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Does Omega-3 Fatty Acid Supplementation Have Favorable Effects on the Lipid Profile in Postmenopausal Women? A Systematic Review and Dose–response Meta-analysis of Randomized Controlled Trials
Faculty of Medicine, "Carol Davila" University of Medicine and Pharmacy, Bucharest, Romania & Department of Hematology, Center of Hematology and Bone Marrow Transplantation, Fundeni Clinical Institute, Bucharest, Romania
Department of Clinical Nutrition & Dietetics, Faculty of Nutrition and Food Technology, Student Research Committee, Shahid Beheshti University of Medical Sciences, Tehran, Iran
Address for correspondence: Ahmed Abu-Zaid, MD, College of Graduate Health Sciences, University of Tennessee Health Science Center, Memphis, TN 38163, USA
College of Medicine, Alfaisal University, Riyadh, Saudi ArabiaCollege of Graduate Health Sciences, University of Tennessee Health Science Center, Memphis, TN, USA
Menopause is associated with disturbances in the metabolism of lipids. Moreover, during the postmenopausal period, female subjects are more prone to develop dyslipidemia. Omega-3 fatty acids, which exert cardioprotective, anti-inflammatory, and lipid-lowering actions, are commonly recommended in postmenopausal women. However, their effect on serum lipids in this population remains unclear. This systematic review and meta-analysis of randomized controlled trials (RCTs) was conducted to clarify this research question.
Methods
We systematically searched the Web of Science, Scopus, PubMed/MEDLINE, and EMBASE databases from their inception until January 3, 2022. The DerSimonian and Laird random-effects model was used to combine effect sizes.
Findings
Omega-3 fatty acid supplementation resulted in a decrease in triglyceride concentrations (weighted mean difference [WMD], –17.8 mg/dL; 95% CI, –26 to –9.6; P < 0.001), particularly in the RCTs that lasted ≤16 weeks (WMD, –18.6 mg/dL), when the baseline triglyceride concentrations were ≥150 mg/dL (WMD, –22.8 mg/dL), in individuals with a body mass index ≥30 kg/m2 (WMD, –19.3 mg/dL), and when the dose of omega-3 fatty acids was ≥1 g/d (WMD, –21.10 mg/dL). LDL-C (WMD, 4.1 mg/dL; 95% CI, 1.80 to 6.36; P < 0.001) and HDL-C (WMD, 2.1 mg/dL; 95% CI, 0.97 to 3.2; P < 0.001) values increased. Total cholesterol levels (WMD, –0.15 mg/dL; 95% CI, –4 to 3.74; P = 0.94) remained unchanged after administration of omega-3 fatty acids.
Implications
In postmenopausal women, supplementation with omega-3 fatty acids resulted in a significant reduction in triglyceride concentrations and a modest elevation in HDL-C and LDL-C levels, whereas this intervention did not affect total cholesterol values.
Serum lipids play an important role in atherogenesis. Postmenopausal changes, including changes in the lipid profile, are independent risk factors for CVD, as an increase in LDL-C and triglyceride (TG) levels and a decrease in HDL-C concentrations are noted following menopause.
In female subjects, the decline in estrogen levels that accompanies menopause and the postmenopausal period is paralleled by an increased risk of developing cardiometabolic disorders; that is, CVD, type 2 diabetes mellitus, obesity, dyslipidemia, the metabolic syndrome, and others.
Because the cardioprotective effect of estradiol, the main estrogen hormone, is lost, postmenopausal women experience an elevation in body fat mass and adiposity, as well as disturbances in lipid and energy metabolism. These actions subsequently result in alterations of the concentrations of the main components of the lipid profile in the serum; that is, TG, LDL-C, HDL-C, and total cholesterol (TC).
In turn, as TC, LDL-C, and TG levels rise and HDL-C values drop, female subjects exhibit an elevation in their cardiovascular risk and should be screened accordingly for the presence of dyslipidemia. Intake of fish oil or fish has been shown to improve the lipid profile and to exert anti-inflammatory effects as well.
Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial Gruppo Italiano per lo Studio della Sopravvivena nell'Infarto miocardico.
Supplementation with omega-3 fatty acids has been recommended in postmenopausal women due to the numerous health benefits associated with consumption of these compounds.
Omega-3 fatty acids are known to exhibit cardioprotective, anti-inflammatory, antidiabetic, and antineoplastic effects, and a satisfactory dietary intake can be reached by eating fish, nuts, seeds, poultry fat, and vegetable oils.
Effects of DHA-rich n-3 fatty acid supplementation and/or resistance training on body composition and cardiometabolic biomarkers in overweight and obese post-menopausal women.
The comparison of the effect of soybean and fish oil on supplementation on menopausal symptoms in postmenopausal women: a randomized, double-blind, placebo-controlled trial.
Complementary therapies in clinical practice.2020; : 41
Randomized multicenter placebo-controlled trial of omega-3 fatty acids for the control of aromatase inhibitor–induced musculoskeletal pain: SWOG S0927.
Differential eicosapentaenoic acid elevations and altered cardiovascular disease risk factor responses after supplementation with docosahexaenoic acid in postmenopausal women receiving and not receiving hormone replacement therapy.
American journal of clinical nutrition.2004; 79: 765-773
Although several randomized controlled trials (RCTs) have explored the impact of omega-3 fatty acids on serum lipid concentrations in postmenopausal women, their results have produced conflicting results, and no meta-analysis of RCTs has been conducted to date to clarify their effect on the lipid profile. Thus, we conducted a systematic review and meta-analysis of RCTs to investigate the effect of omega-3 fatty acid supplementation on serum lipid levels in postmenopausal female subjects.
Materials and Methods
Study Design and Literature Search
The Preferred Reporting Items for Systematic Reviews and Meta-Analysis statement was used as a guideline for the development of the present study.
This meta-analysis of the literature was executed by searching several electronic databases, namely Web of Science, Scopus, PubMed/MEDLINE, and EMBASE, from their inception to January 3, 2022. No time restrictions were applied to the search. A combination of key words and MeSH headings was applied to ascertain the potentially relevant studies (see Supplemental Table I). Lastly, additional publications were detected by hand-searching the reference lists of related original articles and/or reviews.
Inclusion and Exclusion Criteria
The Population, Intervention, Comparator, Outcome model was used to select relevant RCTs. We decided upon the following inclusion criteria: (1) Population: postmenopausal adult women aged ≥18 years; (2) Intervention: supplementation with omega-3 fatty acids; (3) Comparator: placebo group; and (4) Outcome: mean and SD for TG, HDL-C, TC, and LDL-C concentrations at baseline and at the end of the RCT. Manuscripts published in languages other than English, conference abstracts, publications without sufficient data reported, non-RCT studies, and trials without a suitable placebo group were excluded.
Data Extraction
We extracted and collected the necessary data from each RCT using a standardized Microsoft Office Excel sheet (Microsoft Corporation, Redmond, WA, USA). The extraction was performed independently by 2 investigators, and any discrepancy was resolved by consensus with a third author. The following data were extracted from the included RCTs: publication year, first author's name, omega-3 fatty acid daily dose, data on the health status of the participants, mean (SD) of the outcomes before and after the RCT, study country, sample size, mean age of the participants, and follow-up time.
Risk of Bias Assessment
The quality of the included RCTs was assessed based on the revised Cochrane risk-of-bias tool (Risk of Bias 2). This tool was used to assess several types of bias: those due to deviations from the intended interventions, the randomization process, missing outcome data, selection of the reported result, and measurement of the outcome.
The variations in the outcome variables were analyzed to compute the pooled results (ie, the weighted mean difference [WMD] with pertinent 95% CIs) by using the DerSimonian and Laird random-effects model. For WMD, P values <0.05 were considered statistically significant.
We applied a suitable formula when the mean and SD had not been reported in a standard format (SE and SD of change).
Higgins JPT, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, Welch VA (editors). Cochrane Handbook for Systematic Reviews of Interventions version 6.3 (updated February 2022). Cochrane (London, United Kingdom), 2022. Available from www.training.cochrane.org/handbook. Date Accessed: January 15, 2022.
The SEM was converted to SD using the following formula: SD = SEM × √n (n = number of participants in each group). In addition, if the SD of the mean change was not described in the publications, we calculated it using the next formula: SD alteration = square root [(SD baseline2 + SD end2) – (2 × R × SD baseline × SD end)].
According to previous studies in which mean differences were mentioned, a correlation coefficient of 0.8 was supposed as the R value in the aforementioned formula.
Statistical heterogeneity among the RCTs was tested by means of the Cochran's Q statistic and quantified by the I2 test (which was interpreted to signify high heterogeneity at >50%; moderate heterogeneity at 26%–50%; and low heterogeneity at ˂25%), and a P value <0.10 was viewed as statistically significant. In addition, an a priori subgroup analysis was planned to discover the influence of the daily dose of omega-3 fatty acids, duration of the intervention, the baseline body mass index (BMI), and the baseline variables on the lipid profile variations. The aforementioned evaluation was executed as a sensitivity analysis by eliminating one trial at a time and recalculating the overall results to assess the stability of the effect size. A funnel plot figure and the Egger's test (P value <0.1 = statistical significance for publication bias) were used to assess publication bias in the RCTs.
Computations were performed with Stata version 14 (Stata Corp, College Station, TX, USA).
Results
Study Selection
The database search yielded a total of 513 articles. During the next stage, we removed 127 records because they were duplicates. We omitted 355 publications based on the screening of titles and/or abstracts. In total, 32 papers were retrieved for full-text examination. Finally, 10 articles
Effects of DHA-rich n-3 fatty acid supplementation and/or resistance training on body composition and cardiometabolic biomarkers in overweight and obese post-menopausal women.
The comparison of the effect of soybean and fish oil on supplementation on menopausal symptoms in postmenopausal women: a randomized, double-blind, placebo-controlled trial.
Complementary therapies in clinical practice.2020; : 41
Randomized multicenter placebo-controlled trial of omega-3 fatty acids for the control of aromatase inhibitor–induced musculoskeletal pain: SWOG S0927.
Differential eicosapentaenoic acid elevations and altered cardiovascular disease risk factor responses after supplementation with docosahexaenoic acid in postmenopausal women receiving and not receiving hormone replacement therapy.
American journal of clinical nutrition.2004; 79: 765-773
with 14 arms on TC, 14 arms on TG, 13 arms on HDL-C, and 13 arms on LDL-C were included in the present meta-analysis (Figure 1).
Figure 1Flowchart depicting the study selection and inclusion process for the present meta-analysis. RCT = randomized controlled trial; TC = total cholesterol; TG = triglycerides.
The characteristics of the included papers are summarized in the table. The participants’ mean age varied from 53.3 to 60 years. The analyzed manuscripts were published between 1996 and 2021. Duration of omega-3 fatty acid treatment ranged from 2 weeks to 24 months. All RCTs recruited postmenopausal women. The daily recommended dosage of omega-3 fatty acids ranged from 285 mg/d to 14 g/d. The subjects involved in the RCTs were healthy premenopausal female subjects or postmenopausal women diagnosed with metabolic syndrome, type 2 diabetes mellitus, breast cancer, or overweight/obesity. The RCTs were conducted in Spain, Iran, the United States, Brazil, France, Canada, and Kuwait. Supplemental Table II shows the summary of the quality of the included RCTs.
Findings From the Meta-Analysis
Effects of Omega-3 Fatty Acids on LDL-C Concentrations
The overall combined estimate of effect size (13 RCT arms; placebo = 490 subjects; omega-3 fatty acid supplementation = 494 subjects) for LDL-C concentrations is reported in Figure 2. Omega-3 fatty acid treatment significantly increased LDL-C levels (WMD, 4.1 mg/dL; 95% CI, 1.8 to 6.36; P < 0.001), with significant heterogeneity noted among the RCTs (I2 = 44.3%; P = 0.043). Moreover, a notable elevation in LDL-C values was observed in the RCTs that lasted ≤16 weeks (WMD, 5.5 mg/dL; 95% CI, 3.2 to 7.8; P < 0.001) compared with >16 weeks (WMD, 0.35 mg/dL; 95% CI, –3.35 to 4; P = 0.85). The elevation in LDL-C concentrations was more pronounced when the LDL-C baseline value was <130 mg/dL (WMD, 4.2 mg/dL; 95% CI, 0.75 to 7.6; P = 0.01) versus ≥130 mg/dL (WMD, 3.75 mg/dL; 95% CI, 0.6 to 6.9; P = 0.02). Moreover, a significant increase in LDL-C was also detected in subjects with a BMI ≥30 kg/m2 (WMD, 4.90 mg/dL; 95% CI, –0.76 to 9.05; P = 0.02) versus <30 kg/m2 (WMD, 3.54 mg/dL; 95% CI, 0.05 to 7; P = 0.047). Omega-3 fatty acid supplementation increased LDL-C levels in a notable fashion when the dose was ≥1 g/d (WMD, 3.9 mg/dL; 95% CI, 2 to 5.85; P < 0.001) compared with <1 g/d (WMD, 5.22 mg/dL; 95% CI, –3.85 to 14.30; P = 0.25) (see Supplemental Figure 1).
Figure 2Forest plot of randomized controlled trials investigating the effects of omega-3 fatty acid supplementation on LDL-C levels. A total of 13 randomized controlled trial arms were included in the analysis. The dotted vertical line is a visual assessment of heterogeneity of the studies. The diamond represents the pooled effect estimate. The solid vertical line from 0 on the x-axis is the line of no effect. The short horizontal lines associated with each square represent the CIs. BMI = body mass index; WMD = weighted mean difference.
Effects of Omega-3 Fatty Acids on HDL-C Concentrations
The overall combined estimate of effect size (13 RCT arms; placebo = 490 participants, omega-3 fatty acid supplementation = 494 participants) for HDL-C concentrations is reported in Figure 3. Administration of omega-3 fatty acids produced a notable elevation of HDL-C levels (WMD, 2.1 mg/dL; 95% CI, 0.97 to 3.2; P < 0.001), with significant heterogeneity noted among the RCTs (I2 = 68.8%; P < 0.001). Moreover, a notable elevation in HDL-C was detected in the RCTs that lasted ˃16 weeks (WMD, 2.15 mg/dL; 95% CI, 0.03 to 4.25; P = 0.047) versus ≤16 weeks (WMD, 2.05 mg/dL; 95% CI, 0.70 to 3.5; P = 0.003). In the stratified analysis, a pronounced increase in HDL-C levels was exhibited by the subjects with HDL-C ≥50 mg/dL at baseline (WMD, 2.60 mg/dL; 95% CI, 1.35 to 3.9; P < 0.001) versus <50 mg/dL at baseline (WMD, 0.45 mg/dL; 95% CI, –0.75 to 1.7; P = 0.46). Moreover, the administration of omega-3 fatty acids significantly elevated HDL-C concentrations when the BMI of the subjects was <30 kg/m2 (WMD, 3.48 mg/dL; 95% CI, 1.8 to 5.15; P < 0.001) versus ≥30 kg/m2 (WMD, 0.97 mg/dL; 95% CI, –0.30 to 2.25; P = 0.13). Omega-3 fatty acids increased HDL-C values in a notable fashion when the dose was ≥1 g/d (WMD, 2.6 mg/dL; 95% CI, 1.45 to 3.75; P < 0.001) compared with <1 g/d (WMD, 0.6 mg/dL; 95% CI, –1.65 to 2.8; P = 0.61) (see Supplemental Figure 1).
Figure 3Forest plot of randomized controlled trials investigating the effects of omega-3 fatty acid supplementation on HDL-C levels. A total of 13 randomized controlled trial arms were included in the analysis. The dotted vertical line is a visual assessment of heterogeneity of the studies. The diamond represents the pooled effect estimate. The solid vertical line from 0 on the x-axis is the line of no effect. The short horizontal lines associated with each square represent the CIs. P = 0.000 equals P < 0.001. BMI = body mass index; WMD = weighted mean difference.
Effects of Omega-3 Fatty Acids on TC Concentrations
The overall combined estimate of effect size (14 RCT arms; placebo = 550 participants, omega-3 fatty acid administration = 554 participants) for TC concentrations is reported in Figure 4. Treatment with omega-3 fatty acids did not influence TC levels (WMD, –0.15 mg/dL; 95% CI, –4 to 3.74; P = 0.94), with significant heterogeneity noted among the RCTs (I2 = 80.6%; P < 0.001). In the stratified analysis based on treatment duration, there was no impact of the dose (grams per day), of the baseline TC values, or of the baseline BMI on the effects of omega-3 fatty acid supplementation on TC concentrations.
Figure 4Forest plot of randomized controlled trials investigating the effects of omega-3 fatty acid supplementation on total cholesterol levels. A total of 14 randomized controlled trial arms were included in the analysis. The dotted vertical line is a visual assessment of heterogeneity of the studies. The diamond represents the pooled effect estimate. The solid vertical line from 0 on the x-axis is the line of no effect. The short horizontal lines associated with each square represent the CIs. P = 0.000 equals P < 0.001. BMI = body mass index; WMD = weighted mean difference.
Effects of Omega-3 Fatty Acids on TG Concentrations
The overall combined estimate of effect size (14 RCT arms; placebo = 550 subjects, omega-3 fatty acid supplementation = 554 subjects) for TG concentrations is reported in Figure 5. Administration of omega-3 fatty acids significantly decreased TG values (WMD, –17.8 mg/dL; 95% CI, –26 to –9.6; P < 0.001), with significant heterogeneity noted among the RCTs (I2 = 90%; P < 0.001). Moreover, a more notable reduction in TG levels was detected in the RCTs that lasted ≤16 weeks (WMD, –18.6 mg/dL; 95% CI, –29.35 to –7.80; P = 0.001) versus >16 weeks (WMD, –15.8 mg/dL; 95% CI, –23.7 to –7.85; P < 0.001). In the stratified analysis, a pronounced decrease of TG levels was noted when the baseline TG concentrations were ≥150 mg/dL (WMD, –22.8 mg/dL; 95% CI, –36.20 to –9.30; P = 0.001) versus <150 mg/dL (WMD, –17.05 mg/dL; 95% CI, –26 to –8.10; P < 0.001). Moreover, TG values significantly decreased in the individuals with a BMI ≥30 kg/m2 (WMD, –19.30 mg/dL; 95% CI, –31.95 to –6.7; P = 0.003) versus BMI <30 kg/m2 (WMD, –15.6 mg/dL; 95% CI, –29.6 to –1.60; P = 0.02). Omega-3 fatty acids reduced TG in a notable fashion when the dose was ≥1 g/d (WMD, –21.10 mg/dL; 95% CI, –30.65 to –11.6; P < 0.001) compared with <1 g/d (WMD, –10.30 mg/dL; 95% CI, –29.35 to 8.70; P = 0.28) (see Supplemental Figure 1).
Figure 5Forest plot of randomized controlled trials investigating the effects of omega-3 fatty acid supplementation on triglyceride levels. A total of 14 randomized controlled trial arms were included in the analysis. The dotted vertical line is a visual assessment of heterogeneity of the studies. The diamond represents the pooled effect estimate. The solid vertical line from 0 on the x-axis is the line of no effect. The short horizontal lines associated with each square represent the CIs. P = 0.000 equals P < 0.001. BMI = body mass index; WMD = weighted mean difference.
In the nonlinear dose–response assessment, a negative correlation was detected between the changes in TG levels and serum TG concentrations at baseline (milligrams per deciliter), as well as the omega-3 fatty acid supplementation dosage (grams per day) (P < 0.001) (see Supplemental Figure 2).
Sensitivity Analysis
Sensitivity analyses were executed by sequentially abolishing each RCT arm to estimate the vigor of the pooled meta-analysis results. The results of the present research were stable when a trial was eliminated and significant changes of our findings did not occur (see Supplemental Figure 3).
Publication Bias
No publication bias was detected regarding the combined effect size of HDL-C, LDL-C, TG, and TC concentrations in the funnel plots, which was also confirmed by the Egger's tests (see Supplemental Figure 4).
Discussion
The present systematic review and meta-analysis of RCTs analyzed the impact of omega-3 fatty acid supplementation on the lipid profile in postmenopausal female subjects. Based on data derived from 14 RCT arms, our findings suggest that the administration of omega-3 fatty acids in postmenopausal women results in a significant reduction in TG concentrations and a modest elevation in HDL-C and LDL-C levels. However, TC values were not influenced by the consumption of these compounds.
Omega-3 fatty acids were effective in reducing TG concentrations, irrespective of the duration of the intervention, preadministration TG levels, or the BMI of the recruited participants. However, these compounds displayed a more potent effect in the RCTs that lasted ≤16 weeks and in patients with baseline hypertriglyceridemia or obesity. Nevertheless, only doses ≥1 g/d exerted TG-lowering actions. This benefit of omega-3 prescription is particularly relevant because postmenopausal female subjects, compared with female subjects in premenopause, are 3.20 times more likely to be diagnosed with elevated TG concentrations, according to a meta-analysis that pooled data from ∼95,000 postmenopausal and 67,000 premenopausal women.
Metabolic syndrome and its components in premenopausal and postmenopausal women: a comprehensive systematic review and meta-analysis on observational studies.
In addition, another meta-analysis noted that the difference in TG levels between postmenopausal and premenopausal female subjects is ∼24 mg/dL, increasing cardiovascular risk in the former population.
reporting that TG values are higher by 50 mg/dL in postmenopausal versus premenopausal women (P = 0.029) and that TG concentrations are associated with 2 species of phosphatidylethanolamines that were measured in elevated concentrations postmenopause (r = 0.65, P < 0.001 for PC.ae.C38:1; r = 0.60, P < 0.001 for PC.ae.C38:2). A recent RCT also confirmed that omega-3 fatty acids in a dose of 1950 mg daily exhibit TG-lowering effects, in particular when the intervention was combined with resistance training in postmenopausal female subjects diagnosed with overweight or obesity.
Effects of DHA-rich n-3 fatty acid supplementation and/or resistance training on body composition and cardiometabolic biomarkers in overweight and obese post-menopausal women.
In our study, administration of omega-3 fatty acids was also clinically effective in decreasing TG values with 10% to 15% depending on the context of administration and in a dose intermediary between the aforementioned ones. Because hypertriglyceridemia increases the risk of coronary heart disease, omega-3 fatty acid supplementation has been recommended by international forums (eg, the Spanish Menopause Society), particularly in postmenopausal female subjects who do not consume 2 servings of bluefish per week, irrespective if they already suffer from ischemic heart disease.
However, the recommended dosage was of at least 3 g/d, whereas our research revealed that 1 g/d was sufficient to decrease TG levels by 10% to 15%.
In terms of their impact on HDL-C, omega-3 fatty acids only produced a 5% to 7% elevation of HDL-C concentrations, irrespective of the duration of the intervention. However, these compounds were more potent in increasing HDL-C values when the administration lasted >16 weeks, the preadministration HDL-C levels were low, the subjects were not diagnosed with obesity, or the dose of prescription was ≥1 g/d. In postmenopausal women, HDL-C concentrations are 1.45 times lower than in female subjects in premenopause
Metabolic syndrome and its components in premenopausal and postmenopausal women: a comprehensive systematic review and meta-analysis on observational studies.
and, thus, our finding might support the use of omega-3 fatty acids to elevate HDL-C values and reduce cardiovascular risk during premenopause. However, the impact on HDL-C concentrations was rather minor, clinically negligible, and would possibly be of aid only to individuals with borderline HDL-C levels. Contrastingly, a recent RCT discovered that omega-3 fatty acids, when combined with resistance training, decreased rather than increased HDL-C values.
Effects of DHA-rich n-3 fatty acid supplementation and/or resistance training on body composition and cardiometabolic biomarkers in overweight and obese post-menopausal women.
However, the maintenance of HDL-C within the normal range remains an effective strategy in reducing cardiovascular risk and in the prevention of cardiovascular events in adults.
Omega-3 fatty acid supplementation led to a clinically irrelevant elevation in LDL-C levels (ie, <5%) and did not affect TC concentrations. Studies have revealed that the difference between postmenopausal and premenopausal female subjects is ∼23 mg/dL for TC and 17 mg/dL for LDL-C, thus increasing cardiovascular risk in the former population.
The analysis of the plasma lipidome during postmenopause also showed that, compared with the premenopausal period, there is an elevation in LDL-C, TC, and TG values, as well as a reduction in HDL-C levels after the menopause,
Metabolic syndrome and its components in premenopausal and postmenopausal women: a comprehensive systematic review and meta-analysis on observational studies.
Thus, identifying other strategies to manage elevated LDL-C and TC concentrations in this population remains an important task for physicians and researchers in the field of lipidology. Statins and other lipid-lowering drugs continue to be key elements in the control of serum lipid concentrations in patients with dyslipidemia and/or in the primary prevention of CVD.
However, it must be taken into consideration that postmenopausal women may undergo hormone replacement therapy that can also influence the lipid profile. Tibolone can decrease the concentrations of TC, TG, LDL-C, and HDL-C, whereas raloxifene increases HDL-C and lowers TC, TG, and LDL-C levels,
Raloxifene has favorable effects on the lipid profile in women explaining its beneficial effect on cardiovascular risk: a meta-analysis of randomized controlled trials.
The effect of vitamin D on the lipid profile as a risk factor for coronary heart disease in postmenopausal women: a meta-analysis and systematic review of randomized controlled trials.
The influence of omega-3 supplementation on vitamin D levels in humans: a systematic review and dose-response meta-analysis of randomized controlled trials.
Critical reviews in food science and nutrition.2020; : 1-8
In terms of health risks, omega-3 fatty acids are generally considered safe. Potential adverse effects associated with the consumption of these supplements consist of mild gastrointestinal symptoms, off-tastes, and headache.
in: Egbuna C Dable Tupas G Functional Foods and Nutraceuticals: Bioactive Components, Formulations and Innovations. Springer International Publishing,
2020: 219-239
However, the National Center for Complementary and Integrative Health of the National Institutes of Health also highlights the risk of food–drug interactions, especially with antithrombotic agents, as well as the risk of allergies to fish/seafood. Moreover, it has been shown that fish can accumulate toxic mercury, and thus caution is required when fish is consumed. In the examined RCTs, only 2 adverse events were reported in the omega-3 fatty acid intervention group. Hershman et al
Randomized multicenter placebo-controlled trial of omega-3 fatty acids for the control of aromatase inhibitor–induced musculoskeletal pain: SWOG S0927.
reported one case each of grade 3 pain in the extremity, dyspepsia, and diarrhea; 27 cases of grade ≥1 and 13 cases of ≥2 adverse events potentially related to joint pain/stiffness (arthralgia, range of motion decrease, pain). Sandhu et al
reported grade 1/2 gastrointestinal symptoms and nausea in subjects consuming omega-3 fatty acids; however, some of these subjects might have had these symptoms before trial recruitment.
The present systematic review and meta-analysis has several strengths and limitations. To our knowledge, this meta-analysis is the first to assess the effects of omega-3 fatty acid supplementation on serum lipid concentrations in postmenopausal female subjects based on data derived from RCTs. Because the data were pooled from 14 RCT arms, our results are robust and scientifically sound, particularly as we also evaluated the degree of heterogeneity and the risk of publication bias of the analyzed studies, and we also conducted subgroup analyses to explore the effects of omega-3 fatty acids on serum lipid concentrations. Thus, the appraisal of the data was as objective as allowed by the evaluated RCTs. In terms of limitations, we must stress the heterogeneity of the analyzed data and the fact that the RCTs did not evaluate the impact of the intervention on other relevant lipid classes/subtypes/fractions (eg, lipoprotein[a], HDL-C subtypes), which can also affect cardiovascular risk. Moreover, various types of omega-3 fatty acids from different brands/producers might have been used in the RCTs that could have influenced the results of the assessment. In addition, we could not investigate the dietary intake, physical activity, or genetics of the participants recruited in the RCTs that could have also influenced their serum lipid concentrations. Furthermore, the sample sizes of the analyzed RCTs were relatively small, with only one RCT having >200 participants and most RCTs having <100 recruited subjects. In addition, the RCTs were conducted in a limited number of countries, which might influence the generalizability of the findings.Table 1
Table 1Characteristics of the eligible randomized controlled trials.
First Author
Year
Country
Population
Participants’ Age (y)
Sample Size: Omega-3/Placebo
Duration
Baseline BMI (kg/m2)
Outcome
Omega-3 Dose (g/d)
Félix-Soriano
2021
Spain
Overweight and obese postmenopausal women
58
15/20
16 weeks
30.4
LDL-C, TC, HDL-C, TG
1.95
Félix-Soriano
2021
Spain
Overweight and obese postmenopausal women
58
16/20
16 weeks
31.07
LDL-C, TC, HDL-C, TG
1.95
Purzand
2020
Iran
Postmenopausal women
53.35
60/60
3 months
25.5
TC, TG
1
Shen (BMI <30 kg/m2)
2018
United States
Postmenopausal breast cancer patients
58
68/71
24 weeks
26
LDL-C, TC, HDL-C, TG
3.3
Shen (BMI ≥30 kg/m2)
2018
United States
Postmenopausal breast cancer patients
59
54/56
24 weeks
35
LDL-C, HDL-C, TG
3.3
Sandhu
2016
United States
Healthy postmenopausal women
56.6
49/47
24 months
25.7
LDL-C, TC, HDL-C, TG
4
Sandhu
2016
United States
Healthy postmenopausal women
58
44/36
24 months
26.2
LDL-C, TC, HDL-C, TG
4
Véricel
2015
France
Patients with type 2 diabetes, postmenopausal women
59.8
11/11
2 weeks
34
LDL-C, TC, HDL-C, TG
0.40
Tardivo
2015
Brazil
Postmenopausal women with metabolic syndrome
55
33/30
6 months
33
LDL-C, TC, HDL-C, TG
0.900
Hershman
2015
United States
Postmenopausal women with a history of stage I to III hormone-sensitive breast cancer
59.5
122/127
12 weeks
NR
LDL-C, TC, HDL-C, TG
3.3
Stark
2004
Canada
Postmenopausal women
56
32/32
28 days
26
LDL-C, TC, HDL-C, TG
2.8
Ciubotaru
2003
United States
Postmenopausal women on HRT
60
10/10
5 weeks
26
LDL-C, TC, HDL-C, TG
14
Baker
1996
Kuwait
Postmenopausal women
57
20/20
12 weeks
25
LDL-C, TC, HDL-C, TG
0.285
Baker
1996
Kuwait
Postmenopausal women
56
20/10
12 weeks
24
LDL-C, TC, HDL-C, TG
0.285
BMI = body mass index; HRT = hormone replacement therapy; NR = not reported; TC = total cholesterol; TG = triglycerides.
In postmenopausal women, supplementation with omega-3 fatty acids resulted in a significant reduction in TG concentrations and a modest elevation in HDL-C and LDL-C levels, whereas this intervention did not affect TC values.
Acknowledgments
No funding was received for this study.
Authors’ contributions
Wang, Varkaneh-Kord, and Abu-Zaid are responsible for the concept, design, and drafting of this study. Gaman, Albadawi, Salem, Alomar, and Al-Badawi reviewed the literature, searched databases, screened articles, and extracted data. Wang, Gaman, Okunade, and Abu-Zaid performed the acquisition, analysis, and interpretation of data. All authors revised the manuscript for editorial and intellectual contents. All authors approved the final version of the manuscript.
Effects of DHA-rich n-3 fatty acid supplementation and/or resistance training on body composition and cardiometabolic biomarkers in overweight and obese post-menopausal women.
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