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Omega-3 Fatty Acid Supplementation on Lipid Profiles in Dialysis Patients: Meta-analysis
Archives of Medical Research 45 (2014) 469e477
ORIGINAL ARTICLE
Omega-3 Fatty Acid Supplementation on Lipid Profiles in Dialysis Patients: Meta-analysis Honggang Chi,a,* Xiaoru Lin,b,* Haohai Huang,b Xuebao Zheng,a Tao Li,c and Ying Zoua,d a
Department of Traditional Chinese Medicine, The Second Clinical Medical College, bSchool of Pharmacy, Guangdong Medical College, Dongguan, Guangdong, China c Department of Chemotherapy, People’s Hospital of Gaozhou, Gaozhou, Guangdong, China d Sino-American Cancer Research Institute, Guangdong Medical College, Dongguan, Guangdong, China Received for publication March 2, 2014; accepted June 19, 2014 (ARCMED-D-14-00126).
Background and Aims. Studies of omega-3 supplementation in dialysis patients describe salutary effects on lipid profiles. However, study results have been inconsistent. The aim of this study was to evaluate the influence of omega-3 supplementation on serum lipids in chronic dialysis patients. Methods. A systematic literature search was performed to identify the relevant randomized controlled trials (RCTs) that investigated the effects of omega-3 supplementation on dialysis patients. The outcomes included the levels of triglycerides (TG), total cholesterol (TC), low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol and albumin. Mean differences (MDs) and 95% confidence intervals (CIs) were calculated and heterogeneity was assessed with the I2 test. Results. A total of 678 patients from 14 trials were subjected to meta-analysis. Omega-3 supplementation could significantly decrease the levels of TG (MD, 34.8 mg/dL; 95% CI, 62.32 to 7.28) and LDL (MD, 7.15 mg/dL; 95% CI, 10.11 to 4.2). However, no statistically significant effects were observed for TC, HDL and albumin levels. In a subgroup meta-analysis, a statistically significant effect of omega-3 consumption on TG and LDL was observed in a short-term interventional duration and hemodialysis populations. Conclusion. Our findings indicate that omega-3 supplementation significantly reduced serum TG and LDL level in dialysis patients. However, there is no conclusive evidence that it can modulate the TC, HDL and albumin level. Ó 2014 IMSS. Published by Elsevier Inc. Key Words: Dialysis, Lipid, Meta-analysis, Omega-3.
Introduction Chronic kidney disease (CKD) is strongly associated with an increased risk of cardiovascular disease (CVD), which still remains to be one of the major causes of morbidity and mortality in hemodialysis (HD) patient groups. Annual mortality rates from CVD in this population group are 20 *
These authors contributed equally to this work. Address reprint requests to: Ying Zou, Department of Traditional Chinese Medicine, The Second Clinical Medical College, Sino-American Cancer Research Institute, Guangdong Medical College, No.1, Xincheng Road of Songshan Lake Science and Technology Industry Park, Dongguan, Guangdong Province 523808 China; Phone: þ86 15899695881; FAX: þ86 769 22896403; E-mail: [email protected]
times higher than in the general population (1,2). Although the pathogenesis of CVD in the CKD population is not clearly understood, a number of clinical and epidemiological studies have demonstrated that HD patient status has been strongly associated with lipid abnormalities (3,4). Further research has demonstrated that chronic inflammation is also a contributor to higher CVD incidence among HD patients (5). Moreover, a meta-analysis has shown a significant inverse relation between serum albumin and cardiovascular mortalities (6). Evidence supported the role of lipid-lowering therapy as a means to decrease cardiac death and atherosclerosis-mediated cardiovascular events in persons with CKD (7). In recent decades, the efficacy of pharmacologic interventions on lipid-lowering therapy has been
0188-4409/$ - see front matter. Copyright Ó 2014 IMSS. Published by Elsevier Inc. http://dx.doi.org/10.1016/j.arcmed.2014.06.008
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extensively researched, especially the inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (statins) are gaining widespread acceptance as a principal therapy for the primary and secondary prevention of atherosclerosis and CVD. However, current guidelines and some meta-analyses have provided evidence that the use of statins should not be recommended in dialysisdependent CKD patients (8e12). Thus, the best strategies to treat dyslipidemia in the HD population remain to be established. Omega-3 fatty acids included a-linolenic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA), mainly obtained from fish and fish oils, and are a family of fatty acids that contain two or more double bonds. Several studies have shown that omega-3 fatty acids play an important role in many other health disorders such as prevention of arrhythmias, chronic heart failure, dyslipidemia regulation, modulation of blood pressure levels, progression of arteriosclerosis, rheumatological diseases and osteoporosis, mood depression, chronic kidney disease, chronic inflammatory diseases and others (13e15). Recently, several randomized controlled trials (RCTs) have confirmed the effects of omega-3 supplementation on HD patients. However, these studies have a modest sample size and convey inconsistent results. We therefore deemed a comprehensive systematic review and meta-analysis of RCTs to assess the influence of omega-3 supplementation on serum lipid profile in HD patients.
Materials and Methods Literature Search and Inclusion Criteria According to the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement (16), relevant RCTs were identified by searching PubMed, Embase databases and Cochrane Central Register of Controlled Trials (CENTRAL). All searches were up to date as of December 2013. The structured search strategies used the following format of search terms: (‘‘kidney failure, chronic’’[Mesh] OR ‘dialysis’ OR ‘‘chronic renal failure’’ OR ‘hemodialysis’ OR ‘‘peritoneal dialysis’’ OR ‘‘kidney replacement therapy’’) AND (‘‘omega-3 fatty acids’’ OR ‘‘n-3 fatty acids’’ OR ‘‘fatty acid’’ OR ‘‘omega3’’ OR ‘‘fish oil’’ OR ‘‘a-linolenic acid’’ OR ‘‘eicosapentanoic acid’’ OR ‘‘docosahexanoic acid’’). Our searches were limited to English-language publications and human trials. In addition to electronic search original papers, we also reviewed the references of included RCTs to look for potentially eligible articles. Two investigators (XL and HH) independently did the literature search. Any disagreements were resolved by discussion and consensus. For each of the relevant articles, full publications were retrieved for evaluation on the basis of criteria established a priori. The following inclusive selection criteria in PICOS
order included: a) study population: patients (no matter how many patients recruited) who are receiving renal dialysis (including HD or peritoneal dialysis); b) intervention: omega-3 supplement (no matter what type and regimen applied); c) comparison intervention: placebo or no intervention; d) outcome measure: reported ‘baseline’ and ‘end of intervention’ mean and standard deviation values of lipid measurements and albumin for the active (omega3) and control groups; and e) study design: only RCT reported in a full paper article, and non-randomized and cross-over studies were excluded. Data Extraction and Outcome Measures Two investigators independently collected the data, crosschecked and reached a consensus on all items. The following information was extracted from the included studies: first author’s name, publication year, sample volume (intervention/control), dialysis modality, population information (mean age, gender and location), intervention group (types, grams per day), control group (placebo or other), duration of treatment. It should be emphasized that if the same population was reported in several publications, we only retained the most informative article or complete study to avoid duplication of information. We were interested in the following outcomes or endpoints, including information on baseline and final concentrations (or net changes) of serum total cholesterol (TC), LDL cholesterol, HDL cholesterol, triglycerides (TG) and albumin. Studies that reported results in mmol/l were converted to mg/dL using the standard conversion factors (which was a division of the mmol/l value by 0.02586 for TC, LDL and HDL; and by 0.01129 for TG). These values were captured as the mean change from baseline to followup (with mean SD or mean SE, respectively). Quality Scoring and Risk-of-Bias Assessment We quantified the methodological qualities of studies using validated Jadad 5-point scale (17). Jadad scores ranged from 0 to 5 in which the Jadad score not more than 2 indicates the lowest quality and the score of at least 3 means the highest quality (18). Risk-of-bias assessment was performed in accordance with guidelines outlined in the Cochrane Handbook for Systematic Reviews of Interventions (version 5.1.0) (19). For each study, we made judgments about risk of bias from each of the six domains of the tool. In all cases, an answer ‘‘Yes’’ indicated a low risk of bias, an answer ‘‘No’’ indicated high risk of bias, and if insufficient detail is reported of what happened in the study, the judgment would usually be ‘‘Unclear’’ risk of bias. Statistical Analysis For continuous data, mean differences (MDs) with 95% CIs were calculated. Clinical heterogeneity was assessed
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471
Figure 1. Flowchart of the study selection process.
by considering the design of each study. Statistical heterogeneity across studies was tested by using the I2 statistic, which was a quantitative measure of inconsistency across studies. Studies with an I2 statistic of 25e50% were considered to have low heterogeneity, those with an I2 statistic of 50% to 75% were considered to have moderate heterogeneity, and those with an I2 statistic of O75% were considered to have a high degree of heterogeneity (20). A random-effects model meta-analysis will be conducted for heterogeneous outcomes (I2 O10%). Otherwise, random effect will be employed. Whenever heterogeneity was present, sensitivity analyses and previously defined subgroup analyses were carried out to identify potential sources. In addition, we also investigated the influence of a single study on the overall pooled estimate by omitting one study in each turn. A p value !0.05 was considered to be statistically significant. All statistical analyses were performed by using Review Manager (Version 5.1.Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2011).
Results Study Identification and Selection The flow chart of search strategy is shown in Figure 1. Of the 863 titles identified from the three databases, 46 RCTs were excluded because of duplicate studies and 800 RCTs were excluded based on the titles and abstracts (reviews or not relevant to our analysis). Moreover, according to the inclusion and exclusion criteria, five articles were further excluded for the following reasons: three studies were cross-over trials and two studies with the combination therapy. It should be noted that two trials conducted by Kooshki et al. (21,22) were reported in the same population; therefore, we combined the informative data and retained only the complete article to avoid duplication of information (22). Finally, 14 RCTs met our inclusion criteria and were included in the analysis (22e35) of which three studies (23,25,26) were determined through checking reference lists of retrieved articles.
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Study Characteristics, Quality Assessment and Bias Assessment Descriptive data for the studies included in our analysis were summarized in Table 1. These studies were published from 1990e2013. A total of 678 patients (334 in the omega-3 group and 344 in control group) were included in this analysis. Of these 14 included studies, 12 studies compared omega-3 to placebo (22e27,29e32,35), whereas two studies compared to no treatment (28,33). The total dosage of omega-3 supplementation daily in the intervention groups ranged from 1.3e6 g. The baseline characteristics of the patients were balanced between the treatment and control arm. The quality of the included studies was assessed by the Jadad score (Table 1). Of 14 studies, all satisfied the criteria of complete outcome data, selective reporting and other bias. All included trials were mentioned as ‘‘random’’, but seven studies lacked appropriately described randomization procedures (23e28,34). Risk-of-bias analysis is shown in Figure S1.
Obvious heterogeneity was observed (I2 5 96%). Random effect model was used to analyze the effect size (Figure 2C). Eleven RCTs were included in the metaanalysis (22,25,27e35), which demonstrated that the level of LDL was significantly decreased in omega-3 treatment group compared with the control group (MD, 7.15 mg/ dL; 95% CI, 10.11 to 4.2; p !0.00001) without significant heterogeneity (I2 5 0%). The fixed effect model was applicable (Figure 2D). Effect of Omega-3 on Albumin The effect of omega-3 on albumin was also assessed in three trials (27,32,33). The present meta-analysis indicated that the omega-3 treatment group did not significantly change the serum albumin level when compared with that of the control group (MD, 0.19 g/dL; 95% CI, 0.50 to 0.13; p 5 0.25). Heterogeneity was significant for this outcome (I2 5 82%). Random effects model was used to analyze the effect size (Figure 3). Subgroup Analysis and Sensitivity Analyses
Effect of Omega-3 on TG Figure 2A shows the pooled results from the random-effects model combing the MD for TG. Thirteen included studies reported the TG in the study population (22,24e35), 12 articles were included in the meta-analysis (22,24e33,35), which suggested that TG levels were decreased significantly in the omega-3 treatment group compared with that of the control group (MD, 34.8 mg/dL; 95% CI, 62.32 to 7.28; p 5 0.01). The test for heterogeneity was significant (I2 5 92%). One study was not included in the metaanalysis because serum TG data were reported as median and range (34). In this article, serum TG level was significantly decreased from 177 mg/dL (128e266 mg/dL) to 147 mg/dL (111e231 mg/dL) for 120 days in the treatment group ( p 5 0.004), yet similar findings were not observed in the control group. Effect of Omega-3 on Cholesterol, HDL-cholesterol, LDLcholesterol Thirteen included studies reported changes in cholesterol (22e25,27e35), which demonstrated that the level of TC was not significantly changed in the omega-3 treatment group compared with the control group (MD, 5.31 mg/dL; 95% CI, 5.02 to 15.65; p 5 0.31). Heterogeneity was noted for this outcome (I2 5 80%). The random effect model was applicable (Figure 2B). The effect of omega-3 on HDL-cholesterol was assessed in 12 trials based on the results of the meta-analysis (22,24,25,27e35). The omega3 treatment group may not significantly change in serum HDL-cholesterol level compared with that of controls (MD, 5.92 mg/dL; 95% CI, 0.50 to 12.35; p 5 0.07).
The effects of omega-3 supplementation on lipid profile in a subgroup of trials defined according to participant characteristics are summarized in Table 2. Trials of short duration (#3 months) showed a significant reduction in the level of serum TG (MD, 45.6 mg/L; 95% CI, 76.9 to 14.3; p 5 0.004) and LDL (MD, 7.29 mg/L; 95% CI, 10.52 to 4.05; p !0.00001), but a nonsignificant reduction in serum TC and HDL levels. Studies with longer duration (O3 months) showed a nonsignificant reduction in TG, TC, HDL and LDL levels. The subgroup analyses according to dialysis modality showed a significant reduction in level of serum TG (MD, 28.2 mg/L; 95% CI, 52.7 to 4.93; p 5 0.02) and LDL (MD, 7.4 mg/L; 95% CI, 10.38 to 4.42; p !0.00001), but a nonsignificant reduction in serum TC and HDL levels in HD patients. Subgroup analyses according to the dose of omega-3 daily supplementation showed that administered omega-3 (doses of #2 g) could significantly decrease the TG level (MD, 60.5 mg/L; 95% CI, 98.3 to 22.7; p 5 0.002) and significantly increase HDL levels (MD, 7.92 mg/L; 95% CI, 1.56 to 14.28; p 5 0.01). Analysis by administered omega-3 (doses O2 g) revealed a significant reduction in serum LDL concentration 7.17 mg/L (95% CI, 10.4 to 3.94; p !0.00001). No significant changes in lipid profile were observed across any subgroup. In addition, we also performed sensitivity analysis by omitting the studies with low quality (Jadad score !3). The pooled results did not change substantially (Table 2). Further exclusions were conducted by omitting any single study that did not materially alter the overall combined MD (data not shown), which adds robustness to our main finding.
Table 1. Principal characteristics of individual studies included in the meta-analysis Gender (M/F)
Treatment group (types/ regimens/dosage)
Duration (months)
Jadad score
No. of patients
Dialysis modality
Age (treatment vs. control)a
Diskin et al. (1990) Ando et al. (1999) Khajehdehi et al. (2000) Schmitz et al. (2002) Saifullah et al. (2007)
7 38 30 24 23
(4/3) (19/19) (15/15) (12/12) (15/8)
HD HD/CAPD HD HD HD
NA 54 vs. 51 32.7 vs. 31.1 52 vs. 54 58 vs. 57
NA 5/33 15/15 11/13 18/5
EPA, caps, 3 g/d EPA, caps, 1.8 g/d Fish oil, caps, 1.5 g/d Fish oil, caps; 4 g/d Fish oil, caps, 1.3g/d
Placebo Placebo Placebo Placebo oil Placebo (linoleic acid)
USA Japan Iran USA India
6 3 2 3 3
4 4 4 4 4
Tzaiki et al. (2007) Svensson et al. (2008) Bowden (1) et al. (2009) Bowden (2) et al. (2009) Kooshki et al. (2011) An (1) et al. (2012)
33 79 87 33 34 14
(15/18) (41/38) (44/43) (18/15) (17/17) (7/7)
HD HD HD HD HD PD
47 vs. 59.5 66 vs. 58 59.3 vs. 60.8 57.2 vs. 64.3 50 vs. 50 52.6 vs. 51.6
11/22 NA 45/42 19/14 21/13 7/7
Omega-3, Omega-3, Omega-3, Omega-3, Omega-3, Omega-3,
No intervention Placebo (olive oil) Placebo (corn oil) Placebo (corn oil) Placebo Placebo (Olive oil)
Iran Denmark USA USA Iran Korea
3 3 6 6 2.5 3
2 5 5 5 5 5
An (2) et al. (2012)
43 (23/20)
HD/PD
58.1 vs. 56.7
20/23
Omega-3, caps, 3 g/d
No intervention
Korea
6
3
HD HD
55.7 vs. 58.3 51.5 vs. 48.6
85/60 63/25
Flaxseed oil, caps, 2 g/d Omega-3, pill, 3 g/d
Placebo (mineral oil) Placebo
Brazil Iran
4 2
4 5
Lemos et al. (2012) Khosroshahi et al. (2013)
145 (70/75) 88 (44/44)
caps, 2 g/d caps, 1.7 g/d caps, 6 g/d pill, 6 g/d caps, 2.08 g/d caps, 3 g/d
Control group
Location
Outcomes of interest TC, Albumin TG, TC, HDL TG, TC, HDL, TG TG, TC, HDL, Albumin TG, TC, HDL, TG, TC, HDL, TG, TC, HDL, TG, TC, HDL, TG, TC, HDL, TG, TC, HDL, Albumin TG, TC, HDL, Albumin TG, TC, HDL, TG, TC, HDL,
LDL LDL, LDL LDL LDL LDL LDL LDL, LDL, LDL LDL
Omega-3 Supplementation in Dialysis Patients
Study/Year
HD, hemodialysis; CAPD, continuous ambulatory peritoneal dialysis; PD, peritoneal dialysis; NA, not available; EPA, eicosapentaenoic acid; TG, triglyceride; TC, total cholesterol; HDL, high-density lipoprotein; LDL, low-density lipoprotein; CRP, C-reactive protein. a Shown as means.
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Figure 2. (AeD) Results of primary meta-analyses.
Discussion Hypercholesterolemia is present in |50% of patients on dialysis. At present, dietary therapy and drug therapy (mainly statins) were used in HD patients to improve their lipid profiles. However, guidelines from the update of the
National Kidney Foundation Kidney Disease Outcomes Quality Initiative (NKF-KDOQI) Clinical Practice Guideline for Diabetes and Chronic Kidney Disease as well as results of the meta-analyses demonstrated that statins should not be recommended in patients undergoing dialysis
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Figure 3. Forest plot of studies comparing the effect of omega-3 vs. control on albumin in dialysis patients.
(8e12). Thus, to find other effective treatments in this population is of great importance. The pooled results from our meta-analysis of all included RCTs showed that omega-3 fatty acids significantly reduced serum TG and LDL level in dialysis patients. However, no statistically significant effects were observed for TC, HDL and albumin levels. The omega-3 effect seemed stronger in studies with a relatively shorter duration and in subjects with HD. For the present meta-analysis, in an attempt to produce robust results, we conducted rigorous inclusion criteria and included only RCTs that clearly stated the enrollment of patients undergoing HD or peritoneal dialysis (PD). Our meta-analysis suggested that omega-3 can significantly decrease the levels of TG and LDL. Moreover, exclusion of any single study and sensitivity analyses based on various exclusion criteria did not materially alter the pooled results, which adds robustness to our main results. However, substantial heterogeneity was observed among these studies. This was not surprising because of the differences in characteristics of populations, amounts of omega-3 consumption compared, and study designs. The main finding of our meta-analysis seems to measure the effects of omega-3 supplementation on lipid status in the dialysis population. A published review conducted by Friedman and Moe (36) implied that omega-3 supplementation dramatically reduced TG and had mixed effects on other lipoproteins. But most of the included studies in this review were uncontrolled trials. Meanwhile, most of the trials used supraphysiological omega-3 doses ($2e3 g/day), so the normal doses effects of omega-3 supplementation are unknown. Moreover, long-term effect of omega-3 supplementation also remains unclear. Compared with the previous review (36), our meta-analysis has some advantages: first, we performed a quantitative combination statistical method to assess the lipid-altering effect of omega-3 in dialysis patients. Second, our subgroup analysis based on participant characteristics (Table 2), implied that omega-3 have salutary effects on TG and LDL levels in HD population, short-term interventional duration (#3 months) and a normal does (!2g/d) group. Besides, we also performed sensitivity analysis by omitting the studies with low quality (Jadad score !3), the pooled results did not change
substantially. Overall, these additional findings in our meta-analysis make our result more robustness. The mechanism of the dramatic lipid-altering effects of omega-3 fatty acids might be through modifying cell membrane structure and function, as well as synthesis of lipid mediators (such as eicosanoids), and fatty acids gene expression (37). 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 (38,39). We also assessed the effect of omega-3 on nutrition status. Evidence from the studies have shown that malnutrition is an important contributor to morbidity and mortality of CVD in renal dialysis patients (6,40). In the present analysis we use albumin to reflect the nutrition status. Moreover, actually albumin is also considered as a risk factor for mortality in patients with CKD. The main finding based on this study indicated that there is no conclusive evidence that omega-3 can improve the nutritional status. However, these results are inconclusive and further adequately powered studies are needed. Although certain positive results were seen with these trials, there are some limitations. Primarily, a majority of the included articles have a small sample size and a limited number of double-blind-designed studies, leaving a potential investigator bias. Furthermore, some studies cannot be included in meta-analysis because data were reported as median and range; however, results of these studies confirm our meta-analysis. Third, although clear inclusion and exclusion criteria were made, significant differences still existed among study design, intervention, and outcome measurement. These factors may have a potential impact on our results. Finally, because lipid profiles change soon after switching diets, omega-3 supplementation would need to be maintained indefinitely to maintain lower lipid concentrations. Compliance with consumption was acceptable according to the authors, but long-term adherence is often a concern with dietary interventions. Further studies should focus on the following points. First, there is a need for further clarification and consistency regarding dosage, route, timing, and duration of omega-3 for lipid-altering effect. To date, a number of trials demonstrated that fish oil seems to improve the lipid profile
0 7.21 (10.26 to 4.16)a 8 96
0 1 7.05 (14.42 to 0.31) 7.17 (10.4 to 3.94)a 93 97 7.92 (1.56 to 14.28)a 2.80 (12.6 to 18.19)
5 6
0 1 7.29 (10.52 to 4.05)a 6.47 (13.77 to 0.84) 94 97 4.03 (2.29 to 10.36) 8.69 (8.93 to 26.31)
7 4
0 0 7.4 (10.38 to 4.42)a 0.22 (0.73 to 0.28) 97 0
9 2
I2 (%)
at supraphysiological doses. Its effects at more modest doses are unknown. Second, emerging evidence suggests that omega-3, the blood and tissue status of omega-3 (particularly EPA and DHA), may be inadequate in the dialysis population (41). Therefore, compliance should be confirmed routinely by tissue omega-3 measurements during the study period. Further studies should pay more attention to this point. Third, although omega-3 were generally considered safe and well tolerated, future studies are needed to determine the adverse effects after long-term supplementation. Finally, in such future studies, the effect of omega-3 on all-cause and cardiovascular mortality in the dialysis patient group should also be given more attention. In conclusion, our analysis indicates that omega-3 supplementation is significantly associated with a decrease in the level of serum TG and HDL cholesterol, whereas TC, LDL and albumin level are not significantly modified after treatment. Our subgroup analyses also suggested that these data are consistent with the beneficial effects of omega-3 supplementation on TG and LDL cholesterol and no major effects on HDL and TC in short-term intervention trials, normal dose studies and HD populations. However, this result needs to be further confirmed in more high-quality randomized clinical trials.
6.44 (1.42 to 14.3) 10 70
87 18 6.43 (15.74 to 28.59) 3.48 (2.48 to 9.44)
6 6
86 0 9.26 (4.29 to 22.81) 5.12 (16.06 to 5.82)
8 4
8.41 (1.19 to 17.47) 0.18 (1.62 to 1.26) 9 3 79 0 2.22 (9.52 to 13.95) 23.92 (15.20 to 32.65)
MD (95% CI)
HDL cholesterol
No. I (%) trials
0.73 (8.24 to 9.88)
10 3
8 5
7 6
11
94 0
86 48
93
Supplementary Data
35.8 (66.3 to 5.27)a
This work was supported by the National Natural Science Foundation of China (No. 81173240) and the PhD Start-up Fund of Guangdong Medical College (No.2013005; No.2013006). All authors declare no conflicts of interest.
86 84
MD (95% CI)
2
Total cholesterol
No. I (%) trials
Acknowledgments
Supplementary data related to this article can be found at http://dx.doi.org/10.1016/j.arcmed.2014.06.008
Indicates a significant result.
45.6 (76.9 to 14.3)a 7.64 (31.5 to 46.83)
60.5 (98.3 to 22.7)a 11.43 (27.3 to 4.44)
9 3
5 7
10
References
a
28.2 (52.7 to 4.93)a 52.3 (133.6 to 29.03)
Subgroup analysis Dialysis modality HD PD or CAPD Interventional duration Shorter term #3 months Longer term O3 months Dose of omega-3 #2 g/d O2 g/d Sensitivity analysis High-quality (Jadad score $3)
Variables
9 3
2
Triglycerides No. trials MD (95% CI)
Table 2. Subgroup and sensitivity analyses of triglycerides, TC, HDL, and LDL stratified by previously defined study characteristics
2
No. I (%) trials
MD (95% CI)
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LDL cholesterol
476
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25. Khajehdehi P. Lipid-lowering effect of polyunsaturated fatty acids in hemodialysis patients. J Renal Nutr 2000;10:191e195. 26. Schmitz PG, McCloud LK, Reikes ST, et al. Prophylaxis of hemodialysis graft thrombosis with fish oil: double-blind, randomized, prospective trial. J Am Soc Nephrol 2002;13:184e190. 27. Saifullah A, Watkins BA, Saha C, et al. Oral fish oil supplementation raises blood omega-3 levels and lowers C-reactive protein in haemodialysis patientsea pilot study. Nephrol Dial Transplant 2007;22: 3561e3567. 28. Taziki O, Lessan-Pezeshki M, Akha O, et al. The effect of low dose omega-3 on plasma lipids in hemodialysis patients. Saudi J Kidney Dis Transplant 2007;18:571e576. 29. Svensson M, Schmidt EB, Jorgensen KA, et al. The effect of n-3 fatty acids on lipids and lipoproteins in patients treated with chronic haemodialysis: a randomized placebo-controlled intervention study. Nephrol Dial Transplant 2008;23:2918e2924. 30. Bowden RG, Jitomir J, Wilson RL, et al. Effects of omega-3 fatty acid supplementation on lipid levels in endstage renal disease patients. J Renal Nutr 2009;19:259e266. 31. Bowden RG, Wilson RL, Deike E, et al. Fish oil supplementation lowers C-reactive protein levels independent of triglyceride reduction in patients with end-stage renal disease. Nutr Clin Pract 2009;24: 508e512. 32. An WS, Lee SM, Son YK, et al. Effect of omega-3 fatty acids on the modification of erythrocyte membrane fatty acid content including oleic acid in peritoneal dialysis patients. Prostagl Leukotr Essent Fatty Acids 2012;86:29e34. 33. An WS, Lee SM, Son YK, et al. Omega-3 fatty acid supplementation increases 1,25-dihydroxyvitamin D and fetuin-A levels in dialysis patients. Nutr Res 2012;32:495e502. 34. Lemos JR, Alencastro MG, Konrath AV, et al. Flaxseed oil supplementation decreases C-reactive protein levels in chronic hemodialysis patients. Nutr Res 2012;32:921e927. 35. Tayebi-Khosroshahi H, Dehgan R, Habibi Asl B, et al. Effect of omega-3 supplementation on serum level of homocysteine in hemodialysis patients. Iranian J Kidney Dis 2013;7:479e484. 36. Friedman A, Moe S. Review of the effects of omega-3 supplementation in dialysis patients. Clin J Am Soc Nephrol 2006;1:182e192. 37. Lapillonne A, Clarke SD, Heird WC. Polyunsaturated fatty acids and gene expression. Curr Opin Clin Nutr Metabol Care 2004;7:151e156. 38. Kliewer SA, Sundseth SS, Jones SA, et al. Fatty acids and eicosanoids regulate gene expression through direct interactions with peroxisome proliferator-activated receptors alpha and gamma. Proc Natl Acad Sc USA 1997;94:4318e4323. 39. Xu J, Nakamura MT, Cho HP, et al. Sterol regulatory element binding protein-1 expression is suppressed by dietary polyunsaturated fatty acids. A mechanism for the coordinate suppression of lipogenic genes by polyunsaturated fats. J Biol Chem 1999;274:23577e23583. 40. Owen WF Jr, Lew NL, Liu Y, et al. The urea reduction ratio and serum albumin concentration as predictors of mortality in patients undergoing hemodialysis. N Engl J Med 1993;329:1001e1006. 41. Ikizler TA, Morrow JD, Roberts LJ, et al. Plasma F2-isoprostane levels are elevated in chronic hemodialysis patients. Clin Nephrol 2002;58: 190e197.
ORIGINAL ARTICLE
Omega-3 Fatty Acid Supplementation on Lipid Profiles in Dialysis Patients: Meta-analysis Honggang Chi,a,* Xiaoru Lin,b,* Haohai Huang,b Xuebao Zheng,a Tao Li,c and Ying Zoua,d a
Department of Traditional Chinese Medicine, The Second Clinical Medical College, bSchool of Pharmacy, Guangdong Medical College, Dongguan, Guangdong, China c Department of Chemotherapy, People’s Hospital of Gaozhou, Gaozhou, Guangdong, China d Sino-American Cancer Research Institute, Guangdong Medical College, Dongguan, Guangdong, China Received for publication March 2, 2014; accepted June 19, 2014 (ARCMED-D-14-00126).
Background and Aims. Studies of omega-3 supplementation in dialysis patients describe salutary effects on lipid profiles. However, study results have been inconsistent. The aim of this study was to evaluate the influence of omega-3 supplementation on serum lipids in chronic dialysis patients. Methods. A systematic literature search was performed to identify the relevant randomized controlled trials (RCTs) that investigated the effects of omega-3 supplementation on dialysis patients. The outcomes included the levels of triglycerides (TG), total cholesterol (TC), low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol and albumin. Mean differences (MDs) and 95% confidence intervals (CIs) were calculated and heterogeneity was assessed with the I2 test. Results. A total of 678 patients from 14 trials were subjected to meta-analysis. Omega-3 supplementation could significantly decrease the levels of TG (MD, 34.8 mg/dL; 95% CI, 62.32 to 7.28) and LDL (MD, 7.15 mg/dL; 95% CI, 10.11 to 4.2). However, no statistically significant effects were observed for TC, HDL and albumin levels. In a subgroup meta-analysis, a statistically significant effect of omega-3 consumption on TG and LDL was observed in a short-term interventional duration and hemodialysis populations. Conclusion. Our findings indicate that omega-3 supplementation significantly reduced serum TG and LDL level in dialysis patients. However, there is no conclusive evidence that it can modulate the TC, HDL and albumin level. Ó 2014 IMSS. Published by Elsevier Inc. Key Words: Dialysis, Lipid, Meta-analysis, Omega-3.
Introduction Chronic kidney disease (CKD) is strongly associated with an increased risk of cardiovascular disease (CVD), which still remains to be one of the major causes of morbidity and mortality in hemodialysis (HD) patient groups. Annual mortality rates from CVD in this population group are 20 *
These authors contributed equally to this work. Address reprint requests to: Ying Zou, Department of Traditional Chinese Medicine, The Second Clinical Medical College, Sino-American Cancer Research Institute, Guangdong Medical College, No.1, Xincheng Road of Songshan Lake Science and Technology Industry Park, Dongguan, Guangdong Province 523808 China; Phone: þ86 15899695881; FAX: þ86 769 22896403; E-mail: [email protected]
times higher than in the general population (1,2). Although the pathogenesis of CVD in the CKD population is not clearly understood, a number of clinical and epidemiological studies have demonstrated that HD patient status has been strongly associated with lipid abnormalities (3,4). Further research has demonstrated that chronic inflammation is also a contributor to higher CVD incidence among HD patients (5). Moreover, a meta-analysis has shown a significant inverse relation between serum albumin and cardiovascular mortalities (6). Evidence supported the role of lipid-lowering therapy as a means to decrease cardiac death and atherosclerosis-mediated cardiovascular events in persons with CKD (7). In recent decades, the efficacy of pharmacologic interventions on lipid-lowering therapy has been
0188-4409/$ - see front matter. Copyright Ó 2014 IMSS. Published by Elsevier Inc. http://dx.doi.org/10.1016/j.arcmed.2014.06.008
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extensively researched, especially the inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (statins) are gaining widespread acceptance as a principal therapy for the primary and secondary prevention of atherosclerosis and CVD. However, current guidelines and some meta-analyses have provided evidence that the use of statins should not be recommended in dialysisdependent CKD patients (8e12). Thus, the best strategies to treat dyslipidemia in the HD population remain to be established. Omega-3 fatty acids included a-linolenic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA), mainly obtained from fish and fish oils, and are a family of fatty acids that contain two or more double bonds. Several studies have shown that omega-3 fatty acids play an important role in many other health disorders such as prevention of arrhythmias, chronic heart failure, dyslipidemia regulation, modulation of blood pressure levels, progression of arteriosclerosis, rheumatological diseases and osteoporosis, mood depression, chronic kidney disease, chronic inflammatory diseases and others (13e15). Recently, several randomized controlled trials (RCTs) have confirmed the effects of omega-3 supplementation on HD patients. However, these studies have a modest sample size and convey inconsistent results. We therefore deemed a comprehensive systematic review and meta-analysis of RCTs to assess the influence of omega-3 supplementation on serum lipid profile in HD patients.
Materials and Methods Literature Search and Inclusion Criteria According to the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement (16), relevant RCTs were identified by searching PubMed, Embase databases and Cochrane Central Register of Controlled Trials (CENTRAL). All searches were up to date as of December 2013. The structured search strategies used the following format of search terms: (‘‘kidney failure, chronic’’[Mesh] OR ‘dialysis’ OR ‘‘chronic renal failure’’ OR ‘hemodialysis’ OR ‘‘peritoneal dialysis’’ OR ‘‘kidney replacement therapy’’) AND (‘‘omega-3 fatty acids’’ OR ‘‘n-3 fatty acids’’ OR ‘‘fatty acid’’ OR ‘‘omega3’’ OR ‘‘fish oil’’ OR ‘‘a-linolenic acid’’ OR ‘‘eicosapentanoic acid’’ OR ‘‘docosahexanoic acid’’). Our searches were limited to English-language publications and human trials. In addition to electronic search original papers, we also reviewed the references of included RCTs to look for potentially eligible articles. Two investigators (XL and HH) independently did the literature search. Any disagreements were resolved by discussion and consensus. For each of the relevant articles, full publications were retrieved for evaluation on the basis of criteria established a priori. The following inclusive selection criteria in PICOS
order included: a) study population: patients (no matter how many patients recruited) who are receiving renal dialysis (including HD or peritoneal dialysis); b) intervention: omega-3 supplement (no matter what type and regimen applied); c) comparison intervention: placebo or no intervention; d) outcome measure: reported ‘baseline’ and ‘end of intervention’ mean and standard deviation values of lipid measurements and albumin for the active (omega3) and control groups; and e) study design: only RCT reported in a full paper article, and non-randomized and cross-over studies were excluded. Data Extraction and Outcome Measures Two investigators independently collected the data, crosschecked and reached a consensus on all items. The following information was extracted from the included studies: first author’s name, publication year, sample volume (intervention/control), dialysis modality, population information (mean age, gender and location), intervention group (types, grams per day), control group (placebo or other), duration of treatment. It should be emphasized that if the same population was reported in several publications, we only retained the most informative article or complete study to avoid duplication of information. We were interested in the following outcomes or endpoints, including information on baseline and final concentrations (or net changes) of serum total cholesterol (TC), LDL cholesterol, HDL cholesterol, triglycerides (TG) and albumin. Studies that reported results in mmol/l were converted to mg/dL using the standard conversion factors (which was a division of the mmol/l value by 0.02586 for TC, LDL and HDL; and by 0.01129 for TG). These values were captured as the mean change from baseline to followup (with mean SD or mean SE, respectively). Quality Scoring and Risk-of-Bias Assessment We quantified the methodological qualities of studies using validated Jadad 5-point scale (17). Jadad scores ranged from 0 to 5 in which the Jadad score not more than 2 indicates the lowest quality and the score of at least 3 means the highest quality (18). Risk-of-bias assessment was performed in accordance with guidelines outlined in the Cochrane Handbook for Systematic Reviews of Interventions (version 5.1.0) (19). For each study, we made judgments about risk of bias from each of the six domains of the tool. In all cases, an answer ‘‘Yes’’ indicated a low risk of bias, an answer ‘‘No’’ indicated high risk of bias, and if insufficient detail is reported of what happened in the study, the judgment would usually be ‘‘Unclear’’ risk of bias. Statistical Analysis For continuous data, mean differences (MDs) with 95% CIs were calculated. Clinical heterogeneity was assessed
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Figure 1. Flowchart of the study selection process.
by considering the design of each study. Statistical heterogeneity across studies was tested by using the I2 statistic, which was a quantitative measure of inconsistency across studies. Studies with an I2 statistic of 25e50% were considered to have low heterogeneity, those with an I2 statistic of 50% to 75% were considered to have moderate heterogeneity, and those with an I2 statistic of O75% were considered to have a high degree of heterogeneity (20). A random-effects model meta-analysis will be conducted for heterogeneous outcomes (I2 O10%). Otherwise, random effect will be employed. Whenever heterogeneity was present, sensitivity analyses and previously defined subgroup analyses were carried out to identify potential sources. In addition, we also investigated the influence of a single study on the overall pooled estimate by omitting one study in each turn. A p value !0.05 was considered to be statistically significant. All statistical analyses were performed by using Review Manager (Version 5.1.Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2011).
Results Study Identification and Selection The flow chart of search strategy is shown in Figure 1. Of the 863 titles identified from the three databases, 46 RCTs were excluded because of duplicate studies and 800 RCTs were excluded based on the titles and abstracts (reviews or not relevant to our analysis). Moreover, according to the inclusion and exclusion criteria, five articles were further excluded for the following reasons: three studies were cross-over trials and two studies with the combination therapy. It should be noted that two trials conducted by Kooshki et al. (21,22) were reported in the same population; therefore, we combined the informative data and retained only the complete article to avoid duplication of information (22). Finally, 14 RCTs met our inclusion criteria and were included in the analysis (22e35) of which three studies (23,25,26) were determined through checking reference lists of retrieved articles.
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Study Characteristics, Quality Assessment and Bias Assessment Descriptive data for the studies included in our analysis were summarized in Table 1. These studies were published from 1990e2013. A total of 678 patients (334 in the omega-3 group and 344 in control group) were included in this analysis. Of these 14 included studies, 12 studies compared omega-3 to placebo (22e27,29e32,35), whereas two studies compared to no treatment (28,33). The total dosage of omega-3 supplementation daily in the intervention groups ranged from 1.3e6 g. The baseline characteristics of the patients were balanced between the treatment and control arm. The quality of the included studies was assessed by the Jadad score (Table 1). Of 14 studies, all satisfied the criteria of complete outcome data, selective reporting and other bias. All included trials were mentioned as ‘‘random’’, but seven studies lacked appropriately described randomization procedures (23e28,34). Risk-of-bias analysis is shown in Figure S1.
Obvious heterogeneity was observed (I2 5 96%). Random effect model was used to analyze the effect size (Figure 2C). Eleven RCTs were included in the metaanalysis (22,25,27e35), which demonstrated that the level of LDL was significantly decreased in omega-3 treatment group compared with the control group (MD, 7.15 mg/ dL; 95% CI, 10.11 to 4.2; p !0.00001) without significant heterogeneity (I2 5 0%). The fixed effect model was applicable (Figure 2D). Effect of Omega-3 on Albumin The effect of omega-3 on albumin was also assessed in three trials (27,32,33). The present meta-analysis indicated that the omega-3 treatment group did not significantly change the serum albumin level when compared with that of the control group (MD, 0.19 g/dL; 95% CI, 0.50 to 0.13; p 5 0.25). Heterogeneity was significant for this outcome (I2 5 82%). Random effects model was used to analyze the effect size (Figure 3). Subgroup Analysis and Sensitivity Analyses
Effect of Omega-3 on TG Figure 2A shows the pooled results from the random-effects model combing the MD for TG. Thirteen included studies reported the TG in the study population (22,24e35), 12 articles were included in the meta-analysis (22,24e33,35), which suggested that TG levels were decreased significantly in the omega-3 treatment group compared with that of the control group (MD, 34.8 mg/dL; 95% CI, 62.32 to 7.28; p 5 0.01). The test for heterogeneity was significant (I2 5 92%). One study was not included in the metaanalysis because serum TG data were reported as median and range (34). In this article, serum TG level was significantly decreased from 177 mg/dL (128e266 mg/dL) to 147 mg/dL (111e231 mg/dL) for 120 days in the treatment group ( p 5 0.004), yet similar findings were not observed in the control group. Effect of Omega-3 on Cholesterol, HDL-cholesterol, LDLcholesterol Thirteen included studies reported changes in cholesterol (22e25,27e35), which demonstrated that the level of TC was not significantly changed in the omega-3 treatment group compared with the control group (MD, 5.31 mg/dL; 95% CI, 5.02 to 15.65; p 5 0.31). Heterogeneity was noted for this outcome (I2 5 80%). The random effect model was applicable (Figure 2B). The effect of omega-3 on HDL-cholesterol was assessed in 12 trials based on the results of the meta-analysis (22,24,25,27e35). The omega3 treatment group may not significantly change in serum HDL-cholesterol level compared with that of controls (MD, 5.92 mg/dL; 95% CI, 0.50 to 12.35; p 5 0.07).
The effects of omega-3 supplementation on lipid profile in a subgroup of trials defined according to participant characteristics are summarized in Table 2. Trials of short duration (#3 months) showed a significant reduction in the level of serum TG (MD, 45.6 mg/L; 95% CI, 76.9 to 14.3; p 5 0.004) and LDL (MD, 7.29 mg/L; 95% CI, 10.52 to 4.05; p !0.00001), but a nonsignificant reduction in serum TC and HDL levels. Studies with longer duration (O3 months) showed a nonsignificant reduction in TG, TC, HDL and LDL levels. The subgroup analyses according to dialysis modality showed a significant reduction in level of serum TG (MD, 28.2 mg/L; 95% CI, 52.7 to 4.93; p 5 0.02) and LDL (MD, 7.4 mg/L; 95% CI, 10.38 to 4.42; p !0.00001), but a nonsignificant reduction in serum TC and HDL levels in HD patients. Subgroup analyses according to the dose of omega-3 daily supplementation showed that administered omega-3 (doses of #2 g) could significantly decrease the TG level (MD, 60.5 mg/L; 95% CI, 98.3 to 22.7; p 5 0.002) and significantly increase HDL levels (MD, 7.92 mg/L; 95% CI, 1.56 to 14.28; p 5 0.01). Analysis by administered omega-3 (doses O2 g) revealed a significant reduction in serum LDL concentration 7.17 mg/L (95% CI, 10.4 to 3.94; p !0.00001). No significant changes in lipid profile were observed across any subgroup. In addition, we also performed sensitivity analysis by omitting the studies with low quality (Jadad score !3). The pooled results did not change substantially (Table 2). Further exclusions were conducted by omitting any single study that did not materially alter the overall combined MD (data not shown), which adds robustness to our main finding.
Table 1. Principal characteristics of individual studies included in the meta-analysis Gender (M/F)
Treatment group (types/ regimens/dosage)
Duration (months)
Jadad score
No. of patients
Dialysis modality
Age (treatment vs. control)a
Diskin et al. (1990) Ando et al. (1999) Khajehdehi et al. (2000) Schmitz et al. (2002) Saifullah et al. (2007)
7 38 30 24 23
(4/3) (19/19) (15/15) (12/12) (15/8)
HD HD/CAPD HD HD HD
NA 54 vs. 51 32.7 vs. 31.1 52 vs. 54 58 vs. 57
NA 5/33 15/15 11/13 18/5
EPA, caps, 3 g/d EPA, caps, 1.8 g/d Fish oil, caps, 1.5 g/d Fish oil, caps; 4 g/d Fish oil, caps, 1.3g/d
Placebo Placebo Placebo Placebo oil Placebo (linoleic acid)
USA Japan Iran USA India
6 3 2 3 3
4 4 4 4 4
Tzaiki et al. (2007) Svensson et al. (2008) Bowden (1) et al. (2009) Bowden (2) et al. (2009) Kooshki et al. (2011) An (1) et al. (2012)
33 79 87 33 34 14
(15/18) (41/38) (44/43) (18/15) (17/17) (7/7)
HD HD HD HD HD PD
47 vs. 59.5 66 vs. 58 59.3 vs. 60.8 57.2 vs. 64.3 50 vs. 50 52.6 vs. 51.6
11/22 NA 45/42 19/14 21/13 7/7
Omega-3, Omega-3, Omega-3, Omega-3, Omega-3, Omega-3,
No intervention Placebo (olive oil) Placebo (corn oil) Placebo (corn oil) Placebo Placebo (Olive oil)
Iran Denmark USA USA Iran Korea
3 3 6 6 2.5 3
2 5 5 5 5 5
An (2) et al. (2012)
43 (23/20)
HD/PD
58.1 vs. 56.7
20/23
Omega-3, caps, 3 g/d
No intervention
Korea
6
3
HD HD
55.7 vs. 58.3 51.5 vs. 48.6
85/60 63/25
Flaxseed oil, caps, 2 g/d Omega-3, pill, 3 g/d
Placebo (mineral oil) Placebo
Brazil Iran
4 2
4 5
Lemos et al. (2012) Khosroshahi et al. (2013)
145 (70/75) 88 (44/44)
caps, 2 g/d caps, 1.7 g/d caps, 6 g/d pill, 6 g/d caps, 2.08 g/d caps, 3 g/d
Control group
Location
Outcomes of interest TC, Albumin TG, TC, HDL TG, TC, HDL, TG TG, TC, HDL, Albumin TG, TC, HDL, TG, TC, HDL, TG, TC, HDL, TG, TC, HDL, TG, TC, HDL, TG, TC, HDL, Albumin TG, TC, HDL, Albumin TG, TC, HDL, TG, TC, HDL,
LDL LDL, LDL LDL LDL LDL LDL LDL, LDL, LDL LDL
Omega-3 Supplementation in Dialysis Patients
Study/Year
HD, hemodialysis; CAPD, continuous ambulatory peritoneal dialysis; PD, peritoneal dialysis; NA, not available; EPA, eicosapentaenoic acid; TG, triglyceride; TC, total cholesterol; HDL, high-density lipoprotein; LDL, low-density lipoprotein; CRP, C-reactive protein. a Shown as means.
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Figure 2. (AeD) Results of primary meta-analyses.
Discussion Hypercholesterolemia is present in |50% of patients on dialysis. At present, dietary therapy and drug therapy (mainly statins) were used in HD patients to improve their lipid profiles. However, guidelines from the update of the
National Kidney Foundation Kidney Disease Outcomes Quality Initiative (NKF-KDOQI) Clinical Practice Guideline for Diabetes and Chronic Kidney Disease as well as results of the meta-analyses demonstrated that statins should not be recommended in patients undergoing dialysis
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Figure 3. Forest plot of studies comparing the effect of omega-3 vs. control on albumin in dialysis patients.
(8e12). Thus, to find other effective treatments in this population is of great importance. The pooled results from our meta-analysis of all included RCTs showed that omega-3 fatty acids significantly reduced serum TG and LDL level in dialysis patients. However, no statistically significant effects were observed for TC, HDL and albumin levels. The omega-3 effect seemed stronger in studies with a relatively shorter duration and in subjects with HD. For the present meta-analysis, in an attempt to produce robust results, we conducted rigorous inclusion criteria and included only RCTs that clearly stated the enrollment of patients undergoing HD or peritoneal dialysis (PD). Our meta-analysis suggested that omega-3 can significantly decrease the levels of TG and LDL. Moreover, exclusion of any single study and sensitivity analyses based on various exclusion criteria did not materially alter the pooled results, which adds robustness to our main results. However, substantial heterogeneity was observed among these studies. This was not surprising because of the differences in characteristics of populations, amounts of omega-3 consumption compared, and study designs. The main finding of our meta-analysis seems to measure the effects of omega-3 supplementation on lipid status in the dialysis population. A published review conducted by Friedman and Moe (36) implied that omega-3 supplementation dramatically reduced TG and had mixed effects on other lipoproteins. But most of the included studies in this review were uncontrolled trials. Meanwhile, most of the trials used supraphysiological omega-3 doses ($2e3 g/day), so the normal doses effects of omega-3 supplementation are unknown. Moreover, long-term effect of omega-3 supplementation also remains unclear. Compared with the previous review (36), our meta-analysis has some advantages: first, we performed a quantitative combination statistical method to assess the lipid-altering effect of omega-3 in dialysis patients. Second, our subgroup analysis based on participant characteristics (Table 2), implied that omega-3 have salutary effects on TG and LDL levels in HD population, short-term interventional duration (#3 months) and a normal does (!2g/d) group. Besides, we also performed sensitivity analysis by omitting the studies with low quality (Jadad score !3), the pooled results did not change
substantially. Overall, these additional findings in our meta-analysis make our result more robustness. The mechanism of the dramatic lipid-altering effects of omega-3 fatty acids might be through modifying cell membrane structure and function, as well as synthesis of lipid mediators (such as eicosanoids), and fatty acids gene expression (37). 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 (38,39). We also assessed the effect of omega-3 on nutrition status. Evidence from the studies have shown that malnutrition is an important contributor to morbidity and mortality of CVD in renal dialysis patients (6,40). In the present analysis we use albumin to reflect the nutrition status. Moreover, actually albumin is also considered as a risk factor for mortality in patients with CKD. The main finding based on this study indicated that there is no conclusive evidence that omega-3 can improve the nutritional status. However, these results are inconclusive and further adequately powered studies are needed. Although certain positive results were seen with these trials, there are some limitations. Primarily, a majority of the included articles have a small sample size and a limited number of double-blind-designed studies, leaving a potential investigator bias. Furthermore, some studies cannot be included in meta-analysis because data were reported as median and range; however, results of these studies confirm our meta-analysis. Third, although clear inclusion and exclusion criteria were made, significant differences still existed among study design, intervention, and outcome measurement. These factors may have a potential impact on our results. Finally, because lipid profiles change soon after switching diets, omega-3 supplementation would need to be maintained indefinitely to maintain lower lipid concentrations. Compliance with consumption was acceptable according to the authors, but long-term adherence is often a concern with dietary interventions. Further studies should focus on the following points. First, there is a need for further clarification and consistency regarding dosage, route, timing, and duration of omega-3 for lipid-altering effect. To date, a number of trials demonstrated that fish oil seems to improve the lipid profile
0 7.21 (10.26 to 4.16)a 8 96
0 1 7.05 (14.42 to 0.31) 7.17 (10.4 to 3.94)a 93 97 7.92 (1.56 to 14.28)a 2.80 (12.6 to 18.19)
5 6
0 1 7.29 (10.52 to 4.05)a 6.47 (13.77 to 0.84) 94 97 4.03 (2.29 to 10.36) 8.69 (8.93 to 26.31)
7 4
0 0 7.4 (10.38 to 4.42)a 0.22 (0.73 to 0.28) 97 0
9 2
I2 (%)
at supraphysiological doses. Its effects at more modest doses are unknown. Second, emerging evidence suggests that omega-3, the blood and tissue status of omega-3 (particularly EPA and DHA), may be inadequate in the dialysis population (41). Therefore, compliance should be confirmed routinely by tissue omega-3 measurements during the study period. Further studies should pay more attention to this point. Third, although omega-3 were generally considered safe and well tolerated, future studies are needed to determine the adverse effects after long-term supplementation. Finally, in such future studies, the effect of omega-3 on all-cause and cardiovascular mortality in the dialysis patient group should also be given more attention. In conclusion, our analysis indicates that omega-3 supplementation is significantly associated with a decrease in the level of serum TG and HDL cholesterol, whereas TC, LDL and albumin level are not significantly modified after treatment. Our subgroup analyses also suggested that these data are consistent with the beneficial effects of omega-3 supplementation on TG and LDL cholesterol and no major effects on HDL and TC in short-term intervention trials, normal dose studies and HD populations. However, this result needs to be further confirmed in more high-quality randomized clinical trials.
6.44 (1.42 to 14.3) 10 70
87 18 6.43 (15.74 to 28.59) 3.48 (2.48 to 9.44)
6 6
86 0 9.26 (4.29 to 22.81) 5.12 (16.06 to 5.82)
8 4
8.41 (1.19 to 17.47) 0.18 (1.62 to 1.26) 9 3 79 0 2.22 (9.52 to 13.95) 23.92 (15.20 to 32.65)
MD (95% CI)
HDL cholesterol
No. I (%) trials
0.73 (8.24 to 9.88)
10 3
8 5
7 6
11
94 0
86 48
93
Supplementary Data
35.8 (66.3 to 5.27)a
This work was supported by the National Natural Science Foundation of China (No. 81173240) and the PhD Start-up Fund of Guangdong Medical College (No.2013005; No.2013006). All authors declare no conflicts of interest.
86 84
MD (95% CI)
2
Total cholesterol
No. I (%) trials
Acknowledgments
Supplementary data related to this article can be found at http://dx.doi.org/10.1016/j.arcmed.2014.06.008
Indicates a significant result.
45.6 (76.9 to 14.3)a 7.64 (31.5 to 46.83)
60.5 (98.3 to 22.7)a 11.43 (27.3 to 4.44)
9 3
5 7
10
References
a
28.2 (52.7 to 4.93)a 52.3 (133.6 to 29.03)
Subgroup analysis Dialysis modality HD PD or CAPD Interventional duration Shorter term #3 months Longer term O3 months Dose of omega-3 #2 g/d O2 g/d Sensitivity analysis High-quality (Jadad score $3)
Variables
9 3
2
Triglycerides No. trials MD (95% CI)
Table 2. Subgroup and sensitivity analyses of triglycerides, TC, HDL, and LDL stratified by previously defined study characteristics
2
No. I (%) trials
MD (95% CI)
Chi et al./ Archives of Medical Research 45 (2014) 469e477
LDL cholesterol
476
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