The Key Takeaways
✓ There is enough evidence that omega-3s lower triglycerides by 20-30% but the impact of fish oil works beyond lowering triglycerides.
✓ Dose matters. EPA-only or EPA dominant formulas are more effective in reducing cardiac events compared to EPA-DHA combination
✓ High risk patients defined as (coronary calcium score >100, established atherosclerotic disease, on statin therapy with TG >150) benefit the most from omega-3s.
✓ There is no clear benefit in patients who are low risk. If you don’t have risk factors then check an Omega-3 index. By measuring your omega status, you can determine if supplementing makes sense. The goal is to achieve an Omega-3 index >8%.
✓ There is a gene that impacts responsiveness to omega-3s supplements
Want to know the science? Keep reading below 👇
I have heard many patients generically state that fish oil is good for heart health. Social media has this generic statement peppered all over the internet. I took a first principles approach to understand who truly benefits.
The research into benefits of fish oil benefits stemmed from an observation that indigenous people in Greenland had a low risks of heart disease, despite diets extremely high in fat from marine animals. This has lead to extensive research into the potential benefits of fish oil or Omega-3s fatty acids comprise of EPA and DHA.
Current Pathways of Cardiovascular Benefit
It Lowers Triglycerides (TG) — Reliably
Elevated TG are linked to heart disease. At doses of 2-4gm per day, EPA and DHA have demonstrated consistently in studies to reduce TG by 20-30%.
It Fights Inflammation — Sort Of
Omega 3s and Omega-6 Fatty acids compete to be incorporated into the cell membranes. The incorporation of omega-3s into the cell membrane results in promoting pre-resolving mediators that act to resolving inflammation. At the same time by displacing Omega-6 from cell membrane results in inhibition NF-KB, a key mediator of inflammation.
It May Help Artery Health
The evidence is suggesting that Omega-3s may help with dilation of blood vessels and stabilization of plaque buildup in arteries.
⚠ What It Doesn't Do: Fix Your Cholesterol
It does not lower LDL. Omega 3 in high doses may result in a slight rise of LDL
Major Clinical Trials demonstrate conflicting results
EARLY POSITIVE TRIALS
The GISSI-Prevenzione trial (1999) demonstrated that 1 g/day of EPA+DHA reduced cardiovascular mortality by 30% in post-heart attack patients. The Japanese JELIS study showed EPA added to statin therapy reduced major coronary events by 19%.
REDUCE-IT (2019)
8,179 high-risk patients · Elevated triglycerides · On statin therapy
4 g/day of highly purified EPA (icosapent ethyl) reduced major adverse cardiovascular events by 25%, including reductions in cardiovascular death, heart attack, stroke, and revascularization. Post hoc analysis suggest the impact of Omega-3s may be independent of baseline triglycerides.
VITAL (2019)
25,871 primary prevention participants · Largest omega-3 trial to date
Low-dose EPA+DHA (840 mg/day) showed no significant reduction in the primary cardiovascular events. However, secondary analyses found a 28% reduction in total heart attack and a striking 77% reduction in MI among Black participants.
ASCEND (2018)
15,480 diabetic patients · 840 mg/day EPA+DHA
Failed to reduce serious vascular events overall, though exploratory analyses suggested a 19% reduction in vascular deaths.
STRENGTH (2020)
Similar population to REDUCE-IT · 4 g/day EPA+DHA combination
Terminated early for futility with no cardiovascular benefit despite the high dose — highlighting that EPA-only formulations may outperform combined EPA+DHA.
It's Not Only About the Dose — It's the Formula
Here's where it gets interesting. REDUCE-IT (pure EPA, 4g/day) worked great. STRENGTH (EPA+DHA combo, same 4g/day dose, nearly identical patient population) failed completely. Why?
There are many theories. First, the placebo used in REDUCE-IT was mineral oil and in the STRENGTH trial was corn oil. Unlike corn oil, mineral oil did result increase CRP and LDL-C in the REDUCE-IT trial, which could increase the risk of cardiovascular outcomes. However, even after accounting for this explanation, there was still a 25% risk reduction. Another potential explanation is related to DHA. Adding DHA to EPA might actually cancel out EPA's benefits. A 2025 meta-analysis of 127,771 patients compared EPA to EPA+DHA formulations and EPA-only reduced cardiovascular mortality by 21% compared while EPA+DHA reduced it only by 8%.
Why Does DHA Blunt EPA's Benefits?
The structure of EPA is compact and stable and therefore when it is incorporated in the cell membranes its keeps cholesterol evenly distributed. However, DHA is larger and more flexible which helps with cell membranes fluidity and flexibility but also can cause cholesterol to clump together in concentrated pockets.
In artery plaques, where cholesterol is already a problem, EPA tends to stabilize plaques. DHA may contribute to the type of cholesterol crystal formation that can result in plaques that rupture.
A 2025 analysis of 16 trials (127,771 patients) found pure EPA reduced cardiovascular death by 21%, while EPA +DHA formulations only reduced it by 8%.
REFERENCES[1] Nicholls SJ et al. JAMA 2020 (STRENGTH trial). [2] Nissen SE et al. JAMA Cardiol 2021. [3] Sherratt SCR et al. Cardiovasc Res 2024. [4] Sheppard JP et al. JACC Adv 2025. [5] Chapman MJ & Mason RP. Pharmacol Ther 2022. [6] Sherratt SCR et al. Curr Atheroscler Rep 2022.
Your Genes Affect How Well Fish Oil Works for You
Think of your genes like a factory that converts plant-based omega-3s into the more powerful EPA your body actually uses. The FADS1 gene controls how well that factory runs.
Converting plant omega-3s to EPA (e.g. from flaxseed, walnuts, chia):
• CC genotype = Fast factory: Your body is better at converting plant omega-3s into EPA. When people with CC genotype ate more plant omega-3s (ALA), their blood EPA rose by 2.2%.
• TT genotype = Slow factory: Your body struggles to make this conversion. The same increase in plant omega-3s only raised blood EPA by 0.9% — less than half the response of CC types.
What Your Genotype Means in Practice
People with the CC genotype (higher enzyme activity): For every unit increase in dietary EPA, circulating EPA rises by ~3.7%. While people with the TT genotype (lower enzyme activity), the same unit increase raises circulating EPA by ~7.8%.
Now the interesting part (at least for me), the FADS1 gene also is responsible for production of arachidonic acid. People with TT genotype produce less arachidonic acid (omega-6). As a result, there is less arachidonic acid competing with EPA for incorporation into cell membrane.
Practical takeaway: A TT person may hit therapeutic EPA levels at a lower dose than a CC person because there less omega-6 production and thus less competition.
If you’re healthy check your Omega-3 Index
Instead of guessing how much fish oil you need, there's actually a blood test you can take. It's called the Omega-3 Index, and it measures EPA+DHA as a percentage of your red blood cell fatty acids.
This tells you not just how much omega-3 you're consuming, but how much is actually getting into your cells. As a physician, I like to measure efficacy of treatment.
OMEGA-3 INDEX | RISK LEVEL | INTERPRETATION |
|---|---|---|
Below 4% | High Risk | Strongly associated with elevated CVD mortality risk |
4% – 8% | Intermediate | Opportunity for meaningful improvement |
8% – 11% | Target Range | Associated with lowest cardiovascular disease incidence |
Moving from a 4% to an 8% index is associated with ~30% lower risk of dying from coronary heart disease.
In the Framingham Heart Study (one of the longest-running heart studies ever), people in the top quintile for omega-3 index had 34% lower all-cause mortality and 39% lower cardiovascular disease compared to those with the lowest levels.
What if you are on a statin
Meta-analysis of 5 RCTs as well as the REDUCE-iT and JELIS trials demonstrated the benefit of high dose EPA (~2gm) in cardiovascular death, heart attack, stroke even when patients were on statins.
Who Benefits Most?
HIGH-RISK PATIENTS
If a person has any of the following health issues, there is strong evidence that omega-3s are beneficial.
• You've had a heart attack or stroke
• You're on statin therapy but still have elevated triglycerides (≥150 mg/dL)
• You have a high coronary artery calcium score (≥100)
• You have established atherosclerotic cardiovascular disease
INTERMEDIATE AND LOW-RISK PATIENTS
If you're generally healthy with no cardiovascular risk factors, the evidence for fish oil supplements protecting your heart is weak. My recommendation is to check your Omega-3 index to see if you are high risk and would benefit from supplementing.
Did you find the email helpful?
Coming up in future issues: how omega-3s affect your brain and cognitive health, their role in managing inflammation throughout the body, and a practical guide to choosing the right supplement for your individual profile.
References
Innes & Calder, Int J Mol Sci 2020 Elagizi et al., Nutrients 2021 Weinberg et al., JACC 2021 O'Keefe et al., Mayo Clin Proc 2019 von Schacky, Proc Nutr Soc 2020 Harris et al., Am J Clin Nutr 2008 Harris et al., Atherosclerosis 2017 Franco et al., J Clin Lipidology 2025 Nicholls SJ et al., JAMA 2020 Nissen SE et al., JAMA Cardiol 2021 Sherratt SCR et al., Cardiovasc Res 2024 Sheppard JP et al., JACC Adv 2025 Chapman MJ & Mason RP, Pharmacol Ther 2022 Sherratt SCR et al., Curr Atheroscler Rep 2022 Schulze MB et al., Lancet Diabetes Endocrinol 2020 Al-Hilal M et al., J Lipid Res 2013 Juan J et al., Am J Clin Nutr 2018, Doi T, European heart Journal, 2021. Sheppard JP, JACC 2025.