Review of Cardiometabolic Effects of Prescription Omega-3 Fatty Acids
- 916 Downloads
Purpose of Review
Populations with significant dietary fish intake tend to have lower cardiovascular (CV) risk and demonstrable physiologic differences including lower lipid/lipoprotein levels and other direct and indirect effects on the arterial wall and inhibiting factors that promote atherosclerosis. Treatment with high doses of pharmacologic-grade omega-3 fatty acid (n-3FA) supplements achieves significant reductions in triglycerides (TG), non-high-density lipoprotein- (non-HDL-) and TG-rich lipoprotein- (TRL-) cholesterol levels. n-3FA supplements have significant effects on markers of atherosclerosis risk including endothelial function, low-density lipoprotein (LDL) oxidation, cellular and humoral markers of inflammation, hemodynamic factors, and plaque stabilization. This review summarizes the lipid and cardiometabolic effects of prescription-grade n-3FAs and will discuss clinical trials, national/organizational guidelines, and expert opinion on the impact of supplemental n-3FAs on CV health and disease.
Clinical trial evidence supports use of n-3FAs in individuals with established atherosclerotic cardiovascular disease (ASCVD), but the data either does not support or is lacking for other types of cardiometabolic risk including prevention of stroke, treatment in patients with heart failure, diabetes mellitus and prediabetes, and for primary prevention in the general population.
Despite inconsistent findings to support widespread benefit, there is persistent population-wide enthusiasm for n-3FA as a dietary supplement for its cardiometabolic benefits. Fortunately, there are ongoing clinical trials to assess whether the lipid/lipoprotein benefits may be extended to other at-risk populations and whether lower-dose therapy may provide background benefit for primary prevention of ASCVD.
KeywordsDietary supplement Omega-3 FA (n-3FA) Eicosapentaenoic acid (EPA) Docosahexaenoic acid (DHA) Linoleic acid (LA) Alpha-linolenic acid (ALA) Triglycerides (TG) Ethyl ester (EE) Fatty acid (FA) Free FA (FFA)
Compliance with Ethical Standards
Conflict of Interest
Megan F. Burke and Frances M. Burke declare no conflict of interest.
Dr. Soffer reports that he has participated as a local investigator in pharmaceutical company-sponsored clinical trials that provide program support. He has been an investigator with Akcea, Ionis, Novartis, Pfizer, Regeneron, Sanofi, Amgen, Omthera/Astra Zeneca, Regenex/NIH, and Kowa pharmaceuticals, outside the submitted work. He has also received faculty payment for services as a course director for the National Lipid Association.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
- 3.U.S. Department of Health and Human Services and U.S. Department of Agriculture. 2015–2020 dietary guidelines for Americans. 8th Edition. December 2015. Available at http://health.gov/dietaryguidelines/2015/guidelines/. Accessed August 7, 2017.
- 4.Lloyd-Jones DM, Hong Y, Labarthe D, Mozaffarian D, Appel LJ, Van Horn L, et al. Defining and setting national goals for cardiovascular health promotion and disease reduction: the American Heart Association's Strategic Impact Goal through 2020 and beyond. Circulation. 2010;121:586–613. https://doi.org/10.1161/CIRCULATIONAHA.109.192703.CrossRefPubMedGoogle Scholar
- 5.Clark TC, Black LI, Stussman BJ, Barnes PM, Nahin RL. Trends in the use of complementary health approaches among adults: United States, 2002–2012. National Health Statistics reports; no 79. Hyattsville, MD: National Center for Health Statistics. 2015. Available at https://nccih.nih.gov/research/statistics/NHIS/2012/natural-products/omega3. Accessed August 5, 2017.
- 8.•• Siscovick DS, Barringer TA, Fretts AM, JHY W, Lichtenstein AH, Costello RB, et al. Omega-3 polyunsaturated fatty acid (fish oil) supplementation and the prevention of clinical cardiovascular disease: a science advisory from the American Heart Association. Circulation. 2017;135:e876–84. https://doi.org/10.1161/CIR.0000000000000482. Recent and comprehensive review on use of n-3FA supplementation for CVD prevention. CrossRefGoogle Scholar
- 18.Prescribing information for Lovaza. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/021654s023lbl.pdf. Accessed July 21, 2017.
- 19.Prescribing information for Vascepa. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/202057s012lbl.pdf. Accessed July 21, 2017.
- 20.Prescribing information for Omytrg. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/204977s000lbl.pdf. Accessed July 21, 2017.
- 21.Prescribing information for Epanova. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/205060s000lbl.pdf. Accessed July 21, 2017.
- 24.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. 2012;6(6):573–84. https://doi.org/10.1016/j.jacl.2012.01.002.CrossRefPubMedGoogle Scholar
- 26.Graversen CB, Lundbye-Christensen S, Thomsen B, Christensen JH, Schmidt EB. Marine n-3 polyunsaturated fatty acids lower plasma proprotein convertase subtilisin kexin type 9 in pre- and postmenopausal women: a randomised study. Vasc Pharmacol. 2016;76:37–41. https://doi.org/10.1016/j.vph.2015.07.001.CrossRefGoogle Scholar
- 29.Pownall HJ, Brauchi D, Kilinc C, Osmundsen K, Pao Q, Payton-Ross 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(2):285–97. https://doi.org/10.1016/S0021-9150(98)00301-3.CrossRefPubMedGoogle Scholar
- 30.Davidson MH, Stein EA, Bays HE, Maki KC, Doyle RT, Shalwitz RA, 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(7):1354–67. https://doi.org/10.1016/j.clinthera.2007.07.018.CrossRefPubMedGoogle Scholar
- 31.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;108:682–90. https://doi.org/10.1016/j.amjcard.2011.04.015.CrossRefPubMedGoogle Scholar
- 32.Ballantyne CM, Bays HE, Kastelein JJ, Stein E, Isaacsohn JL, Braeckman RA, 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;110:984–92. https://doi.org/10.1016/j.amjcard.2012.05.031.CrossRefPubMedGoogle Scholar
- 33.Kastelein JJ, Maki KC, Susekov A, Ezhov M, Nordestgaard BG, Machielse BN, et al. Omega-3 free fatty acids for the treatment of severe hypertriglyceridemia: the EpanoVa fOr Lowering Very high triglyceridEs (EVOLVE) trial. J Clin Lipidol. 2014;8:94–106. https://doi.org/10.1016/j.jacl.2013.10.003.CrossRefPubMedGoogle Scholar
- 34.Maki KC, Orloff DG, Nicholls SJ, Dunbar RL, Roth EM, Curcio D, et al. A highly bioavailable omega-3 free fatty acid formulation improves the cardiovascular risk profile in high-risk, statin-treated patients with residual hypertriglyceridemia (the ESPRIT trial). Clin Ther. 2013;35:1400–11. https://doi.org/10.1016/j.clinthera.2013.07.420.CrossRefPubMedGoogle Scholar
- 39.Borow KM, Nelson JR, Mason RP. Biologic plausibility, cellular effects, and molecular mechanisms of eicosapentaenoic acid (EPA) in atherosclerosis. Atherosclerosis. 2015;242:357–66. https://doi.org/10.1016/j.atherosclerosis.2015.07.035.CrossRefPubMedGoogle Scholar
- 40.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. 2013;13(1):37–46. https://doi.org/10.1007/s40256-012-0002-3.CrossRefPubMedPubMedCentralGoogle Scholar
- 42.Balk EM, Lichtenstein AH, Chung M, Kupelnick B, Chew P, Lau J. Effects of omega-3 fatty acids on serum markers of cardiovascular disease risk: a systemic review. Atherosclerosis. 2006;189:19–30. https://doi.org/10.1016/j.atherosclerosis.2006.02.012.CrossRefPubMedGoogle Scholar
- 43.Pischon T, Hankinson SE, Hotamisligil GS, Rifai N, Willet WC, Rimm EB. Habitual dietary intake of n-3 and n-6 fatty acids in relation to inflammatory markers among US men and women. Circulation. 2003;108:155–60. https://doi.org/10.1161/01.CIR.0000079224.46084.C2.CrossRefPubMedGoogle Scholar
- 52.Poreba M, Mostowik M, Siniarski A, Golebiowska-Wiatrak R, Malinowski KP, Haberka M, et al. Treatment with high-dose n-3 PUFAS has no effect on platelet function, coagulation, metabolic status or inflammation in patients with atherosclerosis and type 2 diabetes. Cardiovasc Diabetol. 2017;16:50. https://doi.org/10.1186/s12933-017-0523-9.CrossRefPubMedPubMedCentralGoogle Scholar
- 53.Yamakawa K, Shimabukuro M, Higa N, Asahi T, Ohba K, Arasaki O, et al. Eicosapentaenoic acid supplementation changes fatty acid composition and corrects endothelial dysfunction in hyperlipidemic patients. Cardiol Res Pract. 2012;2012:754181. https://doi.org/10.1155/2012/754181.CrossRefPubMedPubMedCentralGoogle Scholar
- 55.Nishio R, Shinke T, Otake H, Nakagawa M, Nagoshi R, Inoue T, et al. Stabilizing effect of combined eicosapentaenoic acid and statin therapy on coronary thin-cap fibroatheroma. Atherosclerosis. 2014;234(1):114–9. https://doi.org/10.1016/j.atherosclerosis.2014.02.025.CrossRefPubMedGoogle Scholar
- 56.Yamano T, Kubo T, Shiono Y, Shimamura K, Orii M, Tanimoto T, et al. Impact of eicosapentaenoic acid treatment on the fibrous cap thickness in patients with coronary atherosclerotic plaque: an optical coherence tomography study. J Atheroscler Thromb. 2015;22(1):52–61. https://doi.org/10.5551/jat.25593.CrossRefPubMedGoogle Scholar
- 58.Vanschoonbeek K, Feijge MA, Paquay M, Rosing J, Saris W, Kluft C, et al. Variable hypocoagulant effect of fish oil intake in humans: modulation of fibrinogen level and thrombin generation. Arterioscler Thromb Vasc Biol. 2004;24:1734–40. https://doi.org/10.1161/01.ATV.0000137119.28893.0b.CrossRefPubMedGoogle Scholar
- 60.Yokoyama M, Origasa H, Matsuzaki M, Matsuzawa Y, Saito Y, Ishikawa Y, et al. Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis. Lancet. 2007;369(9567):1090–8. https://doi.org/10.1016/s0140-6736(07)60527-3.CrossRefPubMedGoogle Scholar
- 63.Wang Q, Liang X, Wang L, Lu X, Huang J, Cao J, et al. Effect of omega-3 fatty acids supplementation on endothelial function: a meta-analysis of randomized controlled trials. Atherosclerosis. 2012;221(2):536–43. https://doi.org/10.1016/j.atherosclerosis.2012.01.006.CrossRefPubMedGoogle Scholar
- 64.Weisman D, Beinart R, Erez A, Koren-Morag N, Goldenberg I, Eldar M, et al. Effect of supplemented intake of omega-3 fatty acids on arrhythmias in patients with ICD: fish oil therapy may reduce ventricular arrhythmia. J Interv Card Electrophysiol. 2017;49(3):255–61. https://doi.org/10.1007/s10840-017-0267-1.CrossRefPubMedGoogle Scholar
- 66.Khoueiry G, Abi Rafeh N, Sullivan E, Saiful F, Jaffery Z, Kenigsberg DN, et al. Do omega-3 polyunsaturated fatty acids reduce risk of sudden cardiac death and ventricular arrhythmias? A meta-analysis of randomized trials. Heart Lung. 2013;42(4):251–6. https://doi.org/10.1016/j.hrtlng.2103.03.006.CrossRefPubMedGoogle Scholar
- 67.Mozaffarian D, Marchioli R, Macchia A, Silletta MG, Ferrazzi P, Gardner TJ, et al. Fish oil and post-operative atrial fibrillation: the Omega-3 Fatty Acids for Prevention of Post-operative Atrial Fibrillation (OPERA) randomized trial. JAMA. 2012;308:2001–11. https://doi.org/10.1001/jama2012.28733.CrossRefPubMedPubMedCentralGoogle Scholar
- 70.Minihane AM, Armah CK, Miles EA, et al. Consumption of fish oil providing amounts of eicosapentaenoic acid and docosahexaenoic acid that can be obtained from the diet reduces blood pressure in adults with systolic hypertension: a retrospective analysis. J Nutr. 2016;146(3):516–23. https://doi.org/10.3945/jn.115.220475.CrossRefPubMedGoogle Scholar
- 73.Helland A, Bratlie M, Hagen IV, Mjos SA, Sornes S, Ingvar Halstensen A, et al. High intake of fatty fish, but not lean fish, improved postprandial glucose regulation and increased the n-PUFA content in the leucocyte membrane in healthy overweight adults: a randomised trial. Br J Nutr. 2017;117(10):1368–78. https://doi.org/10.1017/S0007114517001234.CrossRefPubMedGoogle Scholar
- 74.Methodology manual and policies. From the ACCF/AHA Task Force on Practice Guidelines. June 2010. Available at http://my.americanheart.org/idc/groups/ahamah-public/@wcm/@sop/documents/downloadable/ucm_319826.pdf. Accessed August 3, 2017.Google Scholar
- 75.Manson JE, Bassuk SS, Lee IM, Cook NR, Albert MA, Gordon D, et al. The VITamin D and OmegA-3 Trial (VITAL): rationale and design of a large randomized controlled trial of vitamin D and marine omega-3 fatty acid supplements for the primary prevention of cancer and cardiovascular disease. Contemp Clin Trials. 2012;33(1):159–71. https://doi.org/10.1016/j.cct.2011.09.009.CrossRefPubMedGoogle Scholar
- 77.Risk and Prevention Study Collaborative Group, Roncaglioni MC, Tombesi M, Avanzini F, Barlera S, Caimi V, et al. n-3 fatty acids in patients with multiple cardiovascular risk factors [published correction appears in N Engl J Med. 2013;368:2146]. N Engl J Med. 2013;368:1800–8. https://doi.org/10.1056/NEJMoa1205409.CrossRefGoogle Scholar
- 78.Writing Group for the AREDS2 Research Group, Bonds DE, Harrington M, Worrall BB, Bertoni AG, Eaton CB, et al. Effect of long-chain ω-3 fatty acids and lutein + zeaxanthin supplements on cardiovascular disease outcomes: results of the Age-Related Eye Disease Study 2 (AREDS2) randomized clinical trial. JAMA Intern Med. 2014;174:763–71. https://doi.org/10.1001/jamainternmed.2014.328.CrossRefGoogle Scholar
- 79.GISSI-Prevenzione Investigators (Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico). Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Lancet. 1999;354(9177):447–55.CrossRefGoogle Scholar
- 82.Rauch B, Schiele R, Schneider S, Diller F, Victor N, Gohlke H, 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. 2010;122:2152–9. https://doi.org/10.1161/CIRCULATIONAHA.110.948562.CrossRefPubMedGoogle Scholar
- 85.ASCEND: A Study of Cardiovascular Events iN Diabetes. Available at https://clinicaltrial.gov/ct2/show/NCT00135226. Accessed August 1, 2017.
- 86.Tavazzi L, Maggioni AP, Marchioli R, Barlera S, Franzosi MG, Latini R, et al. Effect of n-3 polyunsaturated fatty acids in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial. Lancet. 2008;372(9645):1223–30. https://doi.org/10.1016/S0140-6736(08)61239-8.CrossRefPubMedGoogle Scholar
- 87.Alexander DD, Miller PE, Van Elswyk ME, Kuratko CN, Bylsma LC. A meta-analysis of randomized controlled trials and prospective cohort studies of eicosapentaenoic and docosahexaenoic long-chain omega-3 fatty acids and coronary heart disease risk. Mayo Clin Proc. 2017;92(1):15–29. https://doi.org/10.1016/j.mayocp.2016.10.018.CrossRefPubMedGoogle Scholar
- 90.ClinicalTrials.gov. A study of AMR101 to evaluate its ability to reduce cardiovascular events in high risk patients with hypertriglyceridemia and on statin. The primary objective is to evaluate the effect of 4 g/day AMR101 for preventing the occurrence of a first major cardiovascular event (REDUCE-IT). Available at https://clinicaltrials.gov/ct2/show/NCT01492361. Accessed July 7, 2017.
- 91.ClinicalTrials.gov. Outcomes study to assess statin residual risk reduction with Epanova in high CV risk patients with hypertriglyceridemia (STRENGTH). Available at https://clinicaltrials.gov/ct2/show/NCT02104817. Accessed July 7, 2017.
- 92.Kris-Etherton PM, Harris WS, Appel LJ, for the American Heart Association, Nutrition Committee. Fish consumption, fish oil, omega-3 fatty acids, and cardiovascular disease. Circulation. 2002;106(21):2747–57. https://doi.org/10.1161/01.CIR.0000038493.65177.94.CrossRefPubMedGoogle Scholar
- 96.Berglund L, Brunzell JD, Goldberg AC, Goldberg IJ, Sacks F, Murad MH, et al. Evaluation and treatment of hypertriglyceridemia: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2012;97(9):2969–89. https://doi.org/10.1210/jc.2011-3213.CrossRefPubMedPubMedCentralGoogle Scholar
- 98.National Institutes of Health, National Center for Complementary and Integrative Health. Using dietary supplements wisely. Available at https://www.cdc.gov/nchs/databriefs/db61.htm. Accessed August 4, 2017.