Omega-3 Fatty Acid & Cardiovascular Risks Reduction
Omega-3 Fatty Acid Supplementation and Coronary Heart Disease Risks:
A Meta-Analysis of Randomized Controlled Clinical Trials
Background: The clinical benefits of omega-3 fatty acids (FAs) supplementation in preventing and treating coronary heart disease (CHD) remain controversial. Therefore, this study aimed to investigate the clinical benefits of omega-3 FA supplementation, with special attention given to specific subgroups.
Methods: Randomized controlled trials (RCTs) that compared the effects of omega-3 FA supplementation for CHD vs. a control group and included at least 1,000 patients were eligible for inclusion in this meta-analysis. The relative risk (RR) of all-cause death, major adverse cardiovascular events (MACEs), cardiovascular death, myocardial infarction (MI), stroke, and revascularization were estimated. We analyzed the association between cardiovascular risk and omega-3 FA supplementation in the total subjects. We focused on the cardiovascular risk compared to omega-3 FA in subgroups with different development stages of CHD, omega-3 FA supplementation application dose, diabetes, and sex. PROSPERO Registration Number: CRD42021282459.
Results: This meta-analysis included 14 clinical RCTs, including 1,35,291 subjects. Omega-3 FA supplementation reduced the risk of MACE (RR; 0.95; CI: 0.91–0.99; p for heterogeneity 0.27; I2 = 20%; p = 0.03), cardiovascular death (RR; 0.94; CI: 0.89–0.99; p for heterogeneity 0.21; I2 = 25%; p = 0.02), and MI (RR; 0.86; CI: 0.79–0.93; p for heterogeneity 0.28; I2 = 19%; p < 0.01), but had no significant effect on all-cause death, stroke, and revascularization. In the subgroup analysis, omega-3 FA supplementation decreased the incidence of MACE and cardiovascular death in acute patients with MI, the risk of MI and stroke in patients with CHD, and the risk of MI in patients with high-risk CHD. 0.8–1.2 g omega-3 FA supplementation reduced the risk of MACE, cardiovascular death, and MI. It was revealed that gender and diabetes have no significant association between omega-3 FA supplementation and MACE risk.
Conclusions: Omega-3 FA supplementation had a positive effect in reducing the incidence of MACE, cardiovascular death, MI. Regardless of the stage of CHD, omega-3 FA supplementation can prevent the occurrence of MI. The 0.8–1.2 g omega-3 FA supplementation alleviated CHD risk more effectively than lower or higher doses.
Omega-3 fatty acids (FAs) are polyunsaturated FA commonly found in marine fish and closely linked to cardiovascular health. Omega-3 FA mainly contains α-linolenic acid (ALA), docosahexaenoic acid (DHA), and eicosapentaenoic acid (EPA). In 1972, Bang and Dyerberg compared the dietary difference and serum lipoprotein levels between Inuit and Danes. They found that Inuit were not prone to coronary heart disease (CHD), and they ate a lot of seal and whale meat and also blubber. Meanwhile, an observational experiment confirmed that the inclusion of marine omega-3 FA was negatively correlated with the risk of CHD as well. Omega-3 FA may reduce the risk of CHD by antiinflammatory effect, improve vasomotor and endothelial cell function, and lower serum lipoprotein levels. In 1994, Lungershausen et al. found that blood pressure and plasma triglycerides (TAGs) were significantly decreased in patients with hypertension following omega-3 FA supplementation treatment. The specific mechanism by which omega-3 FA supplementation reduces TAGs remains unclear. At present, it is generally believed that omega-3 FA supplementation can increase mitochondria β-oxidation and thereby reduced endogenous triglyceride TAG synthesis. Concurrently, omega-3 FA supplementation also increases plasma lipoprotein lipase activity to play a protective role in cardiovascular protection. In the JELIS trial, a lipid intervention trial initiated by Yokoyama et al., daily treatment with 1.8 g EPA in combination with statins proved to be more effective than statins alone in reducing cardiovascular events in patients with high cholesterol.
However, further investigation is required to determine whether omega-3 FA supplementation dose and application in primary prevention or secondary prevention are associated with cardiovascular events. A meta-analysis that was performed by Balk et al. also revealed that omega-3 FA supplementation application could be utilized as an effective lifestyle strategy for preventing CHD. This protective effect is positively correlated with the applied dose. A meta-analysis, including 13 randomized controlled trials (RCTs) with 1,27,477 subjects, indicated that omega-3 FA supplementation could reduce the risk of MI (RR 0.88, 95% CI: 0.83–0.94) and CVD death (RR 0.92, 95%, CI: 0.88–0.97, I2 = 6%). Abdelhamid et al. performed a meta-analysis that included 79 RCTs with enrolled 1,62,796 subjects to evaluate the role of omega-3 FA supplementation in preventing CHD. They demonstrated that based on low-certainty evidence, omega-3 FA supplementation for 12–88 months could reduce CHD risk and death rate. Nonetheless, based on medium to high-certainty evidence, they illustrated that omega-3 FA supplementation has an insignificant effect on cardiovascular mortality and events. REDUCE-IT was a double-blind, multicenter RCT that aimed to determine the effect of ecosapent ethyl on cardiovascular events after providing established statin therapy to patients with CHD or diabetes and other risk factors. The results of REDUCE-IT manifested that compared to the control group, ecosapent ethyl can significantly reduce the risk of ischemic events by 25%, including cardiovascular death. Additionally, ecosapent ethyl can significantly decrease triglyceride levels, and when combined with statin therapy, it appears to be more promising than using statins alone. This appears to be promising that omega-3 FA supplementation can prevent cardiovascular risks, but different results were obtained in the other two large clinical RCTs. The STRENGTH trial was the latest large-scale double-blind RCT involving 13,078 subjects with high cardiovascular risks. The median treatment time with omega-3 FA supplementation and corn oil in the control group was 38.2 months. However, they eventually exhibited no significant difference in cardiovascular events between the two groups. The VITAL trial was a large-scale clinical trial for healthy people. This trial attempted to investigate the effects of omega-3 FA supplementation and vitamin D in the primary prevention of cardiovascular events after a 5-year follow-up. Both the results of VITAL and STRENGTH found that omega-3 FA supplementation had no significant effect on the incidence of cardiovascular events; nevertheless, the secondary endpoints of VITAL revealed that omega-3 FA supplementation reduced the risk of MI by 28%. A newly published meta-analysis stated no clinical benefit for omega-3 FA supplementation in preventing cardiovascular risks in healthy people and patients with CHD. The aforementioned RCTs and meta-analysis results were inconsistent, posing a challenge to the clinical application of omega-3 FA supplementation to prevent cardiovascular events. It is hypothesized that omega-3 FA supplementation effectively prevents cardiovascular events in some specific cases. As recommended by the American Heart Association (AHA), in individuals with preexisting CHD, heart failure (HF), and reduced ejection fraction (EF), employing omega-3 FA supplementation for CHD prevention is a reasonable treatment option.
Our research included RCTs with a large sample size compared with the previous meta-analyses and divided the population enrolled into subgroups of subjects with high risks of CHD, cases with CHD, and patients with acute MI. This study focused on preventing cardiovascular events following omega-3 FA supplementation application. Meanwhile, we focused on cardiovascular risks of the three subgroups after applying omega-3 FA supplementation and explored the association between omega-3 FA supplementation and cardiovascular events, application dose, sex, and having diabetes or not.
This study conducted a meta-analysis of 14 large-scale RCTs to investigate the risk of cardiovascular events after receiving omega-3 FA supplementation. We found that omega-3 FA supplementation can reduce the risk of MACE, cardiovascular death, and MI. Additionally, it exhibits good clinical benefits for primary prevention and secondary prevention of CHD. Omega-3 FA supplementation application dose that ranges from 0.8 to 1.2 g exhibits more superiority than other doses in reducing cardiovascular risks.
The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fnut.2022.809311/full#supplementary-material Omega-3 Fatty Acid Supplementation and Coronary Heart Disease Risks: A Meta-Analysis of Randomized Controlled Clinical Trials SYSTEMATIC REVIEW article Front. Nutr., 03 February 2022 https://doi.org/10.3389/fnut.2022.809311
Systematic Review Registration:
https://www.crd.york.ac.uk/prospero/, identifier CRD42021282459.