Can Eating Deep-Sea Fish Shrimp and Squid Really Prevent Cardiovascular Diseases?
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Can Eating Deep-Sea Fish Shrimp and Squid Really Prevent Cardiovascular Diseases?
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Can Eating Deep-Sea Fish Shrimp and Squid Really Prevent Cardiovascular Diseases?
Low-density lipoprotein cholesterol (LDL-C), commonly known as “bad cholesterol,” is a primary target for reducing atherosclerotic cardiovascular diseases (ASCVD) and decreasing cardiovascular events.
However, despite aggressive statin therapy, including statin use in combination with ezetimibe and/or PCSK9 inhibitors, achieving ideal LDL-C levels according to current guidelines only results in a one-third reduction in cardiovascular events. The remaining two-thirds are described as “residual cardiovascular risk.”
Apart from “bad cholesterol,” elevated levels of triglycerides (TG), lipoprotein(a) [Lp(a)], and triglyceride-rich lipoproteins (TRL) may contribute significantly to this residual cardiovascular risk. Omega-3 fatty acids have gained attention as drugs to lower triglycerides in recent years.
While there is supporting data for a causal relationship between triglycerides and ASCVD risk, the results of trials on omega-3 fatty acids in reducing cardiovascular outcomes have been mixed.
A recent review published in the European Journal of Preventive Cardiology discusses the clinical research progress of omega-3 fatty acids in reducing cardiovascular events and the potential for their clinical application in drug therapy.
Elevated Triglyceride Levels and Cardiovascular Disease Risk
The prevalence of adult dyslipidemia has remained high in recent years. Genetic and whole-genome analysis studies suggest a connection between triglyceride levels and the development of ASCVD. A randomized Mendelian study showed a 54% increase in the risk of myocardial infarction (MI) with each standard deviation increase in triglyceride levels. Prospective research data from European populations demonstrate a significant correlation between triglycerides and coronary heart disease (CHD) risk. However, earlier studies suggested that this relationship weakens after adjusting for other influencing factors, such as high-density lipoprotein cholesterol.
Based on these findings, researchers attempted to use drugs that lower triglyceride levels, such as fibrates and niacin, to reduce the risk of cardiovascular diseases. Unfortunately, the results did not meet expectations. Early results from the ACCORD trial showed no significant reduction in the incidence of fatal cardiovascular events, non-fatal heart attacks, or non-fatal strokes in type 2 diabetes patients treated with fenofibrate in addition to statin therapy compared to statin monotherapy. Similarly, trials like AIM-HIGH, HPS2-THRIVE, PROMINENT, among others, did not achieve the expected outcomes.
The “Expert Consensus on the Role of Omega-3 Fatty Acids in Cardiovascular Disease Prevention and Treatment” indicates that elevated levels of triglycerides and TRL-C are independently positively correlated (causal relationship) with cardiovascular events and major event analysis, potentially contributing to the residual risk of ASCVD.
Clinical Progress of Omega-3 Fatty Acids in Reducing Cardiovascular Events
Omega-3 fatty acids are essential polyunsaturated fatty acids in the human body, mainly comprising eicosapentaenoic acid (EPA) and/or docosahexaenoic acid (DHA) found in fish oil preparations. Eicosapentaenoic acid ethyl ester (IPE) is an ethylated form of EPA. EPA and DHA are primarily sourced from marine fish, krill, and squid.
Results from the GISSI-P trial indicated that heart attack patients using omega-3 fatty acids (1 g EPA+DHA) could reduce the risk of death, non-fatal heart attacks, and strokes by 10%. However, the study had poor generalizability in clinical practice since only 5% of patients were on statin therapy at baseline. Subsequent research with 53% of patients on statin therapy found that patients using 1 g of omega-3 fatty acid ethyl ester capsules experienced a reduction in triglyceride levels, but there was no significant improvement in cardiovascular disease mortality outcomes, and the benefits of omega-3 fatty acids were not confirmed.
The JELIS study brought new hope, revealing a 19% reduction in the risk of major coronary events in the EPA treatment group. The REDUCE-IT study also confirmed that IPE significantly reduced the risk of the composite endpoint (cardiovascular death, non-fatal heart attack, non-fatal stroke, coronary revascularization, or unstable angina) by 25%, while also reducing the incidence of cardiovascular death, fatal or non-fatal heart attacks, and strokes, with no decrease in all-cause mortality risk.
Overall, omega-3 fatty acid-related studies show significant differences in study populations (including primary and secondary prevention) and baseline characteristics (including statin use and baseline triglyceride levels). Studies combining statin drugs with high-purity omega-3 fatty acids only show a trend of reducing ASCVD in meta-analyses. To date, most studies have focused on EPA+DHA, and considering their different mechanisms of action, different ratios may influence the results. Additionally, considering the impact of dose-response, the EPA threshold concentration in trials may be a crucial point for future research.
The “Expert Consensus on the Role of Omega-3 Fatty Acids in Cardiovascular Disease Prevention and Treatment” suggests that the purity, content, and blood EPA levels in omega-3 fatty acids may be the main reasons for the varying cardiovascular benefits in different randomized controlled studies, and the impact of different placebos (corn oil or mineral oil) in control groups requires further investigation.
Future Prospects of Omega-3 Fatty Acids
Patients receiving statin therapy still face residual cardiovascular disease risk even if “bad cholesterol” levels are within the recommended range, and clinical endpoint research results for high-purity omega-3 fatty acids in lowering triglycerides vary significantly. While omega-3 fatty acid trials have not shown a reduction in the risk of cardiovascular events, the REDUCE-IT and JELIS trials confirm that combining high-purity IPE or EPA formulations with statin therapy can significantly reduce ASCVD risk.
Considering the benefits of IPE, further understanding its molecular and pleiotropic mechanisms, as well as validating its effectiveness in real-world studies, is essential to identify and address clinical application barriers. This will be beneficial for ongoing research exploring the role of omega-3 fatty acids in reducing cardiovascular events in the future.
Can Eating Deep-Sea Fish Shrimp and Squid Really Prevent Cardiovascular Diseases?
Reference:
[1]Gurleen Kaur, R Preston Mason, Ph Gabriel Steg, et al. Omega-3 Fatty Acids for Cardiovascular Event Lowering, European Journal of Preventive Cardiology, 2024;, zwae003, https://doi.org/10.1093/eurjpc/zwae003
(source:internet, reference only)
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