Omega-6 fatty acids and risk of cardiovascular disease: insight from systematic review and meta-analysis of randomized controlled trials and a mendelian randomization study

Abstract

Background Omega-6 polyunsaturated fatty acids (PUFAs) represent almost 15% of the total energy intake in the Western countries. Their effects on several cardiovascular (CV) risk factors are still controversial. Purpose We performed a systematic review and meta-analysis of randomized control trials (RCTs) as well as a Mendelian randomization (MR) analysis to evaluate the links (or possible causality) between supplementation or serum levels of omega-6 PUFA, CV disease (CVD) and cardiometabolic risk factors. Methods Selected databases were searched until 31 August 2019 to identify prospective studies investigating the effects of omega-6 PUFAs supplementation on CVD events/mortality. Random-effects model meta-analysis was performed for quantitative data synthesis. Trial sequential analysis (TSA) was used to evaluate the optimal sample size to detect a 20% reduction in outcomes after administration of omega-6 PUFAs. Inverse variance weighted method (IVW), weighted median-based method, MR-Egger and MR-Pleiotropy RESidual Sum and Outlier (PRESSO) were applied for MR. Results In the meta-analysis of 9 studies with 4,433 participants we showed that omega-6 PUFAs supplementation was not associated with CVD event risk - RR 0.94 (95% CI: 0.77–1.15, heterogeneity p=0.031; I2=66.2%, n=4 studies). The pooled estimate (RR) of the effect of omega-6 PUFAs supplementation on CVD death was 1.06 (95% C:I 0.73–1.55, heterogeneity p=0.011; I2=66.2%, n=6 studies), on CHD events 0.84 (95% CI: 0.61–1.16, heterogeneity p=0.001; I2=79.4%), on MI 0.87 (95% CI: 0.74–1.01, heterogeneity p=0.381; I2=2.3%) (Figure), and on stroke 1.36 (95% CI: 0.45–4.07, heterogeneity p=0.082; I2=55.3%). In MR analysis we showed that individuals with genetically higher serum adrenic acid (AA; 22:4, n-6) levels had a greater risk of CHD events (IVW=Beta: 0.526, p=0.007), MI (IVW=Beta: 0.606, p=0.017) and stroke (IVW=Beta: 1.694, p=0.009), as well as higher levels of FBG (IVW=Beta: 0.417, p=1.0x10–3), LDL-C (IVW=Beta: 0.806, p=4.9x10–5), HDL-C (IVW=Beta: −0.820, p=4.3x10–17), whereas lower levels of TG (IVW=Beta: −1.064, p=1.2x10–12) and TC (IVW=Beta: −1.064, p=1.2x10–12). Conclusions In the pooled analysis different omega-6 PUFAs supplementation did not affect the risk of MI, stroke and CHD event/mortality or the serum concentration of cardiometabolic parameters (data not presented), however in MR analysis, higher AA levels significantly associated with the risk of CHD, MI and stroke, as well as with elevated levels of FBG, LDL-C and HDL-C and reduced levels of TC and TG. There is probably lack of class effect for omega-6 PUFAs, therefore further studies are needed to assess the effects of omega-6 PUFAs on cardiometabolic outcomes. Funding Acknowledgement Type of funding source: None

Dietary Supplements—For Whom? The Current State of Knowledge about the Health Effects of Selected Supplement Use

“…In turn, a 2018 meta-analysis of randomized studies of omega-3 fatty acids taken, showed no effects on non-fatal myocardial infarction, coronary heart disease events, or major vascular events [34], a finding that is consistent with another 2018 meta-analysis that also showed no relationship between omega-3 fatty acids consumption and lowered risk of cardiovascular disorders [35]. In contrast, the results of one of two 2019 meta-analyses of randomized clinical trials showed that taking omega-3 fatty acids reduced the risk of major vascular events by 5%, non-fatal myocardial infarction by 11%, and death by coronary heart disease by 9% [36]. The second 2019 meta-analysis of the studies, from which the REDUCE-IT study was excluded because of the comparatively high level of its omega-3 dose, showed that omega-3 supplementation was associated with lower risk of myocardial infarction by 8%, total coronary heart disease by 5%, coronary heart disease death by 8%, and cardiovascular death by 7% [37].…”

PoLA/CFPiP/PCS/PSLD/PSD/PSH guidelines on diagnosis and therapy of lipid disorders in Poland 2021

“…A meta-analysis summarising studies concerning omega-3 acids published in recent years, which finally included 13 studies covering 127,447 individuals, demonstrated significant reduction of the risk of death due to ischaemic heart disease (risk ratio (RR) = 0.91, 95% CI: 0.85–0.97, p = 0.010), major vascular events (RR = 0.95, 95% CI: 0.93–0.98, p = 0.001), nonfatal myocardial infarction (RR = 0.89, 95% CI: 0.83–0.95, p = 0.001) and all-cause mortality (RR = 0.95, 95% CI: 0.92–0.99, p = 0.025) [ 195 ].…”

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“…However, more importantly, the REDUCE-IT randomised, placebo-controlled trial evaluated icosapent ethyl in 8179 participants and demonstrated a 25% relative reduction in cardiovascular events over five years [ 24 , 25 ]. However, the most recent meta-analysis suggest (similarly to the one presented by authors [ 46 ]), that omega-3 FAs reduced CV mortality and improved CVOTs, however, with more prominent cardiovascular risk reduction with EPA monotherapy than with EPA+DHA [ 47 ].…”