What is the current status of omega 3 fatty acids (EPA and DHA) in the treatment of hypertriglyceridemia in 2025?

Current Status of Omega-3 Fatty Acids in Hypertriglyceridemia Treatment in 2025

For patients with hypertriglyceridemia, prescription omega-3 fatty acids at a dose of 4 grams per day are recommended as an effective treatment option, with icosapent ethyl (pure EPA) being the only omega-3 formulation FDA-approved for cardiovascular risk reduction in addition to triglyceride lowering. 1

Dietary Recommendations

• All individuals should consume at least 2 or more servings of fish/seafood per week for a total of 8 or more ounces, preferably fatty fish such as salmon, rainbow trout, and tuna 1
• This dietary intake provides approximately 250 mg per day of EPA+DHA, which has shown benefit for coronary heart disease death in prospective cohort studies and randomized clinical trials 1
• For patients with triglyceride levels of 200-499 mg/dL, fatty fish consumption should be emphasized, while those with levels 500-999 mg/dL may need to consider lean fish options if fat intake restriction is necessary 1
• Patients should prioritize fish varieties that are higher in EPA and DHA but lower in methylmercury (salmon, anchovies, sardines, Pacific oysters, trout) 1
• Dietary intake alone is insufficient for therapeutic triglyceride lowering in patients with hypertriglyceridemia, as current estimates of seafood consumption in the United States are only about 6 servings per month 1

Prescription Omega-3 Formulations

• Three prescription omega-3 fatty acid formulations are available for treatment of severe hypertriglyceridemia (≥500 mg/dL) 2:

  • Omega-3 fatty acid ethyl esters (OM3EE): mixture of EPA and DHA ethyl esters 2, 3
  • Icosapent ethyl (IPE): pure EPA ethyl esters 2, 4
  • Omega-3 carboxylic acids (OM3CA): mixture of EPA, DHA, and docosapentaenoic acid in free fatty acid form 2

• At the therapeutic dose of 4 g/day, these formulations can reduce triglyceride levels by 25-35% and up to 45% in patients with severely elevated triglycerides (≥500 mg/dL) 5, 6

Cardiovascular Risk Reduction

• Icosapent ethyl (IPE) is currently the only triglyceride risk-based nonstatin therapy approved by the FDA for reduction in ASCVD risk 1

• IPE is indicated as an adjunct to maximally tolerated statin therapy to reduce the risk of MI, stroke, coronary revascularization, and unstable angina requiring hospitalization in adult patients with elevated triglyceride levels (≥150 mg/dL) and:

  • Established cardiovascular disease, or
  • Diabetes mellitus and ≥2 additional risk factors for cardiovascular disease 1

• Lower-dose mixtures of EPA and DHA (less than 4g/day) have failed to show significant reduction in cardiovascular endpoints in multiple large randomized controlled trials with contemporary background therapy 1

Differential Effects of EPA vs. EPA+DHA Formulations

• While all prescription omega-3 formulations effectively lower triglycerides, they have different effects on LDL-C 4, 6:

  • DHA-containing formulations may increase LDL-C levels 4
  • Pure EPA formulations (icosapent ethyl) do not increase LDL-C levels 4, 6

• Both formulations reduce non-HDL-C and apolipoprotein B, indicating reductions in total atherogenic lipoproteins 6

Safety Considerations

• Multiple randomized controlled trials of prescription omega-3 fatty acids at higher doses (1.8 to 4 g daily) have demonstrated an increased risk of atrial fibrillation 1
• In the REDUCE-IT trial, patients receiving IPE had higher rates of hospitalization for atrial fibrillation or flutter (3.1% vs 2.1%, P=0.004) compared to placebo 1
• Clinicians should evaluate the potential net benefit of prescription omega-3 fatty acids in patients at high risk of atrial fibrillation 1
• Common adverse effects include:
  • Ethyl ester preparations: eructation, dyspepsia, taste perversion 1
  • IPE: musculoskeletal pain, peripheral edema, constipation, gout 1

Clinical Algorithm for Omega-3 Fatty Acids in Hypertriglyceridemia

1. For all patients with hypertriglyceridemia:

   • Recommend 2+ servings of fatty fish weekly (8+ oz total) 1
   • Address lifestyle factors (weight loss, exercise, limiting alcohol, reducing added sugars) 1

2. For patients with severe hypertriglyceridemia (≥500 mg/dL):

   • Prescribe 4 g/day of omega-3 fatty acids (any formulation) as adjunct to diet 1, 3

3. For patients with elevated triglycerides (150-499 mg/dL) AND:

   • Established cardiovascular disease OR
   • Diabetes with ≥2 additional CV risk factors:
     • Prescribe icosapent ethyl 4 g/day as adjunct to maximally tolerated statin therapy 1, 6

4. Monitor for adverse effects, particularly atrial fibrillation in high-risk patients 1