What is the recommended treatment for hypertriglyceridemia with omega-3 (fatty acids)?

Treatment of Hypertriglyceridemia with Omega-3 Fatty Acids

For hypertriglyceridemia treatment, prescription omega-3 fatty acids are recommended when triglyceride levels remain persistently elevated despite lifestyle modifications, with icosapent ethyl (IPE) being the only FDA-approved omega-3 preparation for ASCVD risk reduction. 1

First-Line Approach

• Begin with comprehensive lifestyle interventions as the foundation of hypertriglyceridemia management, including weight loss (5-10% reduction can decrease triglycerides by 20%), very low-fat diet, elimination of added sugars and alcohol, and addressing secondary causes 1
• Identify and manage secondary causes of hypertriglyceridemia (diabetes, hypothyroidism, medications like beta-blockers, thiazides, estrogens) before initiating triglyceride-lowering therapy 2
• For patients with severe hypertriglyceridemia (≥500 mg/dL), implement a very-low-fat diet (10-15% of calories from fat) 1
• For triglycerides ≥1,000 mg/dL, extreme dietary fat restriction (<5% of total calories) may be necessary until levels decrease to <1,000 mg/dL, at which point triglyceride-lowering medications become more effective 1

Omega-3 Fatty Acid Treatment Options

FDA-Approved Indications

• Icosapent ethyl (IPE): The only triglyceride risk-based omega-3 therapy FDA-approved for ASCVD risk reduction 1

  • Indicated as adjunct to maximally tolerated statin therapy to reduce risk of MI, stroke, coronary revascularization, and unstable angina requiring hospitalization in adults with:
    • Elevated triglycerides (≥150 mg/dL) AND
    • Established cardiovascular disease OR
    • Diabetes mellitus with ≥2 additional cardiovascular risk factors 1
  • Also indicated for severe hypertriglyceridemia (≥500 mg/dL) 1

• Omega-3 carboxylic acid and omega-3-acid ethyl esters: Only indicated for severe hypertriglyceridemia (≥500 mg/dL) 1, 2

Dosing and Administration

• Recommended dose is 4 grams per day for all prescription omega-3 preparations 2, 3
• Can be taken as a single 4-gram dose (4 capsules) or as two 2-gram doses (2 capsules twice daily) 2
• Capsules should be swallowed whole with meals; do not break, crush, dissolve, or chew 2

Efficacy and Mechanism of Action

• At 4 g/day, omega-3 fatty acids reduce triglycerides by approximately 30-45% in patients with severe hypertriglyceridemia 4, 3
• Proposed mechanisms include:
  • Inhibition of diacylglycerol acyltransferase
  • Increased plasma lipoprotein lipase activity
  • Decreased hepatic lipogenesis
  • Increased hepatic β-oxidation 5
• EPA+DHA formulations may increase LDL-C in patients with very high triglycerides, while EPA-only formulations do not 3
• Both formulations reduce non-HDL-C and apolipoprotein B, indicating reductions in total atherogenic lipoproteins 3

Important Clinical Considerations

• Prescription vs. Non-prescription Products: Prescription omega-3 products are not interchangeable with over-the-counter fish oil supplements 1

  • Non-prescription products:
    • Not FDA-approved for treating elevated triglycerides
    • Variable content and quality
    • May contain impurities or contaminants
    • Often require larger pill burden
    • Not recommended for ASCVD risk reduction 1

• Formulation Differences:

  • Omega-3 free fatty acid formulations have up to 4-fold greater bioavailability than ethyl ester forms during low-fat diet periods 6
  • Ethyl ester forms require pancreatic lipase hydrolysis for absorption, while free fatty acid forms do not 5, 7

• Safety Concerns:

  • Most common adverse effects: eructation, dyspepsia, taste perversion (ethyl ester forms); musculoskeletal pain, peripheral edema, constipation, gout (IPE) 1
  • Increased risk of atrial fibrillation: Multiple randomized controlled trials have shown increased risk of AF with higher doses (1.8-4 g daily) of prescription omega-3 preparations 1
    • Evaluate potential net benefit in patients at high risk of AF 1

Treatment Algorithm Based on Triglyceride Levels

• Triglycerides 150-499 mg/dL:

  • Begin with lifestyle modifications
  • Consider statin therapy based on ASCVD risk
  • If triglycerides remain elevated despite statin therapy, consider adding IPE (especially in patients with established ASCVD or diabetes with multiple risk factors) 1

• Triglycerides ≥500 mg/dL:

  • Implement aggressive lifestyle modifications with very-low-fat diet
  • Add prescription omega-3 fatty acids (4 g/day) 1, 2
  • Consider fibrate therapy if necessary to prevent acute pancreatitis 1

• Triglycerides ≥1,000 mg/dL:

  • Implement extreme dietary fat restriction (<5% of calories)
  • Address secondary causes aggressively
  • Add prescription omega-3 fatty acids and consider fibrate therapy 1