Fish Oils to Lower Triglycerides

By Matthew J. Sorrentino, MD, FACC

Elevated triglyceride levels commonly are seen in patients with diabetes mellitus and the metabolic syndrome. Increased triglycerides are associated with more highly atherogenic lipoproteins, insulin resistance, and an increase in cardiovascular risk. Individuals that have high triglyceride levels associated with low HDL cholesterol levels and an elevated LDL/HDL ratio appear to be at a significantly increased cardiovascular risk.1

Table 1

Clinical identification of the metabolic syndrome*

Abdominal obesity (waist circumference)
     men > 40 in (102 cm)
     women > 35 in (88 cm)
Triglycerides >150 mg/dL
HDL
     men < 40 mg/dL
     women < 50 mg/dL
Blood pressure >130/³ 85 mm Hg
Fasting glucose >110 mg/dL
* National Cholesterol Education Program Adult Treatment Panel III. Three of five required.

Triglycerides and Disease

Normalization of high triglyceride levels can be difficult. Lifestyle modification with exercise, weight loss, and a diet low in complex carbohydrates can be effective in many individuals. Certain medications, such as the statin drugs and fibrates, can variably lower triglyceride levels. Omega-3 fatty acids in the form of dietary fish or fish oil capsules can help lower triglyceride levels both as a part of a lifestyle program and in combination with pharmacologic therapy.

Elevated triglycerides are a marker for a clinical condition known as the metabolic syndrome. The criteria for the metabolic syndrome are listed in Table 1. The metabolic syndrome is a pre-diabetic state with a high likelihood of progression to Type II diabetes mellitus.

Patients with the metabolic syndrome tend to have small, dense LDL cholesterol particles that are themselves associated with an increased risk of developing atherosclerosis.2 Triglyceride levels predict the presence of small dense LDL particles. The presence of small, dense LDL particles is associated with a significantly increased risk of coronary events. Small, dense LDL particles are present in nearly 80% of individuals with triglyceride levels greater that 200 mg/dL.3

Several genetic conditions are known to elevate triglyceride levels significantly, at times to values in excess of 1,000 mg/dL.4 Excessively high triglyceride levels are associated with an increased risk of developing pancreatitis.

Occasionally, individuals with acquired hypertriglyceridemia can have elevated triglyceride levels in excess of 1,000 mg/dL, especially if they have glucose intolerance, a high carbohydrate diet, or excessive alcohol intake.

Table 2
Lipoprotein metabolism effects of fish oils6
Inhibition of VLDL synthesis
Decreased apolipoprotein B synthesis
Enhanced VLDL turnover and increased catabolism of VLDL
Depression of LDL synthesis
Reduction of postprandial lipemia

Mechanism of Action

The fatty acids in fish oils that are active in lowering triglycerides are the long-chain polyunsaturated fatty acids: eicosapentenoate (EPA) and docosahexenoate (DHA). These fatty acids typically comprise about 35% of the fatty acids present in fish oils.5

The mechanism of action of fish oils is not fully known. The lipoprotein metabolism effects of fish oils are listed in Table 2. Fish oils appear to lower triglyceride levels by inhibiting the synthesis of VLDL cholesterol particles as well as by increasing turnover and catabolism of VLDL particles.6

Physiologic Effects of Fish Oils

Omega-3 fatty acids may have a number of important cardiovascular benefits (see Table 3). Recent investigations have suggested an anti-arrhythmic effect of fish oils, reducing the risk of sudden cardiac death in myocardial infarction survivors.7 The effects of fish oils on lipoproteins may make fish oils useful in patients that have persistently elevated triglyceride levels.

Triglyceride levels increase in the plasma after ingestion of a fat-containing meal. The magnitude of the postprandial increase in triglycerides depends on the basal triglyceride level. Elevated postprandial hypertriglyceridemia promotes the generation of small, dense LDL particles and may be a predictor of future cardiac events. Omega-3 fatty acids have been shown to reduce significantly the elevation of postprandial triglycerides.8

Table 3
Physiologic effects of fish oils
• Lower triglyceride levels and VLDL synthesis
• Inhibit atherosclerosis
• Lower blood pressure
• Antithrombotic effect (reduce platelet aggregation)
• Suppress cardiac arrhythmias and decrease sudden cardiac death

Clinical Trials

The addition of omega-3 fish oils to the diet lowers triglyceride levels in individuals with pronounced hypertriglyceridemia. Marine-based omega-3 fatty acids are more effective in lowering triglycerides than plant-derived oils.9 A meta-analysis of numerous fish oil trials concluded that omega-3 fatty acid consumption can lower triglycerides by 25-30%, raise HDL cholesterol 1-3%, and raise LDL cholesterol by 5-10%, if saturated fat intake remains constant.9 It is not known if the small increase in LDL cholesterol has any detrimental effects.

Diabetic and metabolic syndrome patients frequently have elevated triglyceride levels. Fish oils have been shown to reduce triglycerides significantly, by 45%, in non-insulin dependent diabetes in a small study.10 There was no effect of fish oils on LDL particle size and insulin resistance; the study did not bring about a normalization of triglyceride levels that may be required to shift particle size to the less atherogenic population.

Triglyceride levels are known to increase in women after menopause. Hormone replacement therapy can increase triglycerides by 25%.11 Supplementation with fish oils can lower triglycerides by 26% in postmenopausal women receiving and not receiving hormone replacement therapy.12 The dose of fish oils used in this study was eight capsules supplying 2.4 g EPA and 1.6 g DHA.

Fish oils also have been used in combination with other lipid-lowering agents. In patients with combined hyperlipidemia, the addition of 7.2 g/d of marine oils to simvastatin 10 mg/d brought about a better reduction in triglycerides than with the statin alone.13 In addition, there was no attenuation of the LDL-lowering effect of the statin with the addition of the fish oils. A second study looked at patients with sustained hypertrigly-ceridemia despite adequate treatment of the LDL cholesterol with a statin drug. Use of a highly concentrated omega-3 product (Omacor) bought about a 20-30% sustained reduction in triglycerides over a year of treatment.5 There was no change in glycemic control in the diabetic patients.

Dose

The dose of fish oils needed to lower triglycerides is at least 1 g/d. Omega-3 fatty acids reduce triglycerides in a dose-dependent manner with 1 g/d lowering triglycerides about 10% on average.8 Greater reductions in triglycerides may occur with longer duration of therapy.

Most of the studies showing a triglyceride-lowering effect used fish oil intakes of 10-12 g of oil per day yielding intakes of about 4 g/d of omega-3 fatty acids.9

Higher doses of fish oils are needed for significant triglyceride lowering than have been used in some of the treatment trials showing a cardiovascular benefit. For example, the GISSI prevention trial used less than 1 g/d of fish oil capsules (equivalent to about 100 g of fatty fish a day) and showed a reduction in the primary endpoint of death, nonfatal myocardial infarction, and stroke in the treatment group.14 Only a small change in triglycerides occurred in the supplementation group.

Table 4

Potential side effects of fish oil capsules6

Fishy odor and gastrointestinal upset

Increased bleeding time, easy bruising or bleeding

Increase in LDL cholesterol

Increase weight gain from increased caloric intake

Decreased cell-mediated immunity (unclear significance)

Toxicity: Vitamin A and D in some preparation; pesticides

Formulation

There are many fish oil products on the market, with dosages ranging from less than 500 mg of EPA/DHA to more than 1,500 mg per serving (capsule or liquid). The GISSI prevention trial used a gelatin capsule containing 850-882 mg of EPA and DHA as ethyl esters in an average EPA/DHA ratio of 1:2. One to two capsules of most currently available brands should give this amount of omega-3 fatty acids. For a greater triglyceride lowering effect of 30-40%, approximately 4 g of EPA/DHA would be required, although over time, equivalent triglyceride reductions may be achieved with half that dose. For individuals with extremely elevated triglycerides, higher doses may be used with further lowering of triglycerides. Doses as high as 24 g/d of fish oils (more than 8 g of omega 3) have been used. Fish in the diet will not be able to achieve these doses.

Side Effects

Doses of approximately 4 g of omega-3 fatty acids daily generally are well tolerated without adverse effects in the clinical trials. Potential side effects are listed in Table 4.6 The most common side effect is a fishy odor and gastrointestinal upset with some preparations. Many products use flavoring and coatings to decrease gastrointestinal effects. In addition, many products claim that careful screening is done to avoid toxic metals and chemicals.

Conclusion

The addition of marine-derived omega-3 fatty acids in the diet lower triglyceride levels and are an important treatment option for individuals with significantly elevated triglyceride levels. Fish oils are as effective in lowering triglycerides as currently available pharmacologic agents (mainly fibrates). Dietary fish intake also may have important cardiovascular benefits, but a substantial intake is required to obtain a significant triglyceride-lowering effect. Because current guidelines recommend lowering triglyceride levels in high-risk patients (diabetics and metabolic syndrome patients), fish oils will be an important therapeutic option for many patients.

Recommendation

Current guidelines indicate that triglyceride levels below 150 mg/dL are normal, between 150 and 200 mg/dL are intermediate, and 200 mg/dL or greater indicate high risk. A lifestyle program concentrating on mild weight loss, moderate exercise, and a diet that restricts complex carbohydrates can significantly reduce triglyceride levels. Dietary fish at least twice a week can give additional cardiac benefit. To lower triglycerides further, daily supplementation with fish oil capsules may be necessary. Recommend beginning with 1-2 g/d of omega-3 fish oil capsules (EPA and DHA), gradually increasing to 3-4 g/d as tolerated. In combination with a good diet and exercise program, this regimen should improve triglyceride levels for most individuals.

References

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2. Lamarche B, et al. Small, dense low-density lipoprotein particles as a predictor of the risk of ischemic heart disease in men. Prospective results from the Quebec Cardiovascular Study. Circulation 1997;95: 69-75.

3. Austin MA, et al. Atherogenic lipoprotein phenotype. A proposed genetic marker for coronary heart disease risk. Circulation 1990;82:495-506.

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5. Durrington PN, et al. An omega-3 polyunsaturated fatty acid concentrate administered for one year decreased triglycerides in simvastatin treated patients with coronary heart disease and persisting hypertriglyceridaemia. Heart 2001;85:544-548.

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9. Harris WS. n-3 fatty acids and serum lipoproteins: Human studies. Am J Clin Nutr 1997;65(5 suppl): 1645S-1654S.

10. Patti L, et al. Long-term effects of fish oil on lipoprotein subfractions and low density lipoprotein size in non-insulin-dependent diabetic patients with hypertriglyceridemia. Atherosclerosis 1999;146:361-367.

11. The Writing Group for the PEPI Trial. Effects of estrogen or estrogen/progestin regimens on heart disease risk factors in postmenopausal women. JAMA 1995; 273:199-208.

12. Stark KD, et al. Effect of a fish-oil concentrate on serum lipids in postmenopausal women receiving and not receiving hormone replacement therapy in a placebo-controlled, double-blind trial. Am J Clin Nutr 2000; 72:389-394.

13. Davidson MH, et al. Separate and joint effects of marine oil and simvastatin in patients with combined hyperlipidemia. Am J Cardiol 1997;80:797-798.

14. GISSI-Prevenzione Investigators. Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: Results of the GISSI-Prevenzione trial. Lancet 1999;354:447-455.