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Omega-3 Fatty Acid Therapy: The Tide Turns for a Fish Story

      In the current issue of Mayo Clinic Proceedings, Alexander et al report on meta-analyses of data addressing the effects of eicosapentaenoic and docosahexaenoic (EPA+DHA) omega-3 fatty acids on the risk of coronary heart disease (CHD) events.
      • Alexander D.
      • Miller P.
      • Van Elswyk M.
      • Kuratko C.
      • Bylsma L.
      A meta-analysis of randomized trials and prospective cohort studies of eicosapentaenoic and docosahexaenoic long chain omega-3 fatty acids and coronary heart disease risk.
      Their research employed data from 2 types of studies: (1) randomized controlled trials (RCTs) (approximately 93,000 patients) and (2) prospective cohort studies (approximately 732,000 patients). Their research is, to date, the most comprehensive analysis of its kind within the indexed biomedical literature. The meta-analysis of RCT data discovered that EPA+DHA supplementation produced a non–statistically significant 6% reduction of CHD (hazard ratio [HR], 0.94; 95% CI, 0.85-1.05). Further subgroup analysis found that EPA+DHA significantly reduced CHD risk by 16% (HR, 0.84; 95% CI, 0.72-0.98) among patients with elevated serum triglyceride (TG) levels (>150 mg/dL) and by 14% (HR, 0.86; 95% CI, 0.76-0.98) among patients with elevated low-density lipoprotein cholesterol (>130 mg/dL). In the subsequent meta-analysis of prospective cohort studies, Alexander et al discovered that EPA+DHA significantly reduced CHD risk by 18% (HR, 0.82; 95% CI, 0.74-0.92).
      Although TG level is a significant independent risk factor for CHD,
      • Nordestgaard B.G.
      • Varbo A.
      Triglycerides and cardiovascular disease.
      several large RCTs have found that diet supplementation with niacin and fibrates, the pharmacological agents traditionally used to lower TG levels, generally do not improve outcomes. Niacin effectively lowers TG levels but does not lower the risk of CHD, and unfortunately, it increases the incidence of infection, bleeding, and diabetes mellitus.
      HPS2-THRIVE Collaborative Group
      Effects of extended-release niacin with laropiprant in high-risk patients.
      Fibrates effectively lower TG levels, but in RCTs, fibrates did not significantly lower CHD events (except possibly in patients who have hypertriglyceridemia) and can actually increase the incidence of serious adverse effects when combined with statins.
      • Lavie C.J.
      • Dinicolantonio J.J.
      • Milani R.V.
      • O'Keefe J.H.
      Niacin therapy lives for another day—maybe [letter]?.
      • Wang D.
      • Liu B.
      • Tao W.
      • Hao Z.
      • Liu M.
      Fibrates for secondary prevention of cardiovascular disease and stroke.
      Diet supplementation with omega-3 fatty acids or fish oils lower TG levels in a dose-dependent fashion; among patients who have hypertriglyceridemia, 3 to 4 g/d of EPA+DHA reduces TG levels by 20% to 50%.
      • Backes J.
      • Anzalone D.
      • Hilleman D.
      • Catini J.
      The clinical relevance of omega-3 fatty acids in the management of hypertriglyceridemia.
      In contrast to niacin and fibrates, ingested omega-3 fatty acids are well tolerated and are largely free from serious adverse effects, liver toxicity, and drug-drug interactions. Furthermore, omega-3 fatty acids are safe even when used in combination with a high dose of one of the potent statins,
      • Harris W.S.
      • Dayspring T.D.
      • Moran T.J.
      Omega-3 fatty acids and cardiovascular disease: new developments and applications.
      and they are reported to provide additional reduction in risk of CHD events when added to statin therapy.
      • Yokoyama M.
      • Origasa H.
      • Matsuzaki M.
      • et al.
      Japan EPA Lipid Intervention Study (JELIS) Investigators
      Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis.
      The American Heart Association has previously recommended “omega-3 fatty acids from fish or fish oil capsules (1 g/d) for cardiovascular disease risk reduction.”
      • Smith Jr., S.C.
      • Benjamin E.J.
      • Bonow R.O.
      • et al.
      AHA/ACCF secondary prevention and risk reduction therapy for patients with coronary and other atherosclerotic vascular disease: 2011 update; a guideline from the American Heart Association and American College of Cardiology Foundation.
      However, most Americans do not consume sufficient quantities of omega-3 fats to acquire the unique cardiovascular disease protection conferred by this class of nutrient.
      • Papanikolaou Y.
      • Brooks J.
      • Reider C.
      • Fulgoni III, V.L.
      U.S. adults are not meeting recommended levels for fish and omega-3 fatty acid intake: results of an analysis using observational data from NHANES 2003-2008.
      Vitamin C bestows dramatic and lifesaving benefits to persons with scurvy but is no better than placebo for persons who are replete with vitamin C.
      • Sesso H.D.
      • Buring J.E.
      • Christen W.G.
      • et al.
      Vitamins E and C in the prevention of cardiovascular disease in men: the Physicians' Health Study II randomized controlled trial.
      In a similar fashion, omega-3 fatty acid supplementation is most beneficial for those who consume inadequate amounts omega-3 and therefore are deficient in EPA+DHA.
      • von Schacky C.
      Omega-3 index and cardiovascular health.
      The omega-3 index—a quantitative measure of omega-3 content in red blood cell membranes—is a novel cardiovascular disease risk metric that is highly modifiable by increasing consumption of EPA+DHA (Figure 1).
      • Harris W.S.
      The omega-3 index as a risk factor for coronary heart disease.
      An omega-3 index of less than 4% is associated with increased CHD risk, particularly for sudden cardiac death. In contrast, an omega-3 index of more than 8% is associated with low CHD risk, whereas the range between 4% and 8% is considered intermediate risk (Figure 2).
      • Siscovick D.S.
      • Raghunathan T.E.
      • King I.
      • et al.
      Dietary intake and cell membrane levels of long-chain n-3 polyunsaturated fatty acids and the risk of primary cardiac arrest.
      • Albert C.M.
      • Campos H.
      • Stampfer M.J.
      • et al.
      Blood levels of long-chain n-3 fatty acids and the risk of sudden death.
      Figure thumbnail gr1
      Figure 1Omega-3 index as a risk factor for coronary heart disease.
      From Am J Clin Nutr,
      • Harris W.S.
      The omega-3 index as a risk factor for coronary heart disease.
      with permission.
      Figure thumbnail gr2
      Figure 2Risk of primary cardiac arrest as a function of quartiles of red blood cell EPA plus DHA levels. This association was consistent in cross-sectional and prospective studies.
      Adapted from Sickovick et al
      • Siscovick D.S.
      • Raghunathan T.E.
      • King I.
      • et al.
      Dietary intake and cell membrane levels of long-chain n-3 polyunsaturated fatty acids and the risk of primary cardiac arrest.
      and Albert et al.
      • Albert C.M.
      • Campos H.
      • Stampfer M.J.
      • et al.
      Blood levels of long-chain n-3 fatty acids and the risk of sudden death.
      The recently published OMEGA-REMODEL (Omega-3 Acid Ethyl Esters on Left Ventricular Remodeling After Acute Myocardial Infarction) study was an RCT involving 360 patients who had survived a myocardial infarction and were receiving current guideline-based background CHD therapies.
      • Heydari B.
      • Abdullah S.
      • Pottala J.V.
      • et al.
      Effect of omega-3 acid ethyl esters on left ventricular remodeling after acute myocardial infarction: the OMEGA-REMODEL randomized clinical trial.
      Within the first 30 days following the acute myocardial infarction, the patients were randomized to either 3.6 grams of EPA+DHA or placebo for 6 months. The omega-3 therapy resulted in a 5.8% (P=.017) reduction in left ventricular end-systolic volume index and a 5.6% (P=.026) reduction in fibrosis in the nondamaged heart muscle. Additionally, the omega-3 significantly lowered the serum levels of biomarkers of systemic and vascular inflammation and myocardial fibrosis.
      Studies also indicate that omega-3 intake and omega-3 levels are inversely associated with blood pressure (BP). Their antihypertensive effects are modest but statistically significant—3 g/d of EPA+DHA is associated with BP reductions of 4 mm/Hg systolic and 2 mm/Hg diastolic.
      • Yang B.
      • Shi M.-Q.
      • Li Z.-H.
      • Yang J.-J.
      • Li D.
      Fish, long-chain n-3 PUFA and incidence of elevated blood pressure: a meta-analysis of prospective cohort studies.
      Of these 2 omega-3 fats, DHA appears to be more potent in its BP-lowering effects.
      To summarize, the meta-analyses of Alexander et al
      • Alexander D.
      • Miller P.
      • Van Elswyk M.
      • Kuratko C.
      • Bylsma L.
      A meta-analysis of randomized trials and prospective cohort studies of eicosapentaenoic and docosahexaenoic long chain omega-3 fatty acids and coronary heart disease risk.
      suggest that omega-3 fatty acid intake may reduce the risk of adverse CHD events, especially among patients with elevated levels of TGs or low-density lipoprotein cholesterol. Several large RCTs are currently under way that should help to clarify the issues surrounding the dosing and indications for omega-3 fatty acids. In the meantime, omega-3 fatty acid intake of at least 1 gram of EPA+DHA per day, either from seafood or supplementation (as recommended by the American Heart Association), continues to be a reasonable strategy.
      Nearly 30 years ago, Rogans wrote in the New England Journal of Medicine that “fish oil is a whale of a story that not surprisingly gets bigger with each telling.”
      • Rogans J.A.
      More on fish oil.
      The current article by Alexander et al adds oil to this engine.

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