What dose of omega-3 fatty acids (EPA and DHA) should be prescribed to help lower triglycerides and increase high-density lipoprotein (HDL) levels?

Omega-3 Fatty Acid Dosing for Triglyceride Reduction

For lowering triglycerides, prescribe 4 grams per day of EPA+DHA (prescription omega-3 fatty acids), which reduces triglycerides by 25-45% depending on baseline levels. 1, 2

Dose Stratification by Clinical Indication

For Severe Hypertriglyceridemia (≥500 mg/dL)

• Prescribe 4 grams per day of prescription omega-3 fatty acids (EPA+DHA) as an adjunct to diet 1, 2
• This dose reduces triglycerides by approximately 45% and VLDL cholesterol by more than 50% 3, 4
• Can be taken as a single 4-gram dose (4 capsules) or divided into two 2-gram doses twice daily 1
• Requires physician supervision at this dose 5

For Moderate Hypertriglyceridemia (200-499 mg/dL)

• Prescribe 2-4 grams per day of EPA+DHA under physician supervision 5, 2
• The 4-gram dose provides optimal triglyceride lowering (≥30% reduction) 2
• At 2-4 grams daily, expect triglyceride reductions of 20-40% depending on baseline levels 6

For Documented Coronary Heart Disease (Secondary Prevention)

• Prescribe 1 gram per day of EPA+DHA for cardiovascular risk reduction 5
• This lower dose is insufficient for therapeutic triglyceride lowering but reduces cardiovascular events 6
• The GISSI-Prevenzione trial demonstrated 45% reduction in sudden death with 850 mg EPA+DHA daily 5, 6

Important Caveat Regarding HDL Cholesterol

Omega-3 fatty acids do NOT meaningfully increase HDL cholesterol. 2, 7

• At therapeutic doses (4 grams/day), HDL cholesterol increases are modest at only 1-3% 8, 2
• One older study showed 16% HDL increase with low-dose omega-3s (1.1-1.4 g/day), but this finding has not been replicated in larger, more rigorous trials 7
• The primary benefit is triglyceride reduction, not HDL elevation 2
• If HDL elevation is the goal, consider alternative therapies such as niacin or fibrates 5

Expected Lipid Effects at Therapeutic Doses

Triglyceride Reduction

• At 4 grams/day: 25-45% reduction depending on baseline levels 1, 2
• Greater reductions occur in patients with higher baseline triglycerides 8, 9
• Dose-response relationship shows approximately 5-10% reduction per gram of EPA+DHA 8

LDL Cholesterol Changes

• Monitor LDL cholesterol periodically during therapy 1
• EPA+DHA formulations may increase LDL-C by 5-10% in patients with very high triglycerides (≥500 mg/dL) 8, 2
• EPA-only formulations (icosapent ethyl) do not raise LDL-C in very high triglycerides 2
• When used as monotherapy or with statins for moderate hypertriglyceridemia (200-499 mg/dL), neither EPA+DHA nor EPA-only increase LDL-C 2

Non-HDL Cholesterol

• At 4 grams/day, non-HDL cholesterol decreases modestly, indicating reduction in total atherogenic lipoproteins 2
• For triglycerides 200-499 mg/dL, target non-HDL-C <130 mg/dL (or <100 mg/dL for more aggressive reduction) 5

Prescription vs. Over-the-Counter Products

Use prescription omega-3 fatty acids to ensure consistent quality, purity, and dosing. 1, 3

• Each 1-gram prescription capsule contains at least 900 mg of EPA+DHA (approximately 465 mg EPA and 375 mg DHA) 1
• Over-the-counter fish oil products vary widely in EPA+DHA content and purity 3
• The American Heart Association advises that therapy with EPA+DHA to lower very high triglycerides should be used only under physician care 3
• Prescription products (Lovaza, Vascepa, Epanova) are FDA-approved for hypertriglyceridemia 1

Safety Monitoring and Precautions

Required Monitoring

• Monitor LDL cholesterol periodically during therapy, especially in patients with very high triglycerides 1, 2
• In patients with hepatic impairment, monitor ALT and AST levels periodically 1
• Patients taking >3 grams/day should be monitored for potential bleeding risk, though no increased bleeding has been observed in trials even with concurrent anticoagulants 6, 8

Atrial Fibrillation Risk

• High-dose omega-3 supplementation (≥4 grams daily) increases atrial fibrillation risk by 25% 6, 8
• This is particularly relevant within the first months of initiating therapy 1
• In REDUCE-IT, hospitalization for atrial fibrillation occurred in 3.1% on 4 grams EPA daily vs. 2.1% on placebo 6
• Evaluate atrial fibrillation risk before initiating high-dose therapy 8

Contraindications and Cautions

• Contraindicated in patients with known hypersensitivity to omega-3 fatty acids or any components 1
• Use with caution in patients with known hypersensitivity to fish and/or shellfish 1
• Patients on anticoagulants or antiplatelet agents should be monitored periodically, though bleeding risk is not increased at doses up to 4 grams/day 6, 1

Administration Recommendations

• Instruct patients to swallow capsules whole—do not break open, crush, dissolve, or chew 1
• Taking with meals reduces gastrointestinal side effects (fishy aftertaste, belching, nausea) without affecting absorption 8
• Most common adverse reactions (>3% incidence) are eructation, dyspepsia, and taste perversion 1

Cardiovascular Outcomes Evidence

The REDUCE-IT trial demonstrated that 4 grams/day of EPA reduced major adverse cardiovascular events by 25% in high-risk patients with elevated triglycerides on statin therapy. 5, 2

• This included 70.7% secondary prevention patients and 29.3% high-risk primary prevention patients with diabetes 5
• Median baseline triglycerides were 216 mg/dL 5
• Number needed to treat was 21 over 4.9 years 5
• The key composite endpoint (cardiovascular death, nonfatal MI, nonfatal stroke, coronary revascularization, or unstable angina) was reduced by 25% 5