Something Smells Fishy
A 52 year old male with Type 2 diabetes and a heart attack 6 months ago, who was treated with a stent to his LAD and placed on rosuvastatin 40 mg daily, 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 of 53 mg/dL and Triglycerides of 163 mg/dL.
He wants to know if there is anything else that may help him out.
Flying Under the Radar
Why do these cases go undertreated?
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 (sdLDL)], 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, 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, and that drug is called 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? Or at least had a discussion about it? Likely not many.
Even if they had, it's quite likely that their insurance payer denied it and suggested they take an alternative such as supplemental fish oil [which by the way should never be confused with over the counter (OTC), which are FDA approved drugs deemed safe enough to, well, be distributed over the counter], generic Lovaza (an FDA approved drug formulation of omega-3 fatty acids that contains DHA and EPA), fibrates or even Niacin (a toxic drug that nobody uses anymore).
But the truth is that there really are no “alternatives” to icosapent ethyl (Vascepa). None of the “alternatives” listed above have proven to have any cardiovascular benefit in any kind of clinical trial (at least in the post-statin era). Which is why none of them have received FDA approval for reducing cardiovascular events.
Lovaza, for instance, 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 - it’s the Wild West. Furthermore, even if one wanted to use supplemental fish oil for this purpose, 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. With those 20 or so tablets, comes oxidized substances (never a good thing) and the saturated fat content contained in a typical cheeseburger.
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 was awarded following the REDUCE-IT trial - a large scale randomized controlled trial, which demonstrated a 25% reduction in cardiovascular death, driven by a reduction in atherothrombotic events (Cardiovascular Risk Reduction with Icosapent Ethyl for Hypertriglyceridemia | New England Journal of Medicine).
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. Continue reading below in Deeper Dive for more about this controversy.
A checklist of targeted recommendations based on published guidelines
CardioAdvocate Checklist:
- Check lipid profile
- Are your TG > 150 mg/dL?
- Are you on maximum tolerated statin dosing?
- If so, you may benefit from icosapent ethyl (Vascepa)
- It is branded, so check with your insurance payer
- 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 a cardiovascular benefit
- Eat more fish.
- Fish lower on the food chain, such as sardines and mackerel are a great way to obtain EPA while minimizing exposure to mercury.
- Some may wish to measure the EPA content of red blood cells (RBC) to make sure they are consuming enough EPA.
- Studies show that the benefits of EPA were more pronounced in those achieving > 8% RBC saturation.
Going into detail on the evidence behind the recommendations and history of treatment for this phenotype.
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. The “positive” ones had one thing in common, however - they included the JELIS trial. This was a single blinded randomized controlled trial using EPA only at 1.8 grams daily to a Japanese population (already consuming high amounts of fish).
REDUCE-IT Trial
The benefits seen in the JELIS trial spurred interest in EPA only formulations of fish oil and lead to the REDUCE-IT , which used the drug icosapent ethyl (Vascepa), an EPA only derived formulation of Omega 3 fatty acid to evaluate high risk patients (established coronary artery disease or type 2 diabetes) with moderately elevated triglycerides (150 - 499 mg/dL) already maximally treated with statins. It was FDA approved at that time for treating severe hypertriglyceridemia (> 500 mg/dL) to prevent pancreatitis.
It is well known that high risk patients (established CAD and type 2 diabetes) who continue to demonstrate moderately elevated triglycerides (150-499 mg/dL) despite maxim statin therapy, represent a subgroup population at highest risk of a repeat event, so-called “residual risk”. This pattern is typically seen in those with diabetes, prediabetes and obesity with visceral adiposity. However it was not known whether a drug capable of lowering triglycerides in those with moderately elevated triglycerides would provide a cardiovascular benefit. JELIS seemed to suggest it might.
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. The REDUCE-IT trial demonstrated a 25% reduction in cardiovascular events. Interestingly, this benefit was INDEPENDENT of its impact on triglyceride lowering and the benefit was observed even at the lowest starting TG levels - as far down as 135 mg/dL at trial entry. Further analysis of the REDUCE-IT trial showed that a 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.
Furthermore, 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. This provides complimentary 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, like Thomas Dayspring (@Drlipid) / X, argue for supplementation. Others are skeptical - just because something is essential, does not necessarily mean that supplementation in the form of a pill or drug (Lovaza) will provide benefit.
Its role as a drug in cardiovascular disease protection is a bit shakier. It has been batted around as being beneficial, neutral or even detrimental, thanks to the REDUCE-IT and STRENGTH trials (Omega-3 for Cardiovascular Diseases: Where Do We Stand After REDUCE-IT and STRENGTH? | Circulation).
The STRENGTH Trial 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 2 trials differed. 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, like Dr. Matt Buddoff 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, such as Dr. R. Preston Mason: High Concentration Mineral And Corn Oils Do Not Influence LDL Oxidation Rates and have theorized that EPA and DHA, due to their carbon chains and configurations, behave differently within phospholipid membranes, with EPA having better antioxidant qualities than DHA. Whereas EPA seems to intercalate nicely between cholesterol domains within the phospholipid membranes, DHA not so much. 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.