Cholesterol Management 101

Lipid Control with Zetia (Ezetimibe)

2008-05-20T16:15:00.005-04:00

The next drug used in lipid modulation we will talk about is Zetia (ezetimibe). I will not go into the ENHANCE study again as I have had two previous postings on it. The only thing I will say is that the official stance of the National Lipid Association is that on the basis of that study, Zetia achieved the expected response in regard to LDL-C lowering and there were absolutely no safety issues.

Zetia is a new class of drugs known as cholesterol absorption inhibitors. It inhibits the absorption of dietary and biliary cholesterol without affecting the absorption of triglycerides or fat soluble vitamins. It works in the small intestine and inhibits cholesterol uptake and absorption. It has a half-life of 22 hours and this allows once daily dosing and it is not affected by food intake.

Zetia has been shown to reduce LDL-C in patients with hypercholesterolemia. Although some physicians use it as monotherapy, most lipidologists use it as an add on drug when cholesterol goals are not met on statin therapy. There is a low potential for drug interactions and Zetia does not interact with statins.

Several randomized clinical trials with Zetia 10 mg have demonstrated decreases of LDL-C of 17-18.2%, decreases in total cholesterol of 12%, and increases of HDL of 1.3%. Zetia combined with statins has been studied in 4 randomized clinical trials and the efficacy of the combination in lowering LDL-C was superior to the statin alone. For example, in one study, Zetia 10mg/Lipitor 10mg was as effective as Lipitor 80mg. One must remember that as the statin dose is increased the side effects are also increased so it is much better to use a lower statin dose combined with Zetia.

In terms of safety, Zetia is a very safe drug. The incidence of elevations in liver enzymes greater than three times normal ranges from 0-0.8% with statin monotherapy compared with 0-2.2% with Zetia plus statin co-administration.

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Technorati Tags: cholesterol, Zetia, ENHANCE, statins, LDL, HDL, health and wellness

Omega-3 Supplements, Environmental Toxins and Fish

2008-04-30T20:14:00.000-04:00

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

ENHANCE and JUPITER Studies Revisited

2008-04-02T02:44:00.001-04:00

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.

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Omega-3 Fatty Acids - Part I

2008-03-24T15:42:00.001-04:00

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.

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Technorati Tags: omega-3, fish oil, cholesterol, heart health

Statins and the Kidneys

2008-03-05T13:29:00.002-05:00

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

Losing Your Mind? It's not the Statins

2008-02-14T13:37:00.000-05:00

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 and Muscle Pain

2008-02-02T19:29:00.000-05:00

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.

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Technorati Tags: statins, muscle pain, lipitor, crestor, zetia, vytorin, cholesterol management

Zetia and Vytorin: Let's Look at the Facts

2008-01-15T15:35:00.001-05:00

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.

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Statins and the Liver

2007-12-31T17:56:00.001-05:00

Happy New Year! We recently started a series in which we will be discussing the safety of all the different classes of medications used in Cholesterol Management. As I stated in the last post, all the information is current and evidence-based. It is provided by the National Lipid Association and was published in the American Journal of Cardiology.

I am asked on a daily basis if statins are safe. I always respond that they are and also are one of the most studied medications. All medicines have both a generic and a brand name but I am sure most people only know the brand names so I will list them for you. The statins include Lipitor, Zocor, Vytorin, Mevacor, Crestor, Pravachol, and Lescol.

When The National Lipid Association Statin Safety Task Force wrote their report, each panel of experts wrote about a different area of the body in which any of these medications had been shown to affect in some way. We will begin with the Liver.

Concerned patients often ask if their statin will damage their liver? Let's start with the final conclusion of the Report of the Expert Liver Panel and then detail how they came to this conclusion.

"Outside of measuring liver biochemistries for the purpose of periodically updating a patient's medical history, we can find no scientific or medical basis for monitoring aminotransferase levels during long-term statin therapy as a measure to enhance patient safety. We acknowledge that the Panel's recommendations are at odds with current prescribing information for marketed statins: however, we are optimistic that the regulatory agencies and pharmaceutical industry will update their recommendations to be consistent with evidence-based data cited in this article."

What does this mean? Well, it simply means that all the liver function tests, which are commonly known as AST and ALT levels, that one's physician routinely draws to check for liver problems are unnecessary with the exception of updating labs during an annual physical exam or if the physician having some concrete reason to do so. The evidence-based data shows that routinely performing these tests do not make statins any safer.

The available data does not support doing so in the "asymptomatic" patient on a statin. Why do they say this? The reason the Panel says this is, believe it or not

"Very rare case reports of liver failure have occurred in patients receiving statin therapy."

Because the association between statin therapy and liver failure is so rare there is absolutely no way one can say with confidence that the liver failure was due to statin use. It is possible that this could be an "idiosyncratic reaction" to the statins. This means that a person could have an unexpected reaction or a type of allergy to the medicine and that is the reason for the liver failure. I like to think of it as the problem is with the way the patient's body responds to the drug rather than the class of drugs causing the problem.

The Liver Panel could find "no direct evidence of death due to liver failure caused by statin therapy." This does not mean that statins will not elevate the liver enzymes -- this is a known side effect. Generally a physician does nothing unless the level is more than 3 times the upper limit of normal but this does not mean that liver damage is occurring. This has been shown to happen less than 1% of the time across the dose range for marketed statins.

I asked a friend of mine who is a liver doctor at the largest hospital in the Western US his opinion on liver problems and statins. He said that he rarely performs liver biopsies any more when patients are on statins and have elevated liver enzymes because he has yet to see a case on statin-induced liver failure. There was always another explanation as to the cause of the liver failure.

My own feeling is that too many physicians stop this medication unnecessarily and forget the benefits of statins in reducing heart disease by at least 40% because they think a small rise in the liver function tests means that there is ongoing damage to the liver. Statins can be used safely in patients with chronic liver disease and well-treated cirrhosis but the physician may need to follow the patient a little more closely than would occur in a normal healthy patient on a statin.

Coming next: The effects of statin use on the kidneys.

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Technorati Tags: cholesterol, statins, liver, heart health

Alex Trebek

2007-12-11T19:01:00.000-05:00

Cross-posted on the WebMD TV Checkup blog

I understand that Alex Trebek, the host of the television show Jeopardy, had a heart attack last night and that he apparently had no risk factors for Coronary Artery Disease.

Is it true that he did not have any of the 5 major risk factors for heart disease? The major risk factors for Coronary Heart Disease are Smoking, Diabetes, Hypertension(high blood pressure), Age, and High Cholesterol. I believe that he did not have the first three, but we all age so that is indeed a risk factor.

Most importantly, did he really have normal cholesterol levels? On his regular lipid panel done by his doctor, I am sure it was "normal" but there is so much more to the story. I will give you something to think about. Last year there were 125 million lipid panels done in the US but the number of patients with Coronary Heart Disease continues to rise.

Also, the CDC states that 50% of people who have heart attacks have "normal" cholesterol at the time of their heart attack. Was Alex Trebek one of the 50% ? My guess was that he was in that group.

Although I am a heart surgeon, I have dedicated my practice to preventing Cardiovascular Disease by opening up The Center for Cholesterol Management in Los Angeles where I perform advanced lipid testing on all my patients. There is more to lipid management than measuring "good" and "bad" cholesterol. Most of today's tests do NOT tell the whole story. In fact many times heart attacks can occur without any warning signs. I will try and describe advanced cholesterol testing in simple terms.

We all know that oil and water do not mix. Well, blood is like water and cholesterol is an oily substance. When too much cholesterol is deposited in one of the Coronary Arteries, a narrowing results which can lead to a heart attack.

Since blood and cholesterol do not mix, the cholesterol has to be transported through the body by particles and these particles include HDL(the good cholesterol) and LDL( the bad cholesterol). Think of these lipoprotein particles as cars on a highway and ask yourself, is it the number of cars that cause a traffic jam or the number of passengers in the cars? We all know that it is the number of cars.

Unfortunately, the cholesterol testing that is done by 99.9% of the physicians in the US measures the numbers of passengers in the cars when it has been show that it is the number of LDL particles(the cars) that cause Atherosclerosis. I perform LDL particle testing on all my patients and measure the number of LDL particles in the blood stream.

This type of testing misses no one with high cholesterol, which can lead to Atherosclerosis, heart attack, and death while conventional lipid testing can miss up to 50-60% of people with high cholesterol but their test shows it to be "normal".

Simply put, the more LDL particles one has, the greater the risk of Cardiovascular disease. An example would be this: Let's say on your cholesterol test at your doctor's office your LDL cholesterol is 120mg/dl. This is considered normal in a low-risk patient. How do I know if you have two big cars(LDL particles) carrying 60 people in each one or 120 small cars (LDL particles) with one person?

It is impossible to know without doing LDL particle testing. The first person has a LDL cholesterol level of 120mg/dl and this is transported through the blood in two big particles. This person is not going to get Atherosclerosis. The second person has exactly the same "normal" LDL cholesterol of 120mg/dl, but it is transported through the blood in 120 small LDL particles. There is no doubt that the second person has had untreated high cholesterol for years because the patient and the physician thought it was "normal".

Years of untreated high cholesterol (high LDL particle number) leads to Atherosclerosis and ultimately Cardiovascular Disease and maybe even death. For a more in depth discussion, you can go to my website at http://www.lipidcenter.com/ and click on the power point presentation titled Advanced Cholesterol Testing - A Basic Understanding.

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The Safety of Lipid Therapy: Statins

2007-12-06T09:31:00.000-05:00

A question I am always asked is "Are statins safe?" In the next series of posts, I will cover this topic and also discuss the safety of all the different classes of drugs used in lipid management.

Many patients and physicians have questioned the safety of statins. These concerns have arisen from information in the news and print media, on the internet, and from direct-to-consumer advertising. Unfortunately, much of the factual evidence is either overlooked or unknown. Because of this 'misinformation', many patients refuse to initiate statin therapy and others stop long term treatment out of fear for their safety.

To address these concerns about the safety of lipid modulating drugs, The National Lipid Association appointed a Safety Assessment Task Force to evaluate statin safety and in a second report, the safety of nonstatin lipid altering drugs. The charge given to this task force was to conduct a "rigorous, scholarly, up-to-date, and unbiased assessment."

Four panels were assembled which focused on the muscle, liver, renal, and neurological effects of statins. To assure a rigorous comprehensive assessment of statin safety, the Task Force further commissioned reviews of special literature on adverse reactions and drug interactions. Reports of the work included an "up-to-the-minute" systematic review of published cohort and clinical trial data on statin safety, the most recent data from the FDA's AERS, an inspection of the data contained in the new drug applications, and the FDA's summary basis of approvals for marketed statins and associated adverse health events in a 22 million person managed health care data base.

The Task Force report on statin safety was published in April 2006 in The American Journal of Cardiology; the report on nonstatin safety was published in the same journal in March 2007. To me, this is the most comprehensive, evidence-based, unbiased assessment of all these drugs, and the guidelines should be followed by all physicians and their patients.

Now a little background. Cardiovascular disease continues to be an epidemic and is responsible for more than half of all deaths in the United States. Each day more than 2600 Americans die from cardiovascular disease. Approximately 80 million American are affected by CVD and more than 125 million lipid panels are performed annually. Despite the increase in cholesterol testing, the number of Americans affected with CVD continues to rise. Why is that? (In subsequent posts I will cover the reason why I believe this is happening.)

Abnormal lipids (Dyslipidemia) is well established as one of the strongest independent predictors of CV morbidity and mortality. There have been large outcome trials that have consistently shown that lowering LDL cholesterol reduces morbidity and mortality associated with coronary heart disease. As the data continues to accumulate, the notion that "lower is better" has uniformly been supported.

As a result of 5 large clinical trials, the National Cholesterol Education Panel (NCEP) Adult Treatment Panel (ATP) III has recognized this and new guidelines recommend further reducing the goal for the LDL cholesterol to less than 70mg/dl in the most high risk patients. You can read the NCEP guidelines on lipid management as well as the newer NCEP guidelines on treatment of the metabolic syndrome on my website.

But despite this new recommendation, the American Heart Association's 2007 statistical update shows that fewer than 20% of patients with CHD have achieved recommended goal levels of LDL cholesterol. In my next post, we will begin to look at the safety of each class of drugs starting with statins.

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Food and Diet: Nutraceuticals, Part 2

2007-11-26T01:00:00.000-05:00

In my first posting, I began a review of "Nutraceuticals" that have been touted in the media as having lipid-lowering properties. We discussed the pros and cons of these supplements and their true impact on lipid levels as supported by good evidence-based medical studies. In part two, we will once again cover other well-known "Nutraceuticals" and their impact on cholesterol management. Certain foods including nuts, soy, and dietary fiber have been reported to lower lipid levels. Other "Nutraceuticals", also known as "functional foods", have been portrayed to have lipid-lowering properties such as garlic, apple-cider vinegar and lecithin.

The FDA recommends that consumption of 1.5 ounces of nuts per day MAY reduce cardiovascular risk. Aside from the fatty acid composition of nuts, other components such as arginine, plant sterols, and phenolic components may play a favorable role in the lowering of lipid levels for those who eat nuts as a regular part of their diet.

Walnuts and almonds have been most comprehensively studied. Most clinical trials evaluating the impact of nuts on lipid profiles have been small scale (10-49 participants). LDL-C (the bad cholesterol) reduction has been consistently shown in these small scale studies, typically in the range of 12-13%. Though less consistent, triglyceride reduction was shown. However, HDL-C (the good cholesterol) generally remained unchanged. One must always remember that these studies are far too small to establish any guidelines and there certainly is not one ounce of outcome data regarding the effect on cardiovascular morbidity and mortality. The American Dietetics Association evidence library concludes that "consumption of 50-113 grams (1/2 cup to 1 cup) of nuts daily with a diet low in saturated fat and cholesterol decreased total cholesterol by 4-21% and LDL-C by 6-29% when weight was not gained."

However, we have to remember that a diet rich in nuts is a heavy caloric load and may lead to weight gain. I recommend somewhat smaller portions of nuts as part of a healthful diet.

There are two kinds of Fiber or Nondigestible Carbohydrates. The first, which is insoluble, aids in bowel function. An example is wheat bran. The second is soluble fiber, now referred to as viscous fiber, which has an additional cholesterol lowering effect. Examples include dried beans, grains, certain fruits and vegetables. Psyllium is a source of soluble fiber and has been shown to augment the lipid lowering response when combined with other lipid lowering medications. Oat products have the most soluble fiber of any grain. Several recent studies have looked specifically at the effects of oats or oat bran on LDL-C. Both oats and oat bran demonstrated favorable results in the lowering of LDL-C. Robitaille's study on overweight pre-menopausal women provided 28 grams of oat bran daily over 4 weeks and not only obtained LDL-C reductions, but also demonstrated an 11.2% increase in HDL-C. In moderately hypercholesterolemic men and women, a study found significant positive results from the consumption of barley. A reduction of 20% in total cholesterol and 24% in LDL-C was obtained in 1 study.

The ATP III (Adult Treatment Panel) recommends a minimum of 5-10 grams a day of total dietary fiber for people with even mildly elevated LDL-C levels but higher intakes of 10-12 grams of fiber per day can be more beneficial in those with more severe hyperlipidemia. In large prospective epidemiological studies, total dietary fiber has been shown to protect against coronary heart disease. These studies examined the relationship between whole grain consumption and CHD.

Researchers found 20-40% reduction in CHD risk for those who habitually consumed whole grains as compared to those who rarely ate whole grains. There are several mechanisms by which it is believed dietary fiber may protect against CHD. They include lowering serum cholesterol and LDL-C, attenuating blood triglyceride levels, and decreasing hypertension. Fiber consumption also predicts insulin levels and weight gain more strongly than a low total fat and saturated fat diet.

High fiber diets may protect against obesity and cardiovascular disease (CVD) by lowering insulin levels. It has been shown that the intake of dietary fiber is inversely correlated with cardiovascular disease risk factors in both sexes. However, most of the evidence shows that a mixture of both soluble and insoluble forms of fiber is an important part of a diet that promotes general good cardiovascular health. Based upon this conclusion, the National Academy of Science recommends 25 grams per day of fiber for women 19-50 years of age and 21 grams per day for women over 50. For men 19-50 years of age, 38 grams per day is recommended and 30 grams for men over 50. This is set from an established 14 grams of fiber per 1,000 calories.

In the last 12 years, Soy has been believed to lower LDL-C. However, recent data has not shown soy to be a practical means to lower LDL-C. In order to achieve any meaningful LDL-C reduction, large amounts of soy are required. Even when individuals consume half their daily protein with soy protein only a very small reduction (3%) in LDL-C is achieved. Soy seems to be a more efficacious lipid-lowering agent in persons with marked hyperlipidemia. It should be noted that reduction in lipids may be due to replacing high-fat animal protein with soy rich foods that may indirectly result in lipid reduction via a reduction in saturated fat intake.

At least 3 well-designed studies failed to document any influence of Garlic on serum lipoproteins. Lecithin is another widely promoted lipid-lowering functional food that is derived from soy beans and sold as a "fat emulsifier". Many people believe that this "emulsifier" actually breaks down fat and cholesterol in the bloodstream. These claims are totally unsubstantiated by any medical literature.

Another promoted cholesterol-lowering remedy is daily a dose of apple-cider vinegar. To date, I have yet to see substantial evidence in the form of any clinical trial evidence that supports these claims.

I have tried to shed some light on the most common "Nutraceuticals" that are promoted to lower lipid levels. I have used solid, evidence-based studies to provide the latest, most accurate information. Perhaps you have found studies on the Internet to support the claims that many of these functional foods will lower cholesterol levels. I would like to bring three important points to your attention:

First, it is important to remember that most of consumer-based literature published has no or little scientific components and are purely retrospective data gathered via questionnaires. Remember, any one can write a paper on any topic and get in published in some type of journal but I can guarantee that none of these journals are "peer review" journals. Second, the Nutraceutical industry is unregulated. It is possible for companies promoting functional foods to fund a study which is designed to show the favorable results they had planned on prior to construction of the study. Finally, what is most important is Outcome Data. This simply means, as a result of the drug or supplement's effect on lipid levels, did that substance affect change that resulted in fewer cardiovascular events and death?

Every week, questions come to me from patients and on my Cholesterol Management message board on WebMD about the use of Statins. Statin drugs are currently the most studied class of drugs and they have changed the face of cardiovascular disease by reducing cardiovascular events by 35-40% in multiple clinical trials.As a Cholesterol Expert, I fully believe it is important to lower cholesterol by any means necessary. My greatest concern for patients and consumers regards the safety of many of the supplements we have discussed. Simply stated, they have not been well studied. Be an informed patient!
When taking any substance, caution should always be exercised. There are many drug interactions with over-the-counter supplements, vitamins and other nutraceuticals and a medical professional well-versed in lipid management should be consulted before considering any drug or non-drug protocol.

Cholesterol Management 101: Nutraceuticals (Part 1)

2007-11-14T13:35:00.000-05:00

I would like to welcome everyone to my new blog dedicated to understanding lipid disorders. Although I will cover many different topics which at times may seem complicated, I will try to explain things in a simplified, yet detailed manner. I like to call it Cholesterol Management 101.

As a cardiothoracic surgeon, the cholesterol medical expert on WebMD, and medical director for the Los Angeles based Center for Cholesterol Management, patients often ask me if they have to take prescription medicines to control cholesterol or can they go to the health food store and buy supplements advertised to do the same thing? Recent data released from various sources suggest that many over-the-counter remedies have lipid-lowering effects. Much of the time, however, these claims are based on poorly conducted clinical trials or no trials at all. Let's talk about four different supplements - guggulipids, policosanol, cinnamon, and red yeast rice extract - and discuss the latest evidence-based literature regarding their true impact on lipid lowering.

Nutraceuticals: Are They Safe and Do They Really Lower Cholesterol? (Part 1)

Guggulipids are found in the arid regions of India and Pakistan, and believed to be the active ingredients in the resin of the commiphora mukul "guggul" tree. This substance is marketed in the US under the name "Guggulipids" as a dietary supplement and is promoted to control cholesterol. The gum resin of the guggul tree has been used in Ayurveda for more than 2,000 years and is believed to have many health benefits including treating obesity. Though there have been numerous studies evaluating the impact of guggul on lipids, these studies have concentrated on the Eastern Indian population. Of the two placebo controlled trials, the study performed in the Indian population found that guggulipids lowered LDL cholesterol by 12%. On the strength of this study, guggul was approved for use in India.

A single study reported in the US was a carefully designed 8-week, double blind randomized, placebo-controlled trial using a parallel design. During this carefully controlled clinical trial, the guggulipids did not lower LDL cholesterol and in fact actually increased LDL cholesterol in the majority of treated patients. Of some concern was the high rate of hypersensitivity rashes (9% of the participants). Interestingly, in both Indian and Western studies, there does appear to be some patients who did respond to guggulipids. The percentage of people responding favorably in the Indian trials suggests that perhaps the Indian population may differ in some basic ways (genetically or environmentally) from the primarily Caucasian population.

Policosanol is a mixture of long-chain primary aliphatic alcohols isolated from sugarcane wax. Policosanol products can also be derived from wheat germ, rice bran and beeswax. The most widely available policosanol product comes from Cuba and is sold as a lipid-lowering product in over 40 countries. Until recently, a single Cuban research group performed nearly all studies conducted on policosanol. These Cuban studies show promise, however, with the recent publication of a number of negative studies outside of Cuba, the beneficial effects of policosanol have been called into question. Overall, recent placebo-controlled trials examining the lipid altering effects of sugarcane-derived policosanol failed to find any significant lipid-altering effects. At the present time, policosanol cannot be recommended for the treatment of hyperlipidemia.

Is cinnamon safe? In 2003 an in-vivo study was concluded on 60 diabetic candidates in Pakistan. The results of this study were released to the Western media and a frenzy of cinnamon capsules were sold in the US and other countries promoting cinnamon's lipid lowering effects. Since that time, numerous studies in Germany and in the Netherlands have been published. The result of these studies differs significantly from the original Pakistani study. Based on the data from these studies, it would appear that the early enthusiasm for cinnamon supplementation might have been premature.

Red yeast rice extract is the fermented product of rice on which red yeast has been grown . The active ingredient in red yeast rice is believed to be Monacolin K, an agent reported to be identical to lovastatin (a commonly prescribed statin). Like statins, red yeast has been found to directly reduce lipids. There is little doubt that the proprietary preparation of red yeast rice, known as Cholestin favorably alters lipids. However, due to legal issues, this preparation is no longer commercially available in the US. In 1998, the FDA determined that red yeast rice did not conform to the definition of a dietary supplement under the 1994 Diet supplement and Health Education Act (DSHEA). This act states that marketed dietary supplements cannot contain a compound already approved as a drug (in this case, lovastatin) unless the substance was available commercially before the drug's approval. At present, Cholestin is still available in Canada, Europe and Asia – however, great caution should be exercised because Cholestin has been reformulated and no longer contains the important Red Yeast Rice extract, but rather polymethoxylated flavones extracted from citrus fruits, geraniol and marine fish oils. It is unclear if this or other proprietary preparations of red yeast extract will provide the same lipid effects. The FDA has issued a warning to consumers regarding three brands of red yeast rice. Follow this link for more information. www.fda.gov and type in red yeast rice in the search box.

When taking any supplement, caution should always be exercised. There are many drug interactions between over-the-counter supplements, vitamins, nutraceuticals, and prescription drugs and a medical professional well-versed in lipid management should be consulted before considering using any type of medicine to lower cholesterol.

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