Omega-3 Fatty Acids for Heart Health: What Patients Need to Know

This article explains the science behind omega-3 fatty acids, what clinical trials have found, and how these findings may affect patients at risk for heart disease.

Table of Contents

• Key Points
• Introduction: The Problem of Heart Disease Despite Treatment
• Elevated Triglycerides and Cardiovascular Risk
• How Omega-3 Fatty Acids Work in the Body
• Benefits Beyond Lowering Triglycerides
• Clinical Trials of Omega-3 Fatty Acids: Mixed Results
• The JELIS Trial: Testing EPA Alone
• The REDUCE-IT Trial: Strong Evidence for Icosapent Ethyl
• What This Means for Patients
• Study Limitations
• Recommendations for Patients
• Frequently Asked Questions
• Source Information

Key Points

• Elevated triglycerides contribute to heart attack and stroke risk even when LDL cholesterol is controlled.
• Over-the-counter fish oil and mixed EPA/DHA supplements showed inconsistent results in major clinical trials.
• Icosapent ethyl, a purified prescription EPA, reduced cardiovascular events in the REDUCE-IT trial.
• Benefits were seen in high-risk statin-treated patients, including those with prior heart attack, bypass, or stent.
• Omega-3 therapy complements statins; it does not replace them, and individualized risk–benefit assessment is essential.

Introduction: The Problem of Heart Disease Despite Treatment

Atherosclerotic cardiovascular disease (ASCVD)—a condition where arteries become narrowed and hardened by plaque buildup—remains the leading cause of death in the United States. For decades, the primary strategy for reducing heart attack and stroke risk has been lowering low-density lipoprotein cholesterol (LDL-C), commonly known as "bad" cholesterol.

However, even when patients successfully lower their LDL cholesterol with statin medications, many still experience cardiovascular events. This leftover danger is called "residual risk," and it is particularly high in patients with type 2 diabetes, metabolic syndrome, and obesity.

Researchers have identified triglyceride-rich lipoproteins as potential contributors to this residual risk. Triglycerides (TG) are a type of fat found in the blood, and elevated levels can be a marker for these dangerous particles. This has led scientists to investigate whether lowering triglycerides can further reduce the risk of heart attacks, strokes, and other cardiovascular events.

Elevated Triglycerides and Cardiovascular Risk

High triglycerides are a common problem in the United States. Data from 2015–2018 shows that 21.1% of American adults have high triglyceride levels (≥150 mg/dL).

The link between triglycerides and heart disease is supported by strong scientific evidence:

• A Mendelian randomization study (a genetic research approach) found that one standard deviation increase in triglyceride levels was associated with a 54% increase in the risk of myocardial infarction (heart attack).
• A meta-analysis of European populations demonstrated an adjusted odds ratio of 1.72 (95% confidence interval 1.56–1.90) for coronary heart disease risk in individuals with triglyceride values in the top third of the population compared to the bottom third.
• Klempfner and colleagues studied 15,355 patients from the Bezafibrate Infarction Prevention (BIP) trial and found that patients with severe hypertriglyceridemia (≥500 mg/dL) had a 68% increased 22-year mortality risk compared to patients with low-normal triglycerides (<100 mg/dL), even after adjusting for other risk factors including HDL cholesterol.
• An observational study using electronic health records found that patients with ASCVD and statin-controlled LDL-C were more likely to have non-fatal heart attacks and coronary or peripheral revascularization procedures over 5 years if they had high triglycerides.
• In a retrospective analysis of more than 20,000 statin-treated patients with diabetes and/or ASCVD, those with high triglycerides had an increased risk of major cardiovascular events (hazard ratio 1.35, 95% CI 1.225–1.485), along with higher average monthly healthcare costs and higher rates of inpatient hospital stays.

Given this evidence, targeting hypertriglyceridemia seems like a logical approach to reducing residual risk. However, earlier efforts with other triglyceride-lowering medications have been disappointing.

In the ACCORD (Action to Control Cardiovascular Risk in Diabetes) trial, combining fenofibrate with simvastatin did not reduce fatal cardiovascular events, non-fatal heart attacks, or non-fatal strokes compared to simvastatin alone in patients with type 2 diabetes. Similarly, the AIM-HIGH trial found that adding niacin to LDL-lowering therapy did not reduce cardiovascular events in patients with established heart disease—though a post hoc analysis suggested a possible benefit in patients with the highest triglyceride levels (≥198 mg/dL).

The HPS2-THRIVE trial also found no difference in major vascular events (15.1% vs 15.5%) when niacin plus laropiprant was added to statin therapy. More recently, the PROMINENT study showed that pemafibrate—a medication that effectively lowers triglycerides—did not reduce cardiovascular events compared to placebo in patients with type 2 diabetes on statins, despite significant triglyceride reduction.

How Omega-3 Fatty Acids Work in the Body

Omega-3 fatty acids lower triglycerides through several biological mechanisms. They reduce the rate at which fatty acids are incorporated into very-low-density lipoprotein (VLDL), the particle that carries triglycerides through the bloodstream. They also stimulate the activity of lipoprotein lipase, an enzyme that helps clear triglycerides from circulation.

Omega-3 fatty acids come in different forms and sources:

• Alpha-linolenic acid (ALA): Found in plant products such as nuts, vegetable oils, chia seeds, walnuts, and flax seeds.
• Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA): Found in dietary sources such as fish. ALA is converted to DHA through enzymatic steps, with EPA as an intermediate.
• Fish oil supplements: Popular over-the-counter products, but their impact on cardiovascular risk is limited due to lack of regulation in processing and unclear quality.
• Prescription formulations: Highly concentrated, purified omega-3 products such as icosapent ethyl, which have been studied in major clinical trials.

Several trials have demonstrated that prescription omega-3 fatty acids effectively lower triglycerides:

• The MARINE trial showed that 4 g/day of icosapent ethyl (a highly purified omega-3 fatty acid containing more than 96% EPA) reduced placebo-corrected triglyceride levels by 33.1% without increasing LDL-C in 229 patients with fasting triglycerides above 500 mg/dL.
• The ANCHOR trial confirmed the safety and effectiveness of icosapent ethyl in 702 high-risk, statin-treated patients with residual high triglycerides (200–500 mg/dL) despite LDL-C below 100 mg/dL. The median placebo-adjusted triglyceride reduction was 21.5% with 4 g/day.
• The EVOLVE trial, which tested a mixed omega-3 formulation containing both EPA and DHA in patients with triglycerides ≥500 mg/dL, showed triglyceride reductions of 25.5–30.9% across various doses. Notably, LDL-C increased significantly (19% vs 3% with placebo) at 2 and 4 g/day doses, though there was no increase in circulating concentrations of atherogenic lipoprotein particles, as evidenced by no change in apolipoprotein B (apoB) concentrations.

Benefits Beyond Lowering Triglycerides

The benefits of omega-3 fatty acids may extend beyond triglyceride reduction. Researchers have hypothesized that so-called "pleiotropic effects"—additional biological actions beyond the primary mechanism—may contribute to reducing atherosclerosis (plaque buildup in arteries).

EPA has been shown to diminish markers of inflammation, which is one of the key drivers of atherosclerosis. The MARINE and ANCHOR trials suggested anti-inflammatory effects of icosapent ethyl, including reductions in oxidized LDL, lipoprotein-associated phospholipase A₂ (Lp-PLA₂), and high-sensitivity C-reactive protein (hsCRP).

Importantly, EPA and DHA are different molecules with distinct effects on the body. They differ in their tissue distributions, effects on cell membrane structure, and ability to modulate inflammation, oxidative stress, and endothelial dysfunction (problems with the inner lining of blood vessels).

EPA stabilizes the phospholipid bilayer—the protective outer layer of cells—by allowing cholesterol to remain more evenly distributed. DHA, in contrast, affects membrane fluidity by promoting the formation of disordered domains, which subsequently disrupts the cell membrane. Reducing cholesterol-rich domains with EPA may alleviate inflammation and improve endothelial function.

Given that atherosclerosis is the product of endothelial dysfunction and inflammation, and is associated with changes in membrane lipid structure—including increased permeability, lipid oxidation, and generation of reactive oxygen species—the ability of EPA to modulate these pathways is promising.

Clinical Trials of Omega-3 Fatty Acids: Mixed Results

Despite the biological plausibility, clinical trials of omega-3 fatty acids for cardiovascular event reduction have produced inconsistent results. The design of these trials varied considerably in patient populations, baseline characteristics (including statin use and triglyceride levels), and the composition and dosing of omega-3 fatty acids.

GISSI-P: An Early Positive Trial

The GISSI-P (Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico-Prevenzione) trial, published in 1999, randomized 11,324 patients with recent heart attacks (within 3 months) to 1 gram of omega-3 fatty acids (containing 460 mg EPA and 380 mg DHA) or placebo. The trial demonstrated a 10% reduction in the composite outcome of death, non-fatal heart attack, and stroke (relative risk 0.90; 95% CI 0.82–1.00; P=0.048). However, only 5% of patients were on statins at baseline, making the results less applicable to today's clinical practice where statins are standard of care.

ORIGIN: No Benefit in High-Risk Patients

The ORIGIN (Outcome Reduction with an Initial Glargine Intervention) trial investigated 12,536 patients at high risk for cardiovascular events who had impaired glucose tolerance or diabetes. Patients were randomized to 1 gram of omega-3 fatty acids or olive oil placebo. Over a median follow-up of 6.2 years, triglyceride levels decreased by 14.5 mg/dL, but there was no difference in the primary outcome of death from cardiovascular causes. In this trial, 53% of patients were on a statin at baseline.

ASCEND: Focus on Diabetes

The ASCEND (A Study of Cardiovascular Events in Diabetes)-Omega 3 trial studied 15,480 patients with diabetes but no evidence of ASCVD. Patients received either 1 gram of omega-3 fatty acids or an olive oil placebo. During a mean follow-up of 7.4 years, there was no difference in the primary endpoint of first serious vascular event—defined as a composite of heart attack, stroke, transient ischaemic attack (a "mini-stroke"), or vascular death (rate ratio 0.97; 95% CI 0.87–1.08). However, in exploratory analyses, there were fewer vascular deaths in the fatty acid group (rate ratio 0.81; 95% CI 0.67–0.99).

VITAL: A Large Primary Prevention Trial

The VITAL (Vitamin D and Omega-3 Trial) involved 25,871 participants who received omega-3 fatty acid supplements or placebo. Over a median follow-up of 5.3 years, there was no difference in the incidence of major adverse cardiovascular events (hazard ratio 0.92; 95% CI 0.80–1.06). However, secondary endpoint analyses revealed a lower incidence of total heart attacks (hazard ratio 0.72; 95% CI 0.59–0.90) and composite coronary heart disease (hazard ratio 0.83; 95% CI 0.71–0.97).

STRENGTH and OMEMI: No Benefit Observed

The STRENGTH (Study to Assess STatin Residual Risk Reduction With EpaNova in HiGh CV Risk PatienTs With Hypertriglyceridaemia) trial included 13,078 patients at high cardiovascular risk with hypertriglyceridemia and low levels of HDL-C. Treatment with 4 g/day of omega-3 carboxylic acid (a formulation containing both EPA and DHA) showed no benefit in the primary composite outcome compared to a corn oil placebo.

The OMEMI (Omega-3 Fatty acids in Elderly with Myocardial Infarction) trial studied 1,027 patients aged 70–82 who had recently experienced an acute heart attack. Treatment with 1.8 g of EPA plus DHA (930 mg EPA + 660 mg DHA) did not reduce cardiovascular events compared to placebo.

What Meta-Analyses Show

Meta-analyses—studies that combine the results of multiple trials—have also produced mixed findings:

• One meta-analysis found no significant association of omega-3 fatty acids with fatal or non-fatal coronary heart disease or any major vascular events.
• However, a meta-analysis of 18 randomized controlled trials and 16 prospective studies found a reduction in coronary heart disease in higher-risk populations with elevated triglycerides and LDL-C, though no decrease in the overall population.
• Another meta-analysis, which did not include the STRENGTH and OMEMI trials, found a lower risk of heart attack, total coronary heart disease, and total cardiovascular disease with omega-3 fatty acids, but no association with stroke.
• A meta-analysis of 40 studies of EPA + DHA supplements showed a lower risk of heart attack (relative risk 0.87; 95% CI 0.80–0.96) with a number needed to treat (NNT) of 272. There was a dose–effect relationship: each additional 1 g/day of omega-3 was associated with a 9% risk reduction in heart attack.

This dose–response observation raises an important question: could the varying concentrations of omega-3 fatty acids used in different trials explain the inconsistent results? Several trials used lower-dose preparations that may have diluted any potential benefit.

The JELIS Trial: Testing EPA Alone

All of the trials discussed so far used formulations combining EPA and DHA. The JELIS (Japan EPA Lipid Intervention Study) trial, published in 2007, took a different approach by testing 1.8 g of EPA alone versus statin therapy alone (low-dose 10 mg pravastatin or 5 mg simvastatin) in a patient population comprised mostly of people without a history of cardiovascular disease.

The results showed a 19% relative risk reduction in ASCVD events at a median follow-up of 4.6 years. This benefit was driven by a statistically significant reduction in hospitalizations for unstable angina, while no other individual endpoints—such as non-fatal heart attack, stroke, revascularization, or cardiovascular mortality—were significantly different.

The JELIS trial had important limitations, including the lack of a placebo and the use of only low-intensity statins as the comparison treatment. Notably, however, the diminished coronary events seen with EPA occurred regardless of LDL-C reduction, suggesting that other factors—potentially the anti-inflammatory and membrane-stabilizing effects of EPA—were at play.

The REDUCE-IT Trial: Strong Evidence for Icosapent Ethyl

The most compelling evidence for omega-3 fatty acids in cardiovascular risk reduction comes from the REDUCE-IT trial, which tested icosapent ethyl—a highly purified, prescription formulation containing more than 96% EPA. The cardiovascular benefits demonstrated in this trial are robust, with consistent and significant reductions in cardiovascular events confirmed by independent, blinded clinical endpoint committee adjudication as well as investigator-reported assessments.

Key findings from REDUCE-IT and its sub-analyses include:

• Early and sustained benefit: The benefit of icosapent ethyl appeared early in the study and persisted across pre-specified interim analyses.
• US patient subgroup: A pre-specified analysis of patients enrolled in the US showed strong risk reductions with no heterogeneity between US and non-US subgroups, confirming that US patients derive as much benefit as the overall trial population.
• Chronic kidney disease (CKD) patients: While some lipid-lowering therapies have reduced efficacy and more side effects in patients with CKD, icosapent ethyl was shown to reduce ischaemic events across a range of estimated glomerular filtration rate (eGFR) levels and CKD stages. Although bleeding rates and atrial fibrillation/flutter event rates were higher with decreasing eGFR, the relative risks with icosapent ethyl were similar across eGFR categories, and tolerability was consistent.
• Prior coronary artery bypass grafting (CABG): In a subgroup analysis of patients who had previously undergone bypass surgery (22.5% of the trial population), there was a decrease in the primary endpoint with an absolute risk reduction of 6.2% and a number needed to treat (NNT) of just 16.
• Prior percutaneous coronary intervention (PCI): Patients who have undergone procedures such as angioplasty and stenting are among the highest-risk groups. Notably, 41.7% of REDUCE-IT participants had prior PCI, and a post hoc analysis demonstrated a 34% reduction in the primary composite endpoint (hazard ratio 0.66).
• Prior heart attack: In a post hoc analysis of patients with a prior myocardial infarction (45.2% of the population), icosapent ethyl reduced the primary endpoint from 26.1% to 20.2% (hazard ratio 0.74; 95% CI 0.65–0.85). There was a 35% relative risk reduction in total ischaemic events, 34% reduction in heart attacks, 30% reduction in cardiovascular death, and 20% reduction in all-cause mortality.
• Total event burden: In a pre-specified analysis, icosapent ethyl reduced total primary endpoint events (rate ratio 0.70; 95% CI 0.62–0.78), highlighting that the medication substantially decreases not just first events but also subsequent and total ischaemic events.

Similar reductions in endpoints were observed in patients who did or did not have a history of prior coronary revascularization. This proof of benefit across such high-risk populations adds to the growing evidence supporting icosapent ethyl.

What This Means for Patients

For patients with elevated triglycerides who are already taking statins, the evidence points to an important distinction between different types of omega-3 products:

• Over-the-counter fish oil supplements containing mixtures of EPA and DHA have shown inconsistent results in clinical trials. Their quality is not regulated, and their processing is unclear, which limits their reliability and potential benefit.
• Combined EPA/DHA prescription formulations have generally not demonstrated cardiovascular event reduction in large trials (STRENGTH, OMEMI).
• Icosapent ethyl (a purified EPA-only prescription formulation) is the only omega-3 fatty acid that has consistently and robustly reduced cardiovascular events in a large outcomes trial (REDUCE-IT), with particular benefit seen in high-risk subgroups including patients with prior heart attacks, prior bypass surgery, prior stent procedures, and chronic kidney disease.

The observed dose–response relationship—where each additional 1 g/day of omega-3 fatty acids was associated with a 9% risk reduction in heart attacks—suggests that the dose and purity of the formulation matter considerably.

Study Limitations

Several limitations should be considered when interpreting this evidence:

• The trials of omega-3 fatty acids differed considerably in study design, patient populations (primary prevention vs secondary prevention), baseline characteristics including statin use and triglyceride levels, and total trial duration.
• Most trials used combinations of EPA and DHA, which have differential biological effects. The varying composition of the omega-3 formulations may have significantly influenced the results.
• The threshold concentration of EPA achieved in the blood may be a relevant factor given the evidence of a dose response. Several trials used lower-dose preparations that may have diluted any potential benefit.
• Some of the strongest findings come from post hoc (after-the-fact) subgroup analyses of REDUCE-IT, which are hypothesis-generating rather than definitive on their own.
• The JELIS trial lacked a placebo control and used only low-intensity statins, limiting its comparability to contemporary practice.
• Bleeding and atrial fibrillation/flutter events were higher with icosapent ethyl in some analyses, particularly in patients with worse kidney function, underscoring the need for individualized risk–benefit assessment.

Recommendations for Patients

Based on this review, patients and clinicians may consider the following:

1. Know your numbers: Ask your doctor about your triglyceride levels. Elevated triglycerides (≥150 mg/dL) are common (affecting more than 1 in 5 US adults) and contribute to cardiovascular risk even when LDL cholesterol is well controlled.
2. Do not substitute over-the-counter fish oil for prescription therapy: Fish oil supplements have limited regulation and unclear quality, and clinical trials of over-the-counter and mixed EPA/DHA formulations have shown inconsistent cardiovascular benefits.
3. Talk to your doctor about icosapent ethyl: If you are a statin-treated patient with elevated triglycerides and other risk factors—especially if you have had a prior heart attack, bypass surgery, or stent—ask whether prescription icosapent ethyl (a purified EPA formulation) might be appropriate for you.
4. Understand the numbers that matter: In REDUCE-IT, icosapent ethyl reduced the primary endpoint from 26.1% to 20.2% in patients with prior heart attacks and had a number needed to treat of only 16 in patients with prior bypass surgery—meaning just 16 such patients need to be treated to prevent one cardiovascular event.
5. Remember that omega-3 therapy is complementary, not a replacement: These findings apply to patients already receiving statin therapy. Statins remain the foundation of cardiovascular risk reduction, and omega-3 therapy should be seen as an additional layer of protection, not a substitute.
6. Discuss potential side effects: While icosapent ethyl was well tolerated overall, bleeding rates and atrial fibrillation/flutter were higher in some analyses. Your doctor can help weigh the benefits and risks based on your individual health profile.

The takeaway is straightforward: not all omega-3 fatty acids are the same. The evidence distinguishes between dietary supplements, combined EPA/DHA formulations, and purified prescription EPA, with the latter showing the most compelling benefit for lowering residual cardiovascular risk in appropriately selected high-risk patients.

Frequently Asked Questions

What are triglycerides and why are high levels risky?

Triglycerides are a type of fat in the blood. High levels (150 mg/dL or higher) affect more than 1 in 5 U.S. adults. Even when LDL cholesterol is well controlled with statins, high triglycerides contribute to residual risk of heart attacks and strokes. Your doctor can check this with a simple blood test.

I take a statin but my triglycerides are still high. What options are there?

Your doctor may consider adding a prescription omega-3 medication. In the REDUCE-IT trial, icosapent ethyl – a purified EPA prescription – reduced cardiovascular events in statin-treated patients with elevated triglycerides. Over-the-counter fish oil supplements have shown inconsistent results and are not regulated for quality. Discuss options with your doctor.

Are over-the-counter fish oil supplements as effective as prescription omega-3?

No. Clinical trials of over-the-counter fish oil and combined EPA/DHA prescription formulations have shown mixed or no benefit. Icosapent ethyl, a highly purified prescription EPA, is the only omega-3 that consistently reduced cardiovascular events in a large trial. Fish oil quality is not regulated, which limits reliability. Ask your doctor before substituting.

What is icosapent ethyl and who might benefit from it?

Icosapent ethyl is a prescription, highly purified form of EPA (over 96% pure). In the REDUCE-IT trial, it reduced heart attacks, strokes, and other events in high-risk statin-treated patients. Benefit was especially seen in patients with prior heart attack, bypass surgery, stent, or chronic kidney disease. Ask your doctor if it might be right for you.

What side effects should I discuss with my doctor about icosapent ethyl?

In REDUCE-IT, icosapent ethyl was generally well tolerated, but some analyses showed higher rates of bleeding and atrial fibrillation/flutter, particularly in patients with worse kidney function. Your doctor can help weigh the potential benefits and risks based on your individual health profile before you start any new medication.

If I take omega-3, can I stop my statin?

No. Omega-3 therapy should be seen as an additional layer of protection, not a replacement. The studies showing benefit from icosapent ethyl included patients already taking statins. Statins remain the foundation of cardiovascular risk reduction. Always continue prescribed statin therapy unless your doctor tells you otherwise.

What does 'number needed to treat of 16' mean for patients with prior bypass surgery?

In the REDUCE-IT subgroup of patients with prior coronary artery bypass grafting, treating 16 such patients with icosapent ethyl for the trial period would prevent one cardiovascular event. This means the medication had a noticeable benefit in this high-risk group. Ask your doctor how this applies to your situation.

I have high triglycerides and take a statin. My doctor suggests prescription icosapent ethyl, but I'm not sure it's worth it. When should I get a second opinion about omega-3 treatment?

For statin-treated patients with elevated triglycerides, especially after a heart attack, bypass surgery, stent, or with chronic kidney disease, prescription icosapent ethyl is the only omega-3 shown in a large trial to consistently reduce cardiovascular events. Over-the-counter fish oil and combined EPA/DHA products have not shown such benefit. A second opinion can help clarify whether icosapent ethyl is appropriate for your risk profile, given potential side effects like bleeding or atrial fibrillation, and confirm that statins remain foundational. Diagnostic Detectives Network provides independent expert second opinions.

Source Information

Original article title: Omega-3 fatty acids for cardiovascular event lowering

Authors: Gurleen Kaur, R. Preston Mason, Ph. Gabriel Steg, and Deepak L. Bhatt

Journal: European Journal of Preventive Cardiology (2024), Volume 31, Issue 8, pages 1005–1014

DOI: https://doi.org/10.1093/eurjpc/zwae003

Institutional affiliations: Brigham and Women's Hospital, Harvard Medical School; Elucida Research LLC; Paris Cité University, Public Hospitals of Paris (AP-HP), Bichat Hospital; and Mount Sinai Fuster Heart Hospital, Icahn School of Medicine at Mount Sinai

Publication dates: Received 28 November 2023; revised 28 December 2023; accepted 31 December 2023; published ahead of print 3 January 2024

Note: This patient-friendly article is based on peer-reviewed research. It has been adapted and paraphrased from the original scientific publication to make the information accessible to non-specialist readers. The original article is an open-access publication distributed under the terms of the Creative Commons Attribution License.