Omega-3 polyunsaturated fatty acids in the treatment of hypertriglyceridaemia

  • Angela Pirillo
    Center for the Study of Atherosclerosis, Bassini Hospital, Cinisello Balsamo, Italy

    IRCCS MultiMedica, Milan, Italy
    Search for articles by this author
  • Alberico Luigi Catapano
    Corresponding author at: Department of Pharmacological and Biomolecular Sciences, University of Milan, Via Balzaretti 9, 20133 Milan, Italy. Tel.: +39 02 5031 8302; fax: +39 02 5031 8386.
    IRCCS MultiMedica, Milan, Italy

    Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy
    Search for articles by this author


      Hypertriglyceridaemia (HTG) is an independent risk factor for cardiovascular disease; high-risk patients with HTG, such as those with metabolic syndrome or diabetes, may benefit from hypolipidaemic therapies. Several lipid-lowering drugs act by reducing triglyceride (TG) levels, including fibrates, nicotinic acid and omega-3 fatty acids. The omega-3 polyunsaturated fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) dose-dependently reduce plasma TG levels; the effect tends to be greater in patients with higher TG levels at baseline. Evidence from clinical trials suggests that EPA + DHA doses of ≥2 g/day are required to achieve significant effects. The optimal TG-lowering doses of EPA + DHA are 3–4 g/day, with little evidence to support lipid-altering efficacy of doses of EPA and DHA <1 g/day. Predicted changes in fasting serum TG levels at the recommended dietary intakes of EPA and/or DHA of 200–500 mg/day are −3.1% to −7.2%. Reductions of plasma TG levels at the optimal doses are from 25–35% up to 45% in the presence of severely elevated TG levels (≥500 mg/dl; ≥5.65 mmol/l), along with a reduction in non-high-density lipoprotein–cholesterol (non-HDL-C) and an increase in HDL-C. This observation has also been confirmed in statin-treated patients.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to International Journal of Cardiology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Nordestgaard B.G.
        • Benn M.
        • Schnohr P.
        • Tybjaerg-Hansen A.
        Nonfasting triglycerides and risk of myocardial infarction, ischemic heart disease, and death in men and women.
        JAMA. 2007; 298: 299-308
        • Freiberg J.J.
        • Tybjaerg-Hansen A.
        • Jensen J.S.
        • Nordestgaard B.G.
        Nonfasting triglycerides and risk of ischemic stroke in the general population.
        JAMA. 2008; 300: 2142-2152
        • Labreuche J.
        • Touboul P.J.
        • Amarenco P.
        Plasma triglyceride levels and risk of stroke and carotid atherosclerosis: a systematic review of the epidemiological studies.
        Atherosclerosis. 2009; 203: 331-345
        • Morrison A.
        • Hokanson J.E.
        The independent relationship between triglycerides and coronary heart disease.
        Vasc Health Risk Manag. 2009; 5: 89-95
        • Sarwar N.
        • Danesh J.
        • Eiriksdottir G.
        • et al.
        Triglycerides and the risk of coronary heart disease: 10,158 incident cases among 262,525 participants in 29 Western prospective studies.
        Circulation. 2007; 115: 450-458
        • Hokanson J.E.
        • Austin M.A.
        Plasma triglyceride level is a risk factor for cardiovascular disease independent of high-density lipoprotein cholesterol level: a meta-analysis of population-based prospective studies.
        J Cardiovasc Risk. 1996; 3: 213-219
        • Varbo A.
        • Benn M.
        • Tybjaerg-Hansen A.
        • Jorgensen A.B.
        • Frikke-Schmidt R.
        • Nordestgaard B.G.
        Remnant cholesterol as a causal risk factor for ischemic heart disease.
        J Am Coll Cardiol. 2013; 61: 427-436
        • Di Angelantonio E.
        • Sarwar N.
        • Perry P.
        • et al.
        Major lipids, apolipoproteins, and risk of vascular disease.
        JAMA. 2009; 302: 1993-2000
      1. Executive Summary of The 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).
        JAMA. 2001; 285: 2486-2497
        • Miller M.
        • Stone N.J.
        • Ballantyne C.
        • et al.
        Triglycerides and cardiovascular disease: a scientific statement from the American Heart Association.
        Circulation. 2011; 123: 2292-2333
        • Catapano A.L.
        • Reiner Z.
        • De Backer G.
        • et al.
        ESC/EAS guidelines for the management of dyslipidaemias. The Task Force for the Management of Dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS).
        Atherosclerosis. 2011; 217: 3-46
        • Kris-Etherton P.M.
        • Harris W.S.
        • Appel L.J.
        Fish consumption, fish oil, omega-3 fatty acids, and cardiovascular disease.
        Circulation. 2002; 106: 2747-2757
        • Jacobson T.A.
        • Glickstein S.B.
        • Rowe J.D.
        • Soni P.N.
        Effects of eicosapentaenoic acid and docosahexaenoic acid on low-density lipoprotein cholesterol and other lipids: a review.
        J Clin Lipidol. 2012; 6: 5-18
        • Harris W.S.
        • Ginsberg H.N.
        • Arunakul N.
        • et al.
        Safety and efficacy of Omacor in severe hypertriglyceridemia.
        J Cardiovasc Risk. 1997; 4: 385-391
        • Musa-Veloso K.
        • Binns M.A.
        • Kocenas A.C.
        • et al.
        Long-chain omega-3 fatty acids eicosapentaenoic acid and docosahexaenoic acid dose-dependently reduce fasting serum triglycerides.
        Nutr Rev. 2010; 68: 155-167
        • Jacobson T.A.
        Role of n3 fatty acids in the treatment of hypertriglyceridemia and cardiovascular disease.
        Am J Clin Nutr. 2008; 87: 1981S-1990S
        • Chan D.C.
        • Watts G.F.
        • Barrett P.H.
        • Beilin L.J.
        • Redgrave T.G.
        • Mori T.A.
        Regulatory effects of HMG CoA reductase inhibitor and fish oils on apolipoprotein B-100 kinetics in insulin-resistant obese male subjects with dyslipidemia.
        Diabetes. 2002; 51: 2377-2386
        • Chan E.J.
        • Cho L.
        What can we expect from omega-3 fatty acids?.
        Cleve Clin J Med. 2009; 76: 245-251
        • Pownall H.J.
        • 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. 1999; 143: 285-297
        • Maki K.C.
        • Lawless A.L.
        • Kelley K.M.
        • et al.
        Effects of prescription omega-3-acid ethyl esters on fasting lipid profile in subjects with primary hypercholesterolemia.
        J Cardiovasc Pharmacol. 2011; 57: 489-494
        • Woodman R.J.
        • Mori T.A.
        • Burke V.
        • et al.
        Docosahexaenoic acid but not eicosapentaenoic acid increases LDL particle size in treated hypertensive type 2 diabetic patients.
        Diabetes Care. 2003; 26: 253
        • Maki K.C.
        • Lubin B.C.
        • Reeves M.S.
        • Dicklin M.R.
        • Harris W.S.
        Prescription omega-3 acid ethyl esters plus simvastatin 20 and 80 mg: effects in mixed dyslipidemia.
        J Clin Lipidol. 2009; 3: 33-38
        • Davidson M.H.
        • Stein E.A.
        • Bays H.E.
        • 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
        • Bays H.E.
        • McKenney J.
        • Maki K.C.
        • Doyle R.T.
        • Carter R.N.
        • Stein E.
        Effects of prescription omega-3-acid ethyl esters on non-high-density lipoprotein cholesterol when coadministered with escalating doses of atorvastatin.
        Mayo Clin Proc. 2010; 85: 122-128
        • Bays H.E.
        • Tighe A.P.
        • Sadovsky R.
        • Davidson M.H.
        Prescription omega-3 fatty acids and their lipid effects: physiologic mechanisms of action and clinical implications.
        Expert Rev Cardiovasc Ther. 2008; 6: 391-409
        • Roth E.M.
        • Bays H.E.
        • Forker A.D.
        • et al.
        Prescription omega-3 fatty acid as an adjunct to fenofibrate therapy in hypertriglyceridemic subjects.
        J Cardiovasc Pharmacol. 2009; 54: 196-203
        • Shearer G.C.
        • Pottala J.V.
        • Hansen S.N.
        • Brandenburg V.
        • Harris W.S.
        Effects of prescription niacin and omega-3 fatty acids on lipids and vascular function in metabolic syndrome: a randomized controlled trial.
        J Lipid Res. 2012; 53: 2429-2435
        • Bays H.E.
        • Ballantyne C.M.
        • Kastelein J.J.
        • Isaacsohn J.L.
        • Braeckman R.A.
        • Soni P.N.
        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
        • Ballantyne C.M.
        • Bays H.E.
        • Kastelein J.J.
        • 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: 984-992
        • Mazzone T.
        • Chait A.
        • Plutzky J.
        Cardiovascular disease risk in type 2 diabetes mellitus: insights from mechanistic studies.
        Lancet. 2008; 371: 1800-1809
        • Kearney P.M.
        • Blackwell L.
        • Collins R.
        • et al.
        Efficacy of cholesterol-lowering therapy in 18,686 people with diabetes in 14 randomised trials of statins: a meta-analysis.
        Lancet. 2008; 371: 117-125
        • Hartweg J.
        • Farmer A.J.
        • Perera R.
        • Holman R.R.
        • Neil H.A.
        Meta-analysis of the effects of n3 polyunsaturated fatty acids on lipoproteins and other emerging lipid cardiovascular risk markers in patients with type 2 diabetes.
        Diabetologia. 2007; 50: 1593-1602
        • Friday K.E.
        • Childs M.T.
        • Tsunehara C.H.
        • Fujimoto W.Y.
        • Bierman E.L.
        • Ensinck J.W.
        Elevated plasma glucose and lowered triglyceride levels from omega-3 fatty acid supplementation in type II diabetes.
        Diabetes Care. 1989; 12: 276-281
        • Borkman M.
        • Chisholm D.J.
        • Furler S.M.
        • et al.
        Effects of fish oil supplementation on glucose and lipid metabolism in NIDDM.
        Diabetes. 1989; 38: 1314-1319
        • Woodman R.J.
        • Mori T.A.
        • Burke V.
        • Puddey I.B.
        • Watts G.F.
        • Beilin L.J.
        Effects of purified eicosapentaenoic and docosahexaenoic acids on glycemic control, blood pressure, and serum lipids in type 2 diabetic patients with treated hypertension.
        Am J Clin Nutr. 2002; 76: 1007-1015
        • Glauber H.
        • Wallace P.
        • Griver K.
        • Brechtel G.
        Adverse metabolic effect of omega-3 fatty acids in non-insulin-dependent diabetes mellitus.
        Ann Intern Med. 1988; 108: 663-668
        • Kasim S.E.
        • Stern B.
        • Khilnani S.
        • McLin P.
        • Baciorowski S.
        • Jen K.L.
        Effects of omega-3 fish oils on lipid metabolism, glycemic control, and blood pressure in type II diabetic patients.
        J Clin Endocrinol Metab. 1988; 67: 1-5
        • Mostad I.L.
        • Bjerve K.S.
        • Lydersen S.
        • Grill V.
        Effects of marine n3 fatty acid supplementation on lipoprotein subclasses measured by nuclear magnetic resonance in subjects with type II diabetes.
        Eur J Clin Nutr. 2008; 62: 419-429
        • Hartweg J.
        • Perera R.
        • Montori V.
        • Dinneen S.
        • Neil H.A.
        • Farmer A.
        Omega-3 polyunsaturated fatty acids (PUFA) for type 2 diabetes mellitus.
        Cochrane Database Syst Rev 20. 2008; : CD003205
        • Montori V.M.
        • Farmer A.
        • Wollan P.C.
        • Dinneen S.F.
        Fish oil supplementation in type 2 diabetes: a quantitative systematic review.
        Diabetes Care. 2000; 23: 1407-1415
        • Friedberg C.E.
        • Janssen M.J.
        • Heine R.J.
        • Grobbee D.E.
        Fish oil and glycemic control in diabetes. A meta-analysis.
        Diabetes Care. 1998; 21: 494-500
        • Hartweg J.
        • Farmer A.J.
        • Holman R.R.
        • Neil A.
        Potential impact of omega-3 treatment on cardiovascular disease in type 2 diabetes.
        Curr Opin Lipidol. 2009; 20: 30-38
        • Kazemian P.
        • Kazemi-Bajestani S.M.
        • Alherbish A.
        • Steed J.
        • Oudit G.Y.
        The use of omega-3 poly-unsaturated fatty acids in heart failure: a preferential role in patients with diabetes.
        Cardiovasc Drugs Ther. 2012; 26: 311-320
        • Poole C.D.
        • Halcox J.P.
        • Jenkins-Jones S.
        • et al.
        Omega-3 fatty acids and mortality outcome in patients with and without type 2 diabetes after myocardial infarction: a retrospective, matched-cohort study.
        Clin Ther. 2013; 35: 40-51
        • Hu F.B.
        • Cho E.
        • Rexrode K.M.
        • Albert C.M.
        • Manson J.E.
        Fish and long-chain omega-3 fatty acid intake and risk of coronary heart disease and total mortality in diabetic women.
        Circulation. 2003; 107: 1852-1857
        • Kromhout D.
        • Geleijnse J.M.
        • de Goede J.
        • et al.
        n3 fatty acids, ventricular arrhythmia-related events, and fatal myocardial infarction in postmyocardial infarction patients with diabetes.
        Diabetes Care. 2011; 34: 2515-2520
        • Bosch J.
        • Gerstein H.C.
        • Dagenais G.R.
        • et al.
        n3 fatty acids and cardiovascular outcomes in patients with dysglycemia.
        N Engl J Med. 2012; 367: 309-318
        • Kaushik M.
        • Mozaffarian D.
        • Spiegelman D.
        • Manson J.E.
        • Willett W.C.
        • Hu F.B.
        Long-chain omega-3 fatty acids, fish intake, and the risk of type 2 diabetes mellitus.
        Am J Clin Nutr. 2009; 90: 613-620
        • Zhou Y.
        • Tian C.
        • Jia C.
        Association of fish and n3 fatty acid intake with the risk of type 2 diabetes: a meta-analysis of prospective studies.
        Br J Nutr. 2012; 108: 408-417
        • Wu J.H.
        • Micha R.
        • Imamura F.
        • et al.
        Omega-3 fatty acids and incident type 2 diabetes: a systematic review and meta-analysis.
        Br J Nutr. 2012; 107: S214-S227
        • Giacco R.
        • Cuomo V.
        • Vessby B.
        • et al.
        Fish oil, insulin sensitivity, insulin secretion and glucose tolerance in healthy people: is there any effect of fish oil supplementation in relation to the type of background diet and habitual dietary intake of n6 and n3 fatty acids?.
        Nutr Metab Cardiovasc Dis. 2007; 17: 572-580
        • Harris W.S.
        n3 fatty acids and serum lipoproteins: human studies.
        Am J Clin Nutr. 1997; 65: 1645S-1654S
        • Glueck C.J.
        • Khan N.
        • Riaz M.
        • Padda J.
        • Khan Z.
        • Wang P.
        Titrating lovaza from 4 to 8 to 12 grams/day in patients with primary hypertriglyceridemia who had triglyceride levels >500 mg/dl despite conventional triglyceride lowering therapy.
        Lipids Health Dis. 2012; 11: 143
        • Svaneborg N.
        • Møller J.M.
        • Schmidt E.B.
        • Varming K.
        • Lervang H.H.
        • Dyerberg J.
        The acute effects of a single very high dose of n3 fatty acids on plasma lipids and lipoproteins in healthy subjects.
        Lipids. 1994; 29: 145-147
        • Harris W.S.
        • Rothrock D.W.
        • Fanning A.
        • et al.
        Fish oils in hypertriglyceridemia: a dose–response study.
        Am J Clin Nutr. 1990; 51: 399-406
        • Schectman G.
        • Kaul S.
        • Cherayil G.D.
        • Lee M.
        • Kissebah A.
        Can the hypotriglyceridemic effect of fish oil concentrate be sustained?.
        Ann Intern Med. 1989; 110: 346-352
        • Norata G.D.
        • Raselli S.
        • Grigore L.
        • et al.
        Small dense LDL and VLDL predict common carotid artery IMT and elicit an inflammatory response in peripheral blood mononuclear and endothelial cells.
        Atherosclerosis. 2009; 206: 556-562
        • Norata G.D.
        • Catapano A.L.
        Triglyceride-rich lipoproteins from normotrygliceridemic subjects and hyperlipidemic patients differently affect endothelial cell activation and gene expression patterns.
        Circ Res. 2007; 100: e81
        • Norata G.D.
        • Grigore L.
        • Raselli S.
        • et al.
        Post-prandial endothelial dysfunction in hypertriglyceridemic subjects: molecular mechanisms and gene expression studies.
        Atherosclerosis. 2007; 193: 321-327