What can we expect from omega-3 fatty acids?
ABSTRACTOmega-3 fatty acids are abundant in fish oil. A high dietary intake of omega-3 fatty acids has been strongly linked to lower rates of cardiovascular disease in epidemiologic studies. Fish oil supplements lower triglyceride levels and may have other benefits such as preventing arrhythmias, reducing inflammation (although they have minimal impact on C-reactive protein), inhibiting platelet aggregation, and lowering blood pressure, all of which should reduce cardiovascular risk.
KEY POINTS
- The American Heart Association recommends that healthy people consume fatty fish at least twice a week. The recommendation for people with coronary artery disease is 1 g of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) per day.
- A formulation of EPA 465 mg plus DHA 375 mg is available by prescription and is approved for treating triglyceridemia in excess of 500 mg/dL. The dose is 2 to 4 capsules per day.
- Experts generally believe that omega-3 fatty acids reduce arrhythmic events. Nevertheless, we lack clear evidence of their clinical effectiveness, and their use for such purposes is off-label.
- Overall, omega-3 fatty acids have minimal side effects.
HOW DO OMEGA-3 FATTY ACIDS REDUCE RISK?
After epidemiologic studies found that Greenland Eskimos (who consume diets rich in omega-3 fatty acids) have low rates of cardiovascular disease,7 omega-3 fatty acids were hypothesized to reduce cardiovascular risk. Over the past 3 decades, their potential benefit in lowering lipid levels, blood pressure, and the risk of death in patients with known heart disease has been widely researched.
Lower triglyceride levels
The growing problem of obesity in the United States has led to more patients presenting with hypertriglyceridemia, a risk factor for coronary heart disease.
In 2001, the National Cholesterol Education Program’s third Adult Treatment Panel (ATP III)8 redefined normal triglyceride levels as less than 150 mg/dL; previously, normal was defined as less than 200 mg/dL. For people with borderline-high triglyceride levels (150–200 mg/dL), the ATP III recommends focusing on lowering the level of low-density lipoprotein cholesterol (LDL-C). For those with high to very high triglyceride levels (> 500 mg/dL), the current treatment options are niacin, fibrates, and omega-3 fatty acids.
Hypertriglyceridemia is thought to increase the risk of coronary heart disease by two mechanisms. First, and more important, triglyceride-rich lipoproteins such as very-low-density lipoprotein (VLDL) and intermediate-density lipoprotein (IDL) are thought to be atherogenic. Secondly, triglyceride-lipoprotein metabolism involves competition with high-density lipoprotein (HDL), leading to a decrease in HDL production and to denser LDL particles.9
How omega-3 fatty acids lower triglyceride levels has been inferred from preclinical studies. One mechanism, seen in animal studies, is by decreasing hepatic synthesis and secretion of VLDL particles by inhibiting various enzyme transcription factors. Another proposed mechanism is that EPA and DHA increase the activity of lipoprotein lipase, leading to an increase in chylomicron clearance.10 This was validated by Khan et al,11 who showed that lipoprotein lipase activity increased in patients who received omega-3 fatty acids 3 g/day for 6 weeks.
How much do they lower triglycerides? Data from the makers of Lovaza3 indicate that in a patient population with a mean baseline triglyceride level of 816 mg/dL, 4 g/day of omega-3 fatty acids lowered triglyceride levels to 488 mg/dL, a 45% reduction (P < .0001). In addition, HDL cholesterol (HDL-C) levels increased by 9%.
The higher the dose and the higher the baseline triglyceride level, the greater the effect. Balk et al12 performed a meta-analysis of 25 randomized trials and calculated that each 1-g increase in fish oil dose per day lowered the triglyceride level by about 8 mg/dL. However, patients with high baseline triglyceride levels had more dramatic reduction of triglycerides with fish oil. The average reduction in triglyceride levels was 27 mg/dL, accompanied by an increase in HDL-C of 1.6 mg/dL, an increase in LDL-C of 6 mg/dL, and no change in total cholesterol levels.
Pownall et al13 report that, in 19 patients with hypertriglyceridemia (median baseline level 801 mg/dL), omega-3 fatty acids 4 g/day reduced triglyceride levels to 512 mg/dL, a 38.9% change (P = .001). In 21 patients receiving placebo, triglyceride levels decreased by 7.8% (P = .001 compared with active therapy). The effect on HDL-C was minimal, but the median LDL-C level increased by 16.7% (from 43 to 53 mg/dL, P = .007) with fish oil therapy.
Fish oil plus a statin may have advantages
Most patients seen in clinical practice present with mixed dyslipidemias. The current ATP III guidelines aim for stricter triglyceride and LDL-C targets than in the past, which monotherapy alone may not be able to achieve.
Statin therapy by itself effectively lowers LDL-C but has modest effects on triglycerides. Omega-3 fatty acids effectively reduce triglycerides but have been known to increase LDL-C levels. This net LDL-C increase averaged around 10 mg/dL as reported in a review by Harris et al,14 and 6 mg/dL as reported by Balk et al.12 However, despite the net effect of an increase in LDL-C, it is hypothesized that the larger LDL particles produced by omega-3 fatty acid treatment may be less atherogenic.15
The effectiveness of combined therapy in reducing triglycerides has been widely studied.
Chan et al,16 in a randomized, placebo-controlled trial, looked at the effectiveness of atorvastatin (Lipitor) and EPA/DHA. Fifty-two obese men were randomized to receive atorvastatin 40 mg/day, EPA/DHA 4 g/day, both in combination, or placebo. After 6 weeks, triglyceride levels had decreased by 26% from baseline in the atorvastatin group, 25% in the EPA/DHA group, and 40% in the combination therapy group (P = .002). LDL-C levels decreased to a similar degree with either atorvastatin monotherapy or combination therapy. Similar studies show similar results.
Combination therapy may also lower the rate of major coronary events (see below).
The Japan EPA Lipid Intervention Study (JELIS)17 randomized more than 18,000 patients to receive either a statin alone or a statin plus EPA 1,800 mg daily, in an open-label fashion. The statins used were pravastatin (Pravachol) 10 mg daily or simvastatin (Zocor) 5 mg daily; if hypercholesterolemia remained uncontrolled, these doses were doubled. The patients were 5,859 men and 12,786 postmenopausal women (mean age 61) with or without coronary artery disease who had total cholesterol levels of 251 mg/dL or greater. The mean baseline LDL-C level was 180 mg/ dL. People who had had an acute myocardial infarction in the past 6 months or unstable angina were excluded. The primary end point examined was any major coronary event, defined as sudden death, fatal or nonfatal myocardial infarction, unstable angina, angioplasty, or coronary artery bypass grafting.
The JELIS trial showed that combination therapy may reduce the risk of coronary events, the aim of treating dyslipidemia. It was the largest randomized trial to date comparing statin use alone and in combination with omega-3 fatty acids. However, it was performed in Japan, where people already have a high intake of fatty fish, and the results may not be applicable to other countries.
