Something Smells Fishy: The Benefits and Controversies of Fish Oil and Icosapent Ethyl
Case Presentation
A 52-year-old male with Type 2 diabetes and a heart attack 6 months ago was treated with a stent to his LAD (left anterior descending artery) and placed on rosuvastatin 40 mg daily. He follows up with his cardiologist in the clinic.
He was told that they fixed the "culprit vessel," but the remaining coronary arteries didn't need any stents because they contained "a bunch of moderate 30-50% blockages" that can be treated medically.
His father died at 56 after suffering his second heart attack, and he is fearful he is heading down that road. He wants to do all he can to prevent another heart attack.
He faithfully attended cardiac rehab, has committed to a Mediterranean-style diet, and now walks briskly each morning for 3 miles with his wife. He has lost 10 lbs and his A1C dropped from 6.9% to 6.4%.
His repeat labs demonstrate:
- LDL-C: 53 mg/dL
- Triglycerides: 163 mg/dL
He wants to know if there is anything else that may help him out.
Flying Under the Radar
The patient described above is a commonly encountered patient in the Cardiology clinic and represents a significant source of "residual risk." Such patients are highly likely to become "Repeat Offenders." In fact, patients who possess the "atherogenic triad" phenotype—or lipid profile (high triglycerides, low HDL-C, and high small dense LDL particles)—are the most likely to have a second major cardiovascular event such as heart attack, stroke, or the need for CABG or stent.
Because of this heightened risk, there has been intense interest in drug therapies specifically targeting this subgroup. There have been many notable failures such as niacin (HPS2-THRIVE, N Engl J Med 2014), fibrates, and many omega-3 fatty acid fish oil formulations. But there is one drug that has shown success in two large-scale randomized controlled trials: icosapent ethyl, also known as Vascepa.
Yet, how many patients with either established coronary artery disease or type 2 diabetes have ever been offered icosapent ethyl (Vascepa) by their cardiologist, endocrinologist, or Primary Care provider? Likely not many.
Even if they had, their insurance payer likely denied it and suggested they take an alternative such as supplemental fish oil, generic Lovaza (an FDA-approved drug formulation of omega-3 fatty acids containing DHA and EPA), fibrates, or even Niacin.
Lovaza is FDA approved to treat severe hypertriglyceridemia (> 500 mg/dL) for the sole purpose of preventing pancreatitis, not heart disease. Supplements are completely unregulated and have no FDA oversight. Furthermore, even if one wanted to use supplemental fish oil, they'd have to choke down about 20 tablets a day to achieve the dose of EPA (2 grams twice daily) that produced cardiovascular benefits in clinical trials.
Icosapent ethyl (Vascepa), on the other hand, is FDA approved for cardiovascular event reduction in individuals with either established cardiovascular disease or type 2 diabetes who have triglycerides greater than 150 mg/dL despite maximum tolerated statin. This approval followed the REDUCE-IT trial (Bhatt DL et al., N Engl J Med 2019)—a large-scale randomized controlled trial that demonstrated a 25% reduction in cardiovascular events, driven by a reduction in atherothrombotic events.
Formulations of fish oil containing DHA have not been shown to produce cardiovascular benefits. This somewhat puzzling outcome has led some to question the findings of the REDUCE-IT trial.
CardioAdvocate Checklist
Patient Questions
- Have you had your lipid profile checked?
- Are your triglycerides (TG) > 150 mg/dL?
- Are you on maximum tolerated statin dosing?
- If so, you may benefit from icosapent ethyl (Vascepa)—check with your insurance payer as it is branded
- Remember: other formulations of Omega-3 containing both DHA and EPA (Lovaza) are NOT substitutes
- Remember: other drugs that lower triglycerides (Niacin, Fibrates) are NOT substitutes and have NOT demonstrated cardiovascular benefit
- Are you eating more fish? Fish lower on the food chain (sardines, mackerel) are great sources of EPA while minimizing mercury exposure
- Have you considered measuring EPA content of red blood cells (RBC) to ensure you're consuming enough EPA? Studies show benefits were more pronounced in those achieving > 8% RBC saturation
Clinician Assessment
- Check lipid panel and calculate nonHDL-C if TG > 150 mg/dL
- Assess for atherogenic triad phenotype
- Consider icosapent ethyl for eligible patients with residual risk
- Document insurance barriers to therapy
- Counsel on lifestyle modifications and dietary fish consumption
- Consider RBC-EPA testing for monitoring supplementation adequacy
Deep Dive
Are All Fish Oils Created Equal?
This is a hotly debated topic without firm answers but with some interesting theories. This controversy represents another example of why large-scale randomized controlled trials are needed to inform us about substances and treatments which may seem like a good idea, until they are put to the test.
For decades, fish oil supplementation has been touted as a healthy addition to any medicine cabinet aiming to reduce cardiovascular risk. It was felt that 1 gram of fish oil supplementation daily reduced cardiovascular arrhythmias, sudden cardiac death, and improved overall cardiovascular health. Over the years, several meta-analyses have been performed with inconsistent results.
JELIS Trial Legacy
The "positive" meta-analyses had one thing in common: they included the JELIS trial (Yokoyama M et al., Lancet 2007). This was a single-blinded randomized controlled trial using EPA only at 1.8 grams daily in a Japanese population (already consuming high amounts of fish), demonstrating a 19% reduction in major coronary events. This trial laid the groundwork for subsequent investigations into EPA-only formulations.
The REDUCE-IT Trial
The benefits seen in the JELIS trial spurred interest in EPA-only formulations of fish oil, leading to the REDUCE-IT trial (Bhatt DL et al., N Engl J Med 2019), which used icosapent ethyl (Vascepa)—an EPA-only derived formulation of Omega-3 fatty acid. This trial evaluated high-risk patients (established coronary artery disease or type 2 diabetes) with moderately elevated triglycerides (150–499 mg/dL) already maximally treated with statins.
The dose of icosapent ethyl was 2 grams twice daily (the same dose recommended for severe hypertriglyceridemia) because it resulted in the same red blood cell saturation in a Western population as was seen with 1.8 grams daily in the Japanese population of the JELIS trial.
Further analysis of the REDUCE-IT trial showed that greater benefit was seen in those achieving higher levels of EPA saturation of red blood cells, reinforcing that the positive outcomes were in fact a result of EPA, rather than its ability to lower triglycerides.
Additionally, EPA showed favorable changes in plaque morphology consistent with plaque stabilization over an 18-month period, as assessed by Cardiac CTA in the EVAPORATE Trial (Budoff MJ et al., Eur Heart J 2020). This provides complementary mechanistic data with the favorable cardiovascular outcomes data of REDUCE-IT.
What About DHA?
Docosahexaenoic acid (DHA) is essential to brain development. Whether supplementation outside of consuming foods rich in DHA provides any benefit is up for debate. Some experts argue for supplementation, while others are skeptical—just because something is essential does not necessarily mean that supplementation in the form of a pill or drug will provide benefit.
Its role as a drug in cardiovascular disease protection is shakier. It has been debated as being beneficial, neutral, or even detrimental, thanks to the REDUCE-IT and STRENGTH trials.
The STRENGTH Trial (Nicholls SJ et al., JAMA 2020) sought to use a carboxylic acid formulation (better absorption) of the combination of DHA/EPA in similar fashion to the REDUCE-IT trial. It failed. However, the placebo in the two trials differed (Olshansky B et al., Eur Heart J Suppl 2020). Mineral oil was used in the REDUCE-IT trial, whereas corn oil was used in the STRENGTH trial. This is where the controversy comes from.
Some argue that the mineral oil was deleterious and therefore skewed the results of the placebo arm, creating a false benefit of EPA in the REDUCE-IT trial. Others point out that DHA raises ApoB-containing lipoproteins (felt by many to never be a good thing), thereby raising the question of whether supplementation may actually promote atherosclerosis, or at least offset the positive benefits of EPA and explain the lack of positive benefit seen in the STRENGTH trial.
Alternative Mechanism for Plaque Stabilization
Other scientists refute the placebo oil argument and have theorized that EPA and DHA behave differently within phospholipid membranes (Sherratt SCR et al., J Lipid Res 2021). EPA has better antioxidant qualities than DHA (Mason RP & Jacob RF, Biochim Biophys Acta 2015). Whereas EPA seems to intercalate nicely between cholesterol domains within the phospholipid membranes (Mason RP et al., Biochim Biophys Acta 2016), DHA does not.
When cholesterol domains within the phospholipid membrane line up like a picket fence, they reach a critical mass and are extruded into the intima as a "cholesterol crystal," which is highly atherogenic. This proposed mechanism offers a unique and alternative mechanism for plaque progression beyond the infiltration of cholesterol-containing lipoproteins into the intima of the artery wall.
Similarly, treating or preventing this occurrence offers an alternative and complementary mechanism for plaque stabilization beyond lowering cholesterol-containing lipoprotein traffic along the arterial highways via increased clearance through LDL receptors on liver cells.
The Bottom Line
Key Takeaways
- Icosapent ethyl (Vascepa) is the only fish oil-derived therapy with proven cardiovascular benefit in large-scale RCTs
- It is FDA approved for patients with established CVD or type 2 diabetes with TG > 150 mg/dL on maximum statin therapy
- Generic omega-3 supplements, DHA-containing formulations, and other triglyceride-lowering drugs offer no proven cardiovascular benefit
- The benefit of icosapent ethyl appears related to direct plaque-stabilizing effects and EPA incorporation into red blood cells, not just triglyceride reduction
- EPA and DHA have different mechanisms and effects—one size does not fit all
- If you have atherogenic triad phenotype, discuss icosapent ethyl with your cardiologist
