Our meta-analysis showed supplementation with fish oil was associated with a decrease in TG and TC, and an increase in HDL-C, but had no significant effects on LDL-C compared with controls. Funnel plots and Egger’s regression test showed possible publication bias for HDL-C, but not for other parameters.
The results of the current meta-analysis on TC, TG, LDL-C and HDL-C were similar to those of Pei , in which fish oil was found to reduce serum TG levels significantly by −0.78 mmol/L (95% CI: −1.12, −0.44 mmol/L, P <0.01), but had no significant effect on TC, HDL-C and LDL-C compared with controls. However, there were several differences between the two studies. The two studies by Svensson and Bouzidi [33, 34] were included in the study of Pei, but were excluded in the current study, because the patients enrolled in the two studies did not undergo dialysis treatment. We were able to confirm that two studies of Bowden were based on the same population [20, 21], so we excluded the smaller sample study . The trial by Taziki was excluded in our meta-analysis , but included in the analysis of Pei. We also added seven studies not included in Pei’s review because of small sample sizes (<15 patients in either arm) and search dates [15–18, 24, 29, 30]. Furthermore, we added several subgroup analyses based on components of fish oil and initial lipid levels.
Subgroup analyses revealed good long-term trends in the effects of supplements of fish oil on serum HDL-C and LDL-C levels. However, as mentioned before, the degree of improvement did not achieve statistical significance, which may have been due to a lack of statistical power. If we want to clarify the long-term effect, more specific studies should be conducted.
There are two issues that need to be carefully scrutinized. The first is that the optimal daily dose in dialysis patients that has a lipid-altering effect is still not established. In our study, the content of fish oil supplements varied significantly. It is impossible to determine the precise content of each supplement, thus the dose of DHA and EPA varied, so we used the dose of EPA + DHA for subgroup analysis. We found no difference in the effects on lipid profile when comparing <2 g EPA + DHA supplement with ≥2 g, therefore a high dose of fish oil supplement for lowering lipid levels might not be needed. As a result of dietary restrictions on fish consumption, to control phosphorus intake, dialysis patients have significantly lower levels of omega-3 fatty acids in their erythrocyte membranes , and based on randomized controlled trials, we suggest that the daily supplement dose of fish oil for dialysis patients should be >1 g. This is different from the current recommended dose of up to 1 g/day, by the American Heart Association (AHA) and various international health organizations [36, 37].
Second, the truly active component of fish oil accounting for the lipid-altering effects is still unclear. After a period of DHA supplementation, Harrison reported no significant changes in LDL-C or TC, and a concomitant increase in HDL-C. The authors further speculated that only EPA has lipid-modulating effects . We tried to establish whether EPA and DHA had a different impact on lipid profile through subgroup analyses. Our study confirmed that EPA had a significant influence on lipid profile, and EPA + DHA showed the same lipid-modulating effects as EPA alone. Unfortunately, we could not draw any conclusion about the effect of DHA alone on lipid profile in dialysis patients.
The lipid-altering effects of fish oil may be attributed to many factors . Cell membrane fatty acids play an important role in signal transduction, therefore omega-3 fatty acids are capable of modifying gene expression. It is believed that the dramatic lipid-altering effects of omega-3 fatty acids are mediated via this mechanism . Specifically, omega-3 fatty acids modulate the function of peroxisome proliferator-activated receptors and sterol regulatory binding proteins, both of which are involved in lipid homeostasis [40, 41].
Although fish oil is generally well tolerated, attention should be paid to the safety of fish oil supplementation at doses >1 g/day. Most adverse effects involve a transient minimal decrease in the desire for food , gastrointestinal complaints (e.g. gas, bloating, fishy aftertaste , nausea and burping ), and prolonged bleeding time . Serious bleeding complications were restricted to a single patient in one study . However, the majority of studies were not designed to measure side effects and tolerability after long-term use.
CVDs are the most important cause of mortality in patients undergoing hemodialysis. The frequency of CVD in dialysis patients has been reported as 3–45 times that observed in the general population and 50% of deaths in these patients are related to CVD . Lipid abnormalities often complicate chronic renal failure and persist or are aggravated during renal replacement treatment [4, 43]. Large cohort studies have shown an inverse association between cardiovascular morbidity and mortality and fish oil ingestion [44, 36]. Lok found that among patients with new hemodialysis grafts, daily ingestion of fish oil improved cardiovascular event-free survival . Friedman showed that long-chain omega-3 fatty acids are strongly and independently associated with a lower risk of sudden cardiac death in hemodialysis patients throughout the first year of dialysis . Except for lipid modulation, fish oil may reduce cardiovascular events by several mechanisms, including anti-inflammatory, antiarrhythmic and plaque-stabilizing effects as well as improved endothelial effects [46, 47]. However the potential benefits of fish oil on cardiovascular events deserve confirmation in future studies.
There were some strengths and limitations to our study. We had more strict inclusion criteria, and analyzed almost all the lipid parameters mentioned in the literature. A series of important subgroup analyses were also performed. However, the following limitations must be mentioned. First, none of the trials was sufficiently powered because of the small numbers of participants. Second, until now, there has been insufficient evidence for the effectiveness of long-term supplementation with fish oil on lipid profile, because the longest duration in these trials was only 48 weeks . Third, publication bias is a major potential limitation of meta-analysis that has been minimized by contacting investigators for unpublished results. Funnel plots and Egger’s regression test showed possible publication bias for HDL-C, and sensitivity analysis found that the significance of the change in HDL-C level was altered. We must interpret the HDL result with caution. Finally, none of the studies were specifically designed to assess the effects of fish oil in dyslipidemia patients, thus it was not accurate to evaluate the lipid-altering effects in this group. Based on the above, the results derived from this meta-analysis should be treated with considerable caution.