Are the Benefits of Omega 3’s Outweighed by Potential Side Effects?

In last week’s post, I highlighted differences between two omega 3 preparations, 1) purified EPA (Icosapent ethyl) and 2) combination of EPA/DHA as it relates to the risk of heart disease.

This past week we published a new study that examines the association between blood levels of omega 3 -fatty acids and the risk of major side effects (bleeding and atrial fibrillation).   Led by my colleagues Drs. Karan Kapoor and Michael Blaha, the study was designed to determine the extent to which these side effects might occur in participants of MESA (Multi-Ethnic Study of Atherosclerosis), a national study of men and women being monitored for the development of heart related events over a multi-year period.

Decades earlier, Danish physicians Jørn Dyerberg and Hans O. Bang reported that heart disease was rare but bleeding risk increased among Greenlandic Eskimos that they proposed was due to their high consumption of EPA from whale blubber, herring and other omega-3 enriched fish. These studies gained worldwide attention and laid the foundation for the hypothesis that omega-3 supplementation intake might reduce the risk of heart disease.

As an aside, I had the opportunity to meet Dr. Dyerberg when I presented some of our earlier work on triglycerides and heart disease at the International Society for the Study of Fatty Acids and Lipids in Lyon, France in 1998.

And although an increased risk of abnormal heart rhythms was not reported in Greenlandic Eskimos, two recent clinical trials that used high doses of purified EPA (REDUCE IT) or the combination of EPA/DHA (STRENGTH) identified an increased risk of atrial fibrillation.

Back to our study, not only was there a significantly lower (rather than higher) risk of major bleeding in men and women participants from MESA, but also the risk of atrial fibrillation was not increased.

Bottom Line: Adding omega 3 containing fish to your diet in place of saturated animal fat, is heart healthy- based on our current study it is also safe from major bleeding complications and atrial fibrillation. Purified EPA (Icosapent ethyl) as used in the REDUCE-IT study lowered the risk of cardiovascular events. Even though atrial fibrillation was slightly increased in REDUCE-IT, stroke rates-a primary complication of afib- were decreased.

Below are additional reasons why adding omega-3’s to your diet may improve overall health.

1. We recently found supplementation with Icosapent ethyl to maintain bone mineral health in men and women with the Metabolic Syndrome.
2. For each 1 serving per week increase in fish consumption, there is an approximate 7% lower risk of Alzheimer’s disease.
3. Eating salmon 3x weekly may lower blood pressure by 3-5 mmHg.
4. Consumption of fatty fish improves tear production and symptoms related to dry eyes.
5. Adding 1.5 grams of omega-3 fatty acids daily is associated with reduced mental stress and anxiety.
6. High blood levels of omega-3 fatty acids is associated with a trend towards reduced death from COVID-19.
7. In men and women with heart failure, the addition of 1 gram of omega-3 fatty acids may reduce the risk of re-hospitalization for heart failure.

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.

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.

A Long-Standing Love Affair…. with Cholesterol

The year was 1979.  As a first-year medical student at Rutgers, I still vividly recall the enthusiasm of our famed biochemistry professors (Drs. Bjorn Olsen and Darwin Prockop) as they lectured us about a recent discovery that they predicted would someday change the practice of medicine.  With their accompanying 20+ page handout, they detailed the elegant experiments conducted several years earlier by Drs. Michael Brown and Joseph Goldstein on understanding the genetic flaw (defective/deficient LDL receptors) that resulted in very high cholesterol levels and premature heart disease.

Brown and Goldstein were in fact inspired by the seminal work of another pioneering Rutgers professor, Dr. Avedis Khachadurian who studied genetically high cholesterol in a Lebanese population; he classified familial hypercholesterolemia (FH) into 2 distinct forms: homozygous and heterozygous.   In fact, skin cells (fibroblasts) from one of Dr. Khachadurian’s FH patients were used by Brown and Goldstein to uncover a novel cellular process (receptor mediated endocytosis) that culminated in the 1985 Nobel Prize in Medicine or Physiology

Cholesterol disorders were further discussed in our small groups (see picture above…I’m the bearded one in the center) where we drew blood on each other to measure our total cholesterol and HDL levels. Despite all the excitement generated by our professors about cholesterol and heart disease, our favorite lunch offerings continued to be bacon cheeseburgers and fries (yes, guilty as charged)!

Several years later, during my medical residency at the University of Cincinnati, 1^st year residents were assigned to a month at the General Clinical Research Center (GCRC) where studies focused on plasmapheresis treatment for very high cholesterol and triglyceride levels.  The University of Cincinnati was also a national site for the Lipid Research Clinics Coronary Primary Prevention Trial (LRC-CPPT) trial that found that the cholesterol lowering medication, cholestyramine, reduced the risk of heart related events in men with high LDL levels.

Following this study, skeptics came out of the woodwork to voice their concern that lowering cholesterol did not translate into improved overall survival even though the LRC-CPPT trial was not designed to evaluate total mortality.  In fact, following my Senior Resident presentation on ”Cholesterol and Heart Disease”in 1986,  all agreed that while high cholesterol promoted heart disease, there was insufficient evidence that lowering cholesterol improved overall survival.  As a result, cholesterol lowering treatments were primarily used by lipid specialists and endocrinologists rather than specialists treating cardiovascular disease.

Even after statins came on the market in 1987, there was reluctance to use these meds in cardiac patients. In fact as a cardiology fellow in 1990, I added statin treatment to my post-MI patients recovering in the CCU only to have our Attending rescind these orders!  As might be said tongue in cheek,  he was correct in doing so because at that time there was no evidence to support statin treatment for post-MI patients.

In fact, cardiologists did not embrace lipid lowering therapy for heart disease until such evidence came to fruition. In the statin trial known as “4 S” (Scandinavian Simvastatin Survival Study) there was a 30% reduction in total mortality (in addition to reducing risk of heart attack and stroke), among men and women with very high levels of LDL cholesterol who received simvastatin treatment.   The floodgates then opened as study after study demonstrated the benefit of statins for reducing cardiovascular events.  Other add-on treatments including, cholesterol absorption inhibitors (ezetimibe), PCSK9 inhibitors and bempedoic acid have further contributed to LDL lowering and when tested, have demonstrated additional benefit (beyond statins) in reducing heart-related events.

The Bottom Line: In the 1960s, treatment for high cholesterol was not very effective and the medications used (bile acid resins, niacin) were often not well tolerated.  Today, we have therapies that can safely drive LDL levels down to those attained at birth (~30 mg/dL).   Yet, many still fear taking these medications, especially statins, because they have heard/read about myths popularized in lay books and social media.  As past Chair of the American Heart Association Counsel on Clinical Lipidology we recently wrote a Scientific Statement on the safety of statins, led by my colleague Dr. Connie Newman  that dispel falsehoods such as “statins will kill you”, “statins will destroy your liver”, “statins will paralyze you”, etc.

Suffice it to say that my longstanding love affair with cholesterol remains strong as we continue to battle cardiovascular disease, the nation’s top killer. Listed below are some takeaways with regard to cholesterol and heart disease.

1. At birth, the average LDL (bad cholesterol) level is 30 mg/dL. As LDL levels rise above 50-60 mg/dL, “hardening of the arteries” (cholesterol plaques) develop.
2. Heart disease is rare in countries whose average LDL cholesterol and triglycerides levels are less than 100 mg/dL.
3. For every 10 mg/dL decrease in LDL, the risk of heart disease is reduced ~5%.
4. Replacing saturated fat with an equal amount of polyunsaturated fat lowers LDL levels by 2.1 mg/dL.
5. Higher LDL levels in childhood predict cardiovascular disease later in life.
6. If you have heart disease, aim to lower your LDL cholesterol levels to less than 70 mg/dL.
7. On average, statins raise blood glucose 2-5 mg/dL. However, statins do not cause the diabetes disease process. Rather, statins effectively reduce cardiovascular risk in diabetics.

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.

Let’s Keep this Party Going: New Insights into Laughter’s Cardiovascular Benefits

In case you missed it, World Laughter Day was celebrated this past Sunday.  Yet, our understanding of laughter’s influence on the cardiovascular system continues to grow since the inaugural World Laughter Day in 1998.  In fact, my interest in this area began in 1997, when Dr. Adam Clark, a recent graduate of Albert Einstein School of Medicine and one of our Medical Residents, approached me seeking a research project in cardiovascular prevention.  At that time, our laboratory was studying families with extreme levels of HDL (the good cholesterol); one of our interests was evaluating high HDL in protecting against heart disease.

We reasoned that if HDL served to counteract some of the adverse effects of LDL (the bad cholesterol) on the heart, might a similar story be played out when evaluating emotional health and heart disease.  While studies had previously established emotional stress as a contributor to heart disease, information was simply lacking as to whether positive emotions may offset this effect.

Our initial study of a 40% lower risk of heart disease among those who were able to find certain daily stressful situations humorous led to other studies that ultimately supported a direct link between laughter and vascular health; click here for the review paper co-authored with Dr. William Fry, the late Stanford University professor and pioneer in the field.

As additional research has been conducted in recent years, we’ve gained new insights into the role of laughter and cardiovascular health.  Listed below are some of the reasons why we should keep this party going (daily rather than yearly):

1. A Japanese study of nearly 21,000 men and women (aged 65 years and older) found that daily laughter was associated with a 60% lower risk of a stroke compared to those who never or rarely laughed.
2. A 15-year study in Norwegians found a greater than 70% higher survival rate from cardiovascular disease in women with a high sense of humor.
3. Watching a funny video reduces stress cortisol levels (that in turn, increases inflammation/cardiovascular risk), improves short-term memory and learning ability.
4. Laughter reduces/offsets some of the symptoms associated with a stressful event that promote inflammation and cardiovascular disease.
5. Maintaining a humorous perspective about personal experiences is associated with resilience and better psychological -and by extension, cardiovascular, health.
6. In the elderly, laughter therapy has been shown to reduce chronic pain (that in turn, raises blood pressure/cardiovascular risk) and improve overall life satisfaction.
7. Laughter may slow/delay the onset and progression of vascular complications associated with diabetes.

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: The Positive Emotions Prescription to Prevent and Reverse Heart Disease.”: published by Penguin Random House.