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Balk E, Chung M, Lichtenstein A, et al. Effects of Omega-3 Fatty Acids on Cardiovascular Risk Factors and Intermediate Markers of Cardiovascular Disease. Rockville (MD): Agency for Healthcare Research and Quality (US); 2004 Mar. (Evidence Reports/Technology Assessments, No. 93.)

  • This publication is provided for historical reference only and the information may be out of date.

This publication is provided for historical reference only and the information may be out of date.

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Effects of Omega-3 Fatty Acids on Cardiovascular Risk Factors and Intermediate Markers of Cardiovascular Disease.

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3Results

In this chapter, we review the results of our literature search and summarize findings from studies that passed our screening and selection process. Studies examining the relationship between omega-3 fatty acids - eicosapentaenoic acid (EPA, 20:5 n-3), docosahexaenoic acid (DHA, 22:6 n-3), and alpha linolenic acid (ALA, 18:3 n-3) - and selected risk factors of cardiovascular disease (CVD) are summarized first, followed by studies that examine the correlation between omega-3 fatty acid intake and tissue levels of fatty acids.

Summary of Studies Found

Through the literature search we identified and screened over 7,464 abstracts indexed as English language articles concerning humans. We retrieved and screened 807 full text articles for potentially relevant human data. Of these, we rejected 463 articles for the reasons listed in the section “Listing of Excluded Studies” under “Rejected Studies”. Of the remaining 344 articles, we analyzed risk factor and other outcome data from 123 (Table 3.1, “References and Included Studies” under “Included Studies”). The 221 non-rejected studies that were not analyzed are listed in the section “Listing of Excluded Studies” under “Studies Not Analyzed Because of Non-Randomized Design or Small Size”. For most outcomes, we analyzed only the approximately 20 to 30 largest randomized trials. These trials were selected based on criteria described both in Table 3.1 and in the sections describing each risk factor included in this chapter.

We compiled an Evidence Table that provides detailed information about each study we analyzed (Appendix C, available electronically at http://www.ahrq.gov/clinic/epcindex.htm). The summary tables present specific information about each of the studies that we analyzed for a given risk factor or outcome. Information presented in the summary tables include: study design and size, amount of omega-3 fatty acid consumption, baseline level of the relevant risk factor, net change of risk factor level (change in omega-3 fatty acid arm less change in control arm), reported statistical significance of the net change, study quality, study population, and applicability for each study.

Most studies that we analyzed evaluated fish or other marine oils (as supplements, dietary fish, or oil spreads); few evaluated plant oils (as supplements, dietary oils, or oil spreads). Furthermore, few studies compared doses of similar omega-3 fatty acids, compared different omega-3 fatty acids, reported on potential covariates such as age and sex, analyzed effects based on duration of intake, or repeated measurements after subjects had stopped omega-3 fatty acid supplementation. Only 13 articles (reporting on 12 trials) reported any data related to either baseline dietary or experimental dietary intake of both omega-3 fatty acid and omega-6 fatty acid intake to allow an estimate of mean daily omega-6 to omega-3 fatty acid ratio 46–58. However, no study analyzed the relationship between evaluated outcomes and either omega-6 to omega-3 fatty acid consumption ratio or combined omega-6 and omega-3 fatty acid consumption amounts. Any available data relating to relative amounts of omega-6 fatty acid consumption could not be evaluated separately from different doses or types of omega-3 fatty acids.

Each risk factor is discussed separately in the following, largely arbitrary, order:

  • Lipids (total cholesterol, low density lipoprotein [LDL], high density lipoprotein [HDL], triglycerides, lipoprotein (a) [Lp(a)], apolipoproteins [apo] AI, B, B-100, and LDL apo B)
  • Blood pressure
  • Measures of glucose metabolism (hemoglobin A1c [Hgb A1c], fasting blood sugar [FBS], and fasting insulin)
  • C-reactive protein (CRP)
  • Measures of hemostasis (fibrinogen, factors VII and VIII, von Willebrand factor [vWF], and platelet aggregation)
  • Non-serum diagnostic tests (coronary artery restenosis [following angioplasty], carotid intima-media thickness [IMT], exercise tolerance testing [ETT], and heart rate variability).

The final section of this chapter summarizes studies that examine the correlation between omega-3 fatty acid intake and tissue levels, including plasma or serum phospholipid levels, platelet phospholipids, erythrocyte membrane phospholipids, granulocyte membrane phospholipids, and monocyte membrane phospholipids.

Lipids: Total Cholesterol (Table 3.2)

Abnormal levels of serum lipids, primarily low density lipoprotein (LDL), high density lipoprotein (HDL), and triglycerides (Tg) have long been recognized as risk factors for CVD. Of interest is whether consuming omega-3 fatty acids as part of a therapeutic lifestyle change would improve lipid levels, or at least would not be detrimental. Recent National Cholesterol Education Program (NCEP) guidelines recommend a goal for fasting total cholesterol of less than 200 mg/dL in all adults, with lower levels recommended for people at elevated risk for CVD, including diabetics, smokers, people with hypertension or a family history of premature CVD, or who are beyond middle age59.

Table 3.2 Effects of Omega-3 fatty acids on total cholesterol (mg/dL) in randomized trials (6 weeks to 2 years).

Table

Table 3.2 Effects of Omega-3 fatty acids on total cholesterol (mg/dL) in randomized trials (6 weeks to 2 years).

Lipid levels are the most commonly measured CVD risk factor in trials of omega-3 fatty acid consumption. We found 182 studies that met eligibility criteria and reported data on the effect of omega-3 fatty acids on lipid levels in at least 20 subjects (See Table 3.1). Of these, we analyzed the 25 randomized trials with lipid data for at least 60 subjects in parallel trials and 40 subjects in crossover trials who consumed omega-3 fatty acids. It is important to note that because we analyzed only the largest randomized trials, we did not capture many smaller studies of diabetic patients.

Among these studies, 169 reported data on total cholesterol levels. We analyzed the 23 largest randomized trials.

Overall Effect 48, 49, 52, 53, 60–78

Across the 23 studies there was a wide range of effects of omega-3 fatty acids on total cholesterol, although in most studies the net effect was small and generally of an increase in total cholesterol. Most studies found net increases of between 0% and 6% (approximately 0 to 14 mg/dL). Only 3 studies found that the changes in total cholesterol in subjects on omega-3 fatty acids were significantly different than control. Notably, the directions of the treatment effects were not consistent across these studies.

Sub-populations

Only 5 of the studies included generally healthy subjects, 3 of which were all male66, 67, 72. Net effects were generally small but inconsistent in direction. Most of the studies included subjects with a variety of types of CVD. There was no clear consistent effect among the 12 studies. Two studies evaluated subjects at increased risk of CVD with different sets of treatments and came to different conclusions. Sirtori et al. found no effect with fish oil in approximately 900 individuals with dyslipidemia and either hypertension, diabetes or glucose intolerance 77. Singh et al. reported a large, highly significant reduction in total cholesterol with an Indo-Mediterranean diet in approximately 1,000 people with either hypercholesterolemia, hypertension, diabetes, angina or myocardial infarction 76. However, this study found that subjects on the Indo-Mediterranean diet lost significantly more weight (3 kg) than those on the control diet. In addition, they reported uniform highly significant effects on all serum markers despite widely ranging effects. A number of statistical calculation errors were also found.

While no study evaluated a population of all diabetic subjects, Natvig et al., in an early Norwegian trial of linseed oil supplements, reported a sub-analysis of the 98 diabetic subjects and found that the effect of linseed oil was similar in both all subjects and specifically in diabetic subjects, but that total cholesterol decreased by a small amount more in the diabetic subjects 72. The difference was not significant.

Covariates

No subgroup analyses based on covariates were reported. Two studies performed regressions. Bairati et al. reported no change in total cholesterol effect after adjusting for age, sex, baseline lipid level, lipid treatment, body mass index and alcohol use 60. Mori et al. performed a regression adjusting for change in weight and found a highly significant “group effect” increase in total cholesterol with omega-3 fatty acids (P < .001) 71. This study also found larger relative net increases in total cholesterol among subjects on a 40% fat diet, but no net effect (and a decrease in absolute change) in subjects on a 30% fat diet. No clear difference was seen between the 5 studies that included only men and the remaining studies 61, 66, 67, 71, 72.

Dose and Source Effect

Three studies compared different sources - and doses - of marine oil supplements 62, 66, 74. Grimsgaard et al. found a significantly greater decrease in total cholesterol with purified EPA than DHA in healthy, middle-aged men 66. Brox et al. found a substantially greater decrease in total cholesterol with higher omega-3 fatty acid dose cod liver oil supplement than seal oil supplement in healthy subjects with elevated total cholesterol; although they imply that the difference was not statistically significant 62. Osterud et al. found varying degrees of net increases of total cholesterol with different marine oil supplements in healthy subjects 74. No clear pattern was evident among different doses of omega-3 fatty acids and dose effect of marine oil supplements was evident across the studies.

Hanninen et al. compared 5 fish diets 67. No significant effect on total cholesterol was seen with any diet and there was no dose effect based on frequency of fish consumption.

Among subjects on a higher fat diet, there was no clear difference in effect based on source of EPA+DHA among men studied by Mori et al. 71. Despite an apparent larger net increase in total cholesterol among subjects consuming both fish oil margarine and fish oil supplements compared to those consuming only fish oil margarine or rapeseed and linseed margarine, Finnegan et al. found no differences in effect among the treatments 53.

The 4 studies of ALA all reported net increases in total cholesterol, but there was no apparent difference compared to fish and fish oil studies.

Exposure Duration

In 7 studies, total cholesterol levels varied by similar amounts in treatment and control arms at multiple time points 49, 53, 67, 69, 73, 75, 77. No differences in effect were seen at times ranging from 5 weeks to 2 years. No effect across studies is evident based on duration of intervention or exposure.

Sustainment of Effect

No study reported data on an effect after ceasing omega-3 fatty acid treatment.

Lipids: Low Density Lipoprotein (Table 3.3)

Among the lipids commonly measured, the level of low density lipoprotein (LDL) is generally of most concern when determining CVD risk and whether to initiate therapy. The NCEP guidelines note that the relationship between LDL levels and CVD risk is continuous over a broad range of LDL levels from low to high 59. Recommended goals for LDL level depend on an individual's CVD risk factors. Risk factors include diabetes, smoking, hypertension, family history of premature CVD, and being beyond middle age. With no or one risk factor, LDL goal is less than 160 mg/dL; with 2 or more risk factors, LDL goal is less than 130 mg/dL. People who already have CVD or who have diabetes are recommended to achieve an LDL of less than 100 mg/dL. As with total cholesterol, of interest is whether consuming omega-3 fatty acids as part of a therapeutic lifestyle change would improve LDL levels, or at least would not be detrimental.

Table 3.3 Effects of omega-3 fatty acids on low density lipoprotein (mg/dL) in randomized trials (6 weeks to 2 years).

Table

Table 3.3 Effects of omega-3 fatty acids on low density lipoprotein (mg/dL) in randomized trials (6 weeks to 2 years).

Of the 25 randomized trials with lipid data for at least 60 subjects in parallel trials and 40 subjects in crossover trials who consumed omega-3 fatty acids 15 reported data on LDL (See Table 3.1).

Overall Effect 48, 49, 52, 53, 60, 63–66 68–71 76, 79

The effect of omega-3 fatty acid consumption was fairly uniform across studies. Most found a net increase in LDL with treatment, although the range of effects varied substantially. Most studies found net increases of LDL of 10 mg/dL or less, although the complete range of mean net effects was a decrease of 19 mg/dL to an increase of 21 mg/dL. As with a number of other outcomes, Singh et al. found a discordant result 76. In this case, they reported a large, highly significant reduction in LDL with an Indo-Mediterranean diet in subjects at risk for CVD. However, as previously noted, this study found a difference in weight loss between the 2 interventions and reported uniform highly significant effects on all serum markers despite widely ranging effects; also, a number of statistical calculation errors were found.

Sub-populations

Only a single study included generally healthy subjects and no study included exclusively diabetics. Most of the studies included subjects with CVD. There was no clear difference among the 10 studies of CVD populations compared to the 3 dyslipidemia studies or single study of healthy subjects.

Covariates

No subgroup analyses based on covariates were reported. Two studies performed regressions. Bairati et al. reported that the effect of fish oil supplements on LDL (a net increase) was reduced and became borderline non-significant (P = .06) after adjusting for age, sex, baseline lipid level, lipid treatment, body mass index and alcohol use 60. Mori et al. performed a regression adjusting for change in weight and found a highly significant “group effect” increase in LDL with omega-3 fatty acids (P < .001) 71. In contrast to their findings for total cholesterol, they reported similar effects on LDL among subjects on a 40% fat diet and on a 30% fat diet.

Dose and Source Effect

Mori et al. found no difference in effect among men consuming various doses of EPA+DHA either as supplements or as dietary fish 71. Finnegan et al. noted a particularly large increase in LDL in the fish oil margarine/fish oil supplement arm compared to other arms, but the differences were not statistically significant 53. Grimsgaard found no difference in effect on LDL level between purified EPA and purified DHA 66.

The 2 studies of ALA reported smaller net changes in LDL, but it is not clear that this represents a real difference in effect.

Exposure Duration

In 3 studies, LDL levels varied by similar amounts in treatment and control arms at multiple time points 49, 53, 69. No differences in effect were seen at times ranging from 8 weeks to 2 years. No effect across studies is evident based on duration of intervention or exposure.

Sustainment of Effect

No study reported data on an effect after ceasing omega-3 fatty acid treatment.

Lipids: High Density Lipoprotein (Table 3.4)

High density lipoprotein (HDL) plays a primary function in removing lipids from the bloodstream to be processed in the liver. Therefore, people with reduced levels of HDL are at increased risk of CVD independent of LDL or Tg levels. The new NCEP guidelines categorize an HDL level of less than 40 mg/dL as low, implying an increased risk of CVD 59. Commonly used and well-tolerated drugs for dyslipidemia generally have at most a modest effect on HDL levels. Lifestyle changes, including physical exercise and low saturated fat diets are generally recommended to help increase HDL. Of interest is whether consuming omega-3 fatty acids as part of a therapeutic lifestyle change would help improve HDL levels, or at least that it would not be detrimental.

Table 3.4 Effects of omega-3 fatty acids on high density lipoprotein (mg/dL) in randomized trials (6 weeks to 2 years).

Table

Table 3.4 Effects of omega-3 fatty acids on high density lipoprotein (mg/dL) in randomized trials (6 weeks to 2 years).

Of the 25 randomized trials with lipid data for at least 60 subjects in parallel trials and 40 subjects in crossover trials who consumed omega-3 fatty acids 19 reported data on HDL (See Table 3.1).

Overall Effect 48, 49, 52, 53, 60, 62–66 68–71 73–76 79

The effect of omega-3 fatty acid consumption was generally consistent across the 19 studies. Most found a small net increase in HDL with treatment of up to 3 to 5 mg/dL, although 7 found a small net decrease or no effect in at least one tested study arm. Six of the studies reported that the net increase in HDL was statistically significant.

Sub-populations

Across studies, there is no clear difference in effect among the 11 studies of CVD populations, the 4 studies of dyslipidemic patients, the 3 studies of healthy subjects, or the study of Indians at increased risk of CVD. No study included only diabetic patients.

Covariates

No subgroup analyses based on covariates were reported. Two studies performed regressions. Bairati et al. reported that the effect of fish oil supplements on HDL (a net increase) was reduced and became borderline non-significant (P = .06) after adjusting for age, sex, baseline lipid level, lipid treatment, body mass index and alcohol use 60. Mori et al. performed a regression adjusting for change in weight and found a highly significant “group effect” increase in HDL with omega-3 fatty acids (P < .001) 71. In contrast with their findings for total cholesterol, they reported similar effects on HDL among subjects on a 40% fat diet and those on a 30% fat diet.

Dose and Source Effect

Three studies compared different sources - and doses - of marine oil supplements 62, 66, 74. Grimsgaard et al. found a small difference in effect between purified EPA and DHA, but the net increase in HDL was significantly larger in men consuming DHA than those consuming EPA 66. In studies by Brox et al. and Osterud et al., somewhat different net effects were seen with the different types of oils; however, neither study reported on whether the oils differed from each other on their effect on HDL 62, 74. No dose effect of marine oil supplements was evident across the studies.

Mori et al. found no difference in effect among men consuming various doses of EPA+DHA either as supplements or as dietary fish 71. All doses and sources of omega-3 fatty acids resulted in significant increases in HDL. Finnegan et al. reported no difference in effect with different omega-3 fatty acid treatments 53.

Only 2 studies tested ALA supplementation, with minimal effect.

Exposure Duration

Five studies reported data on time trends of HDL levels. Leng et al., de Lorgeril et al. and Finnegan et al. reported no difference in HDL levels at multiple time periods between 8 weeks and 2 years. 49, 53, 69. In contrast, Nilsen et al. reported a steady increase in HDL in patients with recent myocardial infarctions who started fish oil supplements at 6 weeks (+8%), 6 months (+14%), and 12 months (+19%); patients on corn oil had variable HDL levels (-0.3%, +4%, and +7%, respectively). Sacks et al. reported that HDL levels were unchanged at 3 months in healthy subjects taking fish oil supplements compared to control - decreasing by about 1.5 mg/dL in both - but that HDL returned to baseline at 6 months, resulting in a small net difference compared to control. No clear effect across studies is evident based on duration of intervention or exposure.

Sustainment of Effect

No study reported data on an effect after ceasing omega-3 fatty acid treatment.

Lipids: Triglycerides (Table 3.5, Figures 3.1 and 3.2)

Elevated levels of triglycerides (Tg) are increasingly being recognized as a risk factor for CVD, independent of other serum lipids. Elevated Tg are most frequently seen in patients with the metabolic syndrome, although various secondary and genetic factors can raise Tg. The recent NCEP guidelines recommend a goal for fasting Tg of less than 150 mg/dL 59. Fish oil's ability to lower Tg is considered one of the leading mechanisms by which omega-3 fatty acid consumption lowers CVD risk 80.

Table 3.5 Effects of omega-3 fatty acids on triglycerides (mg/dL) in randomized trials (6 weeks to 2 years).

Table

Table 3.5 Effects of omega-3 fatty acids on triglycerides (mg/dL) in randomized trials (6 weeks to 2 years).

Of the 25 randomized trials with lipid data for at least 60 subjects in parallel trials and 40 subjects in crossover trials who consumed omega-3 fatty acids 19 reported data on Tg (See Table 3.1).

Overall Effect 48, 49, 52, 53, 60, 63–68 70, 71, 73, 74, 76, 77, 79, 81

With few exceptions, Tg levels in the 19 studies decreased by substantial amounts in subjects taking omega-3 fatty acids, both in absolute amount and compared to control groups. The changes in Tg were generally highly significant.

Sub-populations

The 3 studies of healthy subjects, whose mean Tg levels were normal, generally found net decreases in Tg levels of about 10% to 25%. Eleven studies included subjects with a variety of types of CVD, all with mean Tg levels above 150 mg/dL. With the exception of Maresta et al., the 11 studies reported net decreases in Tg of between about 10% to 30%, most of which were statistically significant 81. There was no obvious difference between the study by Maresta et al. of patients undergoing PTCA and other studies to explain the discordant finding.

Two studies evaluated subjects at increased risk of CVD with different sets of treatments. Both of these studies found large, significant reductions in Tg. Two of 3 studies of dyslipidemic patients reported large net decreases in Tg of 20% or 33%. Finnegan et al., in a study of moderately hyperlipidemic patients, found different effects of omega-3 fatty acid consumption on Tg depending on dose and source 53. No study evaluated a population of only diabetic subjects.

Covariates

Nilsen et al. found similar decreases in Tg among men and women, where the difference in significance level can be ascribed mostly to sample size 73. Two studies that performed regressions both found no substantial change in the significant Tg reduction after adjusting for age, sex, baseline lipid level, lipid treatment, body mass index and alcohol use 60 or change in weight 71. Grimsgaard et al. reported the effect of purified EPA and DHA on Tg in quartiles of baseline Tg 66. While the authors did not discuss whether the effect of omega-3 fatty acids was associated with baseline Tg level, there does appear to be a trend toward greater reduction of Tg in subjects with higher baseline Tg. Those in the lowest quartile had a net reduction of approximately 7 mg/dL (10 – 14%); those in the middle two quartiles had net reductions of between 15 mg/dL and 27 mg/dL (14 – 30%); and those in the highest quartile (128 mg/dL – 319 mg/dL) had net decreases in Tg of about 50 mg/dL (about 28%). Across studies, the average net decrease in Tg level was larger in studies with higher mean baseline levels, as indicated by Figure 3.1, in which the meta-regression is not adjusted for dose of omega-3 fatty acid or study size. After adjusting for dose and the study variance, the association across studies remains statistically significant. In a separate analysis comparing different percentages of fat in the diet, Mori et al. also found nearly identical effects in subjects on 30% or 40% fat diets who were consuming similar amounts of omega-3 fatty acids 71.

Figure 3.1 Meta-regression of baseline triglyceride (Tg) level versus net change in Tg. Each point represents an individual study or study arm. Marine oils include non-fish animal sources including Minke whale and seal. Regression not adjusted for dose of omega-3 fatty acid or study size.

Figure

Figure 3.1 Meta-regression of baseline triglyceride (Tg) level versus net change in Tg. Each point represents an individual study or study arm. Marine oils include non-fish animal sources including Minke whale and seal. Regression not adjusted for dose (more...)

Dose and Source Effect

The 4 studies that compared different doses of marine oil supplements found that the greatest net decrease in Tg level occurred in study arms receiving the highest dose of EPA+DHA, although none of the articles reported whether there was a significant trend within the study. Across studies there was a clear trend toward greater percent decrease in Tg with higher doses, regardless of source (Figure 3.2). At least a 10% reduction in Tg was found in most studies with doses of at least 1.7 g per day of marine oil supplementation. Most study arms with doses of at least 3 g per day of marine oil supplements resulted in at least a 20% reduction in Tg. Among the studies of dietary fish, only the 2 arms with high omega-3 fatty acid fish diets in Mori, et al. achieved at least a 20% reduction of Tg 71.

Figure 3.2 Meta-regression of dose of EPA + DHA intake versus net change in triglycerides (Tg.). Each point represents an individual study or study arm. Separate simple regressions were performed for each oil source type (except for the individual stydy arm of combined fish and fish oil). Marine oils includes non-fish animal sources including Minke whale and seal. Regression not adjusted for baseline Tg or study size.

Figure

Figure 3.2 Meta-regression of dose of EPA + DHA intake versus net change in triglycerides (Tg.). Each point represents an individual study or study arm. Separate simple regressions were performed for each oil source type (except for the individual stydy (more...)

Grimsgaard et al., overall, found no difference in effect between purified EPA and purified DHA, although the net decreases in Tg were consistently greater in the DHA group than in the EPA group across quartiles of baseline Tg 66. Across studies, and within the Mori et al. study 71, the source of the EPA+DHA, whether as a supplement or from dietary fish, does not appear to make a difference. In contrast, the effect of ALA is uncertain. The single study that evaluated pure ALA supplementation, Finnegan et al., found increases in Tg levels in subjects on both 4.5 g and 9.5 g per day of ALA margarine (the latter dose is not included in the summary table) 53. Both Singh et al. and de Lorgeril et al. provided ALA in the context of a Mediterranean diet, which also included higher dietary fish intake 49, 76.

Exposure Duration

The effect of duration of intervention or exposure was somewhat inconsistent among the 4 studies that reported data on Tg levels at different time points in studies of omega-3 fatty acids. Hanninen et al. found progressive decreases of Tg at 5 and 12 weeks in group of subjects consuming higher amounts of fish 67. Similarly, Nilsen et al found progressive decreases in men, but not in a small group of women, at 6 weeks, 6 months and 12 months 73. Sirtori et al. found that the effect of lower dose fish oil supplementation to reduce Tg occurred by 2 months and remained stable at 4 and 6 months 77. In contrast, Finnegan et al. reported a significant decrease (15%) in mean Tg levels after 2 months which was not sustained at 6 months in the EPA+DHA arms 53. Across studies, there is no apparent correlation between study duration and fish oil supplement effect, even after grouping studies by fish oil dosage.

Sustainment of Effect

No study reported data on an effect after ceasing omega-3 fatty acid treatment.

Lipoprotein(a) (Table 3.6)

Lipoprotein(a) [Lp(a)] consists of an LDL core covalently bound to a plasminogen-like glycoprotein, apolipoprotein(a) 82. Elevated levels of Lp(a) are an independent risk factor for atherosclerotic disease, possibly by promoting thrombosis. Lp(a) levels are largely determined by genetic polymorphism, specifically the number of K-IV repeats. Steroid hormones, and thus menopause, affect levels. There is a very large range of Lp(a) levels, from less than 0.1 mg/dL to more than 300 mg/dL and the distribution can be highly skewed. Treatments available to lower Lp(a) levels include niacin and hormone replacement therapy (in post-menopausal women).

Table 3.6 Effects of omega-3 fatty acids on lipoprotein (a) (mg/dL) in randomized trials (4 weeks to 14 months).

Table

Table 3.6 Effects of omega-3 fatty acids on lipoprotein (a) (mg/dL) in randomized trials (4 weeks to 14 months).

We found 23 studies that met eligibility criteria and reported data on the effect of omega-3 fatty acids on Lp(a) levels (See Table 3.1). Of these, we analyzed the 14 randomized trials. All but 2 were parallel trials. The source of fatty acids was marine oil supplements in 12 studies, dietary fish in 1 study and Mediterranean diet in 1 study.

Overall Effect 49, 55, 58, 62, 83–92

Across the 14 studies there is no consistent effect on Lp(a) levels of omega-3 fatty acid consumption compared to control. In approximately one-third of the studies the omega-3 fatty acid study arms had a net increase in Lp(a) level compared to control; in the remaining studies the net decrease in Lp(a) level was generally small and non-significant. Only 2 studies reported a statistically significant difference between the effect of omega-3 fatty acid and control, both of which found a net decrease in Lp(a). However, the variability of Lp(a) levels among subjects within all the studies resulted in wide confidence intervals which limited the likelihood of statistically significant findings.

Sub-populations

The 5 studies that evaluated generally healthy subjects found no consistent effect of omega-3 fatty acids on Lp(a). Marckmann et al. found a large net increase of Lp(a) with fish oil supplement use and Deslypere et al. found a large net increase of Lp(a) in 1 of 3 treatment arms 85, 89. The remaining studies (and study arms) reported generally small effects, which were not uniform in direction. Five studies evaluated subjects with known CVD, one of which included only patients with hypertriglyceridemia on simvastatin. The apparent large decrease in Lp(a) in the latter study, Durrington et al., occurred because the median Lp(a) level rose by less in the fish oil supplement group than the corn oil group 86. Again no consistent effect was seen. In the only study of diabetic subjects, Luo et al. found a statistically significant net reduction of Lp(a) of about 20% with fish oil supplementation 88. The 4 studies of subjects with dyslipidemia (including the one with subjects with CVD on simvastatin) all found that subjects on marine oil supplements had a net decrease in Lp(a) compared to control; however, none of the changes was significant.

Eritsland et al. found that the effect on Lp(a) was not related to age or sex 87. The 2 studies that excluded pre-menopausal women both found small, non-significant, net reductions in mean Lp(a) with fish oil supplements or fish diet 58, 83. The 4 studies of men generally found small, non-significant, net increases in Lp(a) 84, 85, 89, 91. No study included only women.

Covariates

As shown in the summary table, Eritsland et al. found a differential effect of omega-3 fatty acids based on baseline Lp(a) level in patients referred for coronary artery bypass graft surgery 87. Those with Lp(a) in the upper quintile (≥ 20 mg/dL) had a small but significant absolute and net reduction in Lp(a), while the remaining subjects did not. A similar comparison between subjects with elevated baseline Tg (≥ 245 mg/dL) and those with lower Tg found no difference in effect.

Dose and Source Effect

Only 2 studies directly compared different doses of fish oil supplements or different oils. Deslypere et al. reported no effect on Lp(a) at any of 3 doses of fish oil supplements, although the mean Lp(a) level rose by almost 50% after 1 year in subjects on the highest dose 85. Brox et al. found no difference between similar doses of cod liver oil and seal oil supplements 62. Across studies no differences could be discerned based on marine oil dose or omega-3 fatty acid-rich diet.

Exposure Duration

Two studies reported Lp(a) data at different time periods. de Lorgeril et al. found no difference in effect on Lp(a) at 8, 52, and 104 weeks in a study of Mediterranean diet 49. Prisco et al. also found no difference in effect at 2 and 4 months in a study of fish oil supplements 91. Across studies there is no apparent relationship between effect and duration of intervention or exposure.

Sustainment of Effect

Both Prisco et al. and Deslypere et al. reported no difference between Lp(a) levels while subjects were on fish oil supplements and at multiple time points up to 6 months after stopping supplementation 85, 91.

Apolipoprotein A-I (Table 3.7)

Apolipoprotein A-I (apo A-I) is the major apolipoprotein of HDL. It serves as a cofactor for enzymes that metabolize HDL in plasma. Apo A-I levels are strongly correlated with HDL cholesterol levels, but ratios of HDL to apo A-I do vary. While the effect of omega-3 fatty acids on lipoprotein-associated cholesterol and apolipoprotein assays are of interest, unlike cholesterol levels, apolipoprotein assays, which are antibody specific and are not standardized, are not as amenable to cross-study comparisons. Furthermore, there are no data to suggest that apolipoprotein levels are more predictive of CVD risk than lipoprotein cholesterol levels.

Table 3.7 Effects of omega-3 fatty Acids on apolipoprotein A-I (mg/dL) in randomized trials (4 weeks to 2 years).

Table

Table 3.7 Effects of omega-3 fatty Acids on apolipoprotein A-I (mg/dL) in randomized trials (4 weeks to 2 years).

We found 61 studies that met eligibility criteria and reported data on the effect of omega-3 fatty acids on apo A-I levels (See Table 3.1). Of these, we analyzed the 27 randomized trials with data on at least 20 subjects in parallel trials and 15 subjects in crossover trials who consumed omega-3 fatty acids.

Overall Effect 48, 49, 52, 62, 66, 67, 85, 86, 88, 89, 93–109

Across the 27 studies, effects of omega-3 fatty acids on apo A-I levels were generally heterogeneous but small. Most studies found a small net change in apo A-I with omega-3 fatty acid consumption. Three-quarters of studies found net changes between -5% and +5% (-7 to +10 mg/dL). No study found a large net increase in apo A-I level. A small number of studies found larger net decreases of up to 18% reductions (-33 mg/dL).

Sub-populations

Eight studies evaluated healthy people, all single-sex groups (7 male66, 85, 89, 95, 97, 100, 110, 1 female96), mostly of university students. Four studies evaluated diabetic patients. Thirteen studies evaluated patients with dyslipidemia, 2 of which were also of patients with CVD. There was one additional study of patients with CVD. There were no clear patterns of treatment effect or differences in effect among the sub-populations.

Covariates

Silva et al. reported that sex, body mass index, hypertension, and non-insulin dependent diabetes did not affect the fish oil or soya oil supplement effect on lipid parameters including apo A-I in hyperlipidemic subjects 107. No other study evaluated correlations or sub-analyses based on apo A-I. Agren et al. (1988) compared the effect of daily fish with daily fish with a low saturated fat diet in male university students 95. Among subjects on a fish and low saturated fat diet, apo A-I levels remained essentially unchanged compared to those on a regular diet. In contrast, subjects on a fish diet who were not told to lower their saturated fat intake had a significant net decrease in apo A-I that was among the largest net decreases across studies. However, no comparison was made between the 2 treatment groups, nor were any explanations for the difference examined or discussed. Three studies compared fish oil to placebo oil supplements in dyslipidemic patients who were all taking either atorvastatin or simvastatin 98, 99, 106. The effects of fish oil supplementation on apo A-I were small in all 3 studies. The effects were not uniform in direction.

Dose and Source Effect

Neither Deslypere et al. nor Hanninen et al. reported a dose dependent effect on apo A-I of either fish oil supplements or different frequencies of fish meals 67, 85. No dose effect was seen across studies of EPA+DHA either.

Five studies compared different sources of omega-3 fatty acids. Grimsgaard et al. found a small but significant net decrease in apo A-I with purified EPA compared to a smaller, non-significant, net increase with purified DHA; the difference between the 2 omega-3 fatty acids was statistically significant (P = .008) 66. Brox et al. compared 2 sources of marine oil supplements: cod liver and seal oil 62. No effect was found with either treatment. Cobiac et al. found no treatment effect with either fish oil supplementation or with a fatty fish diet 100. Silva et al. found similarly large, significant reductions in apo A-I level in subjects taking either fish oil or soya oil supplements; however, no non-omega-3 fatty acid was used as a control 107. Agren et al. (1996) compared fish oil supplementation, algae DHA oil supplementation, and fatty fish diet and also found no difference in effect on apo A-I among the groups 97.

Exposure Duration

Two studies reported apo A-I levels at multiple time points. Neither Hanninen et al. nor de Lorgeril et al. found any time-related effects of omega-3 fatty acids on apo A-I, at 5 and 12 weeks, and 8, 52, and 104 weeks, respectively 49, 67.

Sustainment of Effect

Three studies followed subjects after stopping the intervention. Jensen et al. and Deslypere et al. found no change in apo A-I levels 8 weeks and 6 months, respectively, after stopping fish oil supplements 85, 103. In contrast, Agren et al. (1988) reported that 5 months after a 15 week trial of dietary fish apo A-I levels remained at lowered levels in the fish diet group who had no limitation of saturated fat; however, they do not indicate what these students' diets were at subsequent follow-up 95.

Apolipoprotein B, Apolipoprotein B-100, and LDL Apolipoprotein B (Tables 3.8 and 3.9)

Apolipoprotein (apo) B has 2 major subtypes, B-100 and B-48. Apo B-100 is associated with lipoprotein particles of hepatic origin, specifically very low, intermediate, and low density lipoproteins (VLDL, IDL, LDL). Its major function is to serve as a ligand for the receptor that clears these particles from the bloodstream. During the conversion of VLDL to LDL in the circulation, only apo B-100 remains on LDL. Measures of LDL apo B represent the portion of total blood apoB-100 that is associated with the LDL subfraction. There is 1 apo B-100 molecule per LDL particle. A discordance in LDL apoB-100 and LDL cholesterol levels implies a change in the composition of the LDL particle. Total apo B is thus indicative of VLDL, IDL and LDL levels, while apo B-100 and LDL apo B are indicative specifically of LDL levels. While the effect of omega-3 fatty acids on lipoprotein-associated cholesterol and apolipoprotein assays are of interest, unlike cholesterol levels, apolipoprotein assays, which are antibody specific and are not standardized, are not as amenable to cross-study comparisons. Furthermore, there are no data to suggest that apolipoprotein levels are more predictive of CVD risk than lipoprotein cholesterol levels.

We found 52 studies that met eligibility criteria and reported data on the effect of omega-3 fatty acids on total apo B levels, and 11 studies that reported data on either apo B-100 or LDL apo B (See Table 3.1). Of these, we analyzed the 25 randomized trials of apo B that had data on at least 20 subjects in parallel trials and 10 subjects in crossover trials who consumed omega-3 fatty acids. We also analyzed the 10 studies of apo B-100 or LDL apo B, all of which were randomized.

Overall Effect

Total apo B ( Table 3.8 ) 48, 49, 53, 66, 67, 71, 85, 86, 88–90, 93, 95–101, 103–106, 108, 109. Across the 25 studies, we found little consistency in the effect of omega-3 fatty acids on apo B levels. About half the studies found a small net increase and half a small net decrease in apo B levels. Only 2 studies found significant changes in individual study arms, but Deslypere et al. found a significant decrease and Mori et al. found a significant increase 71, 85.

Table 3.8 Effects of omega-3 fatty acids on apolipoprotein B (mg/dL) in randomized trials (4 weeks to 2 years).

Table

Table 3.8 Effects of omega-3 fatty acids on apolipoprotein B (mg/dL) in randomized trials (4 weeks to 2 years).

Apo B-100 ( Table 3.9 , top) 50, 52, 62, 107 and LDL apo B ( Table 3.9 , bottom) 93, 94, 108, 111–113. The 4 studies of apo B-100 found a range of effects with omega-3 fatty acid consumption. Two found a decreases in level of less than 5%; the other 2 studies found net increases of 2% and 15%. In contrast, large, significant net increases in LDL apo B were found in 4 of 6 studies (20 to 45 mg/dL).

Table 3.9 Effects of omega-3 fatty acids on apolipoprotein B-100 and LDL apolipoprotein B (mg/dL) in randomized trials (1 month to 14 months).

Table

Table 3.9 Effects of omega-3 fatty acids on apolipoprotein B-100 and LDL apolipoprotein B (mg/dL) in randomized trials (1 month to 14 months).

Sub-populations

Total apo B. The heterogeneity of effects seen across all studies is apparent among the 10 studies of healthy populations (8 of which were in men66, 67, 71, 85, 89, 95, 97, 100 and one of which was in women96), the 10 studies of dyslipidemic populations (subjects in 2 of which also had CVD), and the 3 studies of CVD populations (including those studies with subjects with dyslipidemia). The 4 studies of diabetics, one of which included insulin-dependent diabetics, all found small, non-significant, net increases in total apo B.

Apo B-100 and LDL apo B. The 2 apo B-100 studies of dyslipidemic patients reported small net decreases in apo B-100, while the study of patients undergoing coronary bypass surgery showed a small net increase and the study of healthy, male college students found a larger net increase in apo B-100. The 5 LDL apo B studies of dyslipidemic or diabetic subjects found generally large increases in LDL apo B, while the single study of hypertensive subjects showed a small net decrease.

Covariates

Total apo B. Nenseter et al. performed a subanalysis based on age of the effect of a low-omega-3 fatty acid fish powder 90. Subjects between ages 30 and 52 years had a significantly greater rise in apo B level compared to subjects 53 to 70 years old; furthermore age negatively correlated with the rise in apo B (r = -0.40, P < .04). The authors also imply that the effect was not correlated with sex. Mori et al. performed a regression adjusting for change in weight and found a highly significant “group effect” increase in apo B with omega-3 fatty acids (P<.01) 71. Agren et al. (1988), in a study of male university students, found no difference in effect between 2 fish diets that differed in the amount of low saturated fats 95. Three studies compared fish oil to placebo oil supplements in dyslipidemic patients who were all taking either atorvastatin or simvastatin 98, 99, 106. The effects of fish oil supplements on apo B were small in all. They were not uniform in direction.

Apo B-100 and LDL apo B. Silva et al. reported that any effect of fish oil and soya oil supplements on apo B was not correlated with sex, BMI, hypertension, or diabetes in hyperlipidemic patients 107. Schectman et al. found that changes in LDL apo B did not correlate with baseline differences in diet or with individual changes in diet or body weight 93. Other studies did not correlate findings with possible covariates. The small number of studies limits hypothesis generating of possible effect mediators across studies.

Dose and Source Effect

Total apo B. Among studies of fish oil supplements, Deslypere et al. found a significant net decrease in apo B in subjects on the highest dose of omega-3 fatty acids but smaller non-significant net decreases with smaller doses 85. Among the individual study arms, apo B levels fell in the arm with a higher dose of fish oil but rose in the lower dose arms (and the olive oil arm). No dose effect was seen across fish oil supplement studies. Among studies of dietary fish, Hanninen et al. reported a trend in effect related to different frequencies of fish meals 67. Subjects most frequently consuming fish had the largest, significant reduction in apo B (compared to baseline). Subjects with intermediate frequencies of fish consumptions (average of 1.5 and 2.3 meals per week) had smaller reductions in apo B with P values (compared to baseline) of less than .10. Subjects on only about 1 fish meal per week had a non-significant increase in apo B.

Five studies compared different sources of omega-3 fatty acids. Grimsgaard et al. found no difference in effect between purified EPA and purified DHA 66. Mori et al. compared a variety of doses of fish oil supplements and combinations of dietary fish and supplemental fish oil, along with higher and lower percentage fat diets 71. Overall, significant net increases in apo B were seen in the subjects who consumed fish oil supplements and were on non-fish diets, but smaller, non-significant increases were seen in the subjects who were on fish diets, regardless of fish oil supplementation or percent fat in the diet. Cobiac et al. similarly found that subjects on fish oil supplement had a net increase in apo B while those on dietary fish had almost no change 100. While neither change was statistically significant, there was a trend toward a difference between the 2 treatments (P = .10). In contrast, Agren et al. (1996) reported small non-significant net reductions in apo B with fish oil and algae DHA oil supplementation and no effect with fatty fish diet; although they do not comment on potential differences between groups 97. Finally, Finnegan et al. reported no effects on apo B and no differences among people consuming different omega-3 fatty acids from margarine and/or supplements 53.

Apo B-100 and LDL apo B. Neither Brox et al. nor Silva et al. found a difference in effect of different omega-3 fatty acids on apo B-100 levels 62, 107. Radack et al. (1990) found a similar large increase in LDL apo B in 2 groups of hypertriglyceridemic patients consuming different doses of fish oil supplements 113. While the increase was greater in the group consuming a higher dose of fish oil, no analysis was done to compare the effect in the 2 arms.

Exposure Duration

Total apo B. While the authors do not describe an effect of duration of fish consumption, the data at 5 and 12 weeks in Hanninen et al. may suggest that any effects of dietary fish on apo B do not occur until after 5 weeks 67. At 5 weeks there were essentially no changes in apo B in any of the study arms, compared to significant and near significant reductions in arms with more frequent fish consumption. In de Lorgeril et al. a Mediterranean and ALA margarine diet had no effect on apo B at 8 weeks, 1 year, and 2 years.

Apo B-100 and LDL apo B. In their study of apo B-100, DeLany et al. found that while there was no difference in effect between 5 g fish oil supplementation and no oil at 5 weeks, there was a significant increase over time at 0, 2, and 5 weeks in subjects on fish oil supplements 50. However, this analysis included 5 subjects who took 20 g fish oil supplements. There was also a small increase in apo B-100 levels in subjects not consuming oil supplements. Radack et al. (1990) reported no change in LDL apo B level between measurements at 8, 12, and 20 weeks 113.

Sustainment of Effect

Total apo B. Three studies followed subjects after stopping the intervention. Both Jensen et al. and Agren et al. (1988) found no change in apo B levels 8 weeks and 5 months, respectively, after stopping fish oil supplements 95, 103. Deslypere et al. found that 6 months after stopping supplements apo B levels rose to similar levels in all groups except those who had been on the lowest dose fish oil, although no analysis was performed on follow-up data 85.

Apo B-100 and LDL apo B. Although Radack et al. (1990) measured LDL apo B levels 4 weeks after stopping treatment 113, no study reported whether changes in apo B-100 or LDL apo B levels were sustained.

Blood Pressure (Tables 3.10 and 3.11)

Hypertension is a well-known risk factor for atherosclerosis and cardiovascular disease. Recently the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) noted that the relationship between blood pressure and risk of cardiovascular events is continuous, consistent and independent of other factors.25 The benefits to lowering blood pressure are evident even in people with “pre-hypertension” (blood pressure of 120–139/80–89).

We found 103 studies that met eligibility criteria and reported data on the effect of omega-3 fatty acids on blood pressure (See Table 3.1). In addition, we found a recent systematic review with a meta-regression of the blood pressure response to fish oil supplementation 114. This thorough review touched on most of the major questions addressed by the current report, therefore this section relies primarily on the findings of Geleijnse et al. However, they explicitly excluded studies of diabetic patients. Therefore, we analyzed the 6 randomized trials with data on blood pressure in diabetic patients that had a minimum of 15 patients in parallel trials and 10 patients in crossover trials who consumed omega-3 fatty acids.

Meta-Regression 114

Geleijnse et al. collected trials of fish oil supplementation and blood pressure through March 2001. Eligibility criteria were: (1) randomized design, (2) adult study population, and (3) publication after 1966. Trials were excluded if they included sick or hospitalized patients, including kidney disease and diabetic patients, or if the intervention was shorter than 2 weeks duration. A total of 36 trials with 50 omega-3 fatty acid study arms were analyzed. Of note, 6 of these studies did not meet our eligibility due to high omega-3 fatty acid dose (3), short washout period in crossover trial (2), or short study duration (1).

The range of trial duration was 3 to 52 weeks and doses of omega-3 fatty acids were less than 1.0 g/day in 1 trial, 1.0 to 1.9 g/day in 5 trials, 2.0 to 2.9 g/day in 4 trials, and 3.0 to 15.0 g/day in 26 trials.

The mean net reduction (controlling for placebo arms) in systolic and diastolic blood pressure, weighted for study size, was -2.1 mm Hg (95% confidence interval -3.2, -1.0) and -1.6 mm Hg (-2.2, -1.0), respectively. The mean reductions in systolic and diastolic blood pressures were somewhat smaller in the 22 double blinded studies. Data on univariate and multivariate weighted meta-regression analyses performed on study subgroups based on mean age, sex, mean baseline blood pressure, and mean body mass index are reported. Briefly, systolic and diastolic blood pressure reductions were significantly larger in older (mean age ≥ 45 years) than younger populations, and in hypertensive (blood pressure ≥ 140/90 mm Hg) compared to normotensive populations. A lack of studies in women precluded adequate analysis based on sex. Body mass index was not associated with blood pressure response to fish oil supplementation. In addition, trial duration and fish oil dose were not associated with effect.

Overall Effect in Diabetes Studies 115–120

Across the 6 studies of diabetic patients, there were generally small, non-significant effects of fish oil supplements on systolic (Table 3.10) and diastolic (Table 3.11) blood pressure. Overall, these study results were similar to the findings of the meta-regression among non-diabetic populations in their small, but generally inconsistent net effects. One study reported a small significant reduction in mean diastolic pressure (-2 mm Hg) and 2 reported significant reductions in mean systolic pressure (-3 and -6 mm Hg).

Table 3.10 Effects of omega-3 fatty acids on systolic blood pressure (mm Hg) in randomized trials of diabetic subjects (6 weeks to 1 year).

Table

Table 3.10 Effects of omega-3 fatty acids on systolic blood pressure (mm Hg) in randomized trials of diabetic subjects (6 weeks to 1 year).

Table 3.11 Effects of omega-3 fatty acids on distolic blood pressure (mm Hg) in randomized trials of diabetic subjects (6 weeks to 1 year).

Table

Table 3.11 Effects of omega-3 fatty acids on distolic blood pressure (mm Hg) in randomized trials of diabetic subjects (6 weeks to 1 year).

Covariates

Haines et al., who found non-significant small net increases in blood pressure, reported that neither sex nor Hgb A1c levels were related to the effect of fish oil supplements on blood pressure 115. No study analyzed data based on age. Across studies there was no clear difference among populations with type I or type II diabetes, and there were insufficient data to comment on age, sex, menopausal status, race, weight or other variables.

Dose and Source Effect

No study compared different doses of omega-3 fatty acids. Woodman et al. compared purified EPA and purified DHA and found a net fall in mean 24 hour ambulatory systolic blood pressure in subjects on EPA and a net increase in diastolic pressure; however, there was no statistical difference between the 2 treatments 120. Across studies, there is no apparent difference in effect on systolic blood pressure based on fish oil supplement dose. However, the largest, and significant, reductions in diastolic pressure were found in the 2 studies with the smallest fish oil supplementation doses.

Exposure Duration

In 3 studies no differences in effect are noted based on duration of intervention or exposure at 3 and 6 weeks 115, 6 and 12 weeks 118, or 6 and 12 months 119.

Sustainment of Effect

No study reported blood pressures after subjects stopped treatment.

Hemoglobin A1c (Table 3.12)

Chronically elevated serum glucose levels, which occur in diabetes, result in elevated levels of glucose binding to hemoglobin. This bound product, hemoglobin A1c (Hgb A1c), or glycohemoglobin, is used to measure long-term control of diabetes.

Table 3.12 Effects of omega-3 fatty acids on hemoglobin A1c (%) in randomized trials (4 weeks to 1 year).

Table

Table 3.12 Effects of omega-3 fatty acids on hemoglobin A1c (%) in randomized trials (4 weeks to 1 year).

We found 32 studies that met eligibility criteria and reported data on the effect of omega-3 fatty acids on Hgb A1c levels (See Table 3.1). Of these, we analyzed the 18 randomized trials with data on at least 10 subjects in either parallel trials or crossover trials who consumed omega-3 fatty acids.

Overall Effect 77, 85, 88, 93, 102, 103, 106, 115, 117–126

Across the 18 studies, omega-3 fatty acids had a very small, if any, effect on Hgb A1c levels compared to control. The range of net effects across the studies was -0.4% to +1.0%. Only 1 study reported a statistically significant reduction in Hgb A1c; however, this study by Jain et al. found one of the smaller net changes of all studies 117.

Sub-populations

As expected, the large majority of studies evaluating Hgb A1c included diabetic patients. Fourteen studies analyzed diabetic populations, 3 of which were also dyslipidemic. An additional 2 studies analyzed dyslipidemic patients; 1 included patients with untreated hypertension; and 1 evaluated healthy monks.

While none of the 4 studies of dyslipidemic patients had net reductions in Hgb A1c levels, given the small differences in almost all studies, there are no clear difference in effect in the different populations, including diabetic patients.

Covariates

Schectman et al. found that the effect of fish oil supplements on Hgb A1c did not correlate with baseline differences in diet or with individual changes in diet or body weight 93. Toft et al. and Westerveld et al. reported no change in effect of fish oil supplements on Hgb A1c after adjustment for body weight 125, 126. Likewise, Haines et al reported no relationship between effect on Hgb A1c and sex 115. Three studies were notable for including only men 85, 88, or because all subjects were taking simvastatin 106. The effect found in these studies was not clearly different than that found in studies.

Dose and Source Effect

Two studies compared different doses of fish oil supplements. Deslypere et al., in a 1 year study of healthy Belgian monks, reported no difference in the effect of 3 doses of fish oil or olive oil 85. Westerveld et al. also reported no difference in the effect of 2 different doses of fish oil, purified EPA, or olive oil in non-insulin dependent diabetics 126. Across studies, there was no apparent dose effect of fish oil supplements. The only study of dietary fish found a lack of effect similar to the fish oil supplement studies. Woodman et al. compared purified EPA to DHA in type II diabetics 120. No difference was noted between the 2 treatments.

Exposure Duration

Two studies reported treatment effect at multiple time points. In Haines et al. there was a transient drop in Hgb A1c by 0.6% (0.5% net) at 3 weeks which reverted to baseline at 6 weeks 115. The change was not statistically significant. Rossing et al. found no difference in effect between 6 and 12 months 119. Across studies there was no apparent effect of treatment duration.

Sustainment of Effect

Jensen et al., in a crossover study, found that Hgb A1c remained unchanged 8 weeks after stopping oil supplementation.

Fasting Blood Sugar (Table 3.13)

Elevated fasting blood sugar (FBS) is a risk factor or indicator of diabetes. People with diabetes or with altered glucose tolerance have a highly elevated risk of CVD. As discussed in the introduction, the effect of omega-3 fatty acids on diabetic control is unclear.

Table 3.13 Effects of omega-3 fatty acids on fasting blood sugar (mg/dL) in randomized trials (4 weeks to 2 years).

Table

Table 3.13 Effects of omega-3 fatty acids on fasting blood sugar (mg/dL) in randomized trials (4 weeks to 2 years).

We found 57 studies that met eligibility criteria and reported data on the effect of omega-3 fatty acids on FBS levels (See Table 3.1). Of these, we analyzed the 17 randomized trials with data on at least 25 subjects in parallel trials and 15 subjects in crossover trials who consumed omega-3 fatty acids.

Overall Effect 52, 53, 68, 76, 77, 103, 116, 117, 120, 123, 125, 127–132

The effect of omega-3 fatty acids on FBS was inconsistent across the 17 studies. Four studies found large and/or near-significant net increases in FBS compared to control; 3 found large and/or significant net decreases in FBS and the rest found small non-significant changes. Across the studies, the net effect ranged between a decrease of 29 mg/dL over 8 weeks and an increase of 25 mg/dL over 6 weeks. Interpretation of the overall data is further complicated by inconsistent patterns of effect within individual study arms. In omega-3 fatty acid arms and in control arms, FBS increased from baseline in half the arms and either decreased or remained unchanged in the other half.

Sub-populations

Seven studies evaluated diabetic populations, 2 of which also had dyslipidemia; an additional 5 studies evaluated patients with dyslipidemia. Three studies included subjects who had CVD or were at increased risk for CVD (due to either diabetes or dyslipidemia). Two studies were of healthy populations.

The findings within the diabetic populations were inconsistent. The largest net decrease in FBS was found by Jensen et al. in the only study of insulin-dependent diabetics 103, while the largest net increase in FBS with omega-3 fatty acids was seen in Woodman et al. in one of the studies of type II diabetics 120. Furthermore in each of the 3 groups of subjects on fish oil supplements in these 2 studies, FBS rose by approximately 10 or 20 mg/dL; the large difference in net effect is due to the difference in effect of the olive oil control (+49 mg/dL and -7 mg/dL, respectively). In the remaining studies of diabetics, the change in FBS was in the same direction in omega-3 fatty acid arms and control arms; in 6 omega-3 study arms FBS rose from 10 mg/dL to 23 mg/dL; in 4 arms FBS fell from -2 mg/dL to -16 mg/dL. In studies of diabetics, factors other than omega-3 fatty acid consumption - such as those related to population characteristics, other treatments, or study design - appear to have had a greater effect on change in FBS than the omega-3 fatty acid treatment itself.

Among the 7 studies of dyslipidemic populations, 2 of which were also diabetic, all found a small non-significant net effect of omega-3 fatty acids on FBS that ranged from -4 to +5 mg/dL. Only Dunstan et al. found large changes in individual omega-3 fatty acid arms, which were related primarily to exercise level and were similar to the changes in the no fish control arms 127.

The 4 studies of CVD patients or people with an elevated risk of CVD all found small absolute and net changes in FBS with omega-3 fatty acid consumption. Only Singh et al. found a significant net change and had a relatively large absolute change (-8 mg/dL) in FBS, although notably about 20% of the subjects were diabetic, two-thirds were vegetarian, and those subjects on the Indo-Mediterranean diet on average lost 3 kg more weight than controls 76. In addition, this study reported uniform, highly significant effects on all serum markers despite widely ranging effects. A number of statistical calculation errors were also found.

The single study of a healthy population, by Freese et al., found small differences in FBS with 2 different omega-3 fatty acid treatments (in opposite directions) 128.

Covariates

Schectman et al. found that changes in FBS did not correlate with baseline differences in diet or with individual changes in diet or body weight 93. Two studies of diabetics reported data on associations between effect and other variables. Hendra et al. reported that the change in FBS was unrelated to change in weight 116. Woodman et al. reported that the significant effect compared to olive oil was unchanged after adjusting for age, sex, and BMI 120. In Mori, et al. (1999), a study of obese hypertensive subjects, the direction of the absolute and net changes in FBS appear related to whether subjects were on a weight-reduction diet or not (those on a weight maintaining diet had increases in FBS, while those on a weight-reduction diet had reductions in FBS); however, they reported no interaction between fish diet and weight loss on FBS 131. No patterns across studies are evident based on reported data on covariates.

Dose and Source Effect

No study directly compared doses of the same source of omega-3 fatty acids. In comparisons of EPA and DHA, Woodman et al. reported no difference in effect on FBS 120; however, Mori et al. (2000) reported a trend toward increasing FBS with EPA, but no change with DHA 132. Freese et al. reported a significant increase from baseline in FBS with fish oil supplementation compared to no change with linseed oil; however the difference between the 2 treatments was reported to be non-significant 128. In a comparison of multiple sources of omega-3 fatty acids, Finnegan et al. found no significant differences in effect between various doses of either fish oils or plant oils 53. Across studies, there was no discernable difference in effect based on either fish oil dose or omega-3 fatty acid source among diabetic or dyslipidemic populations.

Exposure Duration

Two studies measured FBS levels at multiple time points. Hendra et al. found that FBS rose with fish oil supplements at both 3 and 6 weeks, although the net difference with control was significant only at 3 weeks 116. In a longer study that measured FBS at 2, 4, and 6 months, Finnegan et al. found no treatment effect at any time period 53. The heterogeneity does not appear to be related to study duration.

Sustainment of Effect

Jensen et al., in a crossover study which found that FBS rose by large amounts in both the high-dose cod liver oil and olive oil supplement arms, found that FBS fell back near baseline levels 8 weeks after stopping oil supplementation, although none of the levels were significantly different from each other 103. Freese et al., who compared fish oil to linseed oil supplements, reported that FBS, which had risen in the fish oil arm, returned to baseline during a 12 week follow-up period 128.

Fasting Insulin (Table 3.14)

In people with normal glucose levels (euglycemia), elevated fasting insulin levels are suggestive of insulin resistance, a precursor to type II diabetes and an independent risk factor for CVD. The value of insulin levels in those with insulin resistance, including insulin resistance related to obesity, and diabetes (“hyperglycemia”), is questionable. The effect of omega-3 fatty acids on insulin resistance and fasting insulin levels is also unclear.

Table 3.14 Effects of omega-3 fatty acids on fasting insulin (pmol/L) in randomized trials (4 weeks to 9 months).

Table

Table 3.14 Effects of omega-3 fatty acids on fasting insulin (pmol/L) in randomized trials (4 weeks to 9 months).

We found 21 studies that met eligibility criteria and reported data on the effect of omega-3 fatty acids on fasting insulin levels (See Table 3.1). Of these, we analyzed the 15 randomized trials. All but 3 of the trials were also analyzed for data on FBS or Hgb A1c.

Overall Effect 52, 53, 68, 77, 88, 89, 106, 120, 122, 125, 129, 131–134

Baseline levels of fasting insulin varied broadly across studies. In general, studies of non-insulin-dependent diabetics and obese subjects (under “Studies of “Hyperglycemic” Subjects”) had higher mean insulin levels than dyslipidemic, hypertensive, or healthy patients (under Studies of “Euglycemic” Subjects). However, within each population grouping the range of insulin levels remained broad. Mean insulin levels varied within studies also. In 6 studies, baseline insulin levels differed between omega-3 fatty acid arms and control arms by 20% to 60%. Among these, Toft et al. reported a significant difference at baseline and Chan et al. reported no significant difference; the remaining studies did not comment 125, 133. In an attempt to standardize across studies, given the large variation in insulin levels, we calculated net differences in terms of percent change from baseline instead of absolute changes.

Across the 15 studies there were a wide range of apparent treatment effects ranging from net changes of -28% to +29% (or -22 pmol/L in Dunstan et al. 122 to +34 pmol/L in Chan et al. 133). Approximately one-third of the omega-3 fatty acid study arms had net percent changes of either greater than +10%, between -10% and +10%, or less than -10%.

Sub-populations

Nine of the studies reported data on essentially euglycemic populations. The remaining 6 studies evaluated diabetic or obese populations in which the fasting insulin level may be of less value. While the studies with hyperglycemic subjects all had elevated mean fasting insulin levels, there was a wide range of mean insulin levels in the studies of euglycemic subjects.

Among the studies of euglycemic subjects, the heterogeneity of effect was similar to the heterogeneity seen across all studies. The heterogeneity was particularly apparent among the studies of dyslipidemic patients.

Covariates

Among the studies of euglycemic subjects, Mori et al. (1999) reported no interaction between dietary fish intake and weight loss on insulin levels 131. However, a weight loss diet resulted in a reduction of insulin levels, regardless of fish consumption. In addition, there was a net decrease in insulin levels in subjects who were on a weight loss diet with fish compared to a net increase in insulin in subjects who were on a weight-maintaining diet. Otherwise, studies did not attempt to correlate the effect on insulin of covariates. The 3 studies that either included only euglycemic men 89, 132 or excluded pre-menopausal women 131 had a wide range of effects on insulin levels. Thus, no potential sex effect could be seen.

No study of hyperglycemic subjects reported a correlation between insulin and covariates. As in studies of euglycemic subjects the effects on insulin found among the 2 studies of hyperglycemic men 88, 133 and the study that excluded pre-menopausal women 120 were heterogeneous.

Dose and Source Effect

Finnegan et al. compared plant oil margarine to 2 doses of fish oil (as margarine and as both margarine and supplement) and to omega-6 fatty acid margarine 53. None of the differences in insulin levels was statistically significant and the article does not comment on the relative effects of different treatments. However, dyslipidemic subjects on ALA margarine had an absolute and net decrease in fasting insulin, while subjects on low dose fish oil had a small absolute increase in insulin that was less than the increase in the control group, and subjects on high dose fish oil had an increase in insulin similar to controls. Across the studies, the effect on insulin does not appear to be associated with fish oil dose.

Both Mori et al. (2000) and Woodman et al. compared purified EPA to DHA, although in different populations 120, 132. No difference was noted between the 2 treatments in both studies.

Exposure Duration and Sustainment of Effect

Only Finnegan et al. measured insulin levels at multiple time points 53. They reported no treatment-time interaction with insulin levels at 2, 4, and 6 months. No study measured insulin levels after ceasing omega-3 fatty acid consumption.

C-Reactive Protein (Table 3.15)

C-reactive protein (CRP) is an acute phase reactant produced in the liver. It is thought to represent an integrated assessment of the overall state of activation of the inflammatory system. Recently, a high sensitivity assay for measuring CRP has been developed that can detect levels of CRP below what was previously considered the ‘normal’ range. A growing body of studies suggest that elevations in CRP levels detected by the high sensitivity assay predict a poor cardiovascular prognosis 135.

Table 3.15 Effects of omega-3 fatty acids on C-reactive protein (mg/L) in studies (4 wk to 3 mo or cross-sectional).

Table

Table 3.15 Effects of omega-3 fatty acids on C-reactive protein (mg/L) in studies (4 wk to 3 mo or cross-sectional).

All eligible studies that reported on the effect of omega-3 fatty acids on CRP levels were included; 5 studies qualified. Four were randomized trials of oil supplements or diet; 1 was a retrospective cross-sectional analysis of usual diet.

Overall Effect 56, 99, 136–138

No study found a significant effect of omega-3 fatty acid consumption on CRP level. However, CRP levels increased relative to subjects who were on control oils in most study arms among the 4 randomized trials. In contrast, the cross-sectional study did find that CRP levels were lower among subjects who ate fish regularly (fish score >4) but the difference was not statistically significant.

Sub-populations and Covariates

No study directly compared the effect of omega-3 fatty acids with placebo in different populations. There was no clear difference in effect across studies based on population. Baseline CRP levels varied across studies; although the reason for the different CRP levels is not apparent. Madsen et al. reported that when the 11 subjects with baseline CRP greater than 2 mg/L were analyzed separately, no difference in effect was seen with fish oil supplementation (as in all subjects) 137. Likewise, the effect of omega-3 fatty acids does not appear to differ across studies based on average baseline CRP.

The trial by Chan et al. was a factorial study with fish oil supplements and atorvastatin (40 mg/day) in obese men who had a substantially higher baseline CRP than a separate group of 10 lean men (0.49 mg/L) 139. While atorvastatin did significantly reduce CRP levels (by 0.73 mg/L) there was no interaction with fish oil.

Dose and Source Effect

No study compared different sources of omega-3 fatty acids. Any differences in effect due to differing sources across studies could not be appreciated among the few studies. The cross-sectional study did not find an association between fish score (amount of fish in diet) and CRP level.

Exposure Duration

Junker et al. evaluated CRP levels at both 2 and 4 weeks. No differences were noted between baseline and either 2 or 4 weeks 56. Mezzano et al. evaluated CRP levels at 30 days and 90 days (and also at 60 days after 30 days of added red wine). CRP was unchanged at all observation points.

Sustainment of Effect

No study re-examined CRP after subjects stopped taking omega-3 fatty acids.

Fibrinogen (Table 3.16)

Fibrinogen, a liver protein necessary for clotting, has been found to be both increased in patients with ischemic heart disease and a predictor of cardiovascular events. It is unknown whether reducing fibrinogen levels would alter cardiovascular risk. In addition, there is currently no standardized measurement technique.

Table 3.16 Effects of omega-3 fatty acids on fibrinogen (g/L) in randomized trials (4 weeks to 2 years).

Table

Table 3.16 Effects of omega-3 fatty acids on fibrinogen (g/L) in randomized trials (4 weeks to 2 years).

We found 59 studies that met eligibility criteria and reported data on the effect of omega-3 fatty acids on fibrinogen levels (See Table 3.1). Of these, we analyzed the 24 randomized trials with data on at least 15 subjects in parallel trials and 10 subjects in crossover trials who consumed omega-3 fatty acids.

Overall Effect 46, 56, 69, 74, 85, 89, 90, 100, 115, 116, 138, 140–152

Across the 24 studies there was no consistent effect on fibrinogen levels of omega-3 fatty acid consumption compared to control. Approximately half the omega-3 fatty acid study arms resulted in a net increase in fibrinogen level compared to control; in the other half there was either a net decrease or no effect on fibrinogen level. Only 4 studies reported a statistically significant difference between the effect of omega-3 fatty acid and control. In 3 of these, the net decrease of fibrinogen ranged from approximately 5% to 20%. One study reported a significant net increase of fibrinogen of 11%.

Sub-populations

Thirteen of the studies evaluated generally healthy subjects. No consistent effect was found specifically in this population. Four studies evaluated subjects with known CVD: 2 studies of patients with stable claudication (Gans et al. and Leng et al.) 69, 144, one of patients who were undergoing coronary bypass (Eritsland et al.) 142, and one of subjects with hypertension (Toft et al.) 152. All 4 studies found no effect of omega-3 fatty acids on fibrinogen levels. Seven studies included subjects with diabetes and/or dyslipidemia. Again, there was no consistent effect. However, the largest (significant) net decrease in fibrinogen was found by Radack et al. in a group of 10 subjects with hyperlipoproteinemia types IIb or IV on a moderate dose of fish oil supplement 151. A significant net increase in fibrinogen was seen by Haines et al. among 19 subjects with insulin-dependent diabetes on a high dose of fish oil supplement, although the effect was not related to Hgb A1c level. 115.

In the study of patients undergoing coronary bypass, Eritsland et al. found that the (lack of) effect of omega-3 fatty acids on fibrinogen was unchanged after adjusting for multiple factors including age and sex 142. Seven studies included only men 46, 85, 100, 138, 140, 147, 149. The distribution of effects was similar in this subset of studies as in the whole set. Three of these studies of men and an one additional study included only younger adults (generally less than 30 or 40 years old) 46, 138, 140, 146. These studies had results similar to studies of broader age ranges or of older subjects. Overall, the studies provided insufficient data on race or ethnicity to allow analysis of these subpopulations. Almost half the studies were performed in Scandinavia and Finland; most of the remaining are from northern Europe and Australia. Notably the study by Radack et al., which showed the largest benefit from omega-3 fatty acids and was the only study to show a dose effect (see below), was the only study performed in the United States 151.

Covariates

Eritsland et al., Haines et al. and Toft et al. found no association of effect of omega-3 fatty acids on fibrinogen with various factors including sex, baseline and change in weight, baseline blood pressure, change in lipids or insulin, or cardiovascular, lipid or antithrombotic drug use among patients with cardiovascular disease 115, 142, 152. Mezzano et al. found no interaction of wine consumption with a Mediterranean diet in a multiphase trial 138. No differences were found among studies with run-in phases of either high- or low-fat diets. No study quantified baseline fish consumption. Radack et al. reported that the relative effect of higher dose fish oil supplements was greater with higher baseline fibrinogen values (r = -0.59, P < .01) 151.

Dose and Source Effect

Two studies compared different doses of the same omega-3 fatty acid supplements. Radack et al. found that subjects with dyslipidemia who took 6 g of fish oil supplements (2.2 g EPA+DHA) for 20 weeks had a relatively large, statistically significant net reduction in fibrinogen 151. This effect was significantly greater than in the subjects who took 3 g of fish oil (1.1 g EPA+DHA), who had no effect. Deslypere et al., however, found no difference in effect across 3 doses of fish oil supplements (3.4 g, 2.2 g, and 1.1 g EPA+DHA) in monks who took fish oils for 1 year. Across all studies the effect is not related to omega-3 fatty acid dosage.

Hansen et al. (1993a) reported a possible trend toward greater effect of fish oil ethyl esters than fish oil triglycerides 147. Osterud et al. found no difference among different marine oils 74. Two studies evaluated ALA oils. Both found no effect with dietary flaxseed oil or rapeseed oil supplements 46, 56.

Three studies compared fish oil supplements with other sources of omega-3 fatty acids 100, 140, 143. Cobiac et al. found a small significant reduction in fibrinogen only among the subjects consuming dietary fish; however the significance of the difference between the 2 treatments was not reported 100. Overall, there were no clear differences in effect of different sources of omega-3 fatty acids.

Exposure Duration

Across studies, there was no apparent effect on fibrinogen of duration of consumption of omega-3 fatty acids in studies that reported data from 2 weeks to 2 years. Seven studies reported fibrinogen levels at various time points 56, 69, 85, 115, 138, 149, 151. Although mean fibrinogen levels varied with time in most studies, no study found a difference in effect related to time.

Sustainment of Effect

Two studies, which both found no effect of omega-3 fatty acids on fibrinogen levels, reported no further change after stopping treatment. Deslypere et al. reported no difference in fibrinogen levels up to 6 months after 1 year of treatment 85. Freese et al. likewise found no difference 4 weeks after finishing 4 weeks of treatment 143.

Factor VII, Factor VIII, and von Willebrand Factor (Tables 3.17, 3.18, and 3.19)

Omega-3 fatty acids affect the clotting system in a number of ways in animal and in vitro models. Factors VII and VIII and von Willebrand factor (vWF) are factors in the extrinsic coagulation system that have been suggested to play a crucial role in the initiation of blood coagulation in atherosclerotic disease, particularly in diabetes 153. Although the mechanism is not well-established, high vWF levels help to predict cardiovascular events, although the vWF level is not powerfully predictive in the individual at risk 154. However, different laboratories use different methods to measure coagulation factors including antigen or activity level, percent compared to a standard or concentration, and other variations. This makes comparisons across studies difficult.

We found 44 studies that met eligibility criteria and reported data on the effect of omega-3 fatty acids on factor VII, factor VIII, and/or vWF (40, 13, and 20 studies, respectively; See Table 3.1). Of these, we analyzed the 23 randomized trials that met additional criteria. For factor VII, we analyzed studies that had data on at least 15 subjects in parallel trials or 10 subjects in crossover trials who consumed omega-3 fatty acids (19 studies). For factor VIII and vWF, we analyzed all randomized trials (5 and 9 studies, respectively).

Overall Effect

Factor VII (Table 3.17) 46,56,74,89,90,115,116,138,140–143,145–147,149,150,152,155. There is little consistency in effect across the 19 studies of factor VII activity. In general, the net change in factor VII in subjects consuming omega-3 fatty acids is small (7% change from baseline or less), although a nearly equal number of studies found net increases as found net decreases in levels.

Table 3.17 Effects of omega-3 fatty acids on factor VII activity (%) in randomized trials (4 weeks to 9 months).

Table

Table 3.17 Effects of omega-3 fatty acids on factor VII activity (%) in randomized trials (4 weeks to 9 months).

Factor VIII (Table 3.18) 46,84,85,115,138. Five studies reported data on factor VIII activity. (It is unclear whether Conquer et al. measured factor VIII activity or antigen 84.) There is no consistent effect across studies, with some finding a net increase and some a net decrease in factor VIII level.

Table 3.18 Effects of omega-3 fatty acids on factor VIII activity (%) in randomized trials (6 weeks to 1 year).

Table

Table 3.18 Effects of omega-3 fatty acids on factor VIII activity (%) in randomized trials (6 weeks to 1 year).

von Willebrand Factor (Table 3.19)46,69,84,85,89,147,149,150,156. Nine studies reported data on various measurements of vWF using different measurement methods. Some studies were not explicit about the specific measurement used. Most studies found a net decrease in vWF level (of up to a 13% reduction from baseline), although in only 1 study was the difference with placebo reported to be statistically significant.

Table 3.19 Effects of omega-3 fatty acids on von Willebrand factor in randomized trials (4 weeks to 2 years).

Table

Table 3.19 Effects of omega-3 fatty acids on von Willebrand factor in randomized trials (4 weeks to 2 years).

Sub-populations

Factor VII. A small, inconsistent effect across studies was found among the 10 studies of a general population, the 3 studies of populations with CVD, and the 4 studies of people with dyslipidemia. The only statistically significant effects - both net increases in factor VII - were seen in 2 of the 3 studies of diabetic patients (one of which included only diabetics with dyslipidemia). The large increase in factor VII found by Hendra et al. in a 6 week study of fish oil versus olive oil supplements in non-insulin dependent diabetics was noted to be unexpected in light of a large decrease in Tg level 116.

Factor VIII. The single study of insulin dependent diabetics found a larger net increase of factor VIII than the studies of general populations, although the difference in this study was not significant. No study measured factor VIII in CVD or dyslipidemic populations.

von Willebrand Factor. With the exception of a low-dose arm in 1 study, the 6 studies of general populations found either net decreases or no effect in vWF, although none was statistically significant. The single study of a CVD population was the only study to find an overall net increase in vWF level, although Leng et al. was also an anomaly in that the oil analyzed was primarily gamma-linolenic acid (GLA, 18:3 n-6), an omega-6 fatty acid, with a small amount of EPA 69.The only study to find a large, statistically significant decrease in vWF was 1 of the 2 studies of dyslipidemic patients. No study evaluated diabetic patients.

Covariates

Factor VII. Haines et al. found no association between change in factor VII with fish oil supplementation and either sex or Hgb A1c in insulin dependent diabetics 115. In contrast, in a study of non-insulin dependent diabetics, Dunstan et al. reported a significant positive association between the changes in factor VII and fasting blood sugar with a fatty fish diet; however, dietary fish significantly affected factor VII levels only in subjects who were not in a moderate exercise program 141. Eritsland et al. reported no change in (lack of) effect of fish oil supplements in patients undergoing coronary bypass surgery after controlling for multiple factors including age, sex, weight, blood pressure, diabetes and CVD medications 142.

In possible contrast to the rest of the studies, only 1 of the 6 studies of male subjects, 3 of which were of younger men, found a net increase in factor VII; however all effects were small 46, 89, 138, 140, 147, 149. One study in which all subjects were on simvastatin 150 found a non-significant effect of fish oil supplements similar to other studies.

Factor VIII. Haines et al. found no relationship between effect of fish oil supplementation in insulin dependent diabetics who were taking aspirin on factor VIII and either sex or Hgb A1c 115. All other studies were in men, most of whom were under age 40 years. There were no other data relating to other covariates.

von Willebrand Factor. No study reported on correlations between effect on vWF and covariates. Notably, though, only 2 of the studies included women 69, 150. The effect of fish oil supplements in patients on simvastatin was similar to the effect of fish oil alone in other studies 150.

Dose and Source Effect

Factor VII. No study compared different doses of the same omega-3 fatty acid source. Across studies there does not appear to be a dose effect. Four studies compared different sources of omega-3 fatty acids. Hansen et al. (1993a) found no difference between fish oil triglycerides and fish oil ethyl esters 147. Osterud et al. reported no difference in effect of different marine oils 74. Freese et al. compared similar doses of fish oil and linseed oil supplements and found no difference between the 2 oils 143. Agren et al. also did not report a difference in effect among fish oil supplementation, algae DHA oil supplementation, and fatty fish diet 140.

Factor VIII. Only Deslypere et al. compared different doses of fish oil supplements 85. They reported no difference in effect of fish oil on factor VIII related to dose. None of the studies of fish oil supplements showed more than a marginal decrease in factor VIII level. In contrast, the single study of a flaxseed oil diet found a non-significant, approximately 6% net decrease in factor VIII activity and the single study of Mediterranean diet found a highly significant, approximately 7% net reduction in factor VIII activity. In the latter study, Mezzano et al. also found significant reductions in factor VII activity and fibrinogen levels, in contrast to most other studies 138. They found no association between the effect on factor VIII and either ABO blood type (which is related to factor VIII level) or CRP, as a marker of inflammation.

von Willebrand Factor. Deslypere reported no difference in effect on vWF after 1 year in monks taking 3 different doses of fish oil supplements 85. Hansen found similar effects among men taking either fish oil triglycerides or fish oil ethyl ester 147. Across studies, though, the study by Seljeflot et al., which tested the largest dose of omega-3 fatty acid supplementation, found the largest, significant decrease in vWF. However, the study of mackerel paste diet, with a similar omega-3 fatty acid level, found no effect. The single study of plant oils found a non-significant decrease in vWF with an ALA-rich flaxseed oil diet that was similar to most marine oil studies.

Exposure Duration

Factor VII. Five studies measured factor VII levels at different time periods, ranging from 2 to 16 weeks 56, 115, 138, 149, 155. No differences were seen in factor VII levels at any time point.

Factor VIII. Three studies measured factor VIII activity at different time periods. Haines et al. found no effect of fish oil supplements on factor VIII at either 3 or 6 weeks 115. Deslypere et al. did find an occasional significant decrease of factor VIII from the second trial month on in multiple measurements done between 4 weeks and 12 months 85. However, this effect was also seen in the olive oil group and no net differences were found. Mezzano et al. found similar responses to Mediterranean diet at both 1 and 3 months 138.

von Willebrand Factor. Three studies measured vWF at different time periods. Muller et al. found no change in vWF in either study arm at both 3 and 6 weeks 149. Both Deslypere et al. and Leng et al. found that vWF levels fluctuated at different time points ranging from 3 weeks to 1 year, but that there were no differences among arms 69, 85.

Sustainment of Effect

Factor VII. Only Freese et al. reported data on factor VII levels after stopping treatment 143. There was no difference 4 weeks after finishing 4 weeks of treatment compared to either pre- or post-treatment levels.

Factor VIII and von Willebrand Factor. Only Deslypere et al. reported data on factor VIII activity and vWF after stopping treatment 85. There was a large increase in factor VIII activity in all study arms, including the olive oil group, at both 1 and 2 months after stopping treatment. There were no differences between fish oil supplement and control groups. There was no difference in vWF after treatment.

Platelet Aggregation (Table 3.20)

Platelet aggregation plays a central role in the pathogenesis of acute atherothrombosis and has been associated with cardiovascular disease in some, but not all, epidemiological studies. However, pharmacological agents that inhibit platelet aggregation, such as aspirin, clearly reduce the incidence of adverse clinical cardiovascular events. The most common method of measuring platelet aggregation involves in vitro tests of blood samples. Aggregating agents such as adenosine diphosphate (ADP) and collagen are added to the blood samples, or spontaneously occurring aggregation is measured. The resulting platelet aggregation is used as a measurement of the potential for platelets to aggregate in the human body. There is little agreement as to which method is most meaningful and little standardization of dose of aggregating agent or test methodology. Omega-3 fatty acids may directly affect platelets, thus both reducing CVD but also possibly increasing bleeding risk.

Table 3.20 Effects of omega-3 fatty acids on platelet aggregation in randomized trials (4 to 15 weeks).

Table

Table 3.20 Effects of omega-3 fatty acids on platelet aggregation in randomized trials (4 to 15 weeks).

We found 84 studies that met eligibility criteria and reported data on the effect of omega-3 fatty acids on platelet aggregation (See Table 3.1). Of these, we analyzed the 11 randomized trials with data on at least 15 subjects in parallel trials and 10 subjects in crossover trials who consumed omega-3 fatty acids and that also reported platelet aggregation in tabular or text format. Studies that presented platelet aggregation data graphically only were not analyzed. This additional criterion was used because of the particular difficulty in estimating data from graphs for this outcome and because of the large number of specific outcomes reported in each study.

Overall Effect 54, 57, 108, 115, 116, 128, 140, 157–160

Within the 11 studies, heterogeneous effects of omega-3 fatty acids were generally found depending on the aggregating agent, the dose of agent, and the measurement metric used. However, in most studies either no effect on platelet aggregation was found with omega-3 fatty acids or no difference in effect was seen between treatments and controls.

Sub-populations

Seven studies were performed in generally healthy individuals. Salonen et al., Junker et al., and Wensing et al. all found no effect of omega-3 fatty acid consumption and no difference with control groups in healthy men, non-obese individuals and elderly individuals, respectively 56, 159, 160. Freese et al. (1994) found no significant effect from rapeseed oil supplements in male students; however, they did find an apparent comparative effect since Trisun sunflower oil, which was used as the comparison, significantly increased platelet aggregation 54. Hansen et al., Freese et al. (1997a), and Agren et al. found mixed effects in younger individuals (Agren at al. in male students), with significantly decreased platelet aggregation in some study arms with some specific tests 128, 140, 157.

Two studies evaluated hypercholesterolemic subjects, both of which found no effect of omega-3 fatty acids on measures of platelet aggregation. An additional 2 studies included diabetic patients. Haines et al. reported no effect among insulin-dependent diabetics, while Hendra et al. reported small, but significant increases in spontaneous platelet aggregation among type 2 diabetics 115, 116. However, in the latter study it was also reported, without supporting evidence, that epinephrine-induced aggregation was unaffected by either treatment or control. No studies specifically included patients with known or suspected CVD.

Covariates

Hansen et al., recognizing that male and female sex hormones have different effects on platelet function, made an a priori evaluation of the potentially different effect of cod liver oil supplementation on platelet aggregation in men and women 157. Healthy, young, normolipemic men and women were included in the study. A large, significant decrease in platelet aggregation with low dose collagen was seen in men on cod liver oil supplements, but not in women (P < .01 men vs. women). Otherwise the effect of fish oil was generally mixed and not different between the sexes. No explanation was offered for why the effect would have been seen only with low-dose collagen aggregation. In contrast, Haines et al. made the blanket statement that the baseline variables smoking, alcohol consumption, and sex were not related to the response to fish oil supplementation 115. Four other studies included only men 54, 57, 140, 159. No clear difference was seen between these studies and studies that included both men and women. No other covariate was specifically analyzed in any study.

Dose and Source Effect

No study compared different doses of the same type of oil. Among the studies of fish oil supplements or diets, there was no clear association across studies between dose and change in platelet aggregation.

No significant effect was seen in any of the studies of plant oil supplements or diets, regardless of dose. Two studies compared fish oil (EPA+DHA) to linseed oil (ALA). Freese et al (1997a) was inconclusive regarding a difference between fish oil and linseed oil supplements 128. However, Wensing et al. reported that platelet aggregation was prolonged by greater amounts in subject who consumed fish oil shortening compared to those who consumed linseed oil shortening 160. Agren et al. compared 3 sources of EPA and/or DHA 140. Collagen aggregation was reduced in subjects on both fish oil supplementation and fish diet, but not in those consuming pure DHA oil. From this, they concluded that while omega-3 fatty acids impair platelet aggregation, DHA is less potent than fish oil or dietary fish at moderate doses.

Exposure Duration

Three studies measured platelet aggregation at different time points. Haines et al. and Junker et al. reported data at 3 and 6 weeks, and 2 and 4 weeks, respectively, but did not comment on a potential time effect 56, 115. However, no apparent difference in effect was seen between the earlier and later times. Kwon et al. noted that with 2 mg/L collagen aggregation a significant decrease in platelet aggregation was found at 3 weeks on canola oil diet, which reverted to baseline by 8 weeks 57.

Sustainment of Effect

Freese et al. (1997a) reported that the decrease in collagen-induced aggregation in the fish oil supplement arm did not return to baseline during a 12 week follow-up period, although, the other tests did 128.

Coronary Artery Restenosis (Table 3.21, Figure 3.3)

The benefit of treatments given after percutaneous transluminal coronary angioplasty (PTCA) is often measured, in research studies, by performing a subsequent angiography and measuring the change in the luminal diameter at the sites of dilatation performed in the original angioplasty. The most common metric is restenosis rate, although there is no single standard definition of restenosis. Most researchers use minor variations of a 50% narrowing of the dilated vessel from the immediately post-dilation diameter. In theory, this level of restenosis corresponds with recurrence of angina, although clearly some patients develop symptoms with lesser levels of stenosis and some patients stay asymptomatic with greater levels of stenosis. If omega-3 fatty acids are effective at reducing clinical coronary artery disease, including angina and myocardial infarction, then the effect should be manifested in the diagnostic testing by angiography.

We found 17 studies that met eligibility criteria and reported data on coronary arteriography in patients taking omega-3 fatty acids (See Table 3.1). Of these, we analyzed the 12 randomized trials with data on restenosis rate after PTCA. Most studies re-evaluated patients at 6 months after PTCA. Maresta et al. started patients on omega-3 fatty acids 1 month prior to the initial PTCA 81. In general, other studies started omega-3 fatty acid treatment up to a week prior to PTCA.

Overall Effect 63, 64, 81, 161–169

All studies compared a single dosage of fish oil supplementation to control. Definitions of restenosis, however, were not uniform as noted in the footnotes of the summary table. In particular, 3 studies included abnormal exercise tolerance tests (ETT) as a potential definition of restenosis 166, 167, 169. The results of random effects model meta-analysis are presented in both the Table 3.21 and Figure 3.3. Overall, although there is heterogeneity among the studies, there is a trend toward a net reduction of coronary artery restenosis with fish oil supplementation. The meta-analysis estimate is a lowering of risk of 14% (95% confidence interval -29%, +3%).

Table 3.21 Effects of omega-3 fatty acids on restenosis in randomized trials (approximately 3 months to 1 year).

Table

Table 3.21 Effects of omega-3 fatty acids on restenosis in randomized trials (approximately 3 months to 1 year).

Figure 3.3 Random effects model of effect of fish oil on coronary artery restenosis following percutaneous transluminal coronary angioplasty.

Figure

Figure 3.3 Random effects model of effect of fish oil on coronary artery restenosis following percutaneous transluminal coronary angioplasty. N = number of patients, except for 2 studies that reported number of lesions: Nye had 35 patients on fish oil, (more...)

Sub-populations and Covariates

Most studies included all patients who were undergoing first PTCA, therefore with known or suspected coronary artery disease. No study restricted eligibility to patients with either diabetes or dyslipidemia. A number of studies performed multivariate analysis including diabetic, lipid, and cardiovascular variables, generally finding no association between these covariates and restenosis in the randomized trials. Only Bairati et al. commented about the effect of multivariate analysis on the relative risk of restenosis from fish oil supplement treatment 161. The authors reported that after controlling for history of hypertension, myocardial infarction, and diabetes, and for smoking, body mass index, angina class, degree of stenosis, location and number of stenoses, and ejection fraction, the inverse association between fish oil supplementation and restenosis was stronger and of higher statistical significance (because of a higher risk profile in the fish oil group).

Reis et al. and Kaul et al. both compared relative risk of restenosis in men and women; neither found a significant difference in effect, although both found a higher (worse) relative risk in women than in men 166, 169. In men, the relative risks of restenosis were 1.33 and 1.29, respectively, compared to 2.20 and 1.78 in women. Notably, though, these 2 studies had the lowest control rates (the rate of restenosis in the control arm, a commonly used metric to estimate the underlying severity of disease) and were the only 2 studies with relative risks substantially greater than 1.0. Interestingly, the 1 study which was restricted to men, Dehmer et al., had about the lowest relative risk of restenosis among the studies.

Dose and Source Effect

No study compared doses of fish oils and all evaluated only fish oil. Across studies, no effect is apparent based on dose of fish oil supplement.

Exposure Duration

Each study evaluated restenosis at one time point only. Across studies, the duration of treatment does not appear to correlate with the relative risk of restenosis. In fact, both the longest study 168 (12 months) and the shortest study 163 (approximately 3–4 months) had similarly, low and statistically significant relative risks of restenosis.

Sustainment of Effect

No study re-evaluated for restenosis after stopping treatment.

Carotid Intima-Media Thickness (Table 3.22)

Ultrasound measurement of the thickness of the carotid arterial wall, termed carotid intima media thickness (IMT), has emerged as a practical technique that carries significant prognostic information in terms of future cardiovascular outcomes 170, 171. There are numerous methods of measuring carotid IMT, including using different sites and averaging different numbers of measurements. The more commonly reported methods include measurements of the common carotid artery and an average of multiple sites in the common and internal carotid arteries and the carotid bifurcation.

Table 3.22 Effects of omega-3 fatty acids on carotid intima-media thickness (mm) in studies (2 yr or cross-sectional).

Table

Table 3.22 Effects of omega-3 fatty acids on carotid intima-media thickness (mm) in studies (2 yr or cross-sectional).

Four studies met eligibility criteria and reported data on the effect of omega-3 fatty acids on carotid IMT. Only one was a randomized trial of fish oil supplements. A second study reported IMT measurements only from the intervention arm of a randomized trial of ALA margarine. Two cross-sectional studies compared residents of a Japanese fishing village to a farming village and quartiles of white Americans based on ALA intake.

Overall Effect 51, 79, 172, 173

The only placebo-controlled randomized trial found small, non-significant net thickening of carotid IMT, using 4 different measurements at 24 months, with fish oil supplementation. The uncontrolled cohort of subjects consuming ALA margarine had a significant thickening in IMT at 2 years. However, the absolute change in IMT in this cohort of subjects was similar to the absolute change in IMT in the fish oil supplementation arm in the randomized trial (an absolute increase of between 0.05 mm and 0.11 mm in the study by Angerer et al.) 79, 172. The cross-sectional studies both found that people with greater dietary intake of omega-3 fatty acids, either as total linolenic acid or as fish, had significantly thinner IMTs than those with less intake.

Sub-populations and Covariates

Other than study design, the primary difference between the studies that found no effect and the studies that found a beneficial effect of omega-3 fatty acids is that the former were both trials in patients with cardiovascular disease and the latter were both studies of generally healthy individuals. There is insufficient data, however, to conclude that the differences were due to study populations. There is no evidence among people with diabetes or hyperlipidemia. Bemelmans et al. performed a regression analysis of predictors of change in IMT among subjects taking ALA margarine 172. Age, sex, blood pressure, LDL, and weight were not predictive of change in IMT. In addition, change in intake of polyunsaturated fatty acids, cholesterol and alcohol were not predictive of change in IMT. Change in intake of saturated fatty acids (SFA) was positively associated, and change in intake of fruit was negatively associated, with change in IMT in univariate analysis but not in multivariate analysis (although it is not clear what factors were included in multivariate analysis since none was significant).

In the cross-sectional study, IMT was greater in older than younger subjects in both the fishing and farming villages. Among younger villagers, IMT was non-significantly lower in the fishing village than the farming village; however, in subjects in their seventh and eighth decades IMT was marginally greater in the fishing village.

Dose and Source Effect, Exposure Duration, Sustainment of Effect

There are insufficient data to draw conclusions regarding dose effect, oil type, duration of intervention or exposure, or sustainment of effect after stopping omega-3 fatty acids.

Exercise Tolerance Test (Table 3.23)

The exercise tolerance test (ETT), or stress test, measures the heart's aerobic exercise capacity and is a common test to determine clinical severity of coronary artery disease. The standard method of performing ETT is with the modified Bruce protocol on a treadmill. Some studies instead used a bicycle ergometer. A wide range of different metrics are used to measure patients' performance.

Table 3.23 Effects of omega-3 fatty acids on treadmill and bicycle exercise tolerance tests in studies (6 weeks-6 months).

Table

Table 3.23 Effects of omega-3 fatty acids on treadmill and bicycle exercise tolerance tests in studies (6 weeks-6 months).

All eligible studies that reported data on the effect of omega-3 fatty acids on ETT were included; 6 studies qualified. Three were randomized trials and 3 were longitudinal cohort studies without control arms of subjects with known coronary artery disease who were treated with fish oil supplements.

Overall Effect 64, 174–178

The 3 randomized trials each found a small relative improvement in exercise capacity in subjects with coronary artery disease who took fish oil supplements compared to those who took olive oil supplements. However, with a single exception, exercise capacity measurements improved in all study arms, regardless of whether subjects consumed fish oil or olive oil supplements. The maximum double product (heart rate multiplied by blood pressure) fell by a non-significant amount in the olive oil arm in Salachas et al. 174.

Warren et al. evaluated 7 patients with stable angina who took cod liver oil supplements for 6 weeks 178. Exercise workload and time to ischemia improved, although the changes were not significant. The ratio of resting to exercise workload fell significantly. Verheugt et al. studied 5 men with moderate to severe exercise-induced angina 177. They were given fish oil for 6 months. The patients' angina was sufficiently severe that all ETTs both before and after treatment were discontinued because of angina symptoms. Essentially no change was found in either exercise duration or maximal ST depression. Toth et al. enrolled 10 men with coronary artery disease and hyperlipidemia 176. They fish oil supplements for 2 months. A variety of measures of cardiac function significantly improved.

Overall, given the small number of studies and subjects, the different metrics used across studies, and the lack of placebo control in half the studies, only limited conclusions can be drawn about the effect of omega-3 fatty acids in improving cardiac function in patients with coronary artery disease. The studies suggest that fish oil consumption may benefit exercise capacity among patients with coronary artery disease, although the effect may be small.

Sub-populations, Dose Effect, Duration, Sustainment of Effect

There is no evidence regarding different doses, duration of fish oil consumption, other omega-3 fatty acids, the effect in various sub-populations, or sustainment of effect.

Heart Rate Variability (Table 3.24)

Heart rate variability is measured on 24-hour ambulatory electrocardiography recordings. A number of different measurements can be used to estimate heart rate variability. The studies of omega-3 fatty acids primarily measured the mean standard deviation (SD) of the RR interval (the time between heart beats). Abnormal QRS complexes were excluded. The larger the SD of the RR interval (SDNN), the greater the variability of the time between heart beats. An increase in SDNN is protective against ventricular arrhythmias and, in post-myocardial infarction patients, is protective against mortality 179, 180. Notably, both beta blockers and angiotensin converting enzyme inhibitors both increase heart rate variability 179.

Table 3.24 Effects of omega-3 fatty acids on heart rate variability — SD of RR (msec) — in studies (12 weeks or cross-sectional)a.

Table

Table 3.24 Effects of omega-3 fatty acids on heart rate variability — SD of RR (msec) — in studies (12 weeks or cross-sectional)a.

Only one set of investigators, in Denmark, have reported data on the effect of omega-3 fatty acids on heart rate variability in studies that met eligibility criteria. They analyzed 2 sets of subjects in randomized trials and also analyzed the cross-sectional data of one of the sets of subjects.

Overall Effect 181–183

One randomized controlled trial was performed in 60 healthy volunteers who took either low or high dose fish oil supplements, or olive oil capsules for 12 weeks 183. No significant effect was found either within study arms or compared to olive oil. The authors concluded that among all subjects, fish oil supplementation had no effect on heart rate variability.

In a randomized trial of 49 patients who had had a recent myocardial infarction and had a ventricular ejection fraction below 0.40 those who consumed fish oil supplements (for 12 weeks) had a significant increase in SDNN compared to controls 181. The authors concluded that omega-3 fatty acids may increase heart rate variability in survivors of myocardial infarction which may be protective against ventricular arrhythmias and mortality.

The same patients with recent myocardial infarction were divided at baseline into 3 groups based on their regular level of fish consumption 182. Both groups who consumed at least 1 fish meal per week had greater SDNN than those who did not consume fish, though the difference was not statistically significant. This finding may suggest that dietary fish consumption increases SDNN and thus is protective against ventricular arrhythmia.

Sub-populations and Covariates

Neither study directly compared healthy subjects with those with CVD. Neither examined subjects with either diabetes or dyslipidemia. While the effect of fish oil supplementation appeared greater in the study of subjects with recent myocardial infarction, there is insufficient evidence to compare the effect in subjects with or without heart disease.

In the study of healthy subjects, sub-group analyses based on sex and baseline SDNN suggested that the effect of fish oil supplementation was greatest in the 18 men with below median (<150 msec) baseline SDNN. However, data were not reported for the other 3 subgroups (women and those with above median SDNN).

Dose and Source Effect and Exposure Duration

The study among healthy subjects compared low and high dose fish oil supplementation. While it appears that there may be a trend toward increasing SDNN with higher dose fish oil, it is noteworthy that the subjects on high dose fish oil had no change in their SDNN while those on olive oil had a decrease in SDNN. Both trials lasted 12 weeks. There is no evidence regarding the effect of duration of intervention or exposure.

Sustainment of Effect

Neither study re-examined subjects after stopping fish oil supplementation.

Tissue Levels of Dietary Omega-3 Fatty Acids (Tables 3.253.31, Figures 3.43.6 [Figures at end of Tissue Levels section])

As noted in Chapter 1, in theory, the most immediate outcome related to omega-3 fatty acid intake is a change in tissue levels of the fatty acids. In this section, we review studies that examined the correlation between omega-3 fatty acid intake and tissue levels. Among studies analyzed for other outcomes, we found 60 studies that reported data on the association between omega-3 fatty acid consumption and changes in omega-3 fatty acid composition in various tissues. Of these, we analyzed the 33 largest randomized trials that reported percent phospholipid levels in either plasma or serum or in 1 of 4 blood cell membranes (Table 3.25). For plasma and serum phospholipid composition and for platelet phospholipid composition we analyzed randomized trials with data on at least 25 subjects and crossover trials with at least 20 subjects in omega-3 treatment arms. Because few studies reported erythrocyte, granulocyte, or monocyte membrane phospholipid compositions, we analyzed all eligible randomized trials.

Table 3.25 Studies reporting plasma/serum, platelet, erythrocyte, and other phospholipid changes.

Table

Table 3.25 Studies reporting plasma/serum, platelet, erythrocyte, and other phospholipid changes.

Table 3.31 Effect of omega-3 fatty acid supplementation on fatty acid profile of monocyte phospholipids in randomized trials (8 weeks).

Table

Table 3.31 Effect of omega-3 fatty acid supplementation on fatty acid profile of monocyte phospholipids in randomized trials (8 weeks).

Summary (Table 3.26)

Meta-regression revealed direct relationships between dose of consumed EPA+DHA and changes in measured levels of EPA and DHA, either as plasma or serum phospholipids, platelet phospholipids, or erythrocyte membranes. The correlation between dose and change in level appears to be fairly uniform, where 1 g supplementation of EPA and/or DHA is associated with, approximately, a 1% increase in EPA+DHA level. Granulocyte and monocyte membrane phospholipid levels also increased by roughly similar amounts after omega-3 fatty acid supplementation in individual studies. In these studies, ALA level did not change significantly after supplementation in any blood marker. In most studies, there was a decrease in arachidonic acid (AA, 20:4 n-6) level, which corresponded to the increase in EPA+DHA level.

Table 3.26 Association of EPA+DHA consumption and tissue levels. Meta-Regression Results.

Table

Table 3.26 Association of EPA+DHA consumption and tissue levels. Meta-Regression Results.

Among eligible studies, only 3 included ALA supplementation arms 53, 143, 160. The dose of ALA in these 3 studies ranged from 4.5 to 9.5 g/d. The studies consistently found an increase in both ALA and EPA levels in the blood markers, at these doses of ALA. In contrast, there was no significant change in DHA level when lower dose of ALA was used (up to 6.8 g/d) but in the study arm that received 9.5 g/d ALA a significant increase in DHA level was also found.

Plasma or Serum Phospholipid Composition 48, 53, 62, 66, 74, 90, 97, 100, 101, 120, 129, 131, 132, 146, 157, 184 (Table 3.27, Figure 3.4)

EPA/DHA. For plasma and serum phospholipid composition, 16 randomized trials with 30 omega-3 fatty acid arms were initially included; however, we excluded 1 study that reported only total omega-3 fatty acid dose and levels 131. Among the 15 trials of EPA and/or DHA supplementation (which had 28 treatment arms), the dose of EPA+DHA ranged from 0.2 to 5.8 g/day. Study populations include general healthy population, and people with diabetes, dyslipidemia or cardiovascular diseases. Meta-regression shows a significant dose-response relationship between the dietary EPA and DHA supplementations and the changes in EPA+DHA compositions in plasma or serum phospholipids across studies. Across studies, the effect was similar regardless of source of EPA or DHA. Three studies compared purified EPA to purified DHA 66, 120, 132. All found that purified EPA increased EPA and decreased DHA in plasma phospholipid and that purified DHA increased DHA by about 4 to 7 times as much as EPA in plasma phospholipid; however, combined EPA+DHA was increased by about the same amount by both fatty acids.

Table 3.27 Effect of omega-3 fatty acid supplementation on fatty acid profile of serum/plasma phospholipids in randomized trials (6 weeks to 14 months).

Table

Table 3.27 Effect of omega-3 fatty acid supplementation on fatty acid profile of serum/plasma phospholipids in randomized trials (6 weeks to 14 months).

Figure 3.4 Association between EPA and/or DHA supplementation and changes in EPA + DHA composition in plasma or serum phospholipids (PL).

Figure

Figure 3.4 Association between EPA and/or DHA supplementation and changes in EPA + DHA composition in plasma or serum phospholipids (PL).

Meta-regression equation (r2 = 0.45, P < .001): Change in Plasma/Serum EPA+DHA Level (%) = 0.93 × [EPA+DHA Intake (g/day)] + 1.41

Because 4 studies reported only EPA levels, we re-analyzed the data with only the 12 studies with a complete EPA and DHA profile of plasma/serum phospholipids. As expected, since no study excluded DHA levels, the revised meta-regression equation indicates that the EPA+DHA level increases by a greater amount for each unit of omega-3 fatty acid supplementation and the r2 was greater than in the meta-regression that included all studies.

Meta-regression equation (r2 = 0.63, P < .001): Change in Plasma/Serum EPA+DHA Level (%) = 1.24 × [EPA+DHA Intake (g/day)] + 0.89

ALA. One study also evaluated 2 linseed/rapeseed oil supplementation doses, which included primarily ALA with minimal EPA and DHA 53. Finnegan et al. found that with higher dose ALA (9.5 g/d), EPA, DHA and ALA levels all significantly increased. With lower dose ALA (4.5 g/d), EPA and ALA levels rose by a degree consistent with the lower dose of omega-fatty acids; although DHA levels did not change. In the remaining study arms of fish oils and sunflower oils, small amounts of ALA (<= 1.5 g/d) did not affect ALA levels. In this study, a daily dose of 9.5 g or 4.5 g ALA (with 0.3 g EPA+DHA) had similar effects on plasma EPA levels as a daily dose of 1.7 g or 0.8 g EPA+DHA (with 1.4 g ALA), respectively. The plasma level of AA did not decrease in either ALA arm.

Platelet Phospholipid Composition 68, 71, 95, 96, 101, 116, 122, 123, 132, 137, 143, 163 (Table 3.28, Figure 3.5)

EPA/DHA. For platelet phospholipid composition, we analyzed 12 randomized trials with 21 omega-3 fatty acid arms. All of these studies evaluated EPA and/or DHA supplementation. One treatment arm was ALA; therefore, there were 20 EPA and/or DHA treatment arms. The dose of EPA+DHA ranged from 0.8 to 5.9 g/day. Study populations include general healthy population and people with diabetes, dyslipidemia, or cardiovascular diseases. Meta-regression results show a significant dose-response relationship between the dietary EPA and DHA supplementations and the changes in EPA+DHA compositions in platelet phospholipids across studies. Studies that used fish or fish combined with fish oil supplement treatments generally had greater increases in platelet phospholipid EPA+DHA amounts than studies of fish oil supplements. This effect was seen in Mori, et al. (1994), which compared fish, fish oil supplements, and combination fish and fish oil 71. They reported that the largest increase in DHA occurred in the groups consuming fish. In contrast to the finding in plasma phospholipids, Mori et al. (2000) reported that platelet EPA+DHA levels rose more in subjects taking DHA than in subjects taking EPA, although it is not reported whether this difference is statistically significant 132.

Table 3.28 Effect of omega-3 fatty acid supplementation on fatty acid profile of platelet phospholipids in randomized trials (6 weeks to 4 months).

Table

Table 3.28 Effect of omega-3 fatty acid supplementation on fatty acid profile of platelet phospholipids in randomized trials (6 weeks to 4 months).

Figure 3.5 Association between EPA and/or DHA supplementation and changes in EPA + DHA composition in platelet phospholipids (PL).

Figure

Figure 3.5 Association between EPA and/or DHA supplementation and changes in EPA + DHA composition in platelet phospholipids (PL).

Meta-regression equation (r2 = 0.52, P < .001): Change in Platelet EPA+DHA Level (%) = 0.74 × [EPA+DHA Intake (g/day)] + 1.16

As was the case for plasma/serum phospholipid levels, the re-analysis of the platelet phospholipid data that excluded the 2 studies without a complete EPA and DHA profile indicates a larger increase in EPA+DHA level and a larger r2 than in the complete meta-regression.

Meta-regression equation (r2 = 0.72, P < .001): Change in Platelet EPA+DHA Level (%) = 0.80 × [EPA+DHA Intake (g/day)] + 1.25

ALA. One study also evaluated linseed oil supplementation, which included only ALA without EPA or DHA 143. Freese et al. found that a 5.9 g/d ALA supplementation significantly increased EPA and ALA platelet phospholipid levels. However, the effect on EPA levels was small in comparison to the effect of a similar dose of fish oil (+0.41% vs. +3.32% for 5.2 g/d EPA+DHA). In addition, DHA levels were unaffected. The AA level decreased in the ALA arm.

Erythrocyte Membrane Phospholipid Composition79, 88, 95, 96, 101, 115, 134, 141, 160, 175 (Table 3.29, Figure 3.6)

EPA/DHA. For erythrocyte membrane phospholipid composition, 10 randomized trials with 15 omega-3 fatty acid arms were included. All of these studies evaluated EPA and/or DHA supplementation. One study included 2 ALA treatment arms; therefore, there were 13 EPA and/or DHA treatment arms. The dose of EPA+DHA ranged from 0.8 to 4.6 g/day. Study populations include general healthy population and people with diabetes, dyslipidemia or cardiovascular diseases. Meta-regression results show no significant dose-response relationship between the dietary EPA and DHA supplementations and the changes in EPA plus DHA compositions in platelet phospholipids. No clear difference is seen in effect based on source of omega-3 fatty acids. No study compared different sources of EPA+DHA oil.

Table 3.29 Effect of omega-3 fatty acid supplementation on fatty acid profile of red blood cell (erythrocyte) membrane/ghosts in randomized trials (6 weeks to 2 years).

Table

Table 3.29 Effect of omega-3 fatty acid supplementation on fatty acid profile of red blood cell (erythrocyte) membrane/ghosts in randomized trials (6 weeks to 2 years).

Figure 3.6 Association between EPA and/or DHA supplementation and changes in EPA + DHA composition in red blood cell (RBC, erythrocyte) membrane phospholipids (PL).

Figure

Figure 3.6 Association between EPA and/or DHA supplementation and changes in EPA + DHA composition in red blood cell (RBC, erythrocyte) membrane phospholipids (PL).

Meta-regression equation (r2 = 0.11, P = .14): Change in Erythrocyte EPA+DHA Level (%) = 0.63 × [EPA+DHA Intake (g/day)] + 3.22

The re-analysis of the data, excluding 1 study by Green et al. who did not report the change in DHA levels, greatly affected slope and statistical significance of the meta-regression equation 101. The large effect of this single study can be explained by outlier status of the study. The change in EPA level reported in this study is considerably lower than the change in EPA+DHA levels in studies with similar supplementation doses.

Meta-regression equation (r2 = 0.39, P < .02): Change in Erythrocyte EPA+DHA Level (%) = 1.05 × [EPA+DHA Intake (g/day)] + 2.69

ALA. One study also evaluated a diet enriched in ALA and that contained no EPA or DHA among both young (16–33 years old) and old (60–78 years old) subjects 160. Wensing et al. found that a 6.8 g/d ALA supplementation significantly increased both EPA and ALA levels but not DHA level. The effects on the changes in EPA and ALA compositions were larger among older subjects than among younger subjects. The higher dose ALA (6.8 g/d) had a smaller effect on EPA levels (+0.20% and +0.40%, for younger and older subjects, respectively) than a lower dose of EPA+DHA (1.6 g/d, +1.30%). The AA level decreased among old subjects while it increased among young subjects.

Granulocyte Membrane Phospholipid Composition 137 (Table 3.30)

One randomized controlled trial examined the changes of EPA+DHA composition in granulocyte membrane phospholipids after fish oil supplementation. Madsen et al. found that EPA and DHA compositions in granulocyte phospholipids significantly increased after 12 weeks of fish oil supplement treatment, while no significant changes were found in the placebo group 137. In addition, the change in DHA profile was significantly larger in the higher-dose fish oil supplementation group than in the lower-dose fish oil group.

Table 3.30 Effect of omega-3 fatty acid supplementation on fatty acid profile of granulocyte membrane in randomized trials (12 weeks).

Table

Table 3.30 Effect of omega-3 fatty acid supplementation on fatty acid profile of granulocyte membrane in randomized trials (12 weeks).

Monocyte Membrane Phospholipid Composition 146 (Table 3.31)

One crossover study examined the changes of EPA+DHA composition in monocyte phospholipids after cod-liver oil supplementation. Hansen, et al. showed the EPA profile in monocyte phospholipids significantly increased, while the arachidonic acid profile significantly decreased after 8 weeks of cod liver oil supplement treatment compared to the no treatment controls 146.

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