Why are omega-3 fatty acids used in treating hypertriglyceridemia?

Omega-3 Fatty Acids in the Treatment of Hypertriglyceridemia

Prescription omega-3 fatty acids are used in hypertriglyceridemia because they effectively reduce triglyceride levels by 45% at doses of 4g/day, with icosapent ethyl (IPE) being the only FDA-approved omega-3 preparation for both triglyceride reduction and cardiovascular risk reduction. 1

Mechanism and Efficacy

Omega-3 fatty acids work through several mechanisms to lower triglycerides:

• Decrease hepatic production of very low-density lipoprotein (VLDL)
• Increase clearance of triglyceride-rich lipoproteins
• Stimulate lipoprotein lipase activity, accelerating chylomicron degradation 2

The efficacy of omega-3 fatty acids depends on dosage:

• At 4g/day, they reduce triglycerides by approximately 45% and VLDL cholesterol by more than 50% 3
• The effect is dose-dependent, with higher doses providing greater triglyceride reduction 4

FDA-Approved Indications

There are two main types of prescription omega-3 fatty acid preparations:

1. Icosapent ethyl (IPE) - pure EPA ethyl ester:

   • FDA-approved for:
     • Reducing triglycerides in adults with severe hypertriglyceridemia (≥500 mg/dL)
     • Reducing cardiovascular risk in patients with triglycerides ≥150 mg/dL, established cardiovascular disease or diabetes plus ≥2 cardiovascular risk factors, who are on maximally tolerated statin therapy 1

2. Omega-3 carboxylic acid and omega-3-acid ethyl ester preparations (contain both EPA and DHA):

   • FDA-approved only for reducing triglycerides in adults with severe hypertriglyceridemia (≥500 mg/dL) 1

Clinical Application Algorithm

Step 1: Assess Triglyceride Levels and Risk

• Normal: <150 mg/dL
• Mild to Moderate: 150-499 mg/dL
• Severe: 500-999 mg/dL
• Very Severe: ≥1000 mg/dL 2

Step 2: Implement First-Line Interventions

• For all patients with elevated triglycerides, start with lifestyle modifications:
  • Weight management (5-10% weight loss can reduce triglycerides by 20%) 1
  • Regular physical activity (≥150 minutes/week of moderate-intensity exercise) 2
  • Low-fat diet (20-25% of total calories from fat) 2
  • Increased dietary fiber (>10g/day) 2
  • Alcohol restriction 1

Step 3: Determine Need for Pharmacotherapy

• For triglycerides ≥500 mg/dL:

  • Initiate pharmacotherapy immediately to prevent pancreatitis risk 2
  • First-line: Fibrates (fenofibrate 54-160 mg/day) 2
  • Second-line: Prescription omega-3 fatty acids at 4g/day 2

• For triglycerides 150-499 mg/dL with ASCVD or high ASCVD risk:

  • First optimize statin therapy
  • Consider adding IPE 4g/day if on maximally tolerated statin with residual triglyceride elevation 1

Important Clinical Considerations

Prescription vs. Non-prescription Products

• Prescription omega-3 products:

  • FDA-approved for treating hypertriglyceridemia
  • Consistent content and purity
  • Generally well-tolerated 1

• Non-prescription fish oil supplements:

  • Not FDA-approved for treating hypertriglyceridemia
  • Variable content and quality
  • May contain impurities or contaminants
  • Not demonstrated to have cardiovascular outcome benefits 1

Potential Adverse Effects

• Common side effects:

  • Eructation (belching)
  • Dyspepsia
  • Taste perversion 1

• Important safety concern: Increased risk of atrial fibrillation

  • Multiple randomized controlled trials have shown increased risk of atrial fibrillation with higher doses (1.8-4g daily) of prescription omega-3 fatty acids
  • In REDUCE-IT: 3.1% vs 2.1% hospitalization for atrial fibrillation/flutter (p=0.004) 1
  • Carefully evaluate potential net benefit in patients at high risk of atrial fibrillation 1

Monitoring

• Monitor triglyceride levels:
  • Every 4-8 weeks until stabilized
  • Then every 3 months
  • Target: <500 mg/dL to reduce pancreatitis risk 2

Combination Therapy

• For patients not reaching triglyceride goals on monotherapy:
  • Consider combination of statin with omega-3 fatty acids 1
  • Patients with hypertriglyceridemia may show greater improvements with combination therapy compared to statins alone 5

Clinical Pearls

• IPE is the only omega-3 preparation FDA-approved for cardiovascular risk reduction 1
• Newer free fatty acid forms of omega-3s have higher bioavailability than ethyl ester forms 6
• Response to omega-3 fatty acids may be influenced by ApoE genotype 5
• When prescribing omega-3 fatty acids, always use prescription products rather than supplements to ensure consistent quality and purity 1