- ACRONYMS AND DEFINITIONS
- ADA - American Diabetes Association
- A fib - Atrial fibrillation
- AHA - American Heart Association
- ALA - Alpha Linolenic Acid, an omega-3 fatty acid mainly found in nut and seed oils (see fatty acids for more)
- CVD - Cardiovascular disease
- DHA - Docosahexaenoic Acid, one of the two active omega-3 fatty acids found in fish oil
- EPA - Eicosapentaenoic Acid, one of the two active omega-3 fatty acids found in fish oil
- hs-CRP - High sensitivity C-reactive protein
- N-3 Polyunsaturated fatty acids (N-3 PUFA) - collective name for DHA, EPA, and ALA
- Omega-3 fatty acids - collective term for EPA, DHA, and ALA
- RCT - Randomized controlled trial
- USDA - United States Dept of Agriculture
- PRESCRIPTION FISH OIL
- Lovaza® (omega-3-acid ethyl esters) - contains ∼ 465 mg of EPA and 375 mg of DHA per capsule
- Vascepa® (icosapent ethyl) - contains 1000 mg of EPA per capsule
- FDA-APPROVED INDICATIONS
- Lovaza® (omega-3-acid ethyl esters)
- Adjunct to diet to reduce triglyceride levels in adult patients with severe (≥ 500 mg/dL) hypertriglyceridemia
- Vascepa® (icosapent ethyl capsule)
- As an adjunct to maximally tolerated statin therapy to reduce the risk of myocardial infarction, stroke, coronary revascularization, and unstable angina requiring hospitalization in adult patients with elevated triglyceride levels (≥ 150 mg/dL) and established cardiovascular disease or diabetes mellitus and 2 or more additional risk factors for cardiovascular disease.
- Adjunct to diet to reduce triglyceride levels in adult patients with severe (≥ 500 mg/dL) hypertriglyceridemia
- FISH OIL SUPPLEMENTS
- Fish oil is sold in a large number of OTC supplements
- Most supplements list the amount of fish oil in one capsule as one number (ex. 1000 mg)
- This amount is typically the sum of DHA, EPA, N-3 PUFAs (other than DHA/EPA), and other ingredients in the capsule
- The individual amounts of DHA and EPA should be listed separately on reputable products
- The sum of EPA and DHA is the clinically relevant amount of fish oil in each capsule
- For dosing purposes, only the amount of DHA and EPA in the product should be considered
- Example:
- Capsule is described as "1200 mg of fish oil"
- Ingredients list 300 mg of DHA and 400 mg of EPA
- 300 mg DHA + 400 mg EPA = 700 mg of active fish oil component
- DIETARY FISH OIL
- Overview
- The USDA has a searchable database that contains the amounts of DHA and EPA in different fish - USDA searchable database
- The omega-3 fatty acid content of some popular fish is listed below
Fish | Omega-3 fatty acids per 3 oz serving |
---|---|
Salmon | 1100 - 1900 mg |
Flounder or sole | 480 mg |
Pollock | 450 mg |
Crabs | 270 - 400 mg |
Scallops | 180 - 340 mg |
Catfish | 220 - 300 mg |
Shrimp | 290 mg |
Clams | 250 mg |
Canned tuna | 170 - 240 mg |
Cod | 150 - 240 mg |
- MECHANISM OF ACTION
- The mechanism by which fish oil lowers triglycerides is not completely understood. EPA and DHA are known to be poor substrates for the enzymes involved in triglyceride synthesis, and therefore, they may reduce the efficiency of these enzymes. Other potential mechanisms include the following: inhibition of acyl-CoA:1,2-diacylglycerol acyltransferase, increased mitochondrial and peroxisomal β-oxidation in the liver, decreased lipogenesis in the liver, and increased plasma lipoprotein lipase activity.
- A study published in 2020 showed that icosapent ethyl reduced coronary plaque volume in patients with CAD. This may be the overlying effect by which a benefit in CVD has been observed. [PMID 32860032]
- HIGH TRIGLYCERIDES
- Overview
- Fish oil lowers triglycerides, and the effect is greater at higher levels. The table below outlines typical reductions seen with different baseline levels.
Effect of 3 - 4 grams/day of fish oil on triglycerides | |
---|---|
Baseline triglyceride | % reduction |
> 600 mg/dl | 30 - 50% |
< 600 mg/dl | 20 - 30% |
- CARDIOVASCULAR DISEASE
- Overview
- A large number of epidemiological studies have found a decreased risk of cardiovascular disease among people who regularly consume fish or fish oil supplements. These findings led to a number of disappointing placebo-controlled trials that found no effect of fish oil supplements on CVD prevention (see cardiovascular disease trials below). Then in 2018, the REDUCE-IT trial that compared the prescription fish oil product Vascepa® to placebo found that Vascepa® significantly reduced the risk of CVD events in patients with elevated triglycerides (median 216 mg/dl). In 2020, the STRENGTH trial was published that compared the prescription fish oil product Epanova® to placebo. Unlike the REDUCE-IT trial, the STRENGTH trial found no benefit of fish oil over placebo. Epanova contains 550 mg of EPA and 200 mg of DHA per capsule while Vascepa contains 1000 mg of EPA only.
- The REDUCE-IT trial, the STRENGTH trial, and a previous trial that compared a standard fish oil supplement to placebo (ORIGIN trial) are detailed below
- The REDUCE-IT trial enrolled 8179 patients with documented CVD or with DM and one additional risk factor for CVD
Main inclusion criteria
- Established CVD or ≥ 50 years old with DM and one additional risk factor for CVD
- Fasting triglycerides of 135 - 499 mg/dl
- LDL 41 - 100 mg/dl
- Stable statin dose for ≥ 4 weeks
Main exclusion criteria
- HgA1C > 10%
- Severe heart failure
- Severe liver disease
Baseline characteristics
- Median age 64 years
- Established CVD - 71%
- Type two diabetes - 58%
- Median triglyceride level - 216 mg/dl
- Median LDL - 75 mg/dl
- Median HDL - 40 mg/dl
- Triglyceride distribution: < 150 mg/dl: 10% | 150 - 200 mg/dl: 29% | > 200 mg/dl: 60%
Randomized treatment groups
- Group 1 (4089 patients) - Vascepa 2 grams twice daily
- Group 1 (4090 patients) - Mineral oil capsules (placebo) twice daily
- Non-study fish oil products were prohibited
Primary outcome: Composite of cardiovascular death, nonfatal myocardial infarction (including silent myocardial infarction),
nonfatal stroke, coronary revascularization, or unstable angina in a time-to-event analysis
Results
Duration: Median of 4.9 years | |||
Outcome | Vascepa | Mineral oil | Comparisons |
---|---|---|---|
Primary outcome | 17.2% | 22% | HR 0.75, 95% CI [0.68 - 0.83], p<0.001 |
Overall mortality | 6.7% | 7.6% | HR 0.87, 95% CI [0.74 - 1.02] |
Fatal or nonfatal MI | 6.1% | 8.7% | HR 0.69, 95% CI [0.58 - 0.81], p<0.001 |
Fatal or nonfatal Stroke | 2.4% | 3.3% | HR 0.72, 95% CI [0.55 - 0.93], p=0.01 |
Serious bleeding event | 2.7% | 2.1% | p=0.06 |
Atrial fibrillation | 5.3% | 3.9% | p=0.003 |
Hospitalization for A fib/flutter | 3.1% | 2.1% | p=0.004 |
Peripheral edema | 6.5% | 5.0% | p=0.002 |
Constipation | 5.4% | 3.6% | p<0.001 |
Median change in triglycerides at 5 years | -38 mg/dl | -3 mg/dl | p<0.001 |
Median change in LDL at 5 years | -0.8 mg/dl | +6.2 mg/dl | p<0.001 |
|
Findings: Among patients with elevated triglyceride levels despite the use of statins, the risk of ischemic events, including cardiovascular death, was
significantly lower among those who received 2 g of icosapent ethyl twice daily than among those who received placebo
- The STRENGTH trial enrolled 13,078 patients with a history of CVD or multiple risk factors for CVD
Main inclusion criteria
- One of the following:
- History of CVD
- Diabetes + 1 risk factor (smoking, hypertension, hs-CRP ≥ 2 mg/L, albuminuria)
- Age > 50 (60 for women) + 1 risk factor (fam hx of premature CAD, smoking, hypertension, hs-CRP ≥ 2 mg/L, impaired renal function, CAC > 300)
- Statin therapy for ≥ 4 weeks
- LDL < 100 mg/dl or taking maximum tolerated statin
- Triglycerides 180 - 499 mg/dl
- HDL < 42 mg/dl (47 mg/dl for women)
Main exclusion criteria
- Consuming > 1 gram of prescription fish oil or supplement
- CVD event within 30 days
Baseline characteristics
- Average age 63 years
- Baseline CVD - 56%
- Diabetes - 70%
- Median LDL - 75 mg/dl
- Median triglyceride - 240 mg/dl
- Median HDL - 36 mg/dl
Randomized treatment groups
- Group 1 (6539 patients): Omega-3 carboxylic acid (Epanova) 4 grams/day. Each one gram Epanova capsule contains EPA 550 mg and DHA 200 mg [38]
- Group 2 (6539 patients): Corn oil 4 capsules/day (placebo)
- Fibrates and non-study fish oil products were prohibited
Primary outcome: Composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke,
coronary revascularization, and hospitalization for unstable
angina
Results
Duration: After a median of 42 months, the study was stopped early due to futility | |||
Outcome | Epanova | Corn oil | Comparisons |
---|---|---|---|
Primary outcome | 12% | 12.2% | p=0.84 |
Primary outcome (patients with CVD at baseline) | 15.6% | 16.6% | p=0.27 |
CV death | 3.5% | 3.2% | p=0.37 |
Nonfatal MI | 3.3% | 3.5% | p=0.77 |
Nonfatal stroke | 2.2% | 1.9% | p=0.28 |
Revascularization | 6.3% | 6.7% | p=0.41 |
Overall mortality | 5.7% | 5.1% | p=0.11 |
A fib | 2.2% | 1.3% | p<0.001 |
Median triglyceride at 1 year | 191 mg/dl | 235 mg/dl | N/A |
Median LDL at 1 year | 76 mg/dl | 75 mg/dl | N/A |
|
Findings: Among statin-treated patients at high cardiovascular risk, the
addition of omega-3 carboxylic acid, compared with corn oil, to usual background therapies resulted in no
significant difference in a composite outcome of major adverse cardiovascular events. These
findings do not support use of this omega-3 fatty acid formulation to reduce major adverse
cardiovascular events in high-risk patients.
- The ORIGIN trial enrolled 12,536 patients at high risk for cardiovascular events
Main inclusion criteria
- ≥ 50 years old
- Diagnosis of early diabetes or impaired glucose tolerance
- ≥ 1 risk factor for CVD event (e.g. history of MI, stroke, LVH, PVD)
Main exclusion criteria
- HgA1C > 9%
- CABG within 4 years
- Heart failure
Baseline characteristics
- Average age 64 years
- History of CVD - 59%
- Median triglyceride level - 141 mg/dl
- Average LDL - 112 mg/dl
- Median HgA1C - 6.4%
- Taking statin - 54%
- Median dietary DHA/EPA intake - 210 mg/day
Randomized treatment groups
- Group 1 (6319 patients) - Fish oil 1000 mg (465 mg of EPA | 375 mg of DHA) once daily
- Group 1 (6292 patients) - Olive oil 1 gram once daily (placebo)
- No specific dietary recommendations regarding fish were made
- Nonstudy supplements containing n-3 fatty acids were discouraged
Primary outcome: Death from cardiovascular causes
Results
Duration: Median of 6.2 years | |||
Outcome | Fish oil | Olive oil | Comparisons |
---|---|---|---|
Primary outcome | 9.1% | 9.3% | HR 0.98, 95% CI [0.87 - 1.10], p=0.72 |
Myocardial infarction (fatal and nonfatal) | 5.5% | 5.1% | HR 1.09, 95% CI [0.93 - 1.27], p=0.28 |
Stroke (fatal and nonfatal) | 5.0% | 5.4% | HR 0.92, 95% CI [0.79 - 1.08], p=0.32 |
Revascularization procedure | 13.8% | 14.3% | HR 0.96, 95% CI [0.87 - 1.05], p=0.39 |
Overall mortality | 15.1% | 15.4% | HR 0.98, 95% CI [0.89 - 1.07], p=0.63 |
Decrease in triglycerides | 23.5 mg/dl | 9 mg/dl | p<0.001 |
Findings: Daily supplementation with 1 g of n-3 fatty acids did not reduce the rate of cardiovascular events in patients at high risk for cardiovascular events
- Professional recommendations
- The AHA recommends that patients with documented heart disease consume 1 gram (EPA + DHA) of fish oil a day preferably from oily fish, but supplements may also be considered. The AHA recommends that the general public consume 2 servings of oily fish twice a week [30]
- The ADA 2018 recommendations state that eating foods rich in long-chain n-3 fatty acids, such as fatty fish (EPA and DHA) and nuts and seeds (ALA), is recommended to prevent or treat CVD; however, evidence does not support a beneficial role for the routine use of n-3 dietary supplements
- Summary
- Until the REDUCE-IT trial, fish oil products had failed miserably in CVD prevention trials. The REDUCE-IT trial used 4 grams a day of Vascepa®, which only contains EPA. A benefit was seen across all subgroups of baseline triglyceride levels, which suggests a protective mechanism independent of triglyceride reduction. The benefit was only significant in patients with established CVD, although there was a trend towards significance in primary prevention patients. In 2019, Vascepa received an FDA-approved indication for the prevention of CVD.
- Contrarily, the STRENGTH trial did not find a benefit with Epanova. The two products differ in their makeup of omega-3 fatty acids, with Vascepa containing EPA and Epanova containing EPA and DHA. This difference may explain why Vascepa was effective, whereas Epanova was not. Another hypothesis is that the difference in placebo products (mineral oil vs corn oil) may have played a role. In the Vascepa trial, placebo-treated patients had a significant increase in LDL (+6.2 mg/dl at 5 years), whereas there was no change in the Epanova trial. This theory seems to be a bit of a stretch given that the relative risk reduction for the primary outcome was 22% with Vascepa, and the median difference in LDL levels after 5 years was only 7 mg/dl. Past studies have shown that major vascular events are reduced by 22% for every 39 mg/dl decrease in LDL. Another study compared the change in CVD biomarkers in REDUCE-IT participants. Mineral oil-treated patients had an increase from baseline in a number of measures (e.g. homocysteine, C-reactive protein, interleukin-6), whereas the Vascepa-treated patients did not. The authors hypothesize that this may have affected the trial outcomes. [PMID 35762321]
- In both trials, the risk of atrial fibrillation was higher in the fish oil groups (REDUCE-IT 5.3% vs 3.9% |STRENGTH 2.2% vs 1.3%). This is somewhat ironic given that fish oil products have been touted to prevent atrial fibrillation in the past.
- In conclusion, Vascepa showed a clear benefit in the REDUCE-IT trial, but Epanova was ineffective in the STRENGTH trial. The conflicting results may be related to differences in the product formulation (EPA vs EPA/DHA). The theory that the placebo products played a role is thought-provoking but not entirely convincing. Epanova was discontinued by the manufacturer in 2020.
- SIDE EFFECTS
- Gastrointestinal
- The most common side effects of fish oil are gastrointestinal
Side effect | Fish oil 4 grams/day |
Placebo |
---|---|---|
Belching | 3 - 4% | 1% |
Upset stomach | 3 - 5% | 2% |
Abnormal taste in mouth | 4% | 1% |
Diarrhea✝ | 15% | 2% |
- Bleeding
- Fish oil has been shown to inhibit platelet aggregation and prolong bleeding times in some studies. The clinical significance of this effect is unclear.
- In the REDUCE-IT trial, serious bleeding events occurred in 2.7% of Vascepa-treated patients and 2.1% of placebo-treated patients (p=0.06). In the ORIGIN trial, there was no significant difference in bleeding events between fish oil and placebo.
- Patients taking drugs that affect coagulation (see drug interactions below) should be aware that fish oil may potentiate the anticoagulant effect of these drugs
- Atrial fibrillation/flutter
- In the REDUCE-IT trial, the incidence of atrial fibrillation was significantly higher in Vascepa-treated patients than in placebo-treated patients (5.3% vs 3.9%) as was hospitalization for atrial fibrillation/flutter (3.1% vs 2.1%). Patients with a previous history of atrial fibrillation/flutter were at greater risk.
- In a Lovaza study that enrolled patients with paroxysmal and persistent A fib (N=663), the incidence of recurrent A fib was significantly higher in Lovaza-treated patients when compared to placebo-treated patients (53% vs 47% for paroxysmal and 52% vs 35% for persistent)
- Ironically, fish oil has been studied in the prevention of atrial fibrillation (see atrial fibrillation studies below). In those studies, fish oil had no effect on the incidence of atrial fibrillation.
- Patients with A fib should probably avoid Lovaza and use caution with Vascepa
- LDL and HDL effects
- The effects of fish oil on LDL and HDL have been inconsistent across studies, and DHA and EPA appear to affect lipid parameters differently
- In a trial of patients with an average baseline triglyceride level of 816 mg/dl, treatment with Lovaza (EPA + DHA) increased LDL levels by 44% (average baseline LDL 89 mg/dl). In a trial of patients with an average baseline triglyceride level of 680 mg/dl, treatment with Vascepa (EPA only) decreased average LDL levels by 5% (average baseline 91 mg/dl).
- After one year in the REDUCE-IT trial, average LDL cholesterol increased by 3.1% in Vascepa-treated patients and by 10.2% in placebo-treated patients
- As far as HDL is concerned, small changes in both directions have been seen in trials
- People taking high doses of fish oil should have their lipid parameters checked periodically. Patients with very high triglycerides (> 500 mg/dl), may see a significant rise in their LDL when treated with DHA-containing products. [1,2,3,6,7,33,34,35]
- Elevated liver enzymes
- In some Lovaza studies, increases in AST and ALT occurred in Lovaza-treated patients
- CONTRAINDICATIONS
- Known hypersensitivity
- Fish allergy - it is unknown if patients with allergy to fish and/or shellfish are at increased risk of an allergic reaction when taking fish oil. Patients with fish allergy should use caution when taking fish oil for the first time.
- PRECAUTIONS
- Kidney disease
- Fish oil does not undergo kidney excretion
- The package inserts for Lovaza® and Vascepa® state that their respective products have not been studied in kidney disease, and they make no dosage recommendation
- Liver disease
- The package inserts for Lovaza® and Vascepa® state that their respective products have not been studied in liver disease. Both manufacturers recommend monitoring ALT and AST levels periodically in patients with liver disease. They make no dosage recommendations.
- In some Lovaza studies, increases in AST and ALT occurred in Lovaza-treated patients
- Fish allergy
- It is unknown if patients with allergy to fish and/or shellfish are at increased risk of an allergic reaction when taking fish oil
- Patients with fish allergy should use caution when taking fish oil for the first time
- Atrial fibrillation/flutter
- In the REDUCE-IT trial, patients treated with Vascepa had a higher incidence of atrial fibrillation/flutter, and patients with a history of atrial fibrillation/flutter were at greater risk. Lovaza has also been shown to increase the risk of A fib. See atrial fibrillation/flutter above.
- Patients with A fib should probably avoid Lovaza and use caution with Vascepa
- DRUG INTERACTIONS
- NOTE: Drug interactions presented here are NOT all-inclusive. Other interactions may exist. The interactions presented here are meant to encompass commonly prescribed medications and/or interactions that are well-documented. Always consult your physician or pharmacist before taking medications concurrently. CLICK HERE for more information on drug interactions.
- Drugs that increase the risk of bleeding - in some studies (e.g. REDUCE-IT trial), fish oil products have been shown to increase the risk of bleeding. Other studies have not found a risk. Patients who are taking drugs that inhibit coagulation should be aware that the risk of bleeding may be increased with concomitant fish oil.
- Drugs that may increase the risk of bleeding include:
- Anagrelide (Agrylin®)
- Aspirin
- Direct thrombin inhibitors (dabigatran)
- Factor Xa inhibitors (e.g. rivaroxaban, apixaban)
- P2Y12 inhibitors (e.g. clopidogrel, ticagrelor, prasugrel)
- NSAIDs (e.g. ibuprofen, naproxen)
- SSRIs and SNRIs (e.g. fluoxetine, venlafaxine)
- Vorapaxar (Zontivity®)
- Warfarin (Coumadin®)
- Metabolism and clearance
- EPA and DHA are mainly metabolized by the liver via beta-oxidation similar to dietary fatty acids. Beta oxidation splits the long carbon chain of EPA into acetyl Coenzyme A, which is converted into energy via the Krebs cycle.
- Cytochrome P450-mediated metabolism is a minor pathway of elimination of EPA and DHA
- DOSING
- Supplements/Dietary intake
- Fish oil is found in oily fish (see dietary fish oil) and over-the-counter supplements (see supplement) that contain different amounts of DHA and EPA. Dosing recommendations for high triglycerides and CVD prevention are provided below.
- High triglycerides
- In general, taking fish oil supplements that provide > 3 grams/day of EPA, DHA, or their combination will have significant triglyceride-lowering effects. The degree of the effect depends on the baseline triglyceride level (see triglycerides above).
- AHA CVD prevention recommendations
- The AHA recommends that patients with documented heart disease consume 1 gram (EPA + DHA) of fish oil daily, preferably from oily fish, but supplements may also be considered. As for the general public, they recommend 2 servings of oily fish twice a week. [30]
- Lovaza® (omega-3-acid ethyl esters)
- Dosage form
- 1000 mg capsule
- Each capsule contains ∼ 465 mg of EPA and 375 mg of DHA
- Generic / Price: Yes | less than $50 for 120 capsules
- Severe hypertriglyceridemia (≥ 500 mg/dl)
- Dosing: 4000 mg/day
- May take once daily or in 2 divided doses
- May take without regard to food
- Do not break, crush, dissolve, or chew capsule
- In trials, triglyceride levels were rechecked after 6 or 16 weeks
- Vascepa® (icosapent ethyl)
- Dosage form (capsule)
- 500 mg
- 1000 mg
- Vascepa contains EPA only
- Generic / Price: Yes | $50 - $100 for 120 capsules
- Prevention of CVD
- Dosing: 2000 mg twice daily with food
- May take as four 500 mg capsules twice daily or two 1000 mg capsules twice daily
- Do not break, crush, dissolve, or chew capsule
- Severe hypertriglyceridemia (≥ 500 mg/dl)
- Dosing: 2000 mg twice daily with food
- May take as four 500 mg capsules twice daily or two 1000 mg capsules twice daily
- Do not break, crush, dissolve, or chew capsule
- In trials, triglyceride levels were rechecked after 12 weeks
- FISH OIL STUDIES
Atrial fibrillation
- Design: Randomized, placebo-controlled trial (N=337 | length = average of 271 days) in adults with symptomatic paroxysmal or persistent A fib within 6 months of enrollment
- Treatment: Fish oil two capsules (EPA 400 mg/DHA 200 mg per capsule) twice daily vs Placebo two capsules (1 gram of safflower) twice daily
- Primary outcome: Time to first asymptomatic or symptomatic A fib recurrence lasting ≥ 30 seconds. Recurrence of A fib was monitored by weekly trans-telephonic monitor transmissions to detect potentially asymptomatic episodes, whereas symptomatic episodes were assessed by transtelephonic monitor strips, 12-lead electrocardiography or any implanted device
- Results:
- Primary outcome: Fish oil - 64.1%, Placebo - 63.2% (p=0.48)
- Findings: High-dose fish oil does not reduce A fib recurrence in patients with a history of A fib not receiving conventional antiarrhythmic therapy. Furthermore, fish oil does not reduce inflammation or oxidative stress markers in this population, which may explain its lack of efficacy.
- Design: Randomized, placebo-controlled trial (N=1516 | length = 10 days) in adults undergoing cardiac surgery
- Treatment: Fish oil vs Placebo. Fish oil was given as 1 gram capsules (EPA 465 mg/DHA 375 mg) with a dose of 10 grams over 3 - 5 days before surgery followed by 2 g/day until discharge or postop day 10.
- Primary outcome: Occurrence of postoperative A fib lasting longer than 30 seconds
- Results:
- Primary outcome: Fish oil - 30%, Placebo - 30.7% (p=0.74)
- Findings: In this large multinational trial among patients undergoing cardiac surgery, perioperative supplementation with n-3-PUFAs, compared with placebo, did not reduce the risk of postoperative atrial fibrillation
- Design: Randomized, placebo-controlled trial (N=663 | length = 24 weeks) in adults with symptomatic paroxysmal or persistent A fib
- Treatment: Lovaza 1 gram capsule (EPA 465 mg/DHA 375 mg) vs Placebo. Lovaza was dosed at 8 grams/day for the first 7 days followed by 4 grams a day thereafter.
- Primary outcome: Symptomatic recurrence of A fib (first recurrence) in participants with paroxysmal A fib (N=542). Biweekly transtelephonic monitoring was used to document asymptomatic recurrences of A fib and assess symptomatic events.
- Results:
- Primary outcome: Fish oil - 52%, Placebo - 48% (p=0.26)
- Findings: Among participants with paroxysmal A fib, 24-week treatment with prescription omega-3 compared with placebo did not reduce recurrent A fib over 6 months
Autoimmune disease
- Design: Secondary analysis of the VITAL study, a randomized placebo-controlled trial (N=25,871 | length = median 5.3 years) in healthy men ≥ 50 years and women ≥ 55 years
- Treatment: Fish oil (EPA 460 mg / DHA 380 mg) once daily vs Placebo. The study had another factor that involved vitamin D.
- Primary outcome: All incident autoimmune diseases confirmed by medical record review: rheumatoid arthritis, polymyalgia rheumatica, autoimmune thyroid disease, psoriasis, and all others
- Results:
- Primary outcome: Fish oil - 1.0%, Placebo - 1.1% (p=0.19)
- Findings: Vitamin D supplementation for five years, with or without omega 3 fatty acids, reduced autoimmune disease by 22%, while omega 3 fatty acid supplementation with or without vitamin D reduced the autoimmune disease rate by 15% (not statistically significant). Both treatment arms showed larger effects than the reference arm (vitamin D placebo and omega 3 fatty acid placebo).
Cancer prevention
- Design: Randomized, placebo-controlled trial (N=25,871 | length - median 5.3 years) in healthy men ≥ 50 years and women ≥ 55 years with no history of cancer
- Treatment: Fish oil (EPA 460 mg / DHA 380 mg) once daily vs Placebo. The study had another factor that involved vitamin D.
- Primary outcome: Invasive cancer of any type
- Results:
- Primary outcome: Fish oil - 6.3%, Placebo - 6.2% (p=0.56)
- Findings: Supplementation with n−3 fatty acids did not result in a lower incidence of major cardiovascular events or cancer than placebo
Cardiovascular disease (CVD)
- Design: Randomized placebo-controlled trial (N=1,027 | length = 2 years) in patients 70 - 82 years old with a history of myocardial infarction
- Treatment: Fish oil (930 mg EPA and 660 mg DHA) once daily vs Placebo
- Primary outcome: Composite of non-fatal AMI, unscheduled revascularization, stroke, all-cause death, heart failure hospitalization after two years
- Results:
- Primary outcome: Fish oil - 21.4%, Placebo - 20% (p=0.60)
- Findings: We could not detect reduction in clinical events in our elderly patients with a recent AMI, treated with 1.8 g n-3 PUFAs daily for 2 years
- Design: Randomized placebo-controlled trial (N=25,871 | length - median of 5.3 years) in healthy men ≥ 50 years and women ≥ 55 years with no history of cardiovascular disease
- Treatment: Fish oil (EPA 460 mg / DHA 380 mg) once daily vs Placebo. The study had another factor that involved vitamin D.
- Primary outcome: Composite of myocardial infarction, stroke, and death from cardiovascular causes
- Results:
- Primary outcome: Fish oil - 2.98%, Placebo - 3.23% (p=0.24)
- Findings: Supplementation with n−3 fatty acids did not result in a lower incidence of major cardiovascular events or cancer than placebo
- Design: Randomized placebo-controlled trial (N=12,536 | length - median of 6.2 years) in patients with diabetes or prediabetes
- Treatment: Fish oil 1 gram once daily vs Placebo
- Primary outcome: Death from cardiovascular causes
- Results:
- Primary outcome: Fish oil - 9.1%, Placebo - 9.3% (p=0.72)
- Findings: Daily supplementation with 1 gram of n-3 fatty acids did not reduce the rate of cardiovascular events in patients at high risk for cardiovascular events
- Design: Randomized placebo-controlled trial (N=4,837 | length - 40 months) in patients 60 - 80 years old with a history of myocardial infarction in the past 10 years
- Treatment: Daily intake of 4 different margarines: Margarine with no additional n−3 fatty acids (placebo margarine) vs Margarine with 400 mg of EPA–DHA per day vs Margarine with 2 g of ALA per day vs Margarine with combination of EPA–DHA and ALA
- Primary outcome: The rate of major cardiovascular events, which comprised fatal and nonfatal cardiovascular events and cardiac interventions
- Results:
- Primary outcome: During the follow-up period, a major cardiovascular event occurred in 671 patients (13.9%). Neither EPA-DHA nor ALA reduced this primary end point (hazard ratio with EPA-DHA, 1.01; 95% confidence interval [CI], 0.87 to 1.17; P=0.93; hazard ratio with ALA, 0.91; 95% CI, 0.78 to 1.05; P=0.20)
- Findings: Low-dose supplementation with EPA-DHA or ALA did not significantly reduce the rate of major cardiovascular events among patients who had had a myocardial infarction and who were receiving state-of-the-art antihypertensive, antithrombotic, and lipid-modifying therapy
Depression
- Design: Randomized placebo-controlled trial (N=18,353 | length - median 5.3 years) in men aged 50 years or older and women aged 55 years or older. The study was an ancillary study of another study.
- Treatment: EPA 465 mg + DHA 375 mg once daily vs Placebo
- Primary outcome: Coprimary outcomes were (1) risk of depression or clinically relevant depressive symptoms and (2) longitudinal mood scores
- Results:
- Primary outcome (annual depression risk): EPA/DHA - 1.39%, Placebo - 1.23% (p=0.03)
- No significant differences were observed comparing omega-3 with placebo groups in longitudinal mood scores (p=0.19)
- Findings: Among adults aged 50 years or older without clinically relevant depressive symptoms at baseline, treatment with omega-3 supplements compared with placebo yielded mixed results, with a small but statistically significant increase in risk of depression or clinically relevant depressive symptoms but no difference in mood scores, over a median follow-up of 5.3 years. These findings do not support the use of omega-3 supplements in adults to prevent depression.
Diabetes
- Design: Randomized placebo-controlled trial (N=1312 | length = 5 years) in adults with type 2 diabetes
- Treatment: EPA 465 mg + DHA 375 mg once daily vs Placebo. The study had another factor that included vitamin D.
- Primary outcome: Change in glomerular filtration rate estimated from serum creatinine and cystatin C (eGFR) from baseline to year 5
- Results:
- Primary outcome (decrease in GFR): EPA/DHA - 12.2 ml/min, Placebo - 13.1 ml/min (p=0.27)
- Findings: Among adults with type 2 diabetes, supplementation with vitamin D3 or omega-3 fatty acids, compared with placebo, resulted in no significant difference in change in eGFR at 5 years. The findings do not support the use of vitamin D or omega-3 fatty acid supplementation for preserving kidney function in patients with type 2 diabetes.
- Design: Randomized placebo-controlled trials (N=15,480; length = 7.4 years) among patients with type 2 diabetes and no history of CVD
- Treatment: Fish oil (460 mg of EPA + 380 mg DHA) once daily vs Placebo (olive oil)
- Primary outcomes: First serious vascular event, which was defined as a composite of nonfatal myocardial infarction or stroke (excluding confirmed intracranial hemorrhage), TIA, or vascular death excluding intracranial hemorrhage
- Results:
- Primary outcome: Fish oil - 8.9%, Placebo - 9.2% (RR 0.97, 95%CI [0.87 to 1.08], p=0.55)
- Findings: Among patients with diabetes without evidence of cardiovascular disease, there was no significant difference in the risk of serious vascular events between those who were assigned to receive n−3 fatty acid supplementation and those who were assigned to receive placebo.
Dry eyes
- Design: Secondary analysis of the VITAL study, a randomized placebo-controlled trial (N=25,871 | length = median 5.3 years) in healthy men ≥ 50 years and women ≥ 55 years
- Treatment: Fish oil (EPA 460 mg / DHA 380 mg) once daily vs Placebo. The study had another factor that involved vitamin D.
- Primary outcome: Incidence of clinically diagnosed dry eye disease confirmed by review of the medical records in patients without symptoms or a diagnosis of dry eyes at baseline (N=23,523)
- Results:
- Primary outcome: Fish oil - 2%, Placebo - 2% (HR 0.97; 95%CI [0.81-1.16])
- Findings: In this randomized clinical trial, long-term supplementation with 1 g per day of marine ω-3 fatty acids for a median (range) of 5.3 (3.8-6.1) years did not reduce the incidence of diagnosed dry eye disease or a combined end point of diagnosed dry eye disease or incident severe dry eye disease symptoms. These results do not support recommending marine ω-3 fatty acid supplementation to reduce the incidence of dry eye disease.
- Design: Randomized placebo-controlled trial (N=535 | length = 12 months) in patients with moderate-to-severe dry eye disease
- Treatment: Fish oil 3 grams once daily vs Placebo
- Primary outcome: Mean change from baseline in the score on the Ocular Surface Disease Index (OSDI; scores range from 0 to 100, with higher scores indicating greater symptom severity)
- Results:
- Primary outcome (OSDI decrease): Fish oil - 13.9, Placebo - 12.5 (p=0.21)
- Findings: Among patients with dry eye disease, those who were randomly assigned to receive supplements containing 3000 mg of n-3 fatty acids for 12 months did not have significantly better outcomes than those who were assigned to receive placebo
Osteoarthritis
- Design: Fish oil in knee osteoarthritis: a randomised clinical trial of low dose versus high dose
- Findings: In people with symptomatic knee OA, there was no additional benefit of a high-dose fish oil compared with low-dose fish oil. The combination comparator oil appeared to have better efficacy in reducing pain at 2 years, suggesting that this requires further investigation.
Overall health/Physical fitness
- Design: Randomized, 2 X 2 X 2 factorial, placebo-controlled trial (N=2157 | length = 3 years) in adults ≥ 70 years old with no major health events in the last 5 years
- Treatment: Patients were randomly assigned to Vitamin D3 2000 IU/day vs Placebo, Fish oil 1 gram/day vs Placebo, and Strength-training exercise program vs None
- Primary outcome: The 6 primary outcomes were change in systolic and diastolic blood pressure, Short Physical Performance Battery, Montreal Cognitive Assessment, and incidence rates of nonvertebral fractures and infections over 3 years.
- Results:
- Primary outcome: Overall, there were no statistically significant benefits of any intervention individually or in combination for the 6 end points at 3 years
- Findings: Among adults without major comorbidities aged 70 years or older, treatment with vitamin D3, omega-3s, or a strength-training exercise program did not result in statistically significant differences in improvement in systolic or diastolic blood pressure, nonvertebral fractures, physical performance, infection rates, or cognitive function. These findings do not support the effectiveness of these 3 interventions for these clinical outcomes.
Prenatal / infant development
- Design: Substudy of a randomized controlled trial (N=656 | length = 5 years) in infants born before 29 weeks gestation (main study)
- Treatment: Enteral emulsion with DHA 60 mg/kg/day vs Soy (control). Treatment was given from the first 3 days of enteral feeds until 36 weeks of postmenstrual age or discharge home, whichever occurred first.
- Primary outcome: Full-scale intelligence quotient (FSIQ) score on the Wechsler Preschool and Primary Scale of Intelligence (WPPSI) at 5 years of corrected age
- Results:
- Primary outcome (mean score): DHA - 95.4, Control - 91.9 (p=0.03)
- Findings: In infants born before 29 weeks’ gestation who had been enrolled in a trial to assess the effect of DHA supplementation on bronchopulmonary dysplasia, the use of an enteral DHA emulsion until 36 weeks of postmenstrual age was associated with modestly higher FSIQ scores at 5 years of age than control feeding.
- Design: Randomized placebo-controlled trial (N=461 | length = up to 36 weeks postmenstrual age) in women who delivered preterm infants before 29 weeks and were breastfeeding
- Treatment: DHA 1.2 grams/day vs Placebo. The DHA or Placebo was given to the mothers. Treatment was started within 72 hours of delivery and continued to 36 weeks' postmenstrual age.
- Primary outcome: Bronchopulmonary dysplasia-free survival in infants at 36 weeks' postmenstrual age
- Results:
- Primary outcome: DHA - 54.9%, Placebo - 61.6% (p=0.18)
- Enrollment was stopped early due to concern for harm based on interim data from this trial and from another trial that was published during the course of this study
- Findings: Among breastfed preterm infants born before 29 weeks of gestation, maternal docosahexaenoic acid supplementation during the neonatal period did not significantly improve bronchopulmonary dysplasia-free survival at 36 weeks' postmenstrual age compared with placebo. Study interpretation is limited by early trial termination.
- Design: Randomized placebo-controlled trial (N=5517 | length = 9 months) in pregnant women
- Treatment: DHA 800 mg + EPA 100 mg once daily vs Placebo starting before 20 weeks gestation and continuing until 34 weeks gestation or delivery
- Primary outcome: Early preterm delivery, defined as delivery before 34 completed weeks of gestation
- Results:
- Primary outcome: DHA/EPA - 2.2%, Placebo - 2.0% (p=0.50)
- Findings: Supplementation with n−3 long-chain polyunsaturated fatty acids from early pregnancy (< 20 weeks of gestation) until 34 weeks of gestation did not result in a lower incidence of early preterm delivery or a higher incidence of interventions in post-term deliveries than control.
- Design: Randomized placebo-controlled trials (N=377 | length = 6 months) among children born < 35 weeks gestation who were 10 - 16 months corrected age
- Treatment: DHA 200 mg + arachidonic acid (AA) 200 mg once daily vs Corn oil (placebo)
- Primary outcomes: Bayley Scales of Infant and Toddler Development, third edition (Bayley-III), cognitive composite score at 16 to 22 months corrected age
- Results:
- Primary outcome: cognitive scores did not differ between the DHA+AA and placebo groups (difference in change, 0.5, 95%CI [-1.8 to 2.8]; effect size, 0.05; P = .66)
- Findings: Daily supplementation with 200 mg of DHA and 200 mg of AA for 6 months resulted in no improvement in cognitive development and early measures of executive function vs placebo, and may have resulted in negative effects on language development and effortful control in certain subgroups of children. These findings do not support DHA supplementation in the second year of life for children who are born preterm.
- Design: Randomized controlled trial (N=1273 | length = 36 weeks) in infants born before 29 weeks gestation
- Treatment: Enteral emulsion with DHA 60 mg/kg/day vs Soy (control). Treatment was given from the first 3 days of enteral feeds until 36 weeks of postmenstrual age or discharge home, whichever occurred first.
- Primary outcome: Bronchopulmonary dysplasia, defined on a physiological basis (with the use of oxygen-saturation monitoring in selected infants), at 36 weeks of postmenstrual age or discharge home, whichever occurred first
- Results:
- Primary outcome: DHA - 49.1%, Control - 43.9% (p=0.02)
- Findings: Enteral DHA supplementation at a dose of 60 mg per kilogram per day did not result in a lower risk of physiological bronchopulmonary dysplasia than a control emulsion among preterm infants born before 29 weeks of gestation and may have resulted in a greater risk.
- Design: Randomized placebo-controlled trial (N=736 | length = 3 years) in pregnant women at 24 weeks gestation
- Treatment: n−3 LCPUFA (fish oil) 2.4 grams/day vs Olive oil
- Primary outcome: Persistent wheeze or asthma during the first 3 years of life in offspring
- Results:
- Primary outcome: Fish oil - 16.9%, Olive oil - 23.7% (p=0.035)
- Findings: Supplementation with n−3 LCPUFA in the third trimester of pregnancy reduced the absolute risk of persistent wheeze or asthma and infections of the lower respiratory tract in offspring by approximately 7 percentage points, or one third.
- Design: Randomized controlled trial (N=2399 | length = 18 months postpartum) in pregnant women who were less than 21 weeks' gestation with singleton pregnancies
- Treatment: DHA 800 mg/day vs Vegetable oil. Treatment was given from study entry to birth
- Primary outcomes: 1. Postpartum depression at 6 weeks and 6 months 2. Cognitive and language development in offspring as assessed by the Bayley Scales of Infant and Toddler Development, Third Edition, at 18 months.
- Results:
- Primary outcome (postpartum depression): DHA - 9.67%, Vegetable oil - 11.19% (p=0.09)
- Primary outcome (cognitive development): Mean cognitive composite scores (adjusted mean difference, 0.01; 95% CI, -1.36 to 1.37; P = .99) and mean language composite scores (adjusted mean difference, -1.42; 95% CI, -3.07 to 0.22; P = .09) of children in the DHA group did not differ from children in the control group
- Findings: The use of DHA-rich fish oil capsules compared with vegetable oil capsules during pregnancy did not result in lower levels of postpartum depression in mothers or improved cognitive and language development in their offspring during early childhood.
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