Perspectives on a new prescription omega-3 fatty acid, icosapent ethyl, for hypertriglyceridemia

References

• Miller M, Stone NJ, Ballantyne C et al. Triglycerides and cardiovascular disease: a scientific statement from the American Heart Association. Circulation 123(20), 2292–2333 (2011).
   Google Scholar
• Talayero BG, Sacks FM. The role of triglycerides in atherosclerosis. Curr. Cardiol. Rep. 13(6), 544–552 (2011).
   Google Scholar
• Jacobson TA, Miller M, Schaefer EJ. Hypertriglyceridemia and cardiovascular risk reduction. Clin. Ther. 29(5), 763–777 (2007).
   Google Scholar
• Austin MA, King MC, Vranizan KM, Krauss RM. Atherogenic lipoprotein phenotype. A proposed genetic marker for coronary heart disease risk. Circulation 82(2), 495–506 (1990).
   Google Scholar
• Ford ES, Li C, Zhao G, Pearson WS, Mokdad AH. Hypertriglyceridemia and its pharmacologic treatment among US adults. Arch. Intern. Med. 169(6), 572–578 (2009).
   Google Scholar
• Cohen JD, Cziraky MJ, Cai Q et al. 30-year trends in serum lipids among United States adults: results from the National Health and Nutrition Examination Surveys II, III, and 1999–2006. Am. J. Cardiol. 106(7), 969–975 (2010).
   Google Scholar
• 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 106(25), 3143–3421 (2002).
   Google Scholar
• Christian JB, Bourgeois N, Snipes R, Lowe KA. Prevalence of severe (500 to 2,000 mg/dl) hypertriglyceridemia in United States adults. Am. J. Cardiol. 107(6), 891–897 (2011).
   Google Scholar
• Filippatos TD, Elisaf MS. Recommendations for severe hypertriglyceridemia treatment, are there new strategies? Curr. Vasc. Pharmacol. doi:10.1517/17425255.2014.907274 (2013) (Epub ahead of print).
   Google Scholar
• Kostner K, Gupta S. Niacin: a lipid polypill? Expert Opin. Pharmacother. 9(16), 2911–2920 (2008).
   Google Scholar
• Brooks EL, Kuvin JT, Karas RH. Niacin’s role in the statin era. Expert Opin. Pharmacother. 11(14), 2291–2300 (2010).
   Google Scholar
• Boden WE, Probstfield JL, Anderson T et al. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N. Engl. J. Med. 365(24), 2255–2267 (2011).
   Google Scholar
• Niaspan [package insert]. AbbVie Inc., North Chicago, IL, USA (2013).
   Google Scholar
• Reyes-Soffer G, Rondon-Clavo C, Ginsberg HN. Combination therapy with statin and fibrate in patients with dyslipidemia associated with insulin resistance, metabolic syndrome and Type 2 diabetes mellitus. Expert Opin. Pharmacother. 12(9), 1429–1438 (2011).
   Google Scholar
• Mohiuddin SM, Pepine CJ, Kelly MT et al. Efficacy and safety of ABT-335 (fenofibric acid) in combination with simvastatin in patients with mixed dyslipidemia: a Phase 3, randomized, controlled study. Am. Heart J. 157(1), 195–203 (2009).
   Google Scholar
• Jones PH, Davidson MH, Kashyap ML et al. Efficacy and safety of ABT-335 (fenofibric acid) in combination with rosuvastatin in patients with mixed dyslipidemia: a Phase 3 study. Atherosclerosis 204(1), 208–215 (2009).
   Google Scholar
• Davidson MH, Armani A, McKenney JM, Jacobson TA. Safety considerations with fibrate therapy. Am. J. Cardiol. 99(6A), 3C–18C (2007).
   Google Scholar
• Dierkes J, Westphal S, Luley C. Serum homocysteine increases after therapy with fenofibrate or bezafibrate. Lancet 354(9174), 219–220 (1999).
   Google Scholar
• Schima SM, Maciejewski SR, Hilleman DE, Williams MA, Mohiuddin SM. Fibrate therapy in the management of dyslipidemias, alone and in combination with statins: role of delayed-release fenofibric acid. Expert Opin. Pharmacother. 11(5), 731–738 (2010).
   Google Scholar
• Tricor [package insert]. AbbVie Inc., North Chicago, IL, USA (2013).
   Google Scholar
• Trilipix [package insert]. AbbVie Inc., North Chicago, IL, USA (2013).
   Google Scholar
• Ginsberg HN, Elam MB, Lovato LC et al. Effects of combination lipid therapy in Type 2 diabetes mellitus. N. Engl. J. Med. 362(17), 1563–1574 (2010).
   Google Scholar
• HPS2-THRIVE Collaborative Group. HPS2-THRIVE randomized placebo-controlled trial in 25 673 high-risk patients of ER niacin/laropiprant: trial design, pre-specified muscle and liver outcomes, and reasons for stopping study treatment. Eur. Heart J. 34(17), 1279–1291 (2013).
   Google Scholar
• Filippatos TD, Elisaf MS. Fenofibrate plus simvastatin (fixed-dose combination) for the treatment of dyslipidaemia. Expert Opin. Pharmacother. 12(12), 1945–1958 (2011).
   Google Scholar
• Kris-Etherton PM, Harris WS, Appel LJ. Fish consumption, fish oil, omega-3 fatty acids, and cardiovascular disease. Circulation 106(21), 2747–2757 (2002).
   Google Scholar
• Weitz D, Weintraub H, Fisher E, Schwartzbard AZ. Fish oil for the treatment of cardiovascular disease. Cardiol. Rev. 18(5), 258–263 (2010).
   Google Scholar
• Harris WS, Bulchandani D. Why do omega-3 fatty acids lower serum triglycerides? Curr. Opin. Lipidol. 17(4), 387–393 (2006).
   Google Scholar
• Kromhout D, Giltay EJ, Geleijnse JM. n-3 fatty acids and cardiovascular events after myocardial infarction. N. Engl. J. Med. 363(21), 2015–2026 (2010).
   Google Scholar
• Rauch B, Schiele R, Schneider S et al. OMEGA, a randomized, placebo-controlled trial to test the effect of highly purified omega-3 fatty acids on top of modern guideline-adjusted therapy after myocardial infarction. Circulation 122(21), 2152–2159 (2010).
   Google Scholar
• ORIGIN Trial Investigators. n-3 fatty acids and cardiovascular outcomes in patients with dysglycemia. N. Engl. J. Med. 367(4), 309–318 (2012).
   Google Scholar
• 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 369(9567), 1090–1098 (2007).
   Google Scholar
• Lovaza [package insert]. GlaxoSmithKline, Research Triangle Park, NC, USA (2013).
   Google Scholar
• Vascepa [package insert]. Amarin Pharma Inc., Bedminster, NJ, USA (2013).
   Google Scholar
• US FDA. Approval package for application number 202057Orig1s000. Vascepa approval letter (2012). www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202057Orig1s000Approv.pdf
   Google Scholar
• US FDA. Approval package for: application number 21-654. Omacor approval letter (2004). www.accessdata.fda.gov/drugsatfda_docs/nda/2004/21-654_Omacor_Approv.pdf
   Google Scholar
• Davidson MH, Kling D, Maki KC. Novel developments in omega-3 fatty acid-based strategies. Curr. Opin. Lipidol. 22(6), 437–444 (2011).
   Google Scholar
• Davidson MH, Johnson J, Rooney MW, Kyle ML, Kling DF. A novel omega-3 free fatty acid formulation has dramatically improved bioavailability during a low-fat diet compared with omega-3-acid ethyl esters: the ECLIPSE (Epanova Compared to Lovaza In a Pharmacokinetic Single-dose Evaluation) study. J. Clin. Lipidol. 6(6), 573–584 (2012).
   Google Scholar
• Offman E, Marenco T, Ferber S et al. Steady-state bioavailability of prescription omega-3 on a low-fat diet is significantly improved with a free fatty acid formulation compared with an ethyl ester formulation: the ECLIPSE II study. Vasc. Health Risk Manag. 9, 563–573 (2013).
   Google Scholar
• Bunea R, El Farrah K, Deutsch L. Evaluation of the effects of Neptune Krill Oil on the clinical course of hyperlipidemia. Altern. Med. Rev. 9(4), 420–428 (2004).
   Google Scholar
• Zargar A, Ito MK. Long chain omega-3 dietary supplements: a review of the National Library of Medicine Herbal Supplement Database. Metab. Syndr. Relat. Disord. 9(4), 255–271 (2011).
   Google Scholar
• Collins N, Tighe AP, Brunton SA, Kris-Etherton PM. Differences between dietary supplement and prescription drug omega-3 fatty acid formulations: a legislative and regulatory perspective. J. Am. Coll. Nutr. 27(6), 659–666 (2008).
   Google Scholar
• Brunton S, Collins N. Differentiating prescription omega-3-acid ethyl esters (P-OM3) from dietary-supplement omega-3 fatty acids. Curr. Med. Res. Opin. 23(5), 1139–1145 (2007).
   Google Scholar
• Wei MY, Jacobson TA. Effects of eicosapentaenoic acid versus docosahexaenoic acid on serum lipids: a systematic review and meta-analysis. Curr. Atheroscler. Rep. 13(6), 474–483 (2011).
   Google Scholar
• Jacobson TA. A new pure omega-3 eicosapentaenoic acid ethyl ester (AMR101) for the management of hypertriglyceridemia: the MARINE trial. Expert. Rev. Cardiovasc. Ther. 10(6), 687–695 (2012).
   Google Scholar
• Pownall HJ, Brauchi D, Kilinc C et al. Correlation of serum triglyceride and its reduction by omega-3 fatty acids with lipid transfer activity and the neutral lipid compositions of high-density and low-density lipoproteins. Atherosclerosis 143(2), 285–297 (1999).
   Google Scholar
• Harris WS, Ginsberg HN, Arunakul N et al. Safety and efficacy of Omacor in severe hypertriglyceridemia. J. Cardiovasc. Risk 4(5–6), 385–391 (1997).
   Google Scholar
• 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. 29(7), 1354–1367 (2007).
   Google Scholar
• Jacobson TA, Glickstein SB, Rowe JD, Soni PN. Effects of eicosapentaenoic acid and docosahexaenoic acid on low-density lipoprotein cholesterol and other lipids: a review. J. Clin. Lipidol. 6(1), 5–18 (2012).
   Google Scholar
• Tatsuno I, Saito Y, Kudou K, Ootake J. Efficacy and safety of TAK-085 compared with eicosapentaenoic acid in Japanese subjects with hypertriglyceridemia undergoing lifestyle modification: the Omega-3 fatty acids Randomized Double-blind (ORD) study. J. Clin. Lipidol. 7(3), 199–207 (2013).
   Google Scholar
• Kelley DS, Adkins Y. Similarities and differences between the effects of EPA and DHA on markers of atherosclerosis in human subjects. Proc. Nutr. Soc. 71(2), 322–331 (2012).
   Google Scholar
• Mozaffarian D, Lemaitre RN, King IB et al. Plasma phospholipid long-chain omega-3 fatty acids and total and cause-specific mortality in older adults: a cohort study. Ann. Intern. Med. 158(7), 515–525 (2013).
   Google Scholar
• Bays HE, Ballantyne CM, Kastelein JJ et al. Eicosapentaenoic acid ethyl ester (AMR101) therapy in patients with very high triglyceride levels (from the Multicenter, plAcebo-controlled, Randomized, double-blINd, 12-week study with an open-label Extension [MARINE] trial). Am. J. Cardiol. 108(5), 682–690 (2011). •• the MARINE phase III trial compared the effects of two doses of icosapent ethyl (IPE) versus placebo on triglycerides (TG) and lipid parameters in patients with very high tg levels (≥500 and ≤2000 mg/dl). efficacy and safety results led to the us fda approval of ipe and support the current indication.
   Google Scholar
• 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. 110(7), 984–992 (2012). •• the ANCHOR placebo-controlled phase III trial investigated the addition of IPE to statin-treated patients with persistent high tg levels (≥200 to <500 mg/dl) despite having well-controlled ldl-c. this study population represents a common group encountered in clinical practice, for which there is a large unmet need for effective and well-tolerated TG-lowering therapy.
   Google Scholar
• Bays HE, Tighe AP, Sadovsky R, Davidson MH. Prescription omega-3 fatty acids and their lipid effects: physiologic mechanisms of action and clinical implications. Expert Rev. Cardiovasc. Ther. 6(3), 391–409 (2008).
   Google Scholar
• Braeckman RA, Manku MS, Bays HE, Stirtan WG, Soni PN. Icosapent ethyl, a pure EPA omega-3 fatty acid: Effects on plasma and red blood cell fatty acids in patients with very high triglyceride levels (results from the MARINE study). Prostaglandins Leukot. Essent. Fatty Acids 89(4), 195–201 (2013).
   Google Scholar
• Braeckman RA, Stirtan WG, Soni PN. Pharmacokinetics of eicosapentaenoic acid in plasma and red blood cells after multiple oral dosing with icosapent ethyl in healthy subjects. Clin. Pharmacol. Drug. Devel. doi:10.1002/cpdd.84 (2013) (Epub ahead of print). • clinical pharmacokinetics study of IPE showing predictable, dose-dependent exposure.
   Google Scholar
• Braeckman R, Manku MS, Ballantyne CM, Stirtan WG, Soni PN. Effects of AMR101, a pure eicosapentaenoic omega-3 fatty acid, on the fatty acid profile in plasma and red blood cells in statin-treated patients with persistent high triglycerides (results from the ANCHOR study) [abstract]. Circulation 126, A18549 (2012).
   Google Scholar
• Bays H. Fish oils in the treatment of dyslipidemia and cardiovascular disease. In: The Johns Hopkins Textbook of Dyslipidemia. Kwiterovich PO (Ed.). Lippincott Williams & Wolters Kluwer, Philadelphia, PA, USA, 245–257 (2010).
   Google Scholar
• Mozaffarian D, Wu JH. Omega-3 fatty acids and cardiovascular disease: effects on risk factors, molecular pathways, and clinical events. J. Am. Coll. Cardiol. 58(20), 2047–2067 (2011).
   Google Scholar
• Bays HE. Safety considerations with omega-3 fatty acid therapy. Am. J. Cardiol. 99(6A), 35C–43C (2007).
   Google Scholar
• Harris WS. Expert opinion: omega-3 fatty acids and bleeding-cause for concern? Am. J. Cardiol. 99(6A), 44C–46C (2007).
   Google Scholar
• Braeckman RA, Stirtan WG, Soni PN. Phase 1 study of the effect of icosapent ethyl on atorvastatin pharmacokinetics in healthy subjects [abstract]. J. Clin. Lipidol. 7(3), 269–270 (2013).
   Google Scholar
• Braeckman RA, Stirtan WG, Soni PN. Phase 1 study of the effect of icosapent ethyl on warfarin pharmacokinetics and anticoagulation pharmacodynamics in healthy subjects [abstract]. J. Clin. Lipidol. 7(3), 270 (2013).
   Google Scholar
• Braeckman RA, Stirtan WG, Soni PN. Effects of icosapent ethyl (eicosapentaenoic acid ethyl ester) on pharmacokinetic parameters of rosiglitazone in healthy subjects [poster]. Presented at: Annual Scientific Sessions of the Obesity Society, Atlanta, GA, USA, 12–16 November 2013.
   Google Scholar
• Bays HE, Ballantyne CM, Braeckman RA, Stirtan WG, Soni PN. Icosapent ethyl, a pure ethyl ester of eicosapentaenoic acid: effects on circulating markers of inflammation from the MARINE and ANCHOR studies. Am. J. Cardiovasc. Drugs 13(1), 37–46 (2013). • in the MARINE and ANCHOR trials, IPE significantly decreased various inflammation biomarkers known to be important in atherogenesis and CHD risk.
   Google Scholar
• 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. 6(6), 565–572 (2012).
   Google Scholar
• Ishida T, Ohta M, Nakakuki M et al. Distinct regulation of plasma LDL cholesterol by eicosapentaenoic acid and docosahexaenoic acid in high fat diet-fed hamsters: Participation of cholesterol ester transfer protein and LDL receptor. Prostaglandins Leukot. Essent. Fatty Acids 88, 281–288 (2013).
   Google Scholar
• Brinton EA, Ballantyne CM, Bays HE et al. Effects of icosapent ethyl on lipid and inflammatory parameters in patients with diabetes mellitus-2, residual elevated triglycerides (200--500 mg/dl), and on statin therapy at LDL-C goal: the ANCHOR study. Cardiovasc. Diabetol. 12(1), 100 (2013). • analysis of the effects of IPE in the subset of patients with diabetes from the ANCHOR trial. IPE 4 g/day significantly improved lipid and lipid-related parameters without worsening glycemic control, with possibly greater effects among those with less controlled diabetes.
   Google Scholar
• Ramjee V, Sperling LS, Jacobson TA. Non-high-density lipoprotein cholesterol versus apolipoprotein B in cardiovascular risk stratification do the math. J. Am. Coll. Cardiol. 58(5), 457–463 (2011).
   Google Scholar
• Jacobson TA. ‘Trig-onometry’: non-high-density lipoprotein cholesterol as a therapeutic target in dyslipidaemia. Int. J. Clin. Pract. 65(1), 82–101 (2011).
   Google Scholar
• Jacobson TA. Opening a new lipid ‘apo-thecary’: incorporating apolipoproteins as potential risk factors and treatment targets to reduce cardiovascular risk. Mayo Clin. Proc. 86(8), 762–780 (2011).
   Google Scholar
• Robinson JG, Wang S, Jacobson TA. Meta-analysis of comparison of effectiveness of lowering apolipoprotein B versus low-density lipoprotein cholesterol and nonhighdensity lipoprotein cholesterol for cardiovascular risk reduction in randomized trials. Am. J. Cardiol. 110(10), 1468–1476 (2012).
   Google Scholar
• Grundy SM. An International Atherosclerosis Society Position Paper: global recommendations for the management of dyslipidemia. J. Clin. Lipidol. 7(6), 561–565 (2013).
   Google Scholar
• Anderson TJ, Gregoire J, Hegele RA et al. 2012 update of the Canadian Cardiovascular Society guidelines for the diagnosis and treatment of dyslipidemia for the prevention of cardiovascular disease in the adult. Can. J. Cardiol. 29(2), 151–167 (2013).
   Google Scholar
• Perk J, De BG, Gohlke H et al. European Guidelines on cardiovascular disease prevention in clinical practice (version 2012). The Fifth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of nine societies and by invited experts). Eur. Heart J. 33(13), 1635–1701 (2012).
   Google Scholar
• Keech A, Simes RJ, Barter P et al. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. Lancet 366(9500), 1849–1861 (2005).
   Google Scholar
• Scott R, O’Brien R, Fulcher G et al. Effects of fenofibrate treatment on cardiovascular disease risk in 9,795 individuals with Type 2 diabetes and various components of the metabolic syndrome: the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study. Diabetes Care 32(3), 493–498 (2009).
   Google Scholar
• Guyton JR, Slee AE, Anderson T et al. Relationship of Lipoproteins to Cardiovascular Events: The AIM-HIGH Trial (Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides and Impact on Global Health Outcomes). J. Am. Coll. Cardiol. 62(17), 1580–1584 (2013).
   Google Scholar
• Saito Y, Yokoyama M, Origasa H et al. Effects of EPA on coronary artery disease in hypercholesterolemic patients with multiple risk factors: sub-analysis of primary prevention cases from the Japan EPA Lipid Intervention Study (JELIS). Atherosclerosis 200(1), 135–140 (2008).
   Google Scholar
• Sasaki J, Yokoyama M, Matsuzaki M et al. Relationship between coronary artery disease and non-HDL-C, and effect of highly purified EPA on the risk of coronary artery disease in hypercholesterolemic patients treated with statins: sub-analysis of the Japan EPA Lipid Intervention Study (JELIS). J. Atheroscler. Thromb. 19(2), 194–204 (2012).
   Google Scholar
• Farnier M. PCSK9 inhibitors. Curr. Opin. Lipidol. 24(3), 251–258 (2013).
   Google Scholar
• Cuchel M, Rader DJ. Microsomal transfer protein inhibition in humans. Curr. Opin. Lipidol. 24(3), 246–250 (2013).
   Google Scholar
• Hewing B, Fisher EA. Rationale for cholesteryl ester transfer protein inhibition. Curr. Opin. Lipidol. 23(4), 372–376 (2012).
   Google Scholar
• Davidson MH. Novel nonstatin strategies to lower low-density lipoprotein cholesterol. Curr. Atheroscler. Rep. 11(1), 67–70 (2009).
   Google Scholar
• Toth PP. Emerging LDL therapies: Mipomersenantisense oligonucleotide therapy in the management of hypercholesterolemia. J. Clin. Lipidol. 7(3 Suppl.), S6–S10 (2013).
   Google Scholar
• US FDA. Overview of dietary supplements (2009). www.fda.gov/Food/DietarySupplements/ConsumerInformation/ucm110417.htm?utm_campaign=Google2&utm_source=fdaSearch&utm_medium=website&utm_term=dietary
   Google Scholar
• Consumer Lab. Fish oil and omega-3 fatty acid supplements (EPA and DHA from fish, algae, and krill) (2012). www.consumerlab.com/reviews/fish_oil_supplements_review/omega3/
   Google Scholar
• Amarin Coporation. Amarin announces submission of supplemental new drug application (sNDA) for Vascepa® for the treatment of patients with high triglycerides with mixed dyslipidemia (2013). http://investor.amarincorp.com/releasedetail.cfm?ReleaseID=743096
   Google Scholar
• Clinicaltrials.gov. A study of AMR101 to evaluate its ability to reduce cardiovascular events in high risk patients with hypertriglyceridemia and on statin (REDUCE-IT) (2012). http://clinicaltrials.gov/show/NCT01492361
   Google Scholar