http://orcid.org/0000-0002-8656-1444
Abstract
Background: Apolipoprotein C-III (apo C-III) is a key regulator of triglycerides metabolism. The aim of this meta-analysis was to assess the effect of fish omega-3 polyunsaturated fatty acids (PUFAs) on apo C-III levels.
Methods: Randomized placebo-controlled trials investigating the impact of omega-3 on apo C-III levels were searched in PubMed-Medline, SCOPUS, Web of Science and Google Scholar. A random-effects model and generic inverse variance method were used for quantitative data synthesis. Sensitivity analysis was conducted using the leave-one-out method. A weighted random-effects meta-regression was performed to evaluate the impact of potential confounders on glycemic parameters.
Results: This meta-analysis comprising 2062 subjects showed a significant reduction of apo C-III concentrations following treatment with omega-3 (WMD: −22.18 mg/L, 95% confidence interval: −31.61, −12.75, p < .001; I2: 88.24%). Subgroup analysis showed a significant reduction of plasma apo C-III concentrations by eicosapentaenoic acid (EPA) ethyl esters but not omega-3 carboxylic acids or omega-3 ethyl esters. There was a greater apo C-III reduction with only EPA as compared with supplements containing EPA and docosahexaenoic acid (DHA) or only DHA. A positive association between the apo C-III-lowering effect of omega-3 with baseline apo C-III concentrations and treatment duration was found.
Conclusions: This meta-analysis has shown that omega-3 PUFAs might significantly decrease apo C-III.
Omega-3 PUFA supplements significantly reduce apo C-III plasma levels, particularly in hypertriglyceridemic patients when applied in appropriate dose (more than 2 g/day)
Triglyceride (TG)-lowering effect is achieved via peroxisome proliferator-activated receptors α
Further studies should address the effect of omega-3 PUFAs alone or with other lipid-lowering drugs in order to provide a final answer whether apo C-III could be an important target for prevention of cardiovascular disease
New apo C-III antisense oligonucleotide drug (Volanesorsen) showed to be promising in decreasing elevated TGs by reducing levels of apo C-III mRNA
Key messages
Introduction
Long-chain omega-3 (n-3) polyunsaturated fatty acids (PUFAs; eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA]) are organic acids containing more than one carbon–carbon double bond in their aliphatic chain [Citation1]. Although humans and other mammals have the enzyme systems for their in vivo biosynthesis it remains insufficient and they require a regular supply via dietary sources. Omega-3 PUFAs are involved in the maintenance of multiple biological pathways including membrane function, endocrine function and immunity [Citation2,Citation3].
They have a wide range of potentially important properties that might be relevant to the heart and antiatherogenic effects including those anti-arrhythmic, anti-inflammatory, anti-thrombotic, and mildly antihypertensive. They also have triglyceride (TG)-lowering effects but only if applied in pharmacological doses of 2–4 g/day [Citation4,Citation5]. Based upon observational evidence the intake of fish rich with omega-3 (at least twice a week) and/or omega-3 PUFAs supplements at low dosage (1 g/day) may reduce the risk of cardiovascular disease (CVD) events and death in secondary prevention [Citation6]. However, this dosage does not have any major effects on serum lipoproteins but their possible CVD risk reducing applied in such low doses is considered to be based on their antiarrhythmic effects [Citation7–9].
Regarding antiarrhythmic effects of omega-3 PUFAs, the initial enthusiasm was based on the results of The Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico (GISSI)-Prevenzione trial which showed that 1 g/day of omega-3 PUFAs cause a 15% reduction in the nonfatal myocardial infarction, and nonfatal stroke, a 20% in all cause mortality and a 45% reduction in sudden death [Citation10]. In addition, the Japanese EPA Lipid Intervention Study (JELIS) trial showed that EPA reduced major coronary events by 19% compared with the statin-only group and by 53% in the sub-group with TG ≥150 mg/dL (1.70 mmol/L) and high density lipoprotein (HDL)-C < 40 mg/dL (1.04 mmol/L) [Citation11]. However, subsequent clinical trials evaluating the EPA and DHA combination therapy on preventing CVD have been disappointing (e.g. Alpha Omega trial, Outcome Reduction with an Initial Glargine Intervention (ORIGIN) trial, Omega-3 Fatty Acids for Prevention of Post-operative Atrial Fibrillation (OPERA) trial all failed to confirm the positive impact of low-dose omega-3 PUFAs on either CVD risk or arrhytmia) [Citation12–14].
On the other hand, the TG-lowering effect of higher doses of omega-3 PUFAs is unquestionable but it is not sure whether it has an important role in preventing CVD or not. The underlying TG-lowering mechanism is poorly understood, although it may be related, at least in part, to their transcriptional regulation of sterol regulatory element binding protein 1c (SERBP-1c) and peroxisome proliferator-activated receptors (PPARs), decreased secretion of the most important apolipoprotein of the very low density lipoprotein (VLDL) particles – apolipoprotein B (apo B), and decreased catabolism of the most important apolipoprotein of the HDL particles – apolipoprotein AI (apo AI) [Citation10–13].
Apolipoprotein C-III (apo C-III) is a key regulator of VLDL particles and triglycerides metabolism since it inhibits both lipoprotein lipase and hepatic lipases as well as TG-rich particles uptake by the hepatic cells. High plasma apo C-III levels are associated with both high plasma VLDL and high TG levels levels. High TG levels are considered to be a possible risk factor for CVD [Citation4,Citation14,Citation15]. Therefore, also high levels of apo C-III are considered to be an important marker/predictor of CVD risk [Citation16–19]. This concept has been supported relatively recently by finding that loss-of-function mutations in APOC3 gene are associated with low TG concentrations and reduced CVD risk [Citation20–22]. In some studies omega-3 PUFAs have been shown to reduce plasma levels of apo C-III [Citation23,Citation24]. This might be an additional mechanism explaining the TG-lowering effect of omega-3 PUFAs [Citation25].
A number of studies investigated the possible effects of omega-3 PUFAs on apo C-III, their results were in part contradictory [Citation26–30]. Therefore, we performed a meta-analysis of randomized controlled trials that assessed this relationship in order to get a clear answer to this controversy.
Methods
Search strategy
This study was designed according to the guidelines of the preferred reporting items for systematic reviews and meta-analysis (PRISMA) statement [Citation31]. PubMed-Medline, SCOPUS, Web of Science and Google Scholar databases databases were searched using the following search terms in titles and abstracts: ("Omega-3" OR "Omega3" OR "Omega 3" OR "n-3 fatty acids" OR "n3 fatty acids" OR "n 3 fatty acids" OR "polyunsaturated fatty acids" OR OR "ω3" OR "ω3" OR "ω3" OR "eicosapentaen*" OR "docosahexaen*" OR "fish oil" OR “EPA” OR “DHA” OR “ALA” OR “PUFA” OR "alpha-linoleic" OR "alpha linoleic" OR "docosapentaenoic" OR "alpha-linolenic" OR "alpha linolenic" OR eicosapentoenoic) AND (“apoCIII” OR “apoC-III” OR "apo CIII" OR "apo C-III" OR “apoC3” OR "apo C3") AND placebo. The wild-card term ‘‘*’’ was used to increase the sensitivity of the search strategy. The search was limited to articles published in English language. The literature was searched from inception to 26 August 2017.
Study selection
Original studies were included if they met the following inclusion criteria: (i) being a randomized placebo-controlled clinical trial with either parallel or cross-over design, (ii) investigating the impact of omega-3 products versus control on total circulating concentrations of apo C-III, and (iii) presentation of sufficient information on apo C-III concentrations at baseline and at study end in both intervention and placebo groups or providing the net change values. Exclusion criteria were: (i) non-clinical studies, (ii) uncontrolled OR non-placebo-controlled studies, (iii) observational studies with case-control, cross-sectional or cohort design, (iv) reporting non-fasted or postprandial plasma apo C-III levels, and (v) lack of sufficient information on baseline or follow-up total circulating apo C-III levels.
Data extraction
Eligible studies were reviewed and the following data were abstracted: (1) first author's name, (2) year of publication, (3) country where the study was performed, (4) study design, (5) number of participants in the omega-3 and control groups, (6) type of omega-3 product used, (7) omega-3 dose, (8) duration of treatment, (9) age, gender and body mass index (BMI) of study participants, and (10) baseline and follow-up concentrations of plasma lipids, lipoproteins, and apolipoproteins including apo C-III.
Quality assessment
The quality of involved studies in this meta-analysis was evaluated using the Cochrane criteria [Citation32].
Quantitative data synthesis
Meta-analysis was conducted using comprehensive meta-analysis V2 software (Biostat, Englewood, NJ, USA) [Citation33]. A random-effects model (using DerSimonian-Laird method) and the generic inverse variance weighting method were used to compensate for the heterogeneity of studies in terms of study design, treatment duration, and the characteristics of populations being studied [Citation34]. Standard deviations (SDs) of the mean difference were calculated as follows: SD = square root [(SDpost-treatment)2 – (2R × SDpre-treatment×SDpost-treatment)], assuming a correlation coefficient (R) = 0.5. Where standard error of the mean (SEM) was only reported, SD was estimated using the following formula: SD = SEM × sqrt (n), where n is the number of subjects. Heterogeneity was assessed quantitatively using Cochrane Q and I2 statistic. All apo C-III values were collated in mg/L. Effect sizes were expressed as standardized mean difference (WMD) and 95% confidence interval (CI). If the outcome measures were reported in median and range (or 95% CI), mean and SD values were estimated using the method described by Wan et al. [Citation35]. In order to avoid the double-counting problem in trials comparing multiple treatment arms versus a single control group, the number of subjects in the control group was divided by the number of treatment arms. In order to evaluate the influence of each study on the overall effect size, a sensitivity analysis was conducted using the leave-one-out method (i.e. removing one study each time and repeating the analysis) [Citation36,Citation37].
Meta-regression
As potential confounders of treatment response, duration of treatment and baseline plasma apo C-III concentrations were entered into a random-effects meta-regression model to explore their association with the estimated effect size on plasma apo C-III levels.
Publication bias
Evaluation of funnel plot, Begg’s rank correlation and Egger’s weighted regression tests were employed to assess the presence of publication bias in the meta-analysis. When there was an evidence of funnel plot asymmetry, potentially missing studies were imputed using the "trim and fill" method [Citation38]. In case of significant result, the number of potentially missing studies required to make the p-value non-significant was estimated using the “fail-safe N” method as another marker of publication bias.
Results
Overall, 43 articles were found following multi-database search. After screening of titles and abstracts, 15 articles were assessed in full text. Of these four articles were excluded because of lack of reporting serum/plasma total apo C-III concentrations (n = 2) and duplicate reporting of data from the same population (n = 2), leaving 11 eligible articles with 19 treatment arms for meta-analysis.
Study characteristics
Data were pooled from 11 randomized placebo-controlled clinical trials comprising a total of 2062 subjects, including 1240 and 822 participants in the omega-3 and placebo arms (individuals of the cross-over trials were considered in the treatment and control groups), respectively. The clinical trials used different types and doses of omega-3 products. Selected studies were published between 1998 [Citation39] and 2016 [Citation40–42]. The range of treatment duration was from 4 weeks [Citation43] to 16 weeks [Citation24,Citation44]. Almost all of included trials were parallel design, only one was cross-over group [Citation45]. Selected studies enrolled subjects with hypertriglyceridemia [Citation23,Citation40–42,Citation45], dyslipidemia [Citation24,Citation44,Citation46], postmyocardial infarction [Citation39], obesity [Citation47], and healthy adults [Citation43]. Characteristics of the included clinical trials are shown in .
Table 1. Demographic characteristics of the included studies.
Risk of bias assessment
Several studies showed insufficient information regarding to sequence generation. Additionally, almost all of included studies had lack of information related to allocation concealment. Also, most of selected trials were characterized by insufficient information about blinding of participants, personnel and outcome assessors. However, all evaluated studies exhibited a low risk of bias for incomplete outcome data and selective outcome reporting.
Quantitative data synthesis
Meta-analysis of data from 11 trials comprising 19 treatment arms suggested a significant reduction of circulating apo C-III concentrations following treatment with omega-3 products (WMD: −22.18 mg/L, 95% CI: −31.61, −12.75, p < .001; I2: 88.24%; ). The effect size was robust in the subgroup analysis () and not mainly driven by any single study. Subgroup analysis showed significant reduction of plasma apo C-III concentrations by EPA ethyl esters (WMD: −52.96 mg/L, 95% CI: −78.98, −26.93, p < .001; I2: 90.83%) but not omega-3 carboxylic acids (WMD: −35.21 mg/L, 95% CI: −76.03, 5.62, p = .091; I2: 86.01%) or omega-3 ethyl esters (WMD: −10.04 mg/L, 95% CI: −23.13, 3.06, p = .133; I2: 78.66%; ). Consistently, there was a greater apo C-III reduction with supplements containing only EPA (WMD: −41.56 mg/L, 95% CI: −60.26, −22.86, p < .001; I2: 89.10%) compared with supplements containing a mixture of EPA and DHA (WMD: −14.68 mg/L, 95% CI: −27.49, −1.88, p = .025; I2: 89.63%) or only DHA (WMD: −6.5 mg/L, 95% CI: −65.01, 52.01, p = .828; I2: 0%).
Figure 1. Forest plot displaying weighted mean difference and 95% confidence intervals for the impact of omega-3 products on circulating apolipoprotein C-III concentrations. Lower plot shows the results of leave-one-out sensitivity analysis.
Figure 2. Forest plot displaying weighted mean difference and 95% confidence intervals for the impact of different types of omega-3 products on circulating apolipoprotein C-III concentrations.
Figure 3. Forest plot displaying weighted mean difference and 95% confidence intervals for the impact of mixed and eicosapentaenoic acid-only omega-3 products on circulating apolipoprotein C-III concentrations.
Meta-regression
Random-effects meta-regression was performed to assess the impact of potential confounders on the effects of omega-3 supplements on plasma apo C-III levels. The results suggested a significant positive association between the apo C-III-lowering effect of omega-3 supplements with baseline apo C-III concentrations (slope: −0.28; 95% CI: −0.40, −0.16; p < .001) and treatment duration (slope: −4.00; 95% CI: −7.20, −0.80; p = .014; ).
Figure 4. Meta-regression bubble plots of the association between mean changes in plasma apolipoprotein C-III (apo C-III) concentrations with duration of treatment and baseline plasma apo C-III concentrations. The size of each circle is inversely proportional to the variance of change.
Publication bias
Visual inspection of Begg's funnel plots did not reveal any asymmetry in the meta-analyses of omega-3 PUFAs effects on plasma apo C-III levels requiring “trim and fill” correction (). Likewise, Begg's rank correlation (τ= −0.19, z = 1.15, p = .248) and Egger's regression test (t = 0.89, df =17, p = .385) did not suggested the presence of publication bias. The results of “fail-safe N” test suggested that 1307 missing studies would be required to make the observed significant result non-significant.
Figure 5. Funnel plot detailing publication bias in the studies reporting the impact of omega-3 products on plasma apolipoprotein C-III concentrations.
Discussion
The results of this meta-analysis of studies recruiting mostly hypertriglyceridemic patients suggest that omega-3 PUFA supplements significantly reduce plasma apo C-III levels.
Many patients have high plasma TG, low HDL-cholesterol levels and normal or only moderately increased concentrations of LDL-C, a lipoprotein disturbance which is called atherogenic dyslipidemia [Citation48,Citation49]. Atherogenic dyslipidemia often occurs in patients with metabolic syndrome and/or type 2 diabetes mellitus T2DM. High TGs and low HDL-cholesterol are not only predictors for macrovascular atherosclerotic disease and CVD events but they are also risk factors for microvascular disease in type 2 diabetes mellitus (T2DM) [Citation50]. Although fibrates are the treatment of choice for hypertriglyceridemia, omega-3 supplements often need to be added to further decrease elevated TGs because fibrates alone are not enough [Citation51–53]. Their beneficial antiatherogenic effects include not only directly activating anti-inflammatory and antithrombotic effects but by their reducing apo C-III levels they might influence this important risk factor that links TGs to inflammation and vascular cell dysfunction, even with adiponectin [Citation23,Citation54–56]. Evidences from a number of in vitro studies and animal models suggest that effects of omega-3 PUFAs action on apo C-III might be achieved via PPARα [Citation42]. Interactions between PPARα and APOC-III genotypes and omega-3 PUFA have been shown to modulate apo C-III concentrations [Citation57,Citation58]. Most recently it has been shown that elevated plasma omega-3 PUFAs are associated also with APOE genotype with a beneficially lower concentration of apo C-III in E2 carriers [Citation59]. It has been also shown that omega-3 supplements can stabilize atherosclerotic plaques [Citation60]. However, it has to be noted that the reduction of TGs and apo C-III levels in some studies was not accompanied by reductions in inflammation markers or improvements in endothelial function [Citation60].
Although there is a consensus that EPA and DHA, either individually or in combination, reduce elevated TG levels, DHA (but not EPA) has been suggested to be responsible for a simultaneous elevation in LDL-cholesterol, particularly in patients with very high (>500 mg/dL) TG levels [Citation61,Citation62]. Nevertheless, recently it has been shown that omega-3 fatty acids selectively increase the subspecies of LDL particles which has a weaker relation to risk of CVD and does not contain apo C-III [Citation63,Citation64]. Therefore, omega-3 PUFAs might not increase the risk of CVD by increasing the number of LDL particles and this should not compromise their beneficial effects on lowering plasma TGs and apo C-III. Omega-3 PUFAs in appropriate doses also cause a shift toward an increased proportion of larger, buoyant and less atherogenic LDL particles vs. smaller, denser, and potentially more atherogenic LDL particles [Citation23,Citation24,Citation65] thus potentially acting antiatherogenic [Citation66,Citation67].
Most recently a new apo C-III antisense oligonucleotide drug showed to be promising in decreasing elevated TGs by reducing levels of apo C-III mRNA [Citation68]. Volanesorsen, which is the name of this drug, lowered as monotherapy significantly apo C-III levels and this was followed by significant reductions in TG levels by 31.3%–70.9% [Citation69–71].
Our study has several limitations including the heterogeneity with respect to the use of different omega-3 preparations, doses of DHA and EPA or omega-3 carboxylic acids, duration of treatment, patient characteristics and also baseline TG levels. Besides, the number of studies was relatively low to allow robust subgroup analysis of the effects of individual omega-3 preparations.
Conclusions
The results of this meta-analysis suggest that omega-3 PUFA supplements might reduce apo C-III plasma levels, particularly in hypertriglyceridemic patients when applied in appropriate dose, that is more than 2 g/day. Further studies should address the effect of omega-3 PUFAs alone or with other lipid-lowering drugs on apo C-III levels/activity in order to provide a final answer whether apo C-III could be an important target for prevention of CVD.
Disclosure statement
MB has served on the speaker’s bureau and as an advisory board member for Amgen, Sanofi, Aventis and Lilly. DPM has given talks and attended conferences sponsored by MSD, Libytec and AstraZeneca. ZR has given talks and attended conferences sponsored by Sanofi. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
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