3.2 Meta-analysis of efficacy
3.2.1 LDL cholesterol
Four studies measured the changes in LDL cholesterol in 589 patients treated with statin alone and 581 patients treated with statin plus omega-3 fatty acid (Fig. 2A). There were no significant differences in LDL cholesterol changes between the 2 groups, and re-analysis using a random-effects model yielded the same result.
3.2.2 Total cholesterol/HDL cholesterol ratio
Three studies assessed the changes in total cholesterol/HDL cholesterol ratio in 382 patients treated with statin alone and 368 patients treated with statin plus omega-3 fatty acid (Fig. 2B). The combination treatment afforded a significantly greater reduction in total cholesterol/HDL cholesterol than statin alone did. Data re-analysis using a random-effects model also revealed a significant difference between the 2 treatments.
3.3 Qualitative assessments of other lipid parameters
Lipid parameters, except LDL cholesterol and total cholesterol/HDL cholesterol ratio, are presented in Table 2.
3.4 Meta-analysis of safety
3.4.1 Total adverse events
In total, 4 studies described adverse events, including treatment-related side effects. Two hundred fifty-two adverse events occurred in 620 patients (40.6%) treated with statin alone, and 265 adverse events occurred in 611 patients (43.4%) treated with statin plus omega-3 fatty acid (Fig. 3A). There were no significant differences in total adverse events between the 2 groups. Re-analysis using a random-effects model yielded the same result.
3.4.2 Gastrointestinal adverse events
Sixty-seven gastrointestinal adverse events occurred in 620 patients (10.8%) treated with statin alone and 95 occurred in 611 patients (15.5%) treated with statin plus omega-3 fatty acid (Fig. 3B). The gastrointestinal adverse events were significantly increased in patients who received combination therapy with omega-3 fatty acid. However, re-analysis using a random-effects model yielded no significant results (RR = 0.667; 95% CI 0.283–1.996).
3.5 Sensitivity analyses and publication bias
Sensitivity analysis was performed by recalculating all findings after data from each study included in the meta-analysis were omitted in turn. The findings were not altered significantly throughout this process (data available upon request). We also evaluated publication bias. The funnel plots were not obviously asymmetric. The results of Begg rank-correlation test and Egger regression test are shown in Table 3. No publication bias was observed for any tested comparison.
4.1 Summary of the main results
We performed a systematic review and meta-analysis to evaluate the safety and efficacy of statin monotherapy and combination therapy with statin and omega-3 fatty acid in patients with dyslipidemia. First, we found that changes in lipid concentration differed significantly between the 2 drug regimens. Combination therapy with statin and omega-3 fatty acid afforded greater reduction in total cholesterol/HDL cholesterol ratio. Second, treatment with statin plus omega-3 fatty acid was associated with a significant increase in the number of gastrointestinal adverse events, but not in total adverse events.
We performed the qualitative assessment of other lipid concentrations owing to lack of adequate number of studies or different data types to perform a meta-analysis (Table 2). Five studies were included to evaluate non-HDL cholesterol, triglycerides, and HDL cholesterol.[7–10,12] In all studies, the combination treatment afforded significantly greater reductions in non-HDL cholesterol and triglycerides than treatment with statin alone did. In addition, the combination treatment was associated with significant increases in HDL cholesterol. Five studies evaluating VLDL cholesterol showed significant cholesterol-lowering effects by the combination treatment.[7–11] Moreover, the combination treatment was found to be more effective in reducing total cholesterol than statin monotherapy in the 4 included studies.[7–10] Six studies were included to evaluate apoB, and 2 of the studies showed no significant difference between the 2 groups.[7–12] A significant association between combination treatment and apolipoprotein A1 increase was shown in 1 of the 4 included studies. Overall, the results of qualitative assessment showed that combination therapy with statin and omega-3 fatty acid was generally more effective in regulating lipid concentration than statin monotherapy.
LDL cholesterol is clinically the most important measurement in a lipid profile, and it is closely related to cardiovascular disease or death.[20,21] Based on the present meta-analysis, no significant difference in LDL cholesterol levels between statin monotherapy and combination therapy with omega-3 fatty acid was inferred; however, the offsetting effect of omega-3 fatty acid on LDL cholesterol cannot be completely excluded. This finding is in agreement with the results of previous studies in which omega-3 fatty acid consumption was reported to be associated with mild increases in LDL cholesterol in patients with hypertriglycemia and dyslipidemia.[5,6] This change can be explained, at least in part, by the increased rate of conversion of VLDL to LDL particles.[2–4]
The results of the meta-analysis by Sethi et al are noteworthy. The meta-analysis was performed to estimate the total and cardiovascular mortalities in participants receiving omega-3 fatty acid, followed by a metaregression of dose, docosahexaenoic acid/eicosapentaenoic acid (DHA/EPA) ratio, duration of treatment, and use of lipid-lowering/statin therapy in control group. The results showed that omega-3 fatty acid had no effect on total mortality (RR = 0.96; 95% CI, 0.92–1.01), but it reduced cardiovascular mortality (RR = 0.93; 95% CI, 0.87–0.98). In addition, lower control group statin use and higher DHA/EPA ratio was associated with higher reduction in total mortality. In other words, statin use may mitigate the positive effects of omega-3 fatty acid. Further research or clinic trials can provide more evidence on the influence of combination therapy with statin and omega-3 fatty acid on LDL cholesterol.
In the meta-analysis on safety, the incidence of gastrointestinal adverse events was slightly higher in patients receiving statin and omega-3 fatty acid combination therapy. Statin or omega-3 use is associated with several side effects ranging from mild to severe. Gastrointestinal problems are frequently caused by treatment with statins and omega-3 fatty acid alone, and their concomitant use may increase the risk of side effects significantly. Therefore, the adverse events should be monitored more intensively in patients receiving combination treatment.
4.2 Strengths and limitations
There are certain limitations to our present meta-analysis. First, only a small number of relevant studies were included and data were inadequate. Second, our analysis was based on previous reports, which were not necessarily complete or accurate, and we were unable to analyze data, including sex, ages, duration, or other factors. Third, the results based on statistical analysis could be partially different from the evaluations of safety or efficacy in individual patients.
Despite these limitations, to the best of our knowledge, this is the first study to compare the safety and efficacy of statin treatment alone versus combination therapy with statin and omega-3 fatty acid in patients with dyslipidemia. We derived accurate estimates of the clinical efficacies of the 2 types of treatment. Our data have greater statistical power than the data subsets of the reports included in the meta-analysis.
Overall, we suggest that combination therapy with statins and omega-3 fatty acid enhances the lipid profile, except LDL cholesterol, when compared with statin monotherapy. However, controlling LDL cholesterol levels is important for preventing cardiovascular diseases and related deaths. Furthermore, safety issues with the concomitant use of statins and omega-3 fatty acid should be considered. Thus, combination therapy with statins and omega-3 fatty acid should be cautiously recommended after assessing the benefits and risks.
The contributions of the authors to the manuscript are as follows. Choi HD: study design, data collection, data analyses, coordination, and writing the manuscript; S.M.C.: study design, data collection, data analyses, and reviewing the manuscript. All authors read and approved the final manuscript.
Conceptualization: Hye Duck Choi.
Data curation: Hye Duck Choi, Seung Min Chae.
Formal analysis: Hye Duck Choi, Seung Min Chae.
Funding acquisition: Hye Duck Choi.
Investigation: Hye Duck Choi, Seung Min Chae.
Methodology: Hye Duck Choi.
Project administration: Hye Duck Choi.
Resources: Hye Duck Choi.
Software: Hye Duck Choi.
Supervision: Hye Duck Choi.
Validation: Hye Duck Choi.
Visualization: Hye Duck Choi.
Writing – original draft: Hye Duck Choi.
Writing – review and editing: Hye Duck Choi.
Hye Duck Choi orcid: 0000-0003-2292-6827.
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Keywords:Copyright © 2018 The Authors. Published by Wolters Kluwer Health, Inc. All rights reserved.
dyslipidemia; meta-analysis; omega-3 fatty acids; statins; systematic review