What is the role of omega three fatty acids (EPA and DHA) in managing hypertriglyceridemia?

Role of Omega-3 Fatty Acids in Managing Hypertriglyceridemia

Prescription omega-3 fatty acids (4g/day) are effective for reducing triglyceride levels in patients with severe hypertriglyceridemia (≥500 mg/dL), with icosapent ethyl (IPE) being the only FDA-approved omega-3 preparation for cardiovascular risk reduction in patients with elevated triglycerides (≥150 mg/dL) who have established cardiovascular disease or diabetes with additional risk factors. 1

Types of Omega-3 Preparations and FDA Approval Status

There are three main prescription omega-3 fatty acid formulations available:

1. Omega-3 ethyl esters (OM3EE) - Contains both EPA and DHA (Lovaza® and generics)

   • FDA-approved for severe hypertriglyceridemia (≥500 mg/dL)
   • Mechanism: Inhibition of acyl-CoA:1,2-diacylglycerol acyltransferase, increased mitochondrial and peroxisomal β-oxidation, decreased lipogenesis, and increased plasma lipoprotein lipase activity 2

2. Icosapent ethyl (IPE) - Contains EPA only

   • FDA-approved for:
     • Severe hypertriglyceridemia (≥500 mg/dL)
     • Cardiovascular risk reduction in patients with triglycerides ≥150 mg/dL with established cardiovascular disease or diabetes plus ≥2 risk factors 1

3. Omega-3 carboxylic acids (OM3CA) - Free fatty acid form of EPA and DHA

   • FDA-approved for severe hypertriglyceridemia (≥500 mg/dL) 1

Efficacy in Hypertriglyceridemia Management

Severe Hypertriglyceridemia (≥500 mg/dL)

• Prescription omega-3 fatty acids at 4g/day reduce triglycerides by approximately 30-45% 1, 3
• OM3CA has demonstrated efficacy even at intermediate doses (2g/day) with significant triglyceride reductions compared to placebo 4

Moderate Hypertriglyceridemia (150-499 mg/dL)

• For patients with triglycerides 150-499 mg/dL, omega-3 fatty acids can be considered as part of the treatment strategy, particularly in high-risk patients 5
• IPE (4g/day) has demonstrated cardiovascular benefit in the REDUCE-IT trial with a 25% reduction in major adverse cardiovascular events in high-risk statin-treated patients 3

Differential Effects on Lipid Parameters

• EPA+DHA formulations: Reduce triglycerides but may increase LDL-C in patients with very high triglycerides 3
• EPA-only (IPE): Reduces triglycerides without raising LDL-C 1, 3
• Both formulations: Reduce non-HDL cholesterol and apolipoprotein B, indicating reductions in total atherogenic lipoproteins 3

Safety Profile and Adverse Effects

Prescription omega-3 fatty acids are generally well-tolerated with minimal side effects:

• Common adverse effects: Eructation, dyspepsia, taste perversion (for ethyl ester preparations) 1
• IPE-specific adverse effects: Musculoskeletal pain, peripheral edema, constipation, gout 1
• Important safety concern: Increased risk of atrial fibrillation with higher doses (1.8-4g daily) of prescription omega-3 preparations 1
  • REDUCE-IT: 3.1% vs 2.1% hospitalization for AF (p=0.004)
  • STRENGTH trial: 2.2% vs 1.3% new-onset AF (HR: 1.69)

Prescription vs. Non-prescription Products

Non-prescription fish oil supplements are NOT equivalent to prescription products: 1

• Not FDA-approved for treating elevated triglycerides
• Manufacturing process not as strictly regulated
• Variable content and quality
• May contain impurities (saturated fat, oxidized lipids, contaminants)
• May require larger pill burden to achieve equivalent doses
• More likely to cause gastrointestinal side effects
• No demonstrated cardiovascular outcomes benefits

Clinical Recommendations

1. For severe hypertriglyceridemia (≥500 mg/dL):

   • Prescription omega-3 fatty acids (4g/day) as adjunct to diet 1, 5
   • Consider IPE if concerned about LDL-C elevation 1

2. For patients with established ASCVD or diabetes with ≥2 risk factors and triglycerides ≥150 mg/dL:

   • IPE (4g/day) as adjunct to maximally tolerated statin therapy 1

3. For patients with moderate hypertriglyceridemia (150-499 mg/dL):

   • Lifestyle modifications (dietary changes, physical activity) as first-line therapy 5
   • Consider omega-3 fatty acids based on overall cardiovascular risk assessment 5

Monitoring Recommendations

• Assess triglyceride response after 8-12 weeks of therapy 5
• Monitor for potential increases in LDL-C levels, particularly with EPA+DHA formulations 1
• Evaluate for potential risk of atrial fibrillation, especially in high-risk patients 1

Important Caveats

• The effect of omega-3 fatty acids on pancreatitis risk has not been definitively determined 2
• Clinicians should evaluate the potential net benefit of prescription omega-3 fatty acids in patients at high risk of atrial fibrillation 1
• Non-prescription fish oil supplements should not be substituted for prescription products when treating hypertriglyceridemia 1