Lipoprotein (a)

Before we continue our series discussing more lipid-modulating drugs, I want to talk about another topic that I have been asked about frequently on my message board: What is Lp(a) and what can one do for it?

Lipoprotein (a), which is pronounced "little a", is simply an LDL particle to which a protein called apolipoprotein (a) is attached. As I have discussed before in a previous posting about advanced lipoprotein testing, LDL particles are the vehicles that transport cholesterol through the body.

They "drive" the cholesterol into the arterial wall and then the LDL particle becomes a foam cell which is the hallmark of atherosclerosis. Apolipoprotein (a) can also be attached to triglyceride enriched VLDL particles which can also can accelerate plaque formation. Since 90-95% of all the circulating "bad" particles are LDL-P, they become the most important target to modify in order decrease the number of "cars" that move the cholesterol into the arterial wall. So the question remains: If one has an elevated Lp(a), are they at increased risk of a cardiovascular event?

In most epidemiologic studies, the risk of elevated apolipoprotein (a) depends on the LDL cholesterol level. In the large Physicians Health Study, Lp(a) conveyed no risk unless the LDL-C is > 160mg/dl. In the Women's Health Study, Lp(a) was of no risk unless it was very high (>90th percentile) and the LDL cholesterol was also elevated. Thus, elevated Lp(a) in the face of normal cholesterol is not a risk factor.

The proper treatment of elevated Lp(a) is to lower one's bad cholesterol. That means lowering LDL-P or ApoB (or its surrogates - LDL cholesterol and non HDL cholesterol). Although a statin is the primary drug used to treat high cholesterol, they have not been shown to lower Lp(a).

The reason relates to one of the ways a statin works to lower cholesterol. Statins increase the number of receptors made by the liver to bind to the LDL particles. It seems that when apolipoprotein(a) is attached to an LDL particle, it is "camouflaged" from the LDL receptor. Those particles that do not have the apoliporotein (a) attached are cleared in the usual fashion by binding to the LDL receptors. So statins will lower the LDL cholesterol, ApoB, and LDL particle levels but have little to no effect on Lp(a) levels. Despite this, the lowering of the cholesterol carrying particles would greatly lower the clinical risk of a cardiovascular event.

The best way to increase the number of receptors to remove the particles is with a statin, statin/zetia combination, or a bile acid sequestrant( I have had a prior posting on both zetia and bile acid sequestrants).

There are drugs they inhibit the synthesis of apolipoprotein (a) by the liver. These include fibrates, estrogen, evista, and niacin. It is most important to remember that there are no clinical outcome studies relating event reduction to what a drug does to Lp(a). As we have talked about previously, there are numerous studies that have conclusively shown that lowering LDL-C or LDL-P saves lives.

Some people advocate niacin to lower Lp(a) levels, but there is not one ounce of clinical trial data that outcomes would be affected by using niacin to lower Lp(a). As I have said over and over, the name of the game is to lower the LDL-P or ApoB and is still the best way to reduce risk if one has dyslipidemia and high Lp(a).

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Fibrates - Part 2

In my last posting, we began talking about Fibrate therapy and their role in lipid modulation. I want to start out by talking about fibrates and interactions with the kidneys. When the National Lipid Association's Safety Task Force published their recommendations to healthcare professionals in the March 2007 edition of The American Journal of Cardiology, they began by stating that before the initiation of fibrate therapy, the status of one's kidney function should be known.

If significantly impaired renal function is present, the patient should be prescribed Lopid (gemfibrozil), unless taking a statin, or a lower starting dose of Tricor (fenofibrate-48 mg is the most common available dose) should be considered. With impaired kidney function, the periodic monitoring of kidney function is recommended.

Here's why shouldn't you take gemfibrozil while taking a statin. Gemfibrozil increases the likelihood of myopathy (see my posting titled Statins and Muscle) when combined with a statin. Due to pharmacokinetic interactions, gemfibrozil can increase the concentrations of simvistatin, lovastatin, pravastatin, atorvastatin, and rosuvastatin. It has the least effect on the statin called fluvastatin, which is sold under the brand name Lescol.

The evidence shows that if gemfibrozil is necessary, fluvastatin is the appropriate statin option to consider. It baffles me that on a daily basis I see many patients on gemfibrozil combined with all the statins except fluvastatin. Many physicians do not know this fact.

Most insurance company and medicare drug plans are also uninformed because each time I write a prescription for fenofibrate with a statin, it gets denied and it is recommended that I use gemfibrozil. It seems like I spend an hour a couple of days each week writing authorization letters to get my patients on the appropriate drugs. It should be noted that in patients with diabetes, fenofibrate is the safest and most appropriate choice. After the WHO and HHS trials, there was a concern about a possible increase in cancer-related deaths. Ultimately after significant observation, it was deemed to have occurred by chance.

In 2000, a joint ACC/AHA/NHLBI advisory committee on the use and safety of statins reviewed 8 controlled clinical trials of statin-fibrate therapy involving almost 600 patients. This review found that 1% of patients experienced CK levels >3 times the upper limit of normal without muscle symptoms, and 1% withdrew from therapy because of muscle discomfort. No cases rhabdomyolysis were reported. The task force concluded that the combination of a moderately dosed statin with a fibrate "appears to have a relatively low incidence of myopathy, especially when used in persons without multiple-system disease or multiple medications." In conclusion they said that fenofibrate is the preferred option when combined with a statin.

I want to say something about the studies done to support the use of fibrates in lipid management and the reduction of cardiovascular disease and death. One in particular, called the VA-HIT, gemfibrozil was associated with a 22% reduction in death from CAD and a 11% reduction in overall mortality. As I stated in my previous fibrate post, fibrates are recommended and are optimal therapy for patients with high triglycerides and low HDL and the VA-HIT remains the sole trial among other larger fibrate outcome trials to actually study this population group.

In conclusion, the use of gemfibrozil and fenofibrate in patients with abnormal lipids characterized by high triglycerides and low HDL cholesterol in clinical trials demonstrates an improved cardiovascular benefit. In my next posting, we will look at the effect of Niacin on lipid modulation.

Fibrates - Part 1

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Fibrates - Part 1

Fibrates have an important role in treating hypertriglyceridemia, in raising HDL (good cholesterol levels), and in treating patients with diabetes and metabolic syndrome. The two most widely used fibrates are Fenofibrate (Triglide, Tricor, Lofibra, Antara) and Gemfibrozil (Lopid), and Clofibrate (Atromid-S).

The mechanism of action is somewhat complicated. In summary, the main physiologic effect is to reduce VLDL (very low density lipoproteins) which are the main transport vehicle for triglycerides. Triglycerides typically fall 20-70%. They do also lower LDL cholesterol a modest 10% or less but this is not a primary use for the fibrates.

Surprisingly, in patients with very high triglyceride levels, this class of drugs can actually cause LDL cholesterol to rise. HDL cholesterol levels do typically rise. Fenofibrate may be useful for the purpose of LDL reduction with low triglyceride levels when statins, Niaspan, and bile sequestrants cannot be tolerated.

The major side effects of the fibric acid drugs are gallstone disease and abdominal discomfort. In rare cases, myopathy, which I discussed at great length in my posting about statins and the effect on muscles, can occur but usually when it is taken with a statin. While some medical professionals, have reported renal (kidney) dysfunction while on fibrates, this has never been shown to be true.

Although there does exist a case report of fenofibrate associated reversible acute kidney dysfunction in 3 kidney transplant patients, one must remember that transplant patients are on a multitude of drugs which affect kidney function.

Fibrates are, however, infrequently associated with an increase in serum creatinine. Serum creatinine is measured in the blood and is used to measure renal function. Some investigators have found that the source of the creatinine probably reflects and induced elevation of the metabolic production rate of creatinine.

In my next posting, we will talk about the use of fibrates in patients with actual kidney dysfunction or on dialysis prior to their use and also the major studies which have proven their effectiveness and safety as a mainstay of lipid management.

Fibrates - Part 2

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Advanced Cholesterol Testing

I was originally planning on starting to talk about medicines used to lower Triglycerides but due to the untimely death of Tim Russert, I wanted to discuss Advanced Cholesterol Testing. Last week I had the great pleasure of being interviewed on a nationally syndicated radio show. I was asked what I believed could be done to bring more awareness to physicians and the public about the epidemic of Cardiovascular morbidity and mortality? The entire podcast is available on my website and the feedback that I have received from my patients was that I took a difficult topic and made it so easy to understand for the average person. I hope that after listening and reading this posting you will see the need to perform this special type of cholesterol testing.

Over three years ago, I opened The Center for Cholesterol Management as the only free standing lipid clinic in the Los Angeles area dedicated to Advanced Lipoprotein Particle Testing. As a board certified Cardiothoracic surgeon, I feel I have a unique perspective about coronary artery disease in that I am able to clinically correlate angiographic findings with actual operative findings which in so many incidences are discordant. Coronary artery disease is a largely misunderstood entity.

Hyperlipidemia is the most modifiable risk factor leading to Atherosclerosis, yet traditional lipid testing may miss up to 50% of people who have abnormal lipids. Prevention includes identifying people at risk and providing the best treatment individualized to their specific problem.

It is with this background that I will discuss Advanced Lipid Testing and its role in identifying all patients at lipid related risk and as a tool for management of abnormal lipid levels. I often ask myself how come health care providers do not understand this type of testing? I honestly believe that if all people are identified as being at risk, and then if treated appropriately, we would significantly change the face of Cardiovascular morbidity and mortality.

As physicians, we are taught in medical school that it is all about Total Cholesterol, HDL-C, LDL-C, and Triglycerides, yet few really understand the limitations of traditional lipid testing. I hear everyday physicians say that if it is so important why isn't everyone doing it? I believe the answer is that one does not want to change from old patterns of thinking, and according to other physicians, it is too much trouble to learn and understand. Recently, the ADA/ACC released a Joint Concession Statement on Lipoprotein Management in patients with Cardiometabolic Risk(CMR). The full text is available on my website. I believe it is mandatory reading and states that patients with CMR in the moderately high, high, and very high risk groups, it is now the standard of of care to quantify lipoproteins by performing ApoB or LDL-P on all patients to ascertain risk and as a goal of therapy.

As we all know that since sterols are insoluble in the blood, they need to be driven around the body in Lipoproteins. These include HDL-P, VLDL-P, and LDL-P among others. HDL particles are also known as ApoA and all the particles that cause atherosclerosis are known as ApoB. Although NCEP( National Cholesterol Education Panel) recommends calculating the non-HDL cholesterol, this value only can alert the physician that there may too many lipoprotein particles despite having a normal LDL-C. Approximately 90-95% pf the circulating ApoB particles are LDL-P which have a half-life of around 3 days. As varying amounts of Triglycerides and Cholesterol are driven around the body, in what I tell my patients are "cars", the ApoB particles enter the arterial wall if there are too many of the "cars" circulating in the bloodstream.

By simple diffusion, all the bad particles flow from inside the artery and move into its wall and are "eaten" by macrophages which become foam cells and are the hallmark of Atherosclerosis. In eight published studies of over 11,000 subjects using LDL-P and other Lipoprotein concentrations remained the most significant and independent predictor of cardiovascular morbidity and mortality over any other lipid parameter including the usual ratio that all physicians and patients talk about. . In a nutshell, it is the number of LDL particles that matter most... it is the number of cars that cause a traffic jam, not the people in the cars. For example, what if a person with moderate risk has met NCEP guidelines and has a LDL-C of 110mg/dl.

How do I know that there are not 100 cars with one person driving or two big buses with 55 people? The answer is that I do not unless I measure LDL-P directly by using NMR or as a second option measuring ApoB with Gel Electrophoresis. Traditional testing measures the passengers and lipoprotein testing measures the cars, and it is the number of cars(LDL-P) measured by NMR (Nuclear Magnetic Resonance) that are the most numerous ApoB particles in the body and matter most in the development of Atherosclerosis.

Although a comprehensive review of each of the methodologies to perform Lipoprotein Testing is beyond the scope of this post, I feel that measuring LDL particles directly using NMR is the best way to ascertain someone's true risk and then use that number as a guide to management. As I said in my posting about Alex Trebek, the CDC states that 50% of people who have heart attacks have "normal" cholesterol. I hope you now understand why this can happens, having a normal LDL-C but high LDL-P, and be proactive and ask that your physician performs Advanced Cholesterol Testing.

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Lowering LDL Cholesterol: Bile Acid Sequestrants

The next group of Gastrointestinally Active Lipid Lowering Drugs I will talk about are the Bile Acid Sequestrants (BASs). Like Zetia, this class of drugs works in the intestines. They have been used since the 1960s. Since they are not absorbed into the body they are inherently safe and also safe during pregnancy.

They are a good class of drugs for young adults contemplating a potential lifetime of exposure to a medication and are the only class of drugs recommended by NCEP for use in children. The three most common adverse events that have been reported are constipation, rarely leading to obstruction, increase in plasma triglyceride levels, and decrease absorption of some medicines and certain vitamins. The newest agent, Colesevelam (Welchol)-available as a tablet, has greater affinity for bile acids compared with the older medicines such as Cholestyramine(Questran)-available as a powder, so it has fewer drug interactions and is less likely to cause constipation.

The main problem with this class of drugs for patients with hypercholesterolemia can be the taste, the amount that needs to be taken, and the bloating and constipation. I tell my patients to take a stool softener while on this class of drugs or to drink prune juice. Since the development of Welchol and the improved gastrointestinal tolerance, more patients are willing to take BASs. In an analysis of 3 randomized, placebo-controlled trials of Welchol added to statin therapy, constipation was only reported in less than 10% of patients and less than 5% withdrew secondary to side effects.

These classes of drugs are anion-exchangers and cause increased clearance of LDL-C from the blood. As I said previously, they work in the intestines by binding bile acids, and thus, interrupt the circulation of bile acids back to the liver. Since there is less bile acid available, cholesterol is converted to bile acid and the concentration of cholesterol within the liver falls. As this happens, LDL receptor activity of the liver cell increases which then increases LDL clearance from the blood.

The largest set of data on Bile Acid Sequestrants comes from the Lipid Research Clinics Coronary Primary Prevention Trial (LRC-CPPT). Reduction in coronary risk corresponded to LDL-C reduction. When the maximum dose of 24 grams/day of Cholestyramine was used, there was 28% reduction in LDL-C and a 39% reduction in CHD risk. The BASs have been used alone or in combination with other lipid lowering medications in one major trial with a clinical endpoint and in five with angiographic endpoints.

BASs should be avoided in patients with TGs greater than 400mg/dl because they tend to raise TG levels. If it is be used in combination with medicines to lower TGs, this is not a major concern but if used alone should only be used if one's TG level is less than 200mg/dl.

Finally, due to potential drug interactions, coumadin, thiazide diuretics, propanolol, tetracycline, penicillin G, phenobarbital, thyroid preparations, estrogens, progestins, and digoxin should be administered one hour before or four hours after taking the older BAS agents. The current evidence has shown that Welchol can be taken concurrently with these medicines. The next class of drugs we will explore in the coming weeks will be fibrates.

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Lipid Control with Zetia (Ezetimibe)

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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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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