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Something Fishy About Omega-3 Supplements

by Stephen Propatier

July 19, 2014

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Donate The Huffington Post recently published an article by Dr. Neal Barnard, MD.It is titled "New Study explodes the Eskimo Myth" and it makes some very salient points about the development of the supplementfish oil, its historical roots, and subsequent evaluations of its benefits. This was a pleasure to read"a rare science-based examination by the Huffington Post. Dr. Barnard points out that the original conclusions from investigating fish oil appear to be tainted by researcher error. The seminal 1976 surveyhad demonstrated abnormally low rates of heart disease amongInuit despite a high fat diet. But further research has shown that the original study was in fact poorly done and did not properly evaluate the true health history of the Inuit. A recent study in the Canadian Journal of Cardiology reviewed the original 1976 research and outlined its major flaws. In 2003and2009follow-up studies demonstrated higher levels of cardiovascular disease among the Inuit peoples, essentially invalidating the hypotheses. If Inuit diets are not cardio-protective what does that say about diets high in Omega-3 fatty acidsoverall? What does this mean to fish oil supplementation?

Fish oil was developed out of the so-called "Eskimo Anomaly": the observation that Inuit consumed a relatively high-fat diet rich in blubber and fatty fish, yet also appeared to have low rates of heart disease. As with the “French Paradox,” scientists proposed a possible cardiovascular protective benefit from diets high in Omega-3 fatty acids, a proposition that has formed the basis of fish oil supplementation. The idea that fish oil can help prevent heart disease is has now become entrenched conventional wisdom. But if the original study has been invalidated, we must reconsider whether or not fish oil is actually beneficial. Is the discovery of fish oil a lucky accident or is it just snake oil?

It would seem highly improbable that an incorrect guess about the Inuit's health would lead to an effective cardiovascular treatment, but it’s not impossible. Science is filled with happy accidents. The fact that fish oil was discovered due to an erroneous evaluation actually says nothing about the effectiveness of the treatment. Fish oil is one of the very few supplements in the United States to have been developed into a prescription drug, called Lovaza. Its active ingredient is Omega-3-acid ethyl esters, which are metabolized by the body into Omega-3 fatty acids. This drug is prescribed to lower serum triglycerides. Randomized, controlled research does show that it seems to be of moderate benefit for hypertriglyceridemia, a condition that predisposes people to cardiovascular disease and prancreatitis.

Unfortunately, proponents of complementary and alternative medicine (CAM) often suggest that fish oil treats a variety of related and unrelated illness. In CAM, the uses for supplements seem to always exceed the evidence; fish oil is no different for them, and has been recommended to treat everything from cancer to headaches. Despite the large amount of research surrounding fish oil, CAM proponents always seem to find areas that haven't been studied, using what I call the "drug of the gaps argument" and using what we don't know about supplements to make wild speculation about benefits. In other words, if we haven’t done any studies for fish oil’s effect on stubbed toes, their assumption is that it will probably cure stubbed toes. Fish oil has tons of research, a lot is known about it and it is safe to say that we have a good grasp of what it can and cannot do. I think it is useful to review what is currently known about the supplement, highlighting what it is most commonly purported to treat as well as its problems.

Inflammation"Potential anti-inflammatory effects of fish oil have received much attention in review articles and the lay press, given the role of EPA and DHA as precursors to specific eicosanoids and other inflammation mediators. However, production and breakdown of these inflammatory metabolites is highly regulated, and thus it is unclear that consumption of EPA or DHA (from either diet or supplements) has major effects on these pathways in humans. Controlled trials have generally not detected significant effects on C-reactive protein levels from fish oil intake. Conversely, fish oil supplementation does appear to inhibit production of cytokines, small proteins important in cell signaling that can affect inflammation. However, to achieve these effects, relative high doses (>2 g/day) of fish oil may be necessary, and it is not clear that such doses produce substantial anti-inflammatory effects. Bottom line: fish oil is not a good anti-inflammatory!

Blood Pressure and Systemic Vascular Resistance"In a meta-analysis of 36 randomized trials, fish-oil supplementation (with a median dose 3.7 g/day and a median duration eight weeks) among adults older than age 45 lowered systolic blood pressure (BP) by 3.5 mmHg and diastolic BP by 2.4 mmHg. In healthy adults younger than age 45, the BP-lowering effects were less pronounced. Bottom line: fish oil has a tiny effect on blood pressure at high doses.

Anticoagulant (blood thinner)"Randomized trials of fish oil supplementation (often 6 g/day or more) have included patients at relatively high risk for bleeding, including patients undergoing surgeries like percutaneous coronary intervention, carotid endarterectomy, and cardiac surgery. The results of such trials indicate that at doses at least as high as 4g/day (and likely higher) there is probably no clinically significant effect on bleeding risk. Bottom line: fish oil is not a blood thinner.

Cancer"Despite claims of prevention and/or cure there is no known benefit. In related studies, at least one trial has examined the benefit of fish oil for control of cancer-related symptoms in addition to anorexia and cachexia. 60 patients with a variety of cancers were randomly assigned to fish oil capsules or placebo in addition to their conventional treatments. Among the subjects who both began and completed two weeks of their allotted therapy (27 dropped out during treatment because they could not tolerate the regimen), supplemental fish oil did not influence appetite, fatigue, nausea, weight loss, caloric intake, nutritional status or sense of well being. Bottom line: fish oil is not a cancer treatment and doesn't help with lack of appetite or nausea related to conventional treatment.

Cardiovascular, All-Cause Mortality"This is the important one and has been devoted much more study, and therefore a longer explanation follows. A systematic review and meta-analysis pooled data from 19 large prospective cohort studies and randomized trials, including a total of 5,319 cardiac deaths (CHD) in 356,028 participants consuming either fish or fish oil supplements, and found that consumption of marine n-3 polyunsaturated fats (PUFA) significantly lowered the risk of CHD death and sudden cardiac death. In contrast to the apparent graded dose-response for nonfatal CHD events, the dose-response for CHD death and sudden cardiac death appeared nonlinear: compared with little or no intake, modest consumption (approximately 250 to 500 mg/day EPA+DHA) lowered relative risk by approximately 36 percent, but higher intakes did not substantially lower CHD mortality any further. Effects appeared to be very similar comparing studies of generally healthy populations (i.e., primary prevention; largely prospective cohort studies) versus studies of individuals with established heart disease (i.e., secondary prevention; largely randomized trials).

Subsequent meta-analyses have found smaller reductions in cardiovascular mortality than earlier analyses. A 2012 meta-analysis of 13 randomized trials of fish oil supplementation (N = 56,407) found a reduction in the relative risk (RR) of cardiac mortality. The authors adjusted for multiple comparisons and concluded this RR reduction was not statistically significant; however, this adjustment may have been overly conservative. In this same meta-analysis (seven trials, N = 41,751), there was also a statistically non-significant reduction in sudden death. In contrast to these large trials showing benefits for cardiac death, more recent trials have not found significant effects on CHD mortality. The results of the large Risk and Prevention Study, published subsequent to the 2012 meta-analysis, enrolled 13,513 patients with multiple cardiovascular risk factors or known vascular disease and, after a median follow-up of five years, found no reduction in CHD death with n-3 PUFA supplementation compared with placebo. Bottom line: fish oil at low doses may lower your risk of dying from a cardiovascular event; higher doses show little added benefit; and there’s a lot of very contradictory evidence.

Blood Lipids and Cholesterol"Fish oil consumption lowers serum triglyceride concentrations by 25 to 30 percent, an effect within the range of efficacy of other triglyceride-lowering drugs. The potential cellular mechanisms for this effect have been previously reviewed. The dose-response appears to be fairly linear: little triglyceride lowering is seen with dietary doses or low-dose supplementation (<1 g/day), whereas higher doses (3 to 4 g/day) appreciably lower triglyceride levels. Fish oil supplementation also modestly raises concentrations of HDL-C (good cholesterol) and, particularly in patients with hypertriglyceridemia, raises concentrations LDL-C (bad cholesterol) and lowers the proportion of small dense LDL-C particles. This increase in LDL particle size may in part account for the higher LDL-C concentrations; that is, LDL-C concentration may slightly increase but without appreciable change in the number of circulating LDL particles. Given the frequently coexisting relationship of high triglycerides, low HDL-C, and small dense LDL particles in many individuals, the effects of fish oil to lower triglycerides, raise HDL-C, and decrease the proportions of small dense LDL particles appear concordant. Bottom line: at high doses fish oil reduces triglycerides by 20-30%, may elevate HDL by about 3% and slightly reduce LDL.

But there are some purportedconcerns, problems, and side effects to fish oil supplements. Not all of them stand up to scrutiny, but they include the following:
Mercury"Despite common, persistent belief, fish oil contains little mercury. Only a few large predator fish species (e.g., sharks, swordfish, albacore tuna) contain appreciable amounts of mercury. Given cost considerations, such species would be used only very rarely to produce unusual "specialty" supplements. Furthermore, mercury is tightly bound to fish proteins, rather than present in the lipid fraction. Bottom line: similar to most fish species, commercially available fish oil capsules contain little to no mercury.

PCB and Dioxins"Fish oil capsules contain vanishingly small amounts of polychlorinated biphenyls and dioxins, with concentrations proportional to those in the fish species from which the fish oil is derived. Notably, given the small absolute quantities of fish oil that would be consumed (1 to 4 g/day), the absolute amounts of PCBs or dioxins that can be consumed from fish oil supplementation is extremely low. Bottom line: the concentrations of these substances are similar to dietary consumption of the great majority of fish and seafood species. Significant exposure to contaminants from fish oil is not a clinical concern, but should still be avoided by pregnant or lactating women.

Carcinogens"A post hoc subgroup analysis from a randomized trial of 2,501 adults with known cardiovascular disease found an association between supplementation with 600 mg of EPA and DHA and a higher risk of cancer in women, but not in the group as a whole. These findings should be interpreted with caution since, in addition to being a subgroup analysis, they were based on a total of only 29 cancer events. Additionally, other larger randomized trials of fish oil have not reported finding increased cancer risk, and a wide range of animal models demonstrate benefits of fish oil for the incidence and severity of many cancers. Systematic reviews and meta-analyses of numerous large prospective observational studies have generally found no significant effects of fish consumption on the risk of any type of cancer, although one such review suggested a possible lower risk of breast cancer with increased fish oil consumption. Some studies, though not all, have suggested an association between higher levels of long-chain n-3 PUFA and increased risk of prostate cancer; a meta-analysis of these mixed studies found no statistically-significant association between levels of n-3 PUFA and total prostate cancer risk. Bottom line: there may be a risk of prostate cancer but the research is not structured well enough to eliminate variable noise, and there is no evidence for any other cancer risk.

So does a failed dietary theory automatically mean that the benefit from fish oil is false? The short answer is no. After an extensive review of the available research I find that fish oil does appear to have some medical indications. Bringing it all together, as you can see, is very complicated. It is safe to say that 4g of fish oil per day does measurably reduce triglycerides and slightly help cholesterol levels. However, the fish oil doses required to lower triglycerides are several-fold higher than the doses that may reduce coronary mortality. Additionally, the clinical benefits of lowering elevated triglyceride levels, by any pharmacologic means, have not yet been convincingly demonstrated. There is no good evidence that it lowers the frequency or severity of cardiovascular events. It does not seem to reduce atherosclerosis (hardening of the arteries), and does not seem to prevent the formation of thrombi (clots) that cause a heart attack or stroke. It does not seem to have any anti-cancer benefit. Given the conflicting information about anti-oxidant benefits there is little chance that it provides any protective effect at all.

Despite its novel status as a supplement that became a drug there is little to support fish oil as a cardiovascular prevention agent. It does have uses as part of a total lipid-lowering regime for cardiovascular patients. I would not recommend that people take it regularly; although it’s probably not harmful it could have a negative cognitive behavioral effect: people may falsely believe that they can negate the terrible effects of inactivity, obesity, poor diet, and smoking by popping a fish oil capsule. Not true. For the average person, the only thing fish oil is likely to do is give you is fishy burps.


by Stephen Propatier

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