Omega-3 Fatty Acids (EPA/DHA) for Cardiovascular Health — Aging
Essential polyunsaturated fatty acids with FDA-approved indications for severe hypertriglyceridemia and strong evidence for cardiovascular risk reduction.
Overview
Omega-3 polyunsaturated fatty acids, primarily eicosapentaenoic acid (EPA, 20:5n-3) and docosahexaenoic acid (DHA, 22:6n-3), are essential fatty acids that cannot be synthesized de novo by humans and must be obtained from marine sources (fatty fish, algae) or supplementation. Multiple large-scale randomized controlled trials have established their role in cardiovascular risk reduction. The REDUCE-IT trial (n=8,179) demonstrated that icosapent ethyl (Vascepa, purified EPA 4 g/day) reduced the composite endpoint of cardiovascular death, MI, stroke, coronary revascularization, and unstable angina by 25% in statin-treated patients with elevated triglycerides. This led to FDA approval of Vascepa for cardiovascular risk reduction in 2019. EPA and DHA reduce hepatic VLDL synthesis and triglyceride secretion, lower plasma triglycerides by 15-45% in a dose-dependent manner, and exert anti-inflammatory effects through competitive inhibition of arachidonic acid metabolism and generation of specialized pro-resolving lipid mediators (resolvins, protectins, maresins). The American Heart Association recommends 1 g/day of combined EPA/DHA for secondary prevention and 2-4 g/day for triglyceride lowering. DHA additionally plays structural roles in neuronal membranes and retinal photoreceptors.
Indications
- FDA-approved: Severe hypertriglyceridemia (TG >= 500 mg/dL) — Lovaza, Vascepa, Epanova
- FDA-approved: Cardiovascular risk reduction in statin-treated patients with TG >= 150 mg/dL (Vascepa)
- Strong evidence: Secondary prevention of cardiovascular events (AHA recommendation)
- Moderate evidence: Triglyceride reduction (15-45% at therapeutic doses)
- Moderate evidence: Anti-inflammatory effects (rheumatoid arthritis adjunct)
- Moderate evidence: Cognitive maintenance and neuroprotection
Mechanism of Action
EPA and DHA inhibit hepatic diacylglycerol acyltransferase (DGAT) and activate PPAR-alpha, reducing VLDL-triglyceride synthesis and secretion by the liver
Dosing
| Compound | Dose | Frequency | Notes |
|---|---|---|---|
| Fish oil (EPA/DHA combined) | 1 g (EPA+DHA) | Once daily | AHA secondary prevention recommendation |
| Fish oil (EPA/DHA combined) | 2-4 g (EPA+DHA) | Daily, divided with meals | Triglyceride lowering; requires high EPA+DHA content |
| Icosapent ethyl (Vascepa) | 2 g | Twice daily with meals | FDA-approved CV risk reduction; pure EPA; REDUCE-IT protocol |
| Omega-3 acid ethyl esters (Lovaza) | 4 g | Once daily or divided | FDA-approved for severe hypertriglyceridemia (TG >= 500) |
Evidence Grade
GRADE A
Safety & Contraindications
- GI side effects (fishy taste, eructation, dyspepsia, diarrhea) most common
- Increased bleeding risk at high doses (>3 g/day) — monitor if on anticoagulants/antiplatelets
- Atrial fibrillation risk slightly increased in REDUCE-IT and STRENGTH trials at high doses
- Fish oil supplements may contain mercury and PCBs — choose USP-verified or pharmaceutical grade
- May increase LDL cholesterol slightly (DHA component) — EPA-only formulation avoids this
- Discontinue 1 week before surgery at high doses due to antiplatelet effect