EPA

Eicosapentaenoic acid (EPA, 20:5n-3) is a 20-carbon omega-3 polyunsaturated fatty acid with five cis double bonds. Among the three principal dietary omega-3s (ALA, EPA, DHA), EPA has the strongest evidence base for specific cardiovascular benefit at pharmacological doses and is the characteristic substrate for specialized pro-resolving mediators (SPMs) in the resolvin E series.

Biosynthesis and sources

Humans can synthesize EPA endogenously from alpha-linolenic acid (ALA) through sequential elongation and desaturation, but conversion efficiency is low (~5-10%) and further reduced by competition with omega-6 linoleic acid for shared desaturase enzymes. Direct dietary sources include fatty fish (salmon 0.5-1.0 g EPA per 100 g cooked, sardines 0.5-0.7 g, mackerel 0.9-1.0 g, anchovies 0.5-0.7 g, herring 0.7-1.0 g) and algal oil, which has emerged as a plant-source alternative particularly relevant for vegetarians.

Eicosanoid and SPM precursor role

EPA is a substrate for cyclooxygenase (COX) and lipoxygenase (LOX) enzymes, producing 3-series prostaglandins (PGE3, PGI3), 3-series thromboxanes (TXA3), and 5-series leukotrienes — generally less inflammatory than the 2-series and 4-series products from arachidonic acid (AA, 20:4n-6). EPA also serves as the substrate for the E-series resolvins (RvE1, RvE2, RvE3) identified by Charles Serhan and colleagues, which actively resolve inflammation by modulating neutrophil trafficking, macrophage polarization, and cytokine production. This "active resolution" paradigm has shifted understanding of inflammation from a passive decay phenomenon to an actively regulated process.

Cardiovascular evidence

The REDUCE-IT trial (Bhatt et al., NEJM 2019) randomized 8,179 statin-treated patients with elevated triglycerides to 4 g/day icosapent ethyl (pure EPA ethyl ester) or placebo (mineral oil) and observed a 25% relative risk reduction in the primary composite cardiovascular endpoint. The Japanese JELIS trial (Yokoyama et al., Lancet 2007) had previously shown a 19% reduction in coronary events with 1.8 g/day pure EPA added to statin therapy. By contrast, the STRENGTH trial of a 4 g/day EPA+DHA carboxylic acid formulation showed no benefit, raising questions about whether high-dose pure EPA, the ethyl ester form, or some other factor underlies REDUCE-IT's results.

Mechanisms beyond triglyceride lowering

EPA's cardiovascular benefit appears to exceed what can be attributed to triglyceride reduction alone. Proposed mechanisms include: membrane stabilization in atherosclerotic plaque; reduced platelet aggregation via competition with arachidonic acid; reduced endothelial dysfunction; anti-inflammatory effects via resolvins; and potentially direct anti-arrhythmic effects. Plaque imaging substudies have shown reduced plaque volume with icosapent ethyl.

Dosing considerations

General-population omega-3 recommendations (AHA: two fatty fish servings weekly) provide approximately 250-500 mg combined EPA+DHA daily — the dose level consistent with primary prevention. Pharmacological doses (2-4 g/day) are reserved for secondary prevention in high-risk patients under clinical supervision. Fish oil supplements contain highly variable EPA:DHA ratios; prescription icosapent ethyl provides pure EPA without DHA.

Safety

EPA at supplemental and prescription doses is generally well tolerated. Bleeding risk increases modestly at high doses, relevant for patients on anticoagulation. Atrial fibrillation rates were slightly elevated in REDUCE-IT and several other omega-3 trials, a signal requiring awareness in patients with predisposing conditions.