Omega-3 Supplements, Environmental Toxins and Fish

I wanted to start out the second part of the O₃FA (Omega-3) postings by talking about environmental toxins and fish because I have to confess that I was always confused about the true facts about toxins and fish consumption. There is no doubt that high fish oil intake through the consumption of large amounts of fish may present a risk for increased environmental toxin exposure.

Let's begin by talking about mercury. Mercury may come from coal-fired power plants, waste incinerators, and mining operations as well as other sources. Once airborne, the pollutants fall to the ground in rain or snow and get into the water supply and are converted by bacteria to methylmercury which is toxic to humans. Large and older fish have accumulated more mercury than younger small fish. Also, predatory fish near the top of the food chain tend to accumulate more mercury.

Mercury poisoning by fish consumption has resulted in in neuropsychiatric signs and symptoms including numbness in the mouth and extremities, ataxia, auditory impairments, and most importantly, severe neurologic damage to children born to mothers with toxic mercury exposure. Despite this information, the totality of the evidence supports that the benefits of fish oil exceeds the potential risks, including intake in women of childbearing age with the exception of a few. It needs to be clear that these recommendations only apply to fish oil intake through the consumption of fish.

With regard to fish oil intake though select fish oil supplements, testing has shown that the level of mercury and other environmental toxins is very low or negligible. This occurs for two reasons. First, oxidized mercury is only water soluble and insoluble in oil and thus would not be expected to represent a significant toxicity risk with the intake of fish oils. Second, selected fish oil supplements undergo extensive purification processes to remove toxins and with the prescription fish oil preparations undergoing even more rigorous regulatory processes.

PCBs, Organocholorine pesticides , the most common one being DDT, and dioxin has also found their way into the water supply and ultimately fish consumption has been associated with toxicities from these agents. Dioxin is the primary component of Agent Orange which was used as a defoliant in the Vietnam War and is considered a carcinogen. Manufacturers of selected fish oil supplements have implemented purifications and quality controls designed to reduce the risk of exposure to these toxins. Thus, O₃FA supplements may be preferable to fish consumption as a therapeutic source of O₃FA.

The caveat to all this is that the Nutriceutical industry is largely unregulated. Although the FDA designates O₃FA supplements as "generally regarded as safe", they are not subject to premarket review and approval requirements like prescription medicines. Some fish oil manufacturers elect to pursue "USP-Verified" marks on their label which indicates compliance with standards set by the US Pharmacopeia (USP) which is a independent, not-for-profit, organization established in 1820 that has set the legally recognized standards for identity, strength, quality, packaging, purity, and labeling.

Many physicians are unaware of USP monographs. The USP is also involved with the verification of products through the voluntary Dietary Supplement Verification Program. The presence indicates that the USP has rigorously tested and verified the supplement. The O₃FAs that I take and give to my patients are USP certified. Some manufacturers make the false claim the their O₃FA is "pharmaceutical grade" when they have not gone through the rigorous processes and oversight required to receive approval as a prescription pharmaceutical so beware of this misleading statement.

When I am asked if a particular brand of O₃FA contains excessive vitamins or toxins to pose a health risk, I answer by saying that it depends on the operating and purification processes each company uses. The only way to know is if it is "USP-Verified". The only thing that one must know is that this labeling does not address the efficacy of a supplement. For efficacy information a label needs to state the amount of EPA and DHA within the O₃FA and then the proper dose can be determined.

In my office, I show patients five of the most common brands and although they same 1000mg per tablet, if one looks on the back of the label, there is usually about 300mg of EPA and DHA. So when I tell patients to take 4000mg, they would need to take about 12 pills although the front says 1000mg. One would think they only need to take 4 pills. This is misleading. I generally encourage patients to take highly concentrated liquid which contains 3200mg per teaspoon if they are treating high Triglycerides or 2-3 500mg concentrated fish oil tablets if they are using fish oil for only Cardiovascular clinical benefits.. Please beware of this problem especially if the O₃FAs are being used to treat Hypertriglyceridemia.

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• WebMD Video: Toxins and Autism Spike?
• Toxins and Pregnancy

Technorati Tags: omega-3, environmental toxins, mercury, fish oil, cholesterol, heart disease

ENHANCE and JUPITER Studies Revisited

I wanted to once again weigh in on two very important issues discussed at the American College of Cardiology meeting this week in Chicago. The first is about the JUPITER Study and then I will give some further thoughts about the ENHANCE study which I have previously written about in January.

The results of ENHANCE, which was the trial of Vytorin 80/10 vs Zocor 80, was already released in January. Despite the media uproar then, there seems to be more ridiculous hoopla when really nothing is new. The only difference is that the results are now published in the New England Journal of Medicine. As I have said before, this is strictly an imaging study and there is NO OUTCOME DATA!

Despite this, some have made this out to be some groundbreaking study and it is not. The only point new was that Vytorin was superior to Zocor in reducing C-Reactive Protein (48% vs 23%), Apo B, Triglycerides, and most importantly LDL-C. Also there were no adverse outcomes with Vytorin. I am not going to rehash all the facts of the study but there is one important point. Although they looked at patients with Familial Hypercholesterolemia, the baseline Carotid Intimal Thickness (CIMT) was pretty much normal...meaning the arteries were clean in the neck. There was no progression of CIMT meaning both the drugs kept the arteries clean.

How the furor over Zetia and Vytorin has occurred perplexes me but be assured, I will not change my prescribing habits.

Most importantly, the JUPITER trial was stopped using Crestor for ethical reasons because the Crestor arm of the trial had significant improvements in Cardiovascular morbidity and mortality. I have been a fan of Crestor for a long time and once again the superiority of LDL-C lowering was confirmed as was the safety. There is no more effective statin on the market.

I want to also make clear that I have no financial relationship with any pharmaceutical company and my motives for stating this are based on sound evidence-based medicine. Most importantly, I feel it is my obligation as a physician to present the facts and not have my "feelings" based on any financial remuneration. I can tell you that some of the physicians who weigh in on the studies have some kind of financial incentive to do so and I personally believe this clouds their interpretation of the facts.

I will resume Part 2 of O3FA in my next posting.

Related Topics:

• WebMD Video: Predicting Heart Disease
• WebMD Video: Cholesterol Warning for Women

Technorati Tags: studies, cholesterol, zetia, vytorin, zocor, crestor

Omega-3 Fatty Acids - Part I

The American Heart Association has recommended Omega-3 Fatty Acid (O3FA) intake in the form of routine fatty fish such as salmon for patients without Atherosclerotic Coronary Artery Disease (CAD), fish oil supplements in patients with CAD, and high dose O3FA (about 4000 mg/day) in patients with high triglycerides.

Early studies demonstrated that the major effect of O3FA on the lipid profile is to lower triglyceride levels between 10-45% depending on the severity of the triglyceride level and the dose of O3FA used. At the same time there is also a tendency for the LDL cholesterol (bad cholesterol) to rise between 0-30%, for LDL particle size to enlarge, and for HDL cholesterol (good cholesterol) to increase between 0-7%. The purpose of this review is to provide a modern perspective based on recent studies of the role of O3FA as they relate to the management of abnormal lipids.

Until the availability of a prescription O3FA in 2004, which contains 840 mg of EPA and DHA (the two main O3FAs) and 60 mg of other O3FA in a 1000 mg tablet, the treatment of high triglycerides with Omega-3 fatty acids required the ingestion of large amounts of unconcentrated fish oil. Also at this time it was identified that most of these over the counter products were not regulated for content of the environmental contaminants such as heavy metals, pesticides, and dioxin. Now that many insurance companies and Medicare drug plans pay for the prescription O3FA sold under the name Lovaza, many Americans have begun to start taking fish oil.

The most common complaint is an unpleasant fishy taste if one burps. Fish oils are naturally highly unstable and susceptible to oxidation which accounts for their rancid conversion and patient intolerance. One of the most common ways to reduce oxidation and thus maintain shelf life, maintain freshness, and reduce oxidation is to add Vitamin E to supplements.

I generally tell my patients to take their fish oil at night. Another practical way to improve tolerance and reduce the fishy aftertaste of the liquid O3FA is to refrigerate it, once opened. If one is taking the capsules, it is said that refrigeration before use will reduce the fishy taste.

The way the manufacturing process is performed is the most important measure to reduce the aftertaste and remove contaminants. It could be argued that when a patient describes a rancid horrible and bad taste that the product was poorly purified by the manufacturer.

Unfortunately the supplement industry is basically unregulated. I have my O3FA made by one of the few companies that pay to have an oversight board watch their manufacturing process. I tell my patients who need to take high dose fish oil to use the highly concentrated liquid form while others may take the pills.

I think it is extremely important that patients look on the side of the bottle because most purchased O3FA says it contains 1000 mg but may contain as little as 300 mg of EPA and DHA. Thus one would have to take around 7 tablets if they are trying to take 2000 mg a day rather then thinking the correct dose would be 2 of the 1000 mg capsules. I have gone around to the big retail and wholesale stores and the health food stores and was amazed what I saw.

In the next posting we will discuss environmental toxins that may possibly be in the preparation and I will share with you the recommendations from the National Lipid Association to healthcare professionals regarding the use of O3FA supplements.

Related Topics:

• Fish Oils May Be Lifesavers
• WebMD Video: Fish Oil May Not Be for Everyone?

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Statins and the Kidneys

There is no evidence in the literature that statins cause acute renal failure or renal failure not associated with Rhabdomyolysis. (see Statins and the Muscle) The major cardiovascular disease end point trials have not reported renal failure as an adverse event associated with statins. In addition, statins can be used safely in kidney transplant patients and patients on hemodialysis.

Now that we have covered the effects of statins on the various organ systems, we will be starting a series of postings on the safety of the Non-Statins. The National Lipid Association's Statin Safety Task Force reviewed the safety of the Non-Statins and published their findings in the March 19, 2007 issue of the American Journal of Cardiology. We will be covering Fibrates, Omega-3 Fatty Acids, Niacin, and the Gastrointestinally Active Lipid-Lowering Drugs.

Stay tuned...


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• 4 Tips for Lower Cholesterol Fast

Technorati Tags: cholesterol, statins, renal failure, heart health

Losing Your Mind? It's not the Statins

There does not seem to be a day that I don't wake up in the morning and see some negative press regarding statins. Well yesterday was no exception when on Good Morning America, I once again heard that some "expert" said that statins make women lose their memory. It really is getting ridiculous. It would be nice to hear that statins have changed the face of Cardiovascular disease by reducing morbidity and mortality dramatically. Despite this, we still have a long way to go to eradicate Cardiovascular disease which still remains the number 1 killer of men and women in the United States.

I was planning to write on this topic next week, as I have been really busy seeing patients, but thought I needed to take the time to address the new comments. Like I have said before, the Statin Safety Task Force of the National Lipid Association also formed a Neurology Panel to look at the evidence based literature to assess the effects of statins on the Nervous System.

First of all, there is no evidence that statins are a common or significant cause of peripheral neuropathy. This is supported by the large randomized clinical trials including the Heart Protection Study (HPS) and the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER). The HPS was the largest statin trial to date and included 20,536 participants who were followed over a 5 year period. It is always possible that a rare case of peripheral neuropathy could occur but this would most likely represent an idiosyncratic reaction which I talked about in a previous posting.

In regard to the question whether statins impair memory or cognition in some patients, the answer is that there is no evidence of a causal relation between impaired memory and/or cognitive dysfunction. Besides the HPS and PROSPER, two additional studies have specifically evaluated the effect of statin therapy on patients with Alzheimer's disease, a population group at risk for cognitive decline. In one of the trials, there was a statistically significant reduction in the rate of cognitive decline compared with placebo, suggesting a benefit for Atorvastatin in Alzheimer's disease. This is the exact opposite of what I heard this morning.

I think the best way to approach a patient with peripheral neuropathy or impaired cognition while on statins is to first undergo a thorough neurologic exam by a neurologist in an attempt to find a cause. If this is not possible, it is certainly appropriate to stop the statin to see what happens.

Due to the length of time it can take to resolve reversible peripheral neuropathy, the patient should remain off the statin for 6 months. For patients with impaired cognition they should wait about 3 months. If symptoms improve then it is certainly possible that a presumptive diagnosis of being caused by statins can be made.

One might want to consider a different statin, as the benefits of statins in reducing Cardiovascular Morbidity and Mortality have been proven. If the neurologic symptoms do not improve, the problem may be categorized as unrelated to the statin and therapy may want to be restarted based on a risk-benefit analysis.

One must remember that many other causes of impaired cognition and/or peripheral neuropathy in patients taking statins may exist. These include Vascular disease, Diabetes Mellitus, and advancing age. I feel confident in saying that statins do not make women lose their memory.

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• Statins: Heart Health Superstars
• Cholesterol Management: Statins

Technorati Tags: statins, cognitive impairment, heart disease

Statins and Muscle Pain

I have spent the last 2 weeks answering questions about Vytorin and Zetia after the media caused an inexcusable hysteria that in some way Zetia or any combination which included it was bad. One well-known expert always seems to weigh in on every cholesterol issue and gives the thumbs-up if he was involved in the study and the thumbs-down if he was not.

I can tell you that those of us who practice full time clinical medicine and see patients daily have not altered our prescribing practice on the basis of the ENHANCE study which was strictly an imaging study with no outcome data regarding what the findings actually mean in the patients.

It is a shame that the ASTEROID and METEOR studies involving Crestor, which were also imaging studies but showed a decrease in the plaque burden in the heart arteries(ASTEROID) and a regression in some patients and no progression in others(METEOR) of the same thing that was measured in the ENHANCE study (CIMT or Carotid Intimal Medial Thickness) and generated all the confusion, were not mentioned in the media. The point is that all of these studies are imaging studies and there is no outcome data so I really do not know what any of them mean in a practical sense.

Are statins bad for the muscles?

Once again I will present the evidence-based data, but first, some definitions:

• Myalgia is a non-specific common complaint of muscle ache and there are no abnormalities of the muscle enzyme CPK or CK on a blood test. Myalgia has rarely been examined in clinical trials and it is thought that some type of muscle aches can occur in up to 30% of patients on statins. Unfortunately, many of these patients start a vigorous exercise program at the time they start their statin because they decide it is to "get in shape" and one doesn't know where the orgin of the muscle ache is from. There are many other causes of myalgias too. Statin muscle pain typically occurs in the proximal muscle groups(closer to the trunk of the body) and also lower back. Statin-induced myalgias have occurred up to 3 years after starting a statin.



• Myopathy has been used to refer to all muscle complaints or CK elevations more than 10 times the upper limits of normal with or without associated muscle symptoms. Myositis has been defined as muscle symptoms with increased CK levels. This term implies muscle inflammation but this appears to be a secondary event associated with the healing process.



• Rhabdomyolysis, by strict definition exists whenever there is evidence of muscle damage, such as a mildly elevated CK level but is used clinically to refer to severe muscle damage and is usually associated with kidney dysfunction.

The Muscle Expert Panel of the Statin Safety Task Force believes believes that because of all this confusion about terms, a new format should be made as follows:

• Myopathy should be used as a general term for all muscle problems.



• Symptomatic Myopathy should be used to refer to muscle pain (myalgias), weakness, and cramps.



• Asymptomatic Myopathy should be used to refer to CK (enzyme) elevations without any symptoms.



• Rhabdomyolysis should be used to refer to any evidence of muscle cell destruction with resulting change of kidney function.

What does all this mean?

First of all, muscle problems do occur with all statins. Muscle complaints have been documented to increase with increasing blood levels of the statin. There are 2 different classes of statins: Fat soluble and water soluble. The fat-soluble statins include Lipitor and Zocor and the water-soluble include Pravachol and Crestor.

Since fat-soluble statins can easily enter the inside of the muscle cells, theoretically muscle damage should be increased with their use, as water-soluble statins do not easily get into the muscle cells. This hypothesis has not been confirmed and cases of Rhabdomyolysis, while rare, occurring about 1 time for every 15 million prescriptions written, has occurred with all statins.

My practice is to obtain a baseline CK (enzyme) level before starting statins to see if it is elevated. When a patient on a statin develops myalgia symptoms, I closely monitor them and if severe, I will get a CK level to see if there is any muscle damage.

The problem exists, however, that frequent inquiries about muscle pain may prompt symptoms in suggestible patients. Based on clinical experience, statin-related myalgias resolve when stopping the medicine. There is insufficient evidence to conclude whether myalgia that persists after stopping the statin is caused by the medications. All patients who are symptomatic on statin therapy should have thyroid function tests done as hypothyroidism can exacerbate symptoms.

Also, other medications or nutraceuticals that slow down statin metabolism should be known such as red yeast rice (which may contain a statin and produce myopathy) and grapefruit juice consumption, which impedes the breakdown of fat soluble statins mostly affecting patients on Lipitor.

Regardless of the CK level, if the pain is severe, the statin should be stopped until all the symptoms resolve. Once this occurs, the same statin could be started at the same dose to see if symptoms recur or started at a lower dose. Alternatively, a different statin can be tried.

There is no direct comparison of tolerability among statins and therefore no definitive evidence to recommend a specific statin medication. In other words, there isn't one that's any better than the other, based on established studies. In my practice: however, I will change a patient from a fat-soluble statin to a water-soluble statin if myalgias start and this has been successful for me in reducing muscle problems.

As I said earlier, there is no direct evidence that water-soluble statins produce less muscle problems as compared to fat soluble statins. If the muscle pains are tolerable with or without a CK elevation less than 10 times the upper limit of normal, the Muscle Panel recommends that statin therapy be continued at the same dose or a reduced dose. Generally it is my experience that muscle aches do go away or become tolerable to the patients if the statin is continued. Many physicians are too quick to stop statins with any muscle aches.

The risks versus benefits of statins need to be weighed. One must remember that statins have reduced Cardiovascular Morbidity and Mortality by approximately 40%. While there is no definitive clinical evidence of any strategies that can be used to prevent or reduce muscle injury, there is some evidence that coenzyme Q10 may cause a significant reduction in statin-induced pain. Since the response has been variable, the use of coenzyme Q 10 cannot be recommended with any degree of confidence.

Related Topics:

• High Cholesterol Treatment: What Works?
• High Cholesterol Risks: 2 Dangers

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Zetia and Vytorin: Let's Look at the Facts

Let's talk about the current media frenzy about the results of a study that seems to conclude that Zetia may not be effective for treating high cholesterol: the ENHANCE study. After the reports were published, I got a bunch of telephone calls from patients and family who are either on Vytorin or on Zetia in combination with another statin and they want to know about what to do now.

My response to them is to relax, and please read this post. I want to make it perfectly clear that I have absolutely no relationship with Merck in any way but I feel it incumbent upon me to state the facts. As a Cardiothoracic Surgeon, my personal goal is to present my patients with the facts in a clear and concise manner and treat them as I would my own family. I went into medicine to save lives, not to be an alarmist and scare the public. The media seems to do that on a daily basis. It is pretty ironic that the same two or three people always seem to make comments in the media about every study, many of whom were "sponsored" by a drug company, and seem to always put their own spin on things and never calmly state the facts.

I think that it is time for the media to come to us, doctors who actually treat patients on a daily basis, for our thoughts.

I. What Was Studied

The ENHANCE Study results were released in part yesterday. This study is a Vytorin 80 mg, which is a combination pill consisting of Zocor and Zetia, versus Simvistatin (Zocor) on the effects of IMT. IMT is the amount of thickening of the layers of the carotid artery and is assessed using a type of duplex ultrasound.

Increased IMT means the person is at a higher risk of Cardiovascular events. It is often used as a marker for either progression or regression of Atherosclerotic Vascular disease. Whether this thickening represents early atherosclerosis or a change that parallels atherosclerosis is a subject of controversy.

II. What Wasn't Studied

IMT is not a measure of the amount of plaque that can cause a blockage in the artery. The ENHANCE study was performed in people with severe familial hypercholesterolemia, (high cholesterol attributed to genetic causes) -- a group notoriously resistant to treatment, and a group that has nothing in common with most of the patients seen in a clinician's office.

In the ENHANCE study, there was no statistically significant difference between the treatment groups for each of the primary endpoints including the carotid artery, nor did key secondary imaging endpoints show any statistical difference between the treatment groups. There were also no safety issues with the Zocor/Zetia whatsoever.

One must remember that reduction in risk for cardiovascular events is directly related to LDL cholesterol lowering. Lower LDL cholesterol is better than higher and has this been shown to reduce the incidence of cardiovascular deaths and complications. While statins are first line management, if one is unable to bring their patients to the NCEP goal of cholesterol reduction, the majority of clinical events will not be reduced.

What Should We Learn?

So are we supposed to give up on an FDA-approved therapy, statins and ezetimibe (Zetia), to get to the goal and listen to these hysterical rants from some physicians or should those of us who actually treat patients continue down the same course? I personally believe we should do the latter.

I perform LDL particle testing on all my patients (Go to my website to find out more about Advanced Cholesterol Testing.) This test allows me to individualize treatment in all my patients and follow their progress with LDL particle testing. I believe this is the reason why heart disease is increasing while even more conventional lipid testing is being done. Simply put, people are not seeing the entire picture clearly.

Like ENHANCE, five recent major clinical studies have failed to meet their primary endpoints. Due to improvements in cardiovascular care the individuals in trials receive, it is becoming increasingly harder for clinical trials to meet their primary endpoint.

III. Why Outcomes Matter More than Predictions

Dr Robert Harrington from the Duke Clinical Research Institute pointed out on Heartwire yesterday that the ENHANCE study should not provoke such a strong reaction.

"Dr. Nissen's suggestion about a moratorium on ezetimibe (Zetia) is rather alarmist, given that this was just an imaging study, an imaging study should not change clinical practice. So for me, whatever way it went. I would not have been blown away by results from this trial".

I could not agree with him more. Dr. Harrington is involved with one of the large clinical-outcome trials under way with Zetia.

"Enhance is just a biomarker study. Whatever the results were, even if they had been positive, I would still have said we have to wait for the clinical-outcome trials before making our minds up about this drug. The imaging guys all say these imaging studies are predictive of clinical events, but they would say that, wouldn't they? To prove a biomarker is a true surrogate is actually very difficult, and I do not believe that IMT or IVUS (Intravascular Ultrasound) meet the criteria for surrogate markers in this setting," he said. He added, "So I would say not much has changed. If you liked Zetia before ENHANCE because it lowers LDL, I would think you would carry on using it but if you were of the opinion that you would rather wait for clinical outcome results before prescribing it, the there is nothing in this trial to change your mind about that...To me, these results just raise my interest even more in the clinical outcome studies. They are now going to be even more important."

As I have stated repeatedly in my talks as well as on my message board, all these studies are great but without clinical outcome studies, it is impossible to draw conclusions. I want to point out that Lipitor became one the best selling drugs of all time before any shred of outcome data was released. Where were these alarmists then? Maybe they worked for Pfizer at that time? Who knows?

There is absolutely no prospective data from clinical trials about how raising HDL levels will lower clinical events. Nobody seems to know this yet everyone seems to think that if there HDL is high that is great and they won't have a heart attack or stoke. They do not know that the CDC says that 50% of people who suffer heart attacks have "normal cholesterol".

I beg to differ and that is why I recommend advanced testing on everyone. Advanced testing misses nobody at risk even when their traditional lipid testing numbers were normal. They forget about the true villains which are LDL particles. All the HDL data is from animal studies or population/epidemiologic studies.

I hope this helps to quell some of the panic in the public. I will continue to prescribe Zetia when my patients are unable to meet their LDL goal on statins alone with no hesitation.

Related Topics:

• WebMD Video: Predicting Heart Disease
• WebMD Video: Cholesterol Warning for Women

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