent ethyl and 45.5% (P < .0001) in the TG >750 mg/ dL subgroup. There was a nonsignificant decrease in the LDL-C levels between the treatment and placebo groups. Patients taking 2 g/d saw a 19.7% (P < .01) decrease in fasting TG, with a nonsignificant increase in LDL-C. Subgroup analysis showed that there was no significant change in LDL particle size.15 In the subgroup of patients receiving statin therapy, there was a 65% decrease in fasting TG levels (P < .0001), suggesting possible synergy. Additionally, there were statistically significant decreases in non-HDL-C (−17.7%), VLDL-C (−28.6%), VLDL-TG (−25.8%), and apolipoprotein B (−8.5%). The only treatment-related adverse events reported in >3% of patients were gastrointestinal intolerances, which were more common with placebo than icosapent ethyl. The ANCHOR study was a phase III, multicenter, placebo-controlled, randomized, double-blind study conducted in the United States, involving 233 patients taking 4 g/d icosapent ethyl, 236 taking 2 g/d icosapent ethyl, and 233 taking placebo.14 The patients were mainly overweight Caucasians with T2DM on a stable diet with fasting TG levels between 200 and 500 mg/dL. About 93% used a statin, and 73% had T2DM. The patients enrolled had well-controlled LDL-C levels (40-99 mg/dL), and the patients with T2DM had well-controlled blood glucose levels with a mean hemoglobin A1c 1000 mg/dL32 and limited to 1 to 3 drinks a day for men and 1 to 2 drinks for women.2,33,34 TG levels are increased by certain disorders of metabolism and diseases such as poorly controlled T2DM, metabolic syndrome, hypothyroidism, and genetic disorders of lipid metabolism. A positive correlation has been established between hemoglobin A1c and TG levels,35 and therefore, successfully treating T2DM may help treat high TG levels. Drugs that can increase TG levels include HIV antiretrovirals, cyclosporine, tacrolimus, everolimus, estrogen, thiazide diuretics, tamoxifen, and second-generation antipsychotics, among others. Although there are many causes for high TG levels, obesity and physical inactivity are the most common.36 Therefore, lifestyle changes are recommended and play a central role in the treatment of high TG levels, such as improving diet and exercise, improving blood glucose control, and avoiding or limiting alcohol. A link between high TG levels and acute pancreatitis has been established,37-40 but controversy remains as to when treatment should start for primary prevention of acute pancreatitis. The Adult Treatment Panel III (ATP-III) guidelines recommend medication treatment if TG >500 mg/dL to prevent the risk of acute pancreatitis36; however, more recent studies suggest a much higher TG threshold of >1000 mg/dL.2 Elevated TG levels are also associated with an increased coronary risk41; however, statin therapy has the most data supporting its use for the prevention of cardiac risk or events/mortality. Therefore, statins are the recommended first-line therapy in treating dyslipidemias. Even in those with high TG (200-499 mg/dL), lowering LDL-C remains the goal, often with statin therapy along with lifestyle modifications.36 Some patients may require additional therapy if they have TG levels too high for statin monotherapy or if lifestyle changes are not enough to reduce their TG levels.
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Nelson and Munger Table 1. Overview of TG-Lowering Medications.2,8,11,32,33,36,50 Drug
Serum TG (Percentage Change)
Serum LDL-C (Percentage Change)
Serum HDL (Percentage Change)
Statins
↓ 10-30
↓ 20-60
↑ 5-10
Nicotinic acid
↓ 30-50
↓ 10-25
↑ 15-35
Fibrates
↓ 30-50
↑ 5-30
↑ 10-25
Ezetimibe Icosapent ethyl P-OM3
↓ 5-10 ↓ 30-50 ↓ 20-50
↓ 20 ↓ 0-5 ↑ 5-40
NS NS ↑ 5-10
Approximate AWP (dollars/month) Crestor = 161 Atorvastatin = 58 Simvastatin = 2 Niaspan = 206 Niacin IR = 12 Gemfibrozil = 20 Fenofibrate = 59 Zetia = 187 Vascepa = 221 Lovaza = 236
Abbreviations: TG, triglycerides; LDL-C, low-density lipoprotein cholesterol; HDL, high-density lipoprotein; AWP, average wholesale price; P-OM3, prescription omega-3 fatty acid ethyl esters; NS, nonsignificant.
Additional therapies for reducing TG levels include nicotinic acid, fibric acid derivatives, ezetimibe, and P-OM3. These medications have been shown to reduce TG levels up to 50%, as shown in Table 1. Nicotinic acid is an effective therapy for reducing TG levels by 30% to 50% without an increase in LDL-C. Immediate-release nicotinic acid is associated with flushing/pruritus and increases in blood glucose, and the extended-release formulation has been associated with hepatotoxicity. Fibric acid derivatives can decrease TG levels by approximately 50% but when used alone can increase LDL-C by 15% to 25% by forming larger LDL-C particles and are typically given with a statin.36 Caution must be used when giving a statin with a fibrate because of the increased risk of myopathy. Ezetimibe can cause a modest decrease of 5% to 10% in TG levels, which for most patients would not be enough alone. P-OM3 can decrease TG by up to 50% with no drug interactions with statins. Although P-OMG and icosapent ethyl are very similar in their TG-lowering ability (perhaps because of the EPA component), P-OM3 is a mixture of EPA and docosahexaenoic acid, the latter of which can increase LDL-C by 31% in some instances.42,43 Therefore, one advantage of icosapent ethyl over P-OM3 is the ability to lower TG without increasing LDL-C. Despite their ability to lower TG levels, the clinical benefit of decreasing cardiovascular events with these agents remains unclear. In a meta-analysis of 14 randomized controlled trials of nicotinic acid alone or in combination with other lipid-lowering drugs, nicotinic acid was able to reduce the relative odds ratio by 25% for major cardiac events.44 Despite the reduction in major cardiac events, the metaanalysis was unable to determine mortality benefit. A recent meta-analysis of 18 randomized controlled trials assessing the effects of fibrates on cardiovascular outcomes compared with placebo showed that fibrate therapy can reduce the relative risk of major cardiovascular events by 10% but had no effect on mortality.45 In the ENHANCE trial, Ezetimibe
failed to show a difference in carotid artery intima-media thickness (a surrogate measure to assess the progression of atherosclerosis) in patients with familial hypercholesterolemia, despite reductions in TG and LDL-C.46 Likewise, a meta-analysis of 48 randomized controlled trials of P-OM3 failed to show a mortality benefit47; however, 1 study did show a slight reduction in mortality in patients with heart failure taking omega-3 fatty acids.48 Icosapent ethyl can decrease surrogate markers similar to other therapies, but the question remains: is there a difference in clinical outcomes, such as a reduction in major cardiovascular events or mortality? One study of 18 645 patients in Japan taking EPA in combination with pravastatin or simvastatin (the JELIS study) showed a 19% (P = .011) reduction in major coronary events in the treatment group.49 This reduction in major coronary events remained statistically significant in the subset of patients with a prior history of coronary events, whereas those without a prior history had a nonsignificant 18% reduction. Additionally, participants in the treatment arm had a reduction in LDL-C of 25% and no significant difference in mortality. It still remains to be seen if icosapent ethyl can duplicate those findings with the currently ongoing REDUCE-IT study. Common side effects of P-OM3 are eructation (belching) (4%), taste perversion (4%), and dyspepsia (3%). The primary side effect of icosapent ethyl is joint pain (2%), suggesting that icosapent ethyl may have fewer side effects. Both icosapent ethyl (Vascepa) and P-OM3 (Lovaza) are priced similarly, with an average wholesale price per month of $220.80 and $236.39,50 respectively. Pharmacoeconomic analyses of omega-3 fatty acids are lacking, and none are currently available for icosapent ethyl.
Conclusions Icosapent ethyl is effective in reducing TG levels without increasing LDL-C within 4 weeks of therapy. Icosapent
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ethyl seems to have efficacy similar to other TG-lowering therapies. The clinical significance for reducing major cardiovascular events or mortality remains in question and is currently under study. In comparison to P-OM3, icosapent ethyl shows similar TG-lowering ability and costs about the same but may be better tolerated and does not increase LDLC. Although icosapent ethyl is costly, it has few side effects and can easily be used as an add-on to statin therapy without an apparent increase in interactions or myopathy. Because statins are a recommended first-line therapy, icosapent ethyl should be added for those patients whose TG levels remain elevated (>200 mg/dL) despite adequate lifestyle modifications or for those patients who have TG >500 mg/dL and contraindications to statin therapy or other TG-lowering agents. 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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