STATINS There is no such thing as too low a cholesterol level

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1 Statins are a category of drugs that we use to lower elevated cholesterol levels. In the April 8, 2004 edition of the New England Journal of Medicine, an editorial reviewed some history regarding the use of statin drugs and their benefits for lowering cholesterol levels and for improving survival. The editorial described a 2002 study that had shown a 25% reduction in coronary events noted when patients with a normal baseline LDL cholesterol level below 100" were treated with statins. Typically their LDL cholesterol levels fell by an average of 40 milligrams. Patients with normal baseline LDL levels received just as much benefit as those who started with high LDL cholesterol levels. HDL begins with an H. You want it to be high. The higher the HDL, the lower the risk for heart attacks. An HDL of 60 or higher is great. LDL begins with an L. You want it to be low. Just a few years ago, the target LDL level was 130. Today, for a patient with known coronary artery disease, the target LDL is around 60. The editorial pointed out that the benefit of statins was not limited just to lowering cholesterol levels. Statins are thought to have favorable effects in a number of diseases, including neurodegenerative disorders such as Alzheimer s disease and multiple sclerosis; also in nonischemic cardiomyopathy (a form of weak heart muscles). They also help to prevent bone fractures, and have been reported to reduce the incidence of some types of cancers. It is thought that favorable anti-inflammatory effects from statins explain these additional benefits. The statin drug and dose found most effective was Lipitor, 80 milligrams per day. This resulted in maximum benefit. This is the dose that Compassionate Oncology usually recommends, but we start patients on a lower dose and later raise the dose if tolerated. This same study had been presented at the American College of Cardiology Meeting in March The authors summarized their results: There is no such thing as too low a cholesterol level. This is the major conclusion to remember. Based on these new findings, all 64 million

2 Page 2 Americans with heart disease should almost without exception consider taking statins. This particular study involved 4,162 heart attack victims at 349 hospitals in eight countries who were randomized and treated with either fulldose Lipitor or full-dose Pravachol. At this March Cardiology Meeting, the authors reported that in addition to lowering cholesterol levels, statins reduce inflammation in coronary arteries, protect against weakening of the heart s ventricles, and decrease over-activity of the sympathetic nervous system; each one of these beneficial effects reduces the likelihood for having a subsequent heart attack. Most importantly, statins reduced the risk of having heart attacks and strokes even in patients who did not have elevated cholesterol levels prior to starting treatment. This is why they conclude that virtually everyone with heart disease should be taking a statin. The data presented showed that when patients were treated with the maximum FDA approved Pravachol dose of 40 milligrams per day, LDL levels decreased approximately 25% to an average of 95. Using Lipitor in the maximum FDA approved dose of 80 milligrams per day, LDL levels fell to an average of 62. Over a period of two and one-half years, the patients receiving Lipitor were 16% less likely to suffer chest pain, to have a heart attack, stroke, require angioplasty or bypass, or die. The chances of dying from any cause were reduced by 28% for those taking Lipitor compared to those patients treated with Pravachol. Women benefitted from the drugs even more than men. Remarkably, the benefits were already observed within the first 30 days of the study. This extremely short interval to achieve a statistically significant benefit has never been seen in any prior study of statins. This demonstrates that this treatment was remarkably more effective than previously believed possible. In addition, benefits were sustained over the entire study period proving that the benefit seen in the first month was not an anomaly. The side effects observed from these higher doses compared to lower doses were about equal. Approximately 3% of the patients had to have their medication discontinued, primarily because of elevated liver blood tests. When you discontinue statins, the abnormal liver blood tests promptly return to normal. Compassionate Oncology has never seen any patient develop permanent abnormal liver blood tests from using Lipitor. Remember, your liver is the only organ in your body that is

3 Page 3 like a tadpole. You can remove up to 85% of the liver and the remaining 15% can regenerate and fully restore itself. While on statins it is essential to have your blood tests monitored frequently. There is no such thing as too low a cholesterol level. Always remember to discuss this and all of our recommendations with your primary care doctor. The most commonly prescribed statins are Lipitor (atorvastatin), Zocor (simvastatin), Mevacor (lovastatin), Pravachol (pravastatin), and Lescol (fluvastatin). In October 2003, a new statin, Crestor (rosuvastatin) became commercially available. In November 2004, one doctor included Crestor as one of five drugs that he thought might be considered dangerous. In 2005, a study confirmed that Crestor was not as safe to use as another statin. Compassionate Oncology continues to recommend Lipitor for all statin users unless a patient is allergic to it. Can Statins Have Anticancer Benefits? Some articles describe how statins may help to control cancer. In the Journal of the National Cancer Institute, Volume 95, Number 12, June 18, 2003, pages , the authors report that statins have an anticancer benefit that involves a second completely separate mechanism different from their cholesterol lowering effects. Statins lower cholesterol levels by blocking an enzyme, HMG-CaA reductase. This process requires a statin to be converted from an inactive form to its active form. However, not all of the statin in your blood is converted to its active form. The remaining unconverted quantity of statin inhibits cancer growth. One anticancer mechanism that may be involved is activation of the proteosome. When activated, proteosome seems to stop unregulated cell growth that is a characteristic of cancer cells. Statins prevent proteosome activation. Without proteosome the cell cycle brakes (p21 and p27) are not degraded. Active p21 and p27 remain in the cell significantly longer, and can continue to function as brakes, thereby stopping unregulated growth of cancer cells. In the lab, statins are not just cytostatic. This means they do not simply stop cancer cells from growing, but can cause cancer cells to die (cytotoxic). In lab studies, they prevent metastases from developing, and help prevent normal

4 Page 4 tissue invasion by cancer cells. High doses of statins can cause programmed cancer cell death, also termed apoptosis. In the lab, statins also have direct inhibitory effects on breast cancer cell lines. Other types of malignant cell growth cells inhibited by statins include acute myeloid leukemia cells, multiple myeloma cells, squamous cell carcinoma cells, lung cancer cells, lymphoma, melanoma, and colon cancer cells. Some of these anticancer benefits have already been proven in vivo, which means in animal models. Statin effects are amplified when combined with chemotherapy, radiation therapy, or certain products that affect other cancer growth factors or growth receptors. In the August 2003 Urology Times, page 26, an article reports on a Dutch study presented at the American Society of Clinical Oncology Meeting in May This was a 13 year study, and compared the use of statins between 3,219 patients with cancer, and 16,976 patients without. The 13 year period was from 1985 to After controlling for all known prognostic factors, it was found that cholesterollowering statin drugs may reduce the risk of prostate and kidney cancer by 20%. Overall, the reduction in risk for developing any type of cancer was 36%. The investigators also noted that a patient s risk of developing cancer returned to baseline six months after stopping statins. This means you need to remain on statins or the anticancer benefits stop. Dr. Jane Cauley, during an American Society of Clinical Oncology meeting in 2001, reported that statins seemed to lower the risk of breast cancer. In an article published in the October 2003 Journal of Women s Health, Dr. Cauley describes her study that involved 7,500 Caucasian women in four cities, who had an average age of 77. Older age places women in a higher risk group for developing breast cancer. After seven years of study, the women taking statins had a 68% lower risk of developing breast cancer, compared to women who did not take these drugs. The author states that much work still needs to be done in order to confirm these findings, but the evidence is certainly provocative, and can give someone with cancer additional motivation for using a statin to treat their elevated cholesterol levels. Doctors are not yet recommending statins only to reduce the risk of cancer, but if you have an elevated level of cholesterol, statins reduce the risk for developing cardiovascular

5 Page 5 complications and, at the same time, may help control cancer as well. Like any medication, statins have well-known side effects, and you should consult your primary care physician for additional information. A small trial of statins in patients with refractory blood cancers has actually shown some signs of beneficial anticancer activity. Treatment with only a statin resulted in a measurable clinical improvement for some of these patients. This proves that statins benefit patients with cancer, not just laboratory petri dishes. An additional benefit of statins was reported in the Proceedings of the American Society of Clinical Oncology; Volume 23; 2004, a study by Poynter, J.N., et al., which found that use of statins reduces the risk of developing colorectal cancer by 51%. This was published in May 2005 in the New England Journal of Medicine. Since cholesterollowering agents other than statins did not lower the risk for developing colorectal cancer, the benefits from statins involve cell mechanisms different than inhibition of HMG reductase. At the 2005 American Association for Cancer Research Annual Meeting, Dr. Elizabeth Platz from Johns Hopkins, reported that men taking statins reduce their risk of developing advanced prostate cancer by about half, and this effect seems to be cumulative, so the longer men take statins, the lower the risk of advanced prostate cancer. She was reporting in the Health Professionals Follow-Up Study, which is a study involving more than 34,000 doctors, dentists, and veterinarians. She stated that the use of statins reduced the risk of metastatic prostate cancer, or prostate cancer mortality, or both, by MORE THAN 65%. The findings suggest that statins may change the natural history of prostate cancer. Dr. Platz explained that this study did not show that statins prevent prostate cancer, but seem to work by slowing disease progression. At the time the study started in 1990, all 34,000+ men were prostate cancer free. By the year 2000, prostate cancer had developed in 2,074 of the men. This was the first study to

6 Page 6 report an association between prostate cancer stage and statin use. There were no associations between statin use and total prostate cancer risk, or localized prostate cancer risk, but the 65% reduction in risk of developing metastatic prostate cancer, or death from prostate cancer, is truly remarkable. This report is just one of many recent observational studies that suggest a role for statins in preventing cancer. At the 2004 ASCO Meeting, use of statins was associated with a 51% reduction in risk of colon cancer. At the 2003 ASCO Meeting, researchers from the Netherlands reported that statin use was associated with a 36% reduction in the risk of developing prostate and kidney cancers. This information should be especially significant for Asians who had listened to health newsletters, advisories, companies that promise to extend life, and other pseudoscientific publications that have been advising you not to take statins. You should recognize how dangerous it is to read and then follow the advice in these types of publications. Please do not allow yourself to be deceived by these newsletters that are trying to convince you not to take Lipitor, but instead use the natural product they describe, and it just so happens that they can sell it to you. You need to recognize that their papers are nothing more than informationals that they send to you in order to sell their products. Numerous prospective randomized studies have clearly shown that Lipitor prolongs life in patients with heart disease, even if they started with normal cholesterol levels. In addition to the cardiovascular benefits, the reader is now able to appreciate that Lipitor and other statins are being found to have very substantial and impressive anticancer benefits. For those of you who have avoided using Lipitor, believing that you were somehow helping yourself, you should realize how much benefit you have been denied. Statin Cardiovascular Benefits Unrelated to Reducing Cholesterol Levels:

7 Page 7 Statins reduce inflammation in the walls of blood vessels. Cholesterol plaques will not accumulate in arterial blood vessels without a local inflammatory component already in the vessel wall. Lipitor reduces this type of inflammation. It is possible that Lipitor may be the only statin proven to possess this anti-inflammatory capability. We used to believe that cholesterol stuck to the wall of an artery and was the major cause for blockage of arteries. We now understand that first an inflammatory reaction occurs in the arterial wall, and later cholesterol binds to that inflammatory site. This ultimately causes a blocked artery which results in a heart attack, stroke, or other vascular event. We have all been taught that an aspirin a day (we advise one baby-strength Ecotrin with food) helps to prevent a subsequent heart attack. It does so by blocking the inflammatory reaction in the blood vessel wall.

8 It is the opinion of Compassionate Oncology that patients with elevated LDL cholesterol levels, even without known cardiac disease or prior heart attack, should strongly consider the new LDL guidelines, which state: There is no such thing as too low a cholesterol. LDL levels of 60 to 70 may be ideal for patients with known coronary artery disease. We never advise a higher dose of statin than what is FDA approved. Besides lowering total and LDL levels, Lipitor increases the so-called good cholesterol (HDL), and usually lowers triglyceride levels as well, although the effects on HDL and triglycerides are not nearly as dramatic as the falls in total and LDL cholesterol levels. However, raising HDL and lowering elevated triglyceride levels are independently beneficial, and reduce the risk for subsequent cardiac events. All patients treated with any statin drug should immediately tell their primary care doctor if they develop muscle pain and/or weakness. You should discontinue your statin until discussed with your doctor. While on treatment, it is necessary to have liver function and kidney function blood tests monitored regularly. Hopefully, this section explains why experts conclude that we have entered a new era of intense statin therapy, and Compassionate Oncology agrees with lower LDL target levels. Dr. Bob believes that patients who have less pre-existing cardiovascular disease will benefit by lowering LDL levels to around 60 or 70. Although the New England Journal of Medicine study was limited to patients with known coronary events, we believe that when a medication works well in advanced disease, it virtually always works far better in less advanced disease. This is our opinion only, not yet proven. Therefore, we would not wait for a patient to have a heart attack before recommending that our patients with known coronary artery disease and/or elevated LDL cholesterol levels be treated with Lipitor. Dr. Bob has used and championed this same philosophy for treating prostate cancer patients. We believe that using your best prostate cancer medications early and up-front is the most effective way to help to control prostate cancer cells, and not allow prostate cancer the time to grow, mutate, become more aggressive, metastasize, and become incurable.

9 Page 9 As always, discuss any medication with your primary care physician. As always Be happy, Be well, Live long and prosper, DR. BOB Triple hormone blockade, triple androgen blockade, and finasteride maintenance are the registered trademarks of Robert L. Leibowitz, M.D. ADDENDUM #1-8/30/05 In the September 1, 2005 issue of the American Journal of Cardiology, 2005; 96: , by Fonarow, G., et al. The authors report that statin use (Lipitor, Zocor, Pravachol, Crestor, and Mevacor are statins) early after hospitalization for myocardial infarction was extraordinarily beneficial. If a patient took a statin drug within 24 hours of having a heart attack, his risk of inhospital death was reduced by slightly more than 50%. The authors compared the records of in-hospital events for 17,118 patients who had received a statin prior to the hospitalization for their heart attack; 21,978 patients who were given statins within the first 24 hours in the hospital; 126,128 patients who did not receive statins, and 9,411 patients whose statin therapy was discontinued. Besides reducing heart attack mortality, the use of statins was also associated with a lower risk of cardiogenic shock, ventricular fibrillation, cardiac arrest, and cardiac rupture. The authors were surprised that early statin therapy showed such striking effect immediately after a heart attack. This study confirms the enormous cardiovascular benefits that result from treatment with a statin. Dr. Bob strongly believes that the best statin is Lipitor.

10 Page 10 ADDENDUM #2-10/11/05 In 2005, a number of studies have reported that the use of statins is associated with a reduced risk of developing a number of different cancers. I have previously commented on the reduced risk of developing prostate and colon cancers. The September 10, 2005 edition of Oncology Times, pages 23-24, reported on one study involving more than 484,000 patients at Pennsylvania Medical Centers. The use of statins was associated with a 59% reduced incidence for developing pancreatic cancer. In the same study, the use of statins was associated with a 56% reduced incidence for developing esophageal cancer. This was a retrospective study, also known as observational. Nevertheless, the findings are striking. ** None of the above should be construed as medical advice or consultation, and anything discussed in this paper is meant for information only. All medical treatments, consultations, decisions and recommendations can only be made by the patient and his/her treating physician.

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