Got High Triglycerides? Check out our New Decision Pathway from the American College of Cardiology

For decades, triglycerides (TGs) took the proverbial back seat in the lipid/lipoprotein hierarchy.  In recent years, however, TGs have gained increasing traction as a bonafide and independent biomarker of cardiovascular risk based on a series of well conducted epidemiologic and genetic (Mendelian randomization) studies.

Earlier this month, the American College of Cardiology released a new document that systematically outlines a series of decision trees that clinicians and health care professionals might consider when treating patients with elevated TG levels.  It was a great privilege to work with colleagues and “lipid luminaries” in an highly engaging effort spearheaded by Drs. Salim Virani and Pam Morris.

Listed below are some of the highlights of the document that can be accessed by clicking here.

1. Lifestyle interventions should be initiated in adults with fasting triglyceride levels of 150 mg/dL or non-fasting triglycerides of 175 mg/dL or higher.
2. Among lifestyle recommendations for treating high triglycerides, weight loss is among the most robust (10-20% reductions on average) with up to 70% reductions potentially achievable.
3. Dietary recommendations to lower elevated triglyceride levels include switching from a low-fat, high carbohydrate diet to a higher-fat (predominantly mono/polyunsaturated) and low-carb diet (30-40% of calories).
4. In men and women with the metabolic syndrome, a high protein/weight loss diet (greater than 25% of energy intake/500 calorie per day deficit) is associated with ~35% reduction in triglycerides.
5. Physical activity and exercise may contribute up to a 30% reduction in triglyceride with both resistance training and aerobic activity contributing to these effects.
6. Excess alcohol consumption, especially with pre-existing high triglyceride levels can precipitate pancreatitis.

Dr. Michael Miller is Professor of Cardiovascular Medicine at the University of Maryland School of Medicine in Baltimore, Maryland. 

EPA versus EPA/DHA: What Have Clinical Trials Taught Us?

Our new review paper out this week entitled “A Fishy Topic: VITAL, REDUCE-IT, STRENGTH and Beyond; Putting Omega-3 Fatty Acids into Practice in 2021” was designed to reduce the confusion surrounding the use of the marine derived omega 3 fatty acids, EPA (eiscosapentanoic acid) and DHA (docosahexanoic acid).  Coincidentally, this paper compliments last week’s publication in the Lancet journal, EClinical Medicine entitled, “Effect of omega-3 fatty acids on cardiovascular outcomes: A systematic review and meta-analysis” led by my colleagues,  Drs. Safi Khan and Deepak Bhatt and showing that EPA but not the combination of EPA+DHA was associated with reduced risk of cardiovascular events such as heart attacks, strokes and heart related death (see Figure).

As both EPA and DHA are extracted from oily fish including salmon, sardines, anchovies and herring and both lower triglycerides to a similar degree, why have clinical trials using EPA compared to EPA+DHA shown contrasting results?   Elegant work from Dr. Preston Mason and his co-workers have provided important insights at the cellular level demonstrating that EPA possesses cardioprotective anti-inflammatory, anti-oxidant, endothelial normalizing and membrane stabilizing properties that become suppressed in the presence of DHA.  Thus while DHA plays a pivotal role in brain growth and development, clinical trials to date have not borne out similar benefits with respect to cardioprotection.

I’ve been intrigued with EPA for more that a quarter century after we first observed dramatic differences in the way EPA was processed into cellular lipids when compared to prototypic saturated and monounsaturated fatty acids.   As differences between EPA, DHA and other fatty acids continue to emerge, listed below are a series of highlights related to the intake of these fats whether as a supplement or in medicinal form.

1. Dietary supplements such as “fish oil” capsules are NOT regulated by the FDA and should not be viewed in the same context as OTC products (such as Advil) that are regulated.
2. Fish oil capsules, a dietary supplement not regulated by the FDA, has been shown to contain a number of impurities such as saturated fat and oxidized lipids that impair its effectiveness.
3. EPA but not DHA exhibits heart protective antioxidant, anti-inflammatory and membrane/plaque stabilizing properties that help to reduce the risk of cardiovascular disease.
4. In the MESA study, higher blood levels of OM3 (inclusive of EPA) were associated with reduced risk of hospitalization for bleeding events.
5. In the REDUCE-IT USA study, 4 grams of Icosapent ethyl, the prescription form of highly purified EPA, was associated with a 30% reduction of death from all causes.
6. In the REDUCE-IT trial, total primary events (cardiovascular death, heart attack stroke, stent placement, bypass surgery or hospitalization for unstable angina) were reduced by 30%.

Dr. Michael Miller is Professor of Cardiovascular Medicine at the University of Maryland School of Medicine in Baltimore,MD.  He is a Scientific Advisor for Amarin, Corp. and Steering Committee Member of the REDUCE-IT trial.  Dr. Miller is also the author of several books; including his most recent,  “Heal Your Heart…“

Fishing for the Truth…Omega 3’s & your Heart

This past week, the American College of Cardiology’s (ACC) virtual scientific sessions included several presentations that centered around the relationship between the omega 3’s, EPA and DHA and the risk of heart disease.

Before discussing the contentious omega 3 study presented, let me provide a brief historical overview that has led to the current controversy and stems from multiple studies demonstrating heart-related benefits with purified EPA but not with the combination of EPA and DHA.

On the one hand, one might have thought that EPA (eicosapentanoic acid) and DHA (docosahexanoic acid) would behave in a similar manner when it comes to heart protection. After all, eating fish containing EPA and DHA has been shown to be cardioprotective, especially when these polyunsaturated fats replace other animal based saturated fat.  In addition, EPA and DHA reduce high triglyceride (fat) levels associated with elevated cardiovascular risk.

To date, however, all studies testing purified EPA have shown favorable results.  The first study, entitled JELIS (click here for details) was a Japanese study that found purified EPA to be associated with an approximate 20% reduction in initial and recurrent heart attack events.  At the time, many of us were surprised by these results because we did not expect such a robust benefit in a population that already consumes an EPA enriched fish on a regular basis.

Then a second study, entitled REDUCE-IT (click here for details) tested another purified EPA compound (icosapent ethyl) in men and women with high triglycerides and established heart disease or at high risk of a heart attack/stroke (due to a history of diabetes/other risk factors).

REDUCE-IT was embraced by the cardiology community because of the impressive results seen, namely a 25% reduction in heart-related events.  Two additional studies known as EVAPORATE (click here for details) and CHERRY (click here for details) provided further evidence of benefit with purified EPA that included less plaque buildup in coronary arteries.

But what about studies testing purified DHA to prevent heart disease?  Surprisingly, they don’t exist.  Instead, studies assessing DHA have traditionally incorporated EPA and this combination has repeatedly failed to demonstrate cardiovascular benefit.  Among the criticisms voiced for the consistent negative results were the relatively low doses of EPA/DHA used and the lack of testing a population with high triglycerides.

To address these limitations, the STRENGTH study was undertaken (click here for details).  This was a well conducted study that tested men and women with high triglycerides and used sufficiently high doses of EPA/DHA to lower triglycerides.   Unfortunately and like its EPA/DHA predecessors, results of this study were disappointingly neutral with no reduction in cardiovascular events observed.

In other words, all studies to date using purified EPA have shown benefit whereas all studies using the combination of EPA/DHA have not.  In fact, pioneering research by my friend and colleague, Dr. Preston Mason has found opposing effects between EPA and DHA, with EPA exhibiting anti-inflammatory, anti-oxidant and other heart protective properties whereas DHA appears to mitigate these as effects.  Dr. Mason’s groundbreaking research (summarized here) provides the basis for what has been confirmed in clinical trials, namely, that EPA benefits the heart whereas DHA blunts/attenuates these effects.

To return to last week’s ACC meetings, a sub-study from STRENGTH found no benefit in those subjects who achieved the highest blood levels of EPA in the trial.  While these results might appear to directly contradict that of REDUCE IT, it turns out that EPA and DHA were significantly correlated with each other.  In other words, patients with the highest levels of EPA were also more likely to exhibit high, if not the highest levels of DHA.  As we have seen time and again, DHA and EPA don’t mix well when it comes to optimizing heart health because based on current evidence, DHA offsets the benefits of EPA.

Food for thought: If a bar of gold were contaminated with other metals/alloys, would it still be worth its weight in gold?

As we reel in highlights related to Omega-3’s and your heart, remember these:

1. Omega-3 supplements containing EPA and DHA have not been shown to reduce the risk of a heart attack or stroke.
2. The prescription form of purified EPA (Icosapent ethyl) reduced heart attacks, strokes & cardiovascular death by 25% in men and women with high triglycerides (135 mg/dL or greater) and elevated heart disease risk.
3. For each gram of omega-3 fatty acids consumed, triglyceride levels are reduced 8-10%.
4. Fish with a high content of omega-3s are anchovies, herring, mackerel, salmon & sardines.
5. Replacement of animal based saturated fat with plant/fish based polyunsaturated fat reduces the risk of heart disease by nearly 30%!
6. Excellent sources of plant-based omega-3’s include chia seeds, flaxseeds, soybeans and walnuts.
7. Compared to a diet high in saturated animal fats, a diet enriched in plant and fish based omega-3s is associated with a lower risk of heart disease.

Michael Miller, MD is Professor of Cardiovascular Medicine at the University of Maryland School of Medicine in Baltimore, Maryland and author of  “Heal Your Heart….”: published by Penguin Random House.  He served on the International Steering Committee for the REDUCE-IT trial.