Omega-3 fatty acids

Abstract

OBJECTIVE

To examine evidence for the role of omega-3 fatty acids in cardiovascular disease.

QUALITY OF EVIDENCE

PubMed was searched for articles on the role of omega-3 fatty acids in cardiovascular disease. Level I and II evidence indicates that omega-3 fatty acids are beneficial in improving cardiovascular outcomes.

MAIN MESSAGE

Dietary intake of omega-3 fatty acids has declined by 80% during the last 100 years, while intake of omega-6 fatty acids has greatly increased. Omega-3 fatty acids are cardioprotective mainly due to beneficial effects on arrhythmias, atherosclerosis, inflammation, and thrombosis. There is also evidence that they improve endothelial function, lower blood pressure, and significantly lower triglycerides.

CONCLUSION

There is good evidence in the literature that increasing intake of omega-3 fatty acids improves cardiac outcomes. Physicians need to integrate dietary recommendations for consumption of omega-3 fatty acids into their usual cardiovascular care.

EDITOR’S KEY POINTS.

• Historically, the human diet was high in omega-3 fatty acids. The ratio of omega-6 to omega-3 fatty acids in the diet was 1-2:1. During the last 100 years, there has been a marked increase in consumption of omega-6 and a decrease in consumption of omega-3 fatty acids.

• There appears to be good evidence (level I and II) of a lower incidence of hypertension, cardiac disease, all-cause mortality, and familial hypertriglyceridemia in patients who consume adequate amounts of omega-3 fatty acids.

• Canada was the first country to adopt guidelines to reduce consumption of omega-6 and increase consumption of omega-3 fatty acids, with a target ratio of 6:1 in the diet. Most Canadians will not achieve this goal.

• Family doctors can be confident that promoting a diet with increased intake of omega-3 fatty acids is an important preventive measure.

POINTS DE REPÈRE DU RÉDACTEUR.

• Historiquement, l’alimentation humaine contenait beaucoup d’acides gras oméga-3 et il y avait un rapport de 1-2:1 entre les oméga-6 et les oméga-3 consommés. Au cours des 100 dernières années, la consommation des oméga-6 a fortement augmenté tandis que celle des oméga-3 diminuait.

• Il y a des preuves de niveau I et II suggérant que la consommation d’une quantité adéquate d’acides gras oméga-3 réduit la mortalité globale et l’incidence d’hypertension, de maladies cardiaques et d’hypertriglycéridémie familiale.

• Le Canada a été le premier pays à adopter des directives pour réduire la consommation des oméga-6 et augmenter celle des oméga-3, avec comme objectif un rapport de 6:1 dans l’alimentation. La plupart des canadiens n’atteindront toutefois pas cet objectif.

• Le médecin de famille a raison de croire que le fait de préconiser un régime plus riche en oméga-3 est une importante mesure préventive.

During the last decade, the amount of research on omega-3 fatty acids has increased substantially. As a result, new guidelines recommend that patients at risk of cardiovascular (CV) disease increase their dietary intake of omega-3 fatty acids. This article looks at the role of omega-3 fatty acids of marine (eicosapentenoic acid [EPA], docosahexaenoic acid [DHA]) and plant (alpha-linolenic acid [ALA]) origin in CV health in order to bring family physicians up-to-date on current evidence.

Quality of evidence

Studies providing level I, II, and III evidence of the benefits of omega-3 fatty acids are reviewed in this article. MEDLINE was searched using the words “omega-3 fatty acids” and “fish oil” combined with “hypertension,” “coronary artery disease,” and “hypertriglyceridemia.” Trials involving humans were chosen.^1-16

Omega-3 and omega-6 fatty acids

The lipids essential for health are the omega-3 and omega-6 polyunsaturated fatty acids (PUFA).¹⁷ Interest in omega-3 fatty acids began in 1972. Studies by Bang and Dyerberg³ showed that Greenland Inuit who consumed a diet high in protein and fat (mainly from fish) had significantly lower total cholesterol (P < .005), low-density lipoprotein (LDL)(P < .02), and triglyceride (P < .005) levels than most other people had.

Since then, much has been learned about the interaction of omega-6 and omega-3 fatty acids in CV disease and about the ratio between omega-6 and omega-3 fatty acids.^18,19 Dietary intake of omega-3 fatty acids has decreased, and dietary intake of omega-6 fatty acids has substantially increased during the last 100 years due to greater use of vegetable oils high in omega-6 fatty acids.^18,20 The ratio of omega-6 to omega-3 was about 1.5:1 as recently as 200 years ago and now is estimated at 16:1 in the average North American diet.¹⁸ This has resulted in a diet high in omega-6 fatty acids and deficient in omega-3 fatty acids.²¹

Omega-6 and omega-3 fatty acids compete for the same enzymes. An increase in the diet of one decreases metabolism of the other.²² Omega-6 fatty acid metabolites result in prostaglandins that are inflammatory; omega-3 fatty acids result in prostaglandins that are anti-inflammatory. The actions of omega-3 fatty acids on the CV system are listed in Table 1.^1,2,23-33 Omega-3 fatty acids have antiarrhythmic effects, including preventing atrial fibrillation^23,24; antithrombotic action²⁵; antiatherogenic effects²⁶; anti-inflammatory effects^27,28; and the ability to improve endothelial function,²⁹ lower blood pressure,^1,2 lower triglyceride levels,³⁰ increase high-density lipoprotein (HDL) levels,³¹ and decrease apolipoprotein B-100.³²

Table 1.

Cardiovascular effects of omega-3 fatty acids

Data from Din et al.³³

Hypertension

Trials are listed in Table 2.^1-16 Geleijnse et al¹ did a meta-analysis of 36 randomized trials (22 of which were double blind) carried out between 1966 and 2001 (level I evidence). The meta-analysis showed that consuming an average of 3.7 g/d of fish oil reduced systolic blood pressure (BP) by 2.1 mm Hg (P < .01) and diastolic BP by 1.6 mm Hg (P < .01). The BP-lowering effects were greater in people older than 45 years and in those whose BP was higher than 140/90 mm Hg.

Table 2.

Characteristics of studies on use of fish oil

HDL—high-density lipoprotein, RCT—randomized controlled trial.

A meta-analysis (level I evidence) done by Appel et al² found a significant reduction in BP (5.5 mm Hg systolic BP and 3.5 mm Hg diastolic BP) in untreated hypertensive patients taking supplements of more than 3 g/d of omega-3 PUFA. High doses were required to achieve these results, and patients’ acceptance of the fishy taste and subsequent belching was poor (P < .001). Most trials lasted less than 3 months, so the long-term benefits are unclear.

Heart disease

Bang and Dyerberg³ and Dyerberg et al⁴ did epidemiologic studies (level II evidence) to establish the cardioprotective effects of omega-3 fatty acids from marine sources in the Inuit people of Greenland in the 1970s. Despite a high-fat diet, the incidence of CV disease was exceptionally low among these people. A Canadian study⁵ looking at James Bay Cree people reported fewer CV risk factors and higher levels of plasma omega-3 fatty acids in adult Cree living along the coast than in those living inland (level II evidence).

In September 1989, the Diet and Reinfarction Trial (DART)⁶ (level II evidence) was the first study to show that subjects who followed advice to eat fatty fish (high in omega-3 fatty acids) had a 29% reduction in 2-year all-cause mortality (P < .05). The study allocated 2033 men to 3 groups: group 1 reduced their fat intake and increased their intake of PUFA, group 2 increased their fatty fish intake, and group 3 increased their cereal fibre intake.

The Lyon Diet Heart Study,⁷ a secondary prevention trial (level I evidence), followed 605 men after myocardial infarction (MI) for 4 years. One group (n = 303) received a diet rich in omega-3 and omega-9 fatty acids and low in both omega-6 fatty acids and saturated fats (the Mediterranean diet). The second group (n = 302) followed the Prudent Heart Diet, which is similar to the American Heart Association diet. Three end points were used: cardiac death or non-fatal MI; cardiac death or non-fatal MI plus secondary end points including unstable angina, stroke, heart failure, and pulmonary or peripheral embolism; and all of the preceding plus minor events requiring hospital admission. The experimental group following the Mediterranean diet had fewer events at all end points. For the first end point, the first group had 14 events, and the second group 44 events (P < .0002). For the second end point, the first group had 27 events, and the second group had 90 events (P < .0002). For the third end point, the first group had 95 events, and the second group had 180 events (P < .0002)³⁴ (Figure 1⁷). The control group had an omega-6–to–omega-3 ratio of 10:1; the experimental group had a ratio of 4:1. A striking protective effect was reported with a 50% to 70% reduction in risk of recurrence of CV events after 4 years’ follow up.

Figure 1.

Data from the final report of the Lyon Diet Health Study⁷

In the Indo-Mediterranean Diet Heart Study (1000 patients)⁸ (level I evidence), those in the experimental group (diet high in ALA) had fewer CV events than those in the control group (39 vs 76, P < .001). Also reduced were sudden cardiac death (6 vs 16, P < .015) and non-fatal MI (21 vs 43, P < .001) (Figure 2^7,34). Omega-6–to–omega-3 ratios were 38:1 before the trial and 33:1 before the intervention; after 2 years in the trial, ratios were 9:1 in the experimental group and 21:1 among controls. The prevalence of coronary artery disease was 2% to 3% in rural areas of India and 9% to 14% in urban populations. The high incidence in urban areas is thought to be due to intake of Indian ghee or clarified butter (rich in cholesterol oxides) and high omega-6–to–omega-3 ratios.^35,36

Figure 2.

Data from the Indo-Mediterranean Diet Heart Study⁷,³⁴

The GISSI-Prevenzione trial (level I evidence)^9,10 randomly assigned 11 324 patients surviving a recent MI into 4 groups: one took a capsule containing 850 mg/d of omega-3 fatty acids each day, another took 300 IU of vitamin E daily, a third group took both each day, and the control group took nothing. After 3.5 years, overall mortality was reduced by 20% and CV mortality was reduced by 30% in the group taking capsules of omega-3 fatty acids. No benefit was apparent from taking vitamin E alone. A 45% reduction in sudden cardiac death (P = .01) accounted for most of the benefit. Omega-3 fatty acids seem to be able to stabilize contractile heart cells electrically and thus prevent ventricular arrhythmias.²³

A meta-analysis by Bucher et al¹¹ (level I evidence) identified 11 trials published between 1966 and 1999 with a total of 7951 patients in intervention groups and 7855 in control groups. They found that intake of fish or fish oil reduced rates of overall mortality (P < .001), fatal MI (P < .001), and sudden cardiac death (P < .01). Mortality from coronary artery disease was reduced by 40% to 60% with consumption of 40 to 60 g of fish daily.

Several studies, including the Cardiovascular Health Study,³⁷ the Family Heart Study,³⁸ the Health Professionals Follow-up Study,³⁹ the Multiple Risk Factor Intervention Trial,⁴⁰ and the Nurses’ Health Study,⁴¹ showed benefit of ALA in CV disease. The Zutphen Elderly Study,⁴² however, found a modest link between ALA and increased risk of CV disease. Excessive consumption of trans fatty acids might have contributed to this.

Although most studies have shown that omega-3 fatty acids are useful for secondary prevention of CV disease, some have shown no statistical benefit. A study done by Nilsen et al¹² (level I evidence) showed no benefit for prevention of further cardiac events in 300 patients from Norway. Those patients had significantly lower triglyceride levels (P < .0001) and significantly higher HDL levels (P < .0016) than most people. It is thought that no further benefit was possible among these people who already consumed a great deal of fish in their diet. This study was also shorter than many of the studies listed above.

Severe familial hypertriglyceridemia

Supplementation with omega-3 fatty acids has been shown to be of benefit in severe familial hypertriglyceridemia. Richter et al¹³ (level II evidence) demonstrated that adding 4.32 g/d of omega-3 fatty acids to the diet for 8 weeks reduced serum triglycerides from 18.29 to 10.1 mmol/L. Pschierer et al¹⁴ (level II evidence) showed that serum triglycerides had decreased significantly from 16.9 to 11.2 mmol/L after 1 month, and further decreased after 11 months to 10.1 mmol/L on average with supplementation with omega-3 fatty acids.

Fish oil and HMG-CoA reductase inhibitors

The effectiveness of statins can be improved by adding omega-3 fatty acids to the diet.^43,44 A small study looked at combining statins and fish oil (level II evidence).¹⁵ Adding 900 to 1800 mg of EPA to the diet of patients already taking HMG-CoA reductase inhibitors resulted in a further decrease in total cholesterol from 5.63 to 5.02 mmol/L (P < .05) and in triglycerides from 2.07 to 1.08 mmol/L (P < .01). Serum HDL increased significantly from 1.23 to 1.34 mmol/L (P < .01).

Cardiovascular surgery

In a study done by Eritsland et al¹⁶ (level I evidence), 610 patients who underwent coronary artery bypass grafting were assigned to a fish-oil group (4 g/d of fish oil) or to a control group. The end point was patency of the graft at 1 year. A year later, vein graft occlusion was 27% in the experimental group and 33% in the control group (P = .034). Vein graft occlusion was inversely related to the relative change in serum omega-3 fatty acid levels. Initial studies done on coronary angioplasty patients⁴⁵ showed that fish oil had promise for reducing recurring stenosis, but later studies using higher doses did not show any statistically significant reduction.⁴⁶

Dietary suggestions, discussion, and recommendations

In 1990, Canada was the first country to provide separate dietary recommendations for omega-6 and omega-3 fatty acids for people of all ages.⁴⁷ For adults between 25 and 49 years old, Health Canada suggests 1500 mg of omega-3 and 9000 mg of omega-6 polyunsaturates daily for men and 1100 mg of omega-3 and 7000 mg of omega-6 fatty acids daily for women. This results in an omega-6–to–omega-3 ratio of 6:1. It is thought that most Canadians do not have this modest daily intake of omega-3 fatty acids. Dietary sources of omega-3 fatty acids and some instructions for making them palatable are shown in Table 3.⁴⁸ Side effects and interactions associated with consumption of fish oil are listed in Table 4.^49-53

Table 3. Sources of omega-3 essential fatty acids.

To consume the minimum daily amount of 1200 mg of omega-3 fatty acids, people can choose a variety of food from the list in this table or take 3-4 fish oil capsules daily.

ALA—alpha-linolenic acid, DHA—docosahexaenoic acid, EPA—eicosapentenoic acid.

*Includes long-chain polyunsaturated fatty acids, EPA and DHA, and plant-source omega-3 fatty acid, ALA.

^†Flax oil and hemp oil can be mixed into salad dressings and other food. These oils oxidize easily and should never be used for cooking.

^‡Also a good source of vitamins A and D.

^§Fish-oil flavours are milder in capsules, especially if capsules are swallowed cold from the refrigerator.

^||Each designer omega-3 egg has 0.38 g of DHA and EPA (omega-6–to–omega-3 ratio is 1.6:1), 7 times as much vitamin E as, and less cholesterol than, a normal egg.

^¶A Dr Sims designer egg has 0.6 g of DHA and EPA (omega-6–to–omega-3 ratio is 1:1). A normal egg has 0.05 g of DHA and EPA.

Data from Kris-Etherton et al.⁴⁸

Table 4.

Fish-oil interactions and side effects

The American Heart Association issued new recommendations on consumption of omega-3 fatty acids in 2003.⁴⁸ These are listed in Table 5^48,54 along with recommendations from an expert round-table discussion at the 34th Annual Scientific Meeting of the European Society for Clinical Investigation.⁵⁴

Table 5.

Recommendations of the American Heart Association⁴⁸ and the European Society for Clinical Investigation⁵⁴ regarding consumption of omega-3 fatty acids

ALA—alpha-linolenic acid, DHA—docosahexaenoic acid, EPA—eicosapentenoic acid.

*Lean fish have smaller amounts of omega-3 fatty acids; fried fish (frozen breaded fish products or fish from fast-food outlets) have minimal amounts of omega-3 fatty acids

Conclusion

There is now solid evidence that omega-3 fatty acids favourably modulate disease processes, such as hypertension, coronary artery disease, and hypertriglyceridemia. Increasing dietary intake of omega-3 fatty acids and bringing the ratio of omega-3 to omega-6 fatty acids into a healthy balance would improve Canadians’ cardiovascular health.

Levels of evidence.

Level I: At least one properly conducted randomized controlled trial, systematic review, or meta-analysis

Level II: Other comparison trials, non-randomized, cohort, case-control, or epidemiologic studies, and preferably more than one study

Level III: Expert opinion or consensus statements

Biography

Dr Schwalfenberg is a family physician in full-time solo practice. He is a member of the Department of Family Practice at the Misericordia Hospital in Edmonton, Alta.