US Pharm. 2012;37(10):HS-16-HS-19.
Diets rich in fish and fish-oil supplements have long been claimed to prevent heart disease. The evidence to support this is the vast body of research studies and references that support the cardiovascular benefits of fish consumption and omega-3 supplementation. However, a recent large study (Alpha Omega Trial) examining the role of omega-3–enriched margarine as a functional food for secondary prevention of heart attacks revealed negative results.1,2 Using a meta-analysis, other investigators also showed insufficient evidence of a secondary preventive effect of omega-3 fatty acid supplements against overall cardiovascular events among patients with a history of cardiovascular disease.3 Publication of these studies has caused skepticism about the cardioprotective effects of omega-3 fats and has generated controversy over fish-oil and omega-3 supplements.
In 2002 in its scientific statement on fish consumption, fish oil, omega-3 fatty acids, and cardiovascular disease, The American Heart Association announced that “randomized controlled trials have demonstrated that omega-3 fatty acid supplements can reduce cardiac death, nonfatal MI, nonfatal stroke, and atherosclerosis in coronary patients. But, additional research is needed to confirm the health benefits of omega-3 fatty acid supplements for both primary and secondary prevention.”4
The FDA has also approved Lovaza (omega-3-acid ethyl esters) as the only fish-oil supplement. While Lovaza is indicated for lowering elevated triglycerides, its labeling specifically states that “the effect of Lovaza on cardiovascular mortality and morbidity in patients with elevated triglyceride levels has not been determined.”5
In late 2004, the FDA also announced, “Supportive but not conclusive research shows that consumption of eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA] omega-3 fatty acids may reduce the risk of coronary heart disease.”5
A recent investigation showed that 60% of U.S. clinicians surveyed agreed that one of their roles as health care professionals is to provide information to patients about appropriate dietary supplements. The most popular supplements among cardiologists were multivitamins, omega-3/fish oil, and vitamin C.6 A majority of the U.S. population consumes fish-oil supplements daily, and this is due to the fact that a high percentage of health care providers recommend the daily use of these products to the public.
With the results of the above studies, the questions remain: Is fish oil cardioprotective or not? And what happens to the potential advocacy by health care professionals? In this article, we will review recent literature and recommendations on this major food supplement. Ultimately, consumers must educate themselves about the benefits of fish oil as well as consult with their doctors when deciding whether to take the supplements or not.
Fish-Oil Supplementation History
As early as 1944, epidemiological studies supported fish-oil supplementation for cardiovascular diseases (CVD) prevention. Scientists noted the decreased prevalence of CVD in Eskimos who consumed large quantities of omega-3–rich fish and sea mammals.1,2,7 In the 1970s, Danish scientists noted improved cardiovascular profiles and lower MI mortality among Greenland Eskimos consuming a low-carbohydrate, fat-rich diet when compared with subjects consuming a Western diet in this country.8Other large randomized trials have documented the beneficial effects of omega-3 fatty acid in primary and especially in secondary prevention of coronary heart disease (CHD).9 In 1989, the Diet and Reinfarction Trial demonstrated a 30% reduction in cardiovascular mortality in patients consuming high amounts of omega-3 from fish sources or supplements.10 A subsequent prevention trial revealed the benefits of fish-oil supplementation for secondary prevention in patients who survived a first MI using one Lovaza capsule per day (delivering 850 mg of EPA-DHA in a 1.2:1 ratio). The study demonstrated a 30% reduction in total death and cardiovascular death over the 1-year duration of the study.11 In 2007, in a major Japanese EPA Lipid Intervention Study, additional evidence supported the protective effects of omega-3 supplementation. In a mixed trial of primary and secondary prevention, 18,645 patients with high cholesterol (70% women) were randomized to either statins alone or statins and highly purified EPA 1,800 mg/day. At the end of the 5-year study, those randomized to statin plus EPA had a 19% reduction in major cardiovascular events.12
With all these fish-oil background studies, how do clinicians view these results versus those of recent studies such as the Alpha Omega Trial, which demonstrated no secondary prevention benefits of supplementation with an omega-3–enriched margarine spread?
Alpha Omega Trial: Researchers assigned 4,837 MI survivors to one of the four following groups for 40 months. Subjects consumed either 1) placebo margarine; 2) margarine with a combined total of 400 mg of EPA-DHA; 3) margarine with 2 g of alpha-linolenic acid (ALA), a plant-derived precursor to EPA-DHA; or 4) a margarine containing a combination of EPA-DHA and ALA. During the course of the study, all four groups were monitored for hypertension, thrombosis, and lipid-modifying therapy.1,2 The study indicated that the results of none of the three groups were better than placebo. So, does this mean that the omega-3 CVD prevention hypothesis has been wrong?
The publishers of previous studies criticized the methodology and pharmacologic management of the Alpha Omega Trial by saying that the choice of a margarine-like spread as a delivery system might have affected the efficacy of the active omega-3 component. In addition, the consumption of multiple slices of bread with high glycemic index as a vehicle to carry the margarine-like substance spread might have masked and confused the outcome.1,2
Another criticism of the study is the use of a low-dose of EPA-DHA (400 mg), which is well below the threshold noted in some studies to influence cardiovascular outcome. Therefore, it is hard to believe that the Alpha Omega Trial spells the end for omega-3 supplementation benefits in CVD.1,2
Mechanisms of Action
The vast body of research and publications to date support several mechanisms for Omega-3 fatty acids to reduce mortality from CVD.
Antihyperlipidemic: The mechanism of omega-3’s triglyceride reduction is due to its effects on reducing hepatic production and secretion of very-low-density lipoprotein (VLDL) and VLDL apo B particles; its effects on plasma lipolytic activity; and its ability to stimulate beta-oxidation of other fatty acids in the liver. Absolute LDL levels are not significantly impacted by fish-oil supplementation.13
Antiplatelet Activity: Fish oils produce platelet inhibition and reduce fibrinogen. Although some experts claim that higher doses of 3 to 4 g/day are required, others argue for a lower dosing. Platelets are cellular fragments originated from the bone marrow, and they help to form clots at sites of vascular injury. Platelets are able to “sense” the presence of collagen, which is a protein in the walls of blood vessels that is usually not exposed to blood. When the lining of a vessel is disrupted, platelets are activated by the exposed collagen, and they aggregate to form a clot. A 2011 study titled Prostaglandins, Leukotrienes, and Essential Fatty Acids showed that omega-3 fatty acid supplementation decreased platelet sensitivity to collagen, thereby leading to a decreased clotting tendency.14
Antihypertensive: An analysis of randomized trials revealed that consumption of approximately 4.0 g/day of omega-3 fatty acid was associated with a significant 1.7- and 1.5-mmHg reduction in systolic and diastolic blood pressure (BP), respectively. These reductions were more pronounced in older patients and in individuals with higher BP. Evidence suggests that lowering systolic BP by as little as 2 mmHg can yield reductions of 4% in CAD mortality.15
Adiponectin Increase: Adiponectin is a protein-based hormone produced naturally by the body that manages fat lipids and glucose. The research shows that this hormone has direct control over the way a body metabolizes insulin, and so it is believed to play a key role in the management of type 2 diabetes. Low levels of this hormone are associated with obesity, and higher levels have been shown to confer protection against heart disease. In obese individuals, 1.8 g/day of EPA increased the level of adiponectin.1,2,16
Antiarrhythmic: The major cause of sudden cardiac death (SCD) is sustained ventricular arrhythmia. Studies show that EPA-DHA led to slower heart rates and fewer arrhythmias, and, in some studies, reduced incidence of SCD. Some studies have shown impressive results for fish oil in prophylaxis of atrial fibrillation, particularly in patients at risk after coronary artery bypass grafting.1,2,17
Anti-inflammatory: It is reported that elevated high-sensitivity C-reactive protein (hs-CRP), a selective marker of intra-arterial inflammation, is a risk factor for CVD. The inflammation is caused by prostaglandins. Prostaglandins are potent mediators of inflammation and are derivatives of arachidonic acid (AA), a 20-carbon unsaturated fatty acid produced from membrane phospholipids.
Dietary fish oil causes its prostaglandin-lowering effects through three different mechanisms. First, fewer prostaglandins are made from omega-3 fatty acids as compared to the other class of fatty acids in the body, the omega-6 family of fatty acids that originate in the diet from leafy vegetables and other plant sources. Secondly, the omega-3 fatty acids compete with omega-6 fatty acids for the same binding site on the cyclooxygenase (COX)-1 enzyme that converts the omega 6 fatty acids to prostaglandin (which is why the COX-1 enzyme and its COX-2 cousin are the targets of anti-inflammatory drugs like ibuprofen). The more omega-3 fatty acids present to block the binding sites, the fewer omega-6 fatty acids are able to be converted to prostaglandin.18 Thirdly, although omega-3 fatty acids also are converted to prostaglandins, the prostaglandins formed from omega-3 are generally 2 to 50 times less active than those formed from the omega-6 fatty acids from dietary plants.18
Adverse Effects and Contraindications
The most commonly observed adverse effects of omega-3 polyunsaturated fat supplementation are GI disturbances (diarrhea). Enteric-coated forms of fish oil are designed to dissolve distal to the stomach, reducing the potential for these problems. Taking fish-oil supplements can cause the skin, breath, and urine to have a fishy smell.
It is generally believed that higher intakes of omega-3 fatty acids will lead to an increase in hemorrhagic complications. However, a comprehensive review concluded that no increased risk of clinically significant bleeding was noted with doses of up to 7 g of combined DHA and EPA per day, even when coupled with antiplatelet therapy or warfarin.19
Fish-Oil Supplements on the Market
The original fish-oil supplement is cod liver oil. However, it has several disadvantages relative to omega-3 capsules that include a low ratio of EPA-DHA, greater risk of mercury and PCB contamination, and potential for vitamin A and D toxicity with high levels of supplementation.
Fish-oil capsules are manufactured and are free of significant mercury and PCB contamination, and industry standards for monitoring and disclosure are relatively stringent. The new formulation technology permits the offering of EPA-DHA in different ratios designed to target specific clinical goals. EPA and DHA may have differing effects on desirable cardioprotective events; however, the precise ratio of EPA-DHA for heart disease prevention has not yet been determined.
Conclusions
With all these pros and cons, uncertainty remains among health care professionals as to the potential therapeutic application of fish-oil supplements in CVD. On the one hand, a wide range of clinical trials substantiate a role for omega-3 fatty-acid supplementation in both primary and secondary CVD prevention. An extensive margin of safety has also been reported in other studies. On the other hand, the results of the new studies with their negative impact on fish-oil supplements have now generated more work in examining fish oil in different dosage regimens and EPA-DHA ratios to determine the extent of their cardioprotective effects. Finally, the body of research and references available to date greatly support the use of fish-oil supplements, but specific recommendations will be required from health care professionals and clinicians as to how and when to use them.
REFERENCES
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2. Kromhout D, Giltay EJ, Geleijnse JM. Alpha Omega Trial Group. n-3 fatty acids and cardiovascular events after myocardial infarction. N Engl J Med. 2010;363:2015-2026.
3. Kwak MS, Myung KS, Lee JY, et al. Efficacy of omega-3 fatty acid supplements in a secondary prevention of cardiovascular disease. A meta-analysis of randomized, double-blind, placebo-controlled trials. Arch Intern Med. 2012;172(9):686-694.
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5. Lovaza [prescribing information]. Research Triangle Park, NC: GlaxoSmithKline; 2012.
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6. Natural Products Insider. Cardiologists recommend dietary supplements for a healthy heart. http://multivu.prnewswire.com/mnr/lifesupplemented/36723/.
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14. www.modernmedicine.com/modernmedicine/Modern+Medicine+Now/Fish-Oil-Deemed-Safe-for-Antiplatelet-Therapy-Pati/ArticleNewsFeed/Article/detail/634828.
15. Mori TA, Omega-3 fatty acids and blood pressure. Cell Mol Biology. 2010;56(1):83-92.
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18. Wall R, Ross RP, Fitzgeral GF, et al. Fatty acids from fish: the anti-inflammatory potential of long-chain omega-3 fatty acids. Nutr Rev. 2010;68(5):280-289.
19. Harris WS. Expert opinion: omega-3 fatty acids and bleeding—cause for concern? Am J Cardiol. 2007;99:44C-46C.
