By David Kiefer, MD
Dr. Kiefer recently completed a fellowship at the Program in Integrative Medicine, College of Medicine, University of Arizona in Tucson; he reports no consultant, stockholder, speaker’s bureau, research, or other financial relationships with companies having ties to this field of study.
A type of polyunsaturated fatty acid (PUFA), the omega-3 fatty acids (often abbreviated n-3) have attracted attention from the scientific community for about 30 years, ever since the discovery of low serum cholesterol, low low-density lipoprotein (LDL), and low triglycerides in the Greenland Inuit, who have a diet high in fish oils.1 Other observations of a change in the ratio of omega-6 fatty acids to omega-3 fatty acids from approximately 1:1 in early human diets to approximately 10:1 to 20:1 with the development of the modern Western diet,2 combined with an increase in incidence of coronary heart disease (CHD), led researchers to consider the cardioprotective effect of n-3 fatty acids and investigate the antihyperlipidemic effects of n-3 fatty acids.
This review will explore the evidence for the use of n-3 fatty acids for hyperlipidemia.
Source of Omega-3 Fatty Acids
Omega-3 fatty acids are either plant-based (a-linolenic acid, LNA), or marine animal-derived (eicosapentaenoic acid, or EPA, and docosahexaenoic acid, or DHA). LNA is an essential fatty acid (as is a-linoleic acid, an omega-6 fatty acid), that is, it is required in the human diet, and is the most common omega-3 fatty acid in the American diet. LNA is found in flaxseed oil (8.5 g/Tbsp), flaxseeds (2.2 g/Tbsp), canola oil (1.3 g/Tbsp), soybean oil (0.9 g/Tbsp), English walnuts (0.7 g/Tbsp), and olive oil (0.1 g/Tbsp).3 In the human body, one of LNA’s activities is to serve as a precursor primarily to EPA, but also to DHA, although the conversion to these longer-chain n-3 fatty acids is minimal.
Fish are the main dietary source of EPA and DHA; the concentration of EPA and DHA varies by the species of fish, the season harvested, the packaging and cooking methods, whether it was farm-raised or wild (though wild and farmed salmon appear to be similar in this regard), and the diet of the fish.3 The highest n-3 concentrations appear to be in cold-water fish, such as (in order of decreasing EPA and DHA content) herring, sardines, salmon, mackerel, tuna, and halibut.4 For example, 15 g of mackerel or herring provides about 400 mg of n-3 fatty acids.5
Mechanism of Action
There are many proposed mechanisms for the effects of n-3 fatty acids on the physiology of lipid metabolism. Researchers have shown that n-3 fatty acids inhibit hepatic triglyceride (TG) synthesis, such as through the inhibition of TG synthetic enzymes like diacylglycerol acyltransferase, resulting in a decreased rate of very low-density lipoprotein (VLDL)-TG secretion from the liver,6-8 as well as decreased content of TG in VLDL particles.9,10
N-3 fatty acids also shift LDL subfractions to the less-atherogenic, larger, lighter particles. Changes in VLDL as mentioned above will lead to changes in LDL production, including which subfractions are made.9 The VLDL created in these processes are favored precursors for LDL-C, perhaps explaining why LDL may increase with n-3 supplementation.
Other researchers have found that fish oil appears to inhibit VLDL triglyceride and apoB synthesis, but with different effects depending on the baseline TG levels; this may occur because of an underlying disturbance in LDL metabolism that affects the response of LDL to fish oil.11 For example, people with normal TG levels are more likely to have decreased LDL apoB with fish oil supplementation through decreased apoB synthesis because VLDL is efficiently converted to LDL via delipidation.11 Overall, it is possible that LDL responses to fish oil may be linked to underlying differences in LDL composition and LDL metabolic behavior. Some of these genetic nuances agree with animal studies: Strains of mice with different variations of human apolipoprotein B genes have different plasma TG and apoB responses to two weeks of fish oil supplementation.8
One human experiment illustrated more of the mechanism of action of n-3 fatty acids. Ten people with varied plasma TG levels were assigned to either a control diet consisting of 20% fat from cocoa butter and peanut oil or to a test diet of 10-17 g/d of n-3 fatty acids from fish oil.6 The fish oil diet caused a decrease in the VLDL-TG synthetic rate, and increased the VLDL-TG catabolic rate, leading to a 66% reduction in plasma TG levels, mainly because of a 78% decrease in VLDL-TG. Total cholesterol also fell 26% (from 195 mg/dL to 144 mg/dL), LDL had an insignificant increase, and HDL fell 23% (from 31 mg/dL to 24 mg/dL). This shows a reduced rate of TG entering VLDL, and an increase in the rate of TG removal from VLDL. The increase in LDL only occurred in patients with TG > 350 mg/dL, otherwise there was a slight decrease in LDL for patients with normal TG levels. With high TG, fish oil may enhance the conversion of VLDL to LDL.
Clinical Studies
One review looked at all human placebo-controlled, crossover, or parallel-design studies, lasting at least two weeks, and with less than 7 g/d of n-3 fatty acids.10 There were three studies using LNA; LNA causes lipid changes equivalent to omega-6 fatty acids, except when large amounts (38-60 g/d) of flaxseed oil are given, which then causes decreased plasma TG, a finding in line with other published research.12 The review detailed 36 crossover (usually using MaxEPA® [n-3 4 g/d] vs. olive oil [usually 10 g/d] for 7-10 weeks) and 29 parallel design studies (usually MaxEPA [n-3 4 g/d] vs. olive oil for 7 weeks). The results of these trials showed that approximately 3 g/d of marine n-3 fatty acids do not affect total serum cholesterol, cause an increase in LDL (5% to 10%) and HDL (1% to 3%), and decrease serum TG (25% to 30%).
Since that review, clinical trials have further refined the effects of n-3 fatty acids. For example, 19 non-obese people with high TG levels were given two consecutive diets for three weeks each: a high-fat diet (providing 39% of the calories from fat and consisting of 1.6% n-3 marine fatty acids) vs. a low-fat diet (providing 28% of the calories from fat). The high-fat diet decreased TG (63%), total cholesterol (22%), VLDL (54%), and LDL (16%), while increasing HDL (8%).13 The researchers were unable to comment on whether these effects would be observed if people only ate fish 3-4 times weekly, a more likely pattern of consumption.
In a double-blind, placebo-controlled crossover trial 16 people with non-insulin-dependent diabetes and hypertriglyceridemia were randomized to two consecutive six-month interventions: 15 g/d of either olive oil or fish oil.14 The fish oil used was the brand Promega® and it provided 6 g/d of omega-3 fatty acids (4.1 g EPA, 1.9 g DHA). There was a decrease in TG (P = 0.0004), VLDL-cholesterol and VLDL-triglyceride (P = 0.0001), and LDL-cholesterol (P = 0.0003), but no change in total cholesterol or HDL-cholesterol. There was also no change in diabetic parameters, such as fasting glucose or hemoglobin A1C.
Another review investigated the use of n-3 fatty acids for primary and secondary prevention of CHD.5 The authors found numerous clinical trials in hyperlipidemic subjects involving 4 g/d of n-3 fatty acids (often as Omacor® capsules containing 850-882 mg of EPA + DHA, and 4 mg alpha-tocopherol per capsule) alone vs. placebo or in combination with statin medications or estrogen. The range of results showed a decrease in serum TG between 20% and 37% with n-3 fatty acid treatment, and there was a further decrease in TG when n-3 fatty acids were added to simvastatin, including a suppression of postprandial hypertriglyceridemia. One of the studies reviewed included 59 patients with hypertriglyceridemia and CHD on 10-40 mg/d of simvastatin who were randomized to placebo or 2 g twice daily of Omacor for six months.15 Serum TG and VLDL decreased by 20-30% (P < 0.005) and 30-40% (P < 0.005), respectively, in the Omacor group. There was no change in LDL or HDL between the two groups.
As mentioned above, there are differences in the responses to fish oil depending on the baseline lipid levels. One trial examined the effects of EPA and DHA on serum TG levels. People with normal TG and people with elevated TG given 3 g/d of EPA + DHA showed decreases in TG of 12% and 21%, respectively.11
As essential fatty acids, there is a need for both omega-6 and omega-3 fatty acids in the human diet. When examining the overall cardiovascular effect of omega-3 fatty acids, most research points to the importance of considering omega-3 fatty acid intake in the context of the omega-6 fatty acid consumption; although the absolute amount consumed is important, so is the ratio of omega-6 to omega-3 fatty acids.16 The primary omega-6 fatty acid, linoleic acid, is associated with a lower cardiovascular risk, probably through its effects in lowering total and LDL-C cholesterol.17 With this in mind, one recommendation is that for healthy adults, 5-8% of calories (or 11-20 g/d, based on a 2,000 kcal diet) should come from linoleic acid, a level that seems to convey cardiovascular benefits, allows for a positive interaction with omega-3 fatty acids, and yet is low enough not to contribute to increased inflammation.17
In the bigger picture of dietary changes that have clinical relevance, the recommendations to increase omega-3 fatty acid intake are most relevant when measured against the omega-6 intake (see above), and in relation to other components of the diet. For example, when any fats replace carbohydrates, there is an increase in HDL and LDL and a decrease in TG, in amounts that depend on the type of fat and the baseline diet.18
Other Clinical Effects
Epidemiological studies and randomized controlled trials have investigated the role of fish intake, fish oil, dietary LNA, or supplemental n-3 fatty acids in primary and secondary prevention of CHD, finding a decreased risk of sudden cardiac death and cardiac arrest, and a reduction in cardiac death,3,5 the details of which go beyond the scope of this review. Research also seems to support an improvement in myocardial infarction risk and death from ischemic CHD in people with LNA in their diets,3,18 as well as an inverse association between dietary fish intake and CHD risk, stronger for fatal CHD than nonfatal myocardial infarction (MI),18 and for populations with greater-than-average CHD risk.18
LNA also has cardiovascular effects such as decreased arrhythmias, inflammation, and thrombosis, whereas EPA + DHA improve vascular function and decrease thrombosis,17 and might prevent or favorably influence coronary heart disease and stroke; Crohn’s disease; breast, colon, and prostate cancer; hypertension; and rheumatoid diseases.12 Also, EPA and DHA decrease the risk of ischemic heart disease,17 and supplementation with omega-3 fatty acids is thought to be anti-atherogenic and stabilize plaques via its anti-inflammatory properties.19 There is also a slight hypotensive effect with omega-3 fatty acids.3
Dosages and Formulation
The dose of n-3 fatty acids necessary to achieve a reduction in plasma TG is approximately 3 g/d total of EPA + DHA. With 1 g fish oil capsules, which usually contain 180 mg EPA and 120 mg DHA,2 it will be necessary to take approximately 10 capsules daily. To avoid the toxic effects of some of the environmental contaminants of fish (see below), it is important to choose supplements that have been tested and are free of methylmercury, polychlorinated biphenyls (PCBs), and dioxins. The dose of LNA necessary to achieve similar results is difficult to predict due to the incomplete conversion of LNA to EPA and DHA in the body. A review detailing the effect of LNA on plasma TG found that 60 g of flaxseed oil used daily, or 38 g of flaxseed oil substituted for 45 g of linoleic acid, could lead to plasma TG lowering.10
Adverse Effects, Contraindications, and Drug Interactions
N-3 fatty acids can cause an increase of approximately 5% in LDL cholesterol in some people. As mentioned above, the elevation in LDL appears to be most pronounced in people with elevated TG because fish oil may enhance the conversion of VLDL to LDL;6 the LDL consists of the less-pathogenic, larger, less-dense LDL particles. Also, the effect of n-3 fatty acids is more pronounced in carriers of the apoE4 polymorphism, which confers a tendency to have higher baseline serum cholesterol and higher risk of CHD.9
There are concerns about the contamination of fish with methylmercury, PCBs, and dioxins.2 Because of the dangers of these contaminants, the FDA and the Environmental Protection Agency recommend that women who might become pregnant, who are pregnant, or who are breastfeeding, and young children should not eat more highly contaminated fish species such as shark, swordfish, king mackerel, or tilefish, and should eat only 12 oz/wk of less contaminated fish species (canned light tuna, salmon, Pollock, catfish).2,20 Of note, albacore (“white”) tuna is higher in mercury than canned light tuna, and only up to 6 oz should be consumed per week.
There are conflicting reports about whether n-3 fatty acids increase fasting glucose in people with diabetes. One randomized, double-blind trial investigated the use of 4 g/d of EPA, DHA, or olive oil placebo for six weeks in 59 people with Type 2 diabetes mellitus, and found a slight, but significant increase in fasting glucose of 1.40 and 0.98 mol/L in the EPA and DHA groups, respectively, when compared with placebo. There was no change in glycosylated hemoglobin, fasting insulin or C-peptide, insulin sensitivity or secretion, or blood pressure.21 This result is in contrast to other studies that have not found blood glucose elevations.14
There are also dose-dependent adverse effects of n-3 supplementation such as a fishy aftertaste, gastrointestinal disturbances, and increased bleeding time, though no clinically significant abnormal bleeding events have been documented in the medical literature.2
Cohort studies and some, but not all, epidemiological studies demonstrate an increased risk of prostate cancer with dietary consumption of LNA, an interesting finding given that EPA and DHA appear to be protective of prostate cancer and that LNA may be protective against breast cancer.22,23 Some experts state that there is less of a prostate cancer risk, and maybe even a benefit, with the use of ground or whole flaxseeds due to the lignan content; lignans act as phytoestrogens and antioxidants, showing anticancer effects in animal models.24,25
Conclusion
The use of n-3 fatty acids, either as LNA or as EPA + DHA, has been studied extensively in both animals and humans, and been subject to numerous reviews examining their clinical effects. LNA has negligible effects on serum lipids, except for a modest decrease in serum TG when high doses of flaxseed oil that are difficult to achieve are consumed daily. The bulk of the convincing clinical effects have been from the use of supplemental EPA and DHA, the n-3 fatty acids from marine sources. Most research shows that 3-4 g/d of EPA + DHA can lead to a 25-30% decrease in TG, an effect more pronounced for people with higher serum TG. There are also variable effects on other serum lipids, such as a small increase in LDL (again, mainly in people with elevated TG) and HDL, the specifics of which depend on many factors, including genetic differences in LDL metabolism. Some of these effects can be achieved with dietary modifications that include daily fish consumption; it remains to be definitively proven whether the sporadic ingestion of n-3 fatty acids leads to similar clinical effects. The generally recommended dose is approximately 3 g/d of EPA + DHA, about 10 capsules daily of most commonly sold preparations. Some of the adverse effects mentioned in the medical literature include elevated LDL cholesterol, increased fasting glucose in people with diabetes, exposure to environmental contamination of fish (not usually a problem with tested supplements), aberrations of bleeding time, and an increased risk of prostate cancer with LNA consumption.
Recommendation
The n-3 fatty acids, LNA, EPA, and DHA, have documented beneficial effects on plasma TG, especially in people with elevated plasma TG. It is possible to lower TG with a supplement, most effectively by consuming approximately 3 g/d of EPA + DHA due to the inefficient conversion of ingested LNA to EPA and DHA, although regular daily consumption of LNA and/or fish also conveys some benefits. There are official warnings about fish consumption due to environmental contaminants, but these dangers can be avoided by consuming tested fish oil capsules or focusing on LNA ingestion. N-3 fatty acids are generally well-tolerated with minimal side effects, though n-3 fatty acids may affect other lipid parameters, such as causing an increase in LDL; it would be a good idea to monitor patients’ lipid levels regularly to detect any undesirable abnormalities. The consumption of LNA oils or supplements should be avoided in people with prostate cancer, though flax seeds may be safe in reasonable doses; more research is needed to clarify this point.
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