Fish Oil Forms: Triglyceride (TG) vs Ethyl Ester (EE)
For cardiovascular risk reduction and triglyceride lowering, prescription omega-3 products (which include both TG and EE forms) are superior to over-the-counter supplements, but among supplement forms, re-esterified triglycerides demonstrate superior bioavailability (124%) compared to ethyl esters (73%) when measured against natural fish oil. 1
Key Differences Between Forms
Bioavailability and Absorption
- Re-esterified triglycerides (rTG) show the highest bioavailability at 124% compared to natural fish oil, while ethyl esters demonstrate only 73% bioavailability 1
- Free fatty acid forms show 91% bioavailability, which does not differ significantly from natural triglycerides 1
- The degree of re-esterification matters significantly: supplements with >95% rTG content produce greater increases in erythrocyte EPA, DPA, and DHA compared to <70% rTG preparations at 16 weeks 2
- EPA:arachidonic acid ratios and EPA+DHA:arachidonic acid ratios are significantly higher with >95% rTG preparations compared to lower percentage rTG products 2
Clinical Efficacy Considerations
For prescription products specifically:
- Ethyl ester preparations are FDA-approved for treating elevated triglycerides and reducing ASCVD risk 3
- The most frequent adverse effects differ by form: ethyl ester preparations cause eructation, dyspepsia, and taste perversion, while pure EPA ethyl ester (icosapent ethyl/IPE) causes musculoskeletal pain, peripheral edema, constipation, gout, and atrial fibrillation 3
- Prescription omega-3 ethyl ester products have demonstrated cardiovascular outcomes benefits (20% reduction in overall mortality, 45% reduction in sudden death in the GISSI trial with 850 mg EPA+DHA ethyl esters) 3
Over-the-Counter Supplements vs Prescription Products
Nonprescription fish oil products are NOT interchangeable with prescription omega-3 products and have critical limitations: 3
- Not FDA-approved to treat elevated triglycerides
- Variable content and quality between products
- May contain saturated fat, oxidized fatty acids, contaminants, or additional calories
- Require larger pill burdens to achieve therapeutic doses
- Commonly cause gastrointestinal side effects (burping, fishy taste, dyspepsia)
- Have not been demonstrated to have cardiovascular outcomes benefits and are not recommended for ASCVD risk reduction 3
Practical Clinical Implications
When Bioavailability Matters Most
- For patients requiring omega-3 supplementation who cannot access prescription products, choose preparations with >95% re-esterified triglyceride content over ethyl ester or lower percentage rTG products 2, 1
- The percentage of rTG in fish oil preparations serves as a quality control marker that influences pharmacodynamics 2
When Prescription Products Are Indicated
- For triglyceride lowering (≥150 mg/dL) with established cardiovascular disease or diabetes plus ≥2 risk factors, use prescription icosapent ethyl (pure EPA ethyl ester) as the only FDA-approved omega-3 for ASCVD risk reduction 3
- For severe hypertriglyceridemia (≥500 mg/dL), prescription omega-3 products (either EPA+DHA ethyl esters or carboxylic acids) are indicated 3
Important Caveats
- Monitor for atrial fibrillation risk: prescription omega-3 products at doses of 1.8-4 g daily increase AF risk (3.1% vs 2.1% in REDUCE-IT) 3
- Long-term studies comparing TG versus EE forms show similar effects on plasma fatty acid incorporation into phospholipids and platelet function, despite differences in cholesteryl ester incorporation 4
- Both forms equally inhibit collagen-induced platelet aggregation and thromboxane B2 production 4
Dosing Considerations
- For secondary prevention in coronary disease, 850-900 mg EPA+DHA daily (achievable with one fatty fish meal daily or supplements) has demonstrated mortality benefits 3
- For hypertriglyceridemia treatment, 3-4 g daily of prescription products is required 3
- In critically ill patients requiring parenteral nutrition, 0.1-0.2 g fish oil/kg/day is recommended 3