PracticeUpdate Cardiology March 2019

Are Omega-3 Fatty Acids Cardioprotective? It Depends…. By Peter Libby MD TOP STORIES 2018 6

S ince the days of the eccentric Oxford Don Hugh Sinclair, many have ascribed cardioprotective and other benefits to diets enriched in omega-3 fatty acids. 1 Despite generations of observational stud- ies, and the heroic auto-experimentation of Sinclair, who consumed seal meat for 100 days and monitored his own bleeding time, many intervention studies with omega-3 fatty acids have proven disappointing. Among the exceptions, the GISSI-Prevenzione study showed a 15% reduction in cardiovascular endpoints driven primarily by sudden car- diac death in individuals taking 850 mg daily of a mixture of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). 2 The Japan EPA Lipid Intervention Study (JELIS) led by Mitsuhiro Yokoyama exam- ined the effect of a higher dose of purified EPA (1800 mg/day) in Japanese individu- als receiving statin therapy. JELIS showed a 19% reduction in the primary cardiovascu- lar endpoint. 3 Yet, a number of other studies showed no benefit of omega-3 fatty acids, often administered as diet supplements rather than quality-controlled, pharmaceu- tical-grade products of known composition, and often in lower doses than employed in JELIS. 4 Two very recent studies involv- ing low doses of omega-3 fatty acids (1 g/ day, ASCEND and VITAL) showed no ben- efit of administration of a mixture of DHA and EPA. 5,6 In striking contrast to these recent null results, Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial (REDUCE-IT), presented by Dr. Deepak L. Bhatt at the American Heart Association

Scientific Sessions in November 2018, showed amarked reduction in cardiovascular events of 25% in the primary endpoint. 7 This study followed over 8000 individuals with median triglyceride concentrations at baseline of 216 mg/dL. The enrolled population had established cardiovascular disease, diabetes, or other risk factors for atherosclerosis. The participants randomly received 4 g daily of purified EPA ethyl esters or a mineral oil control. Most participants received statin therapy at baseline. The study followed patients for a median of almost 5 years. The participants receiving EPA had a decline in triglyceride concentrations of over 18%. Their baseline LDL was around 75 mg/ dL, and the median baseline high-sensitivity C-reactive protein (hsCRP) was about 2.2 mg/L. The omega-3 fatty acid treatment reduced all components of the primary and secondary composite endpoints significantly, save for all-cause mortality. The intervention did not cause excess serious bleeding, but it was associated with a slight but statistically significant increase in the reports of atrial fibrillation. Yet, there was a decrease in fatal or nonfatal stroke that was greater than or equal to the other components of the composite endpoints. Why did REDUCE-IT show a striking ben- efit while other recent and extremely well-conducted studies were null? First, the enrolled population in REDUCE-IT had hypertriglyceridemia. Evidence has snow- balled that triglyceride-rich lipoproteins, for which triglyceride concentrations serve as a biomarker, play a causal role in athero- thrombosis. 8 Secondly, the dose of EPA

used was substantially higher than in the recent null trials (4 vs 1 g/day). The mix- ture of pharmaceutical-grade EPA and DHA ethyl esters in VITAL and ASCEND differed from the purified EPA used in REDUCE-IT. Many of the trials included in the recent null meta-analysis used dietary supplements rather than pharmaceutical-grade omega-3 fatty acids. 4 These over-the-counter prepa- rations have uncertain quality control and may contain toxins or contaminants. Another well designed study, Outcomes Study to Assess STatin Residual Risk Reduction With EpaNova in HiGh CV Risk PatienTs With Hypertriglyceridemia (STRENGTH), uses a mixture of EPA and DHA (4 g/day) in a population similar to that studied in REDUCE-IT. 9 STRENGTH may provide insight into whether the benefit observed in REDUCE-IT depends on the high EPA content of the treatment. What mechanisms may contribute to the striking reduction in atherothrombotic events observed in REDUCE-IT? Triglyceride lowering likely contributed part of the benefit. An anti-inflammatory effect, manifest by the reduction in hsCRP from about 2.2 to 1.8 mg/L, might also contribute to the event reduction. Alterations in prostaglandin metabolism and that of other lipid mediators including pro-resolving molecules might mediate some of the anti- inflammatory actions of EPA in high doses. Membrane stabilization may account for part of the apparent anti-arrhythmic benefit, manifest by the decline in sudden cardiac death. Altered metabolism of lipid mediators might also contribute to the

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