STATINS CUT HEART ATTACK RISK EVEN WITH NORMAL CHOLESTEROL LEVELS

The cholesterol-lowering statin drugs have become one of the most commonly prescribed classes of medications in the world, and nearly 20 million patients have been prescribed statins in the United States alone.  The statins block a critical enzyme (HMGCoA reductase) that is required for the manufacture of cholesterol in our bodies.  An extensive body of clinical research has shown that statins can significantly reduce the risk of heart attack and stroke in patients with high levels of the “bad cholesterol,” LDL.  There is also some research evidence that patients with LDL levels in the high-normal range may benefit from statin medications as well (it should be remembered that nearly half of all heart attacks and strokes occur in patients who have normal LDL cholesterol levels).  Now, a new study, published online in the New England Journal of Medicine, strongly suggests that statin drugs may also significantly decrease the risk of coronary artery disease, heart attack, stroke, and death from all of these diseases, in at least some patients with completely normal LDL cholesterol levels.

This newly published prospective, randomized, placebo-controlled research study, and referred to as the JUPITER study, enrolled nearly 18,000 adults in the United States and in other countries, and was supposed to have lasted for 5 years.  Because the study’s researchers noted such striking benefits during a recent interim analysis of the study’s data, the JUPITER study was prematurely terminated in March of this year, only 2 years after the study was initiated.

There are several unique and clinically important aspects of this clinical study to be considered.  First unlike many of the previously published clinical studies looking at statins, the JUPITER study included large numbers of women, African-Americans and Hispanics, and the study confirmed that all of these groups appeared to benefit from treatment with statin drugs.  The other important difference in this study is that the volunteer patients participating in this clinical study all had normal total cholesterol and LDL cholesterol levels in their blood.  However, these patients also had abnormally high levels of C-reactive protein (CRP) in their blood. 

CRP is a protein that is manufactured primarily in the liver, and is a marker of both acute and chronic inflammation.  Many cardiovascular disease experts believe that coronary artery disease, peripheral vascular disease and some types of stroke are all associated with chronic inflammation occurring within diseased blood vessels.  CRP has been shown, in some research studies, to act as a marker for cardiovascular disease, especially in patients with elevated cholesterol levels (although elevated LDL cholesterol levels are thought to be more predictive of cardiovascular disease risk than elevated CRP levels).

In the JUPITER study, volunteer patients were randomized to receive either Crestor, a relatively new statin drug, or a placebo (sugar pill).  Neither the patient volunteers nor the researchers knew which pill each patient was randomized to receive.  (Randomized “double-blinded” prospective studies, such as this one, are generally accepted as the most accurate way of validating the effects of new treatments.) 

At the point when this study was prematurely halted, the collected data revealed that the patients receiving the statin drug Crestor, when compared to the patients receiving a placebo, experienced a 55 percent reduction in the risk of heart attack and a 48 percent decrease in the risk of stroke.  Overall, the risk of experiencing a major heart attack, stroke, or death from any cardiovascular disease was reduced by 47 percent in the group of volunteer patients who received Crestor.  The patients who were randomized to receive Crestor experienced, on average, a 50 percent reduction in LDL cholesterol blood levels and a 37 percent reduction in CRP blood levels.  It is very important to point out that the JUPITER study’s patient volunteers better represented the general population in terms of age, gender and race than most of the previously published statin studies, and all of these various subgroups of patients appeared to benefit equally from statin therapy.  

The results of this study are likely to significantly change the existing guidelines for the use of statins in cardiovascular disease prevention, as many of the patients in the JUPITER trial who appeared to benefit from statin therapy would be considered, by current guidelines, to be at relatively low risk for cardiovascular disease (e.g., based upon their age, weight, smoking history, family history, cholesterol levels, and the presence or absence of high blood pressure).  Indeed, many of the JUPITER study patients would not be candidates for statin medications under the current clinical guidelines for the use of these potent drugs.  

At the present time, CRP is not routinely used to screen for cardiovascular disease in the asymptomatic population.  Thus, this study raises the additional question as to whether or not CRP levels should be regularly measured, in addition to cholesterol and triglyceride levels, as part of routine cardiovascular disease screening.  Certainly, the results of this study would suggest that CRP levels should probably be checked more frequently, particularly in patients who do not have other apparent risk factors for cardiovascular disease, such as advanced age, a history of smoking, obesity, diabetes, hypertension, sedentary lifestyle or elevated levels of total and LDL cholesterol.  Based upon the entry criteria for the JUPITER study, men at or above the age of 50 and women at or above the age of 60 who have a CRP blood level greater than 2.0 milligrams per liter should at least be considered for statin therapy, even if their cholesterol levels are within the normal range.  (It should also be noted that CRP levels can become elevated at any single point in time for a variety of reasons, including periods of acute illness and infection, and so single measurements of CRP may therefore not accurately reflect an individual’s risk of cardiovascular disease over the long-term.)

Whether or not everyone should be considered for statin therapy is unclear at this time, and another large scale prospective, randomized, placebo-controlled, double-blinded study, like the JUPITER study, will be necessary to answer this question.  It should also be remembered that statins, like most drugs, are associated with a small but significant risk of potentially serious side effects.  In a small percentage of patients, statin drugs have been associated with serious liver, muscle and kidney toxicity, and all patients who are started on statin drugs must be carefully followed by their physicians for any evidence of these potential complications of statin therapy.

Finally, it is important to note that this study was funded by the manufacturer of Crestor (AstraZeneca).  As I have previously warned, clinical research studies that are conducted with funding from “interested parties” must always be viewed with a critical eye.  As this is an increasingly more common phenomenon, however, as government sources of research funding continue to shrink, it has become impossible to simply reject the findings of all “industry-sponsored” research studies.  In the case of the JUPITER study, the authors have filed disclosures indicating that AstraZeneca was completely excluded from all data collection and data analysis, and from the writing of the study’s soon-to-be published manuscript.

 

STATINS & PSA LEVEL

As the previous study indicates, the clinical role of statin drugs has grown tremendously over the past few years as, increasingly, clinical research studies continue to reveal their potential to reduce death and disability from life-threatening cardiovascular diseases.  However, some experts have proposed that statins may possess other potential health benefits beyond the reduction of cardiovascular diseases alone.  While the data on statins as cancer prevention drugs has been very contradictory thus far, some (but not all) studies have suggested that statins might also reduce the risk of prostate cancer.  Now, a new clinical study, just published in the Journal of the National Cancer Institute, suggests yet another possible prostate-related effect of statin drugs.

In this study, more than 1200 male veterans, all of whom were taking statin drugs for elevated LDL cholesterol, were followed between 1990 and 2006 at the Durham, North Carolina, Veterans Affairs Medical Center.  At the time of their entry into this study, none of these men, with an average age of 60 years, had a history of any previous prostate gland diseases, including prostate cancer.  All of the men underwent testing of their blood prostate-specific antigen (PSA) levels both prior to and following the initiation of statin therapy.

On average, LDL cholesterol levels decreased by 28 percent after beginning treatment with statin drugs.  Interestingly, PSA levels also declined after these men began taking statins and, moreover, the greatest reductions in PSA levels were observed in the men who also had the largest reductions in their LDL cholesterol levels.  Among the men who experienced the largest reduction in LDL cholesterol levels, after initiating statin therapy, a 17 percent reduction in blood PSA levels was observed.

Currently, the measurement of blood PSA levels is an important part of routine screening for prostate cancer, and elevated levels of this protein generally indicate the need to perform biopsies of the prostate gland to rule-out cancer.  The results of this study, therefore, raise the concern that early cases of prostate cancer might conceivably be missed in men who are taking statins, as mildly-to-moderately elevated levels of PSA might be suppressed by long-term statin use.  Whether or not statin-associated reductions in PSA levels might actually be associated with a lower risk of prostate cancer was beyond the scope of this study, and so further prospective randomized clinical trials with statin drugs and placebos must be completed before any claims can be made that statins reduce the risk of prostate cancer.  For now, however, the results of this limited observational research study suggest the need for caution when interpreting PSA results in men who are taking statins.  Certainly, men with a family history of prostate cancer (and at an early age, in particular), and African-American men, should advise their physicians about the results of this research study if they are currently taking statin drugs, and these high-risk men should be carefully monitored for other signs and symptoms of prostate cancer, in addition to PSA levels.  In such cases, a low threshold to perform biopsies of the prostate gland should at least be considered.

 

Dr. Wascher is an oncologic surgeon, professor of surgery, a widely published author, and the Director of the Division of Surgical Oncology at Newark Beth Israel Medical Center:

http://www.sbhcs.com/hospitals/newark_beth_israel/mservices/oncology/surgical.html

Send your feedback to Dr. Wascher at:  rwascher@doctorwascher.net
 

To read more of Dr. Wascher’s Health Report columns, please visit his

website at:  http://doctorwascher.com

Copyright 2008.  Robert A. Wascher, MD, FACS.  

All rights reserved.

 

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The more that we understand about how Vitamin D works in the body, the greater becomes our appreciation of its myriad health-related effects.  Previously, this essential vitamin was considered primarily in terms of its important role in the absorption of calcium.  (Calcium not only provides strength for our bones, but also plays a critical role as a cofactor in thousands of vital chemical reactions occurring in every cell in our body.)  Unique among vitamins, our bodies can actually create Vitamin D as a result of exposure to natural sunlight.  However, variations in exposure to sunlight and in skin pigmentation, and in the availability of adequate Vitamin D in our diets, results in wide variations in the level of the active form of Vitamin D in the blood of individuals.  Because of these variations, an estimated one-third to one-half of all adults, and especially older adults, have low blood levels of this crucial vitamin.

Two new studies add further scientific evidence strongly suggesting that Vitamin D may also be important in maintaining a healthy cardiovascular system, and in reducing the risk of developing at least some forms of cancer. 

In the journal Circulation, researchers from the famed Framingham Heart Study evaluated more than 1,700 adults, with an average age of 59, and without a prior history of cardiovascular disease (except for high blood pressure).  During more than 5 years of follow-up, on average, the incidence of cardiovascular events was tracked in these research study volunteers, and these cardiovascular events were then correlated with Vitamin D levels in the blood of the same participants.  The cardiovascular events tracked in this study included the new onset of cardiac chest pain (angina), heart attacks, heart failure, strokes, and leg pain due to inadequate blood supply.  

During the course of this study, 120 volunteers experienced a new cardiovascular event.  Interestingly, study volunteers with high blood pressure appeared to experience significant cardiovascular protection from high levels of Vitamin D in their blood, while patients without hypertension did not.  Among the volunteer patients with high blood pressure, those with the lowest levels of Vitamin D in their blood experienced more than twice as many serious cardiovascular events when compared with hypertensive patients who had the highest levels of Vitamin D in their blood. 

Recent research has suggested that chronic Vitamin D deficiency may be associated with increased blood pressure, enlargement of the heart, and an increase in the levels of chemicals in the blood that are associated with inflammation.  Vitamin D supplementation, in small research trials, appears to be able to improve these adverse effects of Vitamin D deficiency.  However, to actually verify that Vitamin D supplementation can reduce the risk of cardiovascular events in patients with high blood pressure, it will be necessary to follow this excellent Framingham Heart Study research trial with another study that randomizes hypertensive, Vitamin-D-deficient volunteers between Vitamin D pills and placebo pills (“sugar pills”).  Only then will we be able to clarify the true role of Vitamin D deficiency (and supplementation) in cardiovascular disease and health.  Meanwhile, it would seem prudent to make sure that your diet contains adequate daily levels of Vitamin D, and that you avail yourself to reasonable (though not excessive) levels of sun exposure, especially if you have hypertension.  (If you are fair-skinned, then please observe the present recommendations regarding safe exposure levels to the sun’s rays.)  Of course, please check with your personal physician first, before embarking upon any major changes in diet or dietary supplements, or any other major lifestyle changes. 

VITAMIN D & BREAST CANCER RISK

There have been a number of studies suggesting that higher levels of Vitamin D in the blood may be associated with a somewhat decreased risk of developing certain cancers.  The data for the possible anti-cancer effects of Vitamin D has been most pronounced for colon and rectal cancer, although not all studies have confirmed this beneficial health effect for Vitamin D.  Other studies have also suggested that increased Vitamin D intake may be associated with a modest reduction in the risk of developing breast cancer, as well.  Most of these studies, however, have relied upon surveys in which study volunteers have estimated their dietary Vitamin D intake, a method of research that is subject to significant potential inaccuracies.  A new study from Germany, just published in the journal Carcinogenesis, has taken a scientific approach similar to the study of Vitamin D’s effect on cardiovascular health that I have just reviewed (above).

In this study, two groups of postmenopausal women, each numbering almost 1.400 in size, were evaluated.  One group consisted of women who had been diagnosed with breast cancer between 2002 and 2005, while the second group consisted of age-matched women without a prior history of breast cancer.  The level of Vitamin D was measured in all of these study volunteers, and then correlated with the presence or absence of a history of breast cancer. 

When comparing the women with the highest blood levels of Vitamin D against the women with the lowest levels, the results were rather striking.  Having the highest levels of Vitamin D in the blood was associated with a nearly 70% reduction in the risk of breast cancer, in this population of Northern European women, when compared to similar women with low Vitamin D levels.  Because this research study directly measured levels of Vitamin D in the blood, the results are not dependent upon the subjective recollections of study participants.  One limitation of this study, however, is that it does not completely prove that Vitamin D deficiency alone is directly causing an increased risk of breast cancer.  As I have already mentioned, the absorption of Vitamin D, and the regulation of its level in the blood, are controlled by highly complex biochemical mechanisms.  There may be other factors at work that simultaneously increase the risk for breast cancer and decrease the levels of Vitamin D in the blood (i.e., this is the critically important difference between a “cause-and-effect” relationship, on the one hand, and a mere “association” between two unrelated processes or events, on the other hand).

Once again, the next logical step in this area of study would be to perform a new clinical study in which postmenopausal women with low levels of Vitamin D in the blood were randomized between high-dose Vitamin D supplements and placebo pills, and were then followed for at least 5 years.  Only this type of study would definitively answer the question of whether of not Vitamin D deficiency, by itself, increases the risk of developing breast cancer after menopause.  
 

GREEN TEA & COLON AND RECTAL CANCER

Much has been written about the potential health benefits of green tea, and especially the antioxidant polyphenols contained within this ancient beverage.  As in most areas of cancer research, conflicting results have been published regarding the role of green tea polyphenols as potential cancer prevention aids.  Certainly, however, there is ample laboratory data (in cell cultures and in animal models) suggesting that green tea polyphenols may be able to block key mechanisms of cancer cell development.

A new study, also just published in the journal Carcinogenesis, adds to the growing body of data suggesting that green tea polyphenols can indeed block critical cancer-causing biochemical pathways, at least in laboratory rats.

In this research study, laboratory rats were used to assess the effects of green tea polyphenols in the prevention of colorectal cancer.  The rats were injected with azoxymethane, a chemical known to induce colon cancer in rats fed a high-fat diet.  The rats were divided into 3 groups, with 2 groups receiving green tea dietary supplements (either low-dose or high-dose supplementation), and a third group that received no green tea supplementation in their diet.  At the end of the study, the animals were euthanized, and the cells lining their colons were then examined under a microscope for changes consistent with an early transition to colon cancer.

The researchers in this study discovered that the rats who received green tea supplementation had significantly fewer pre-cancerous changes in the cells lining their colons when compared to the rats that received no green tea supplementation.  Furthermore, the rats that receive the highest dose of green tea supplementation had the least number of pre-cancerous changes in colon cells among the 3 groups of rats.  Several cancer-associated proteins (including beta-catenin and cyclin D1) were also studied in the colon cells of each group of rats and, once again, the levels of these proteins were significantly lower in the rats who had consumed the green tea supplements, and especially in the group of rats that received the highest dose of green tea polyphenols.  These results strongly suggest that, at least in rats, several key cancer-associated biochemical reactions can be blocked by green tea polyphenols, and that microscopic evidence of early pre-cancerous changes in the cells lining the colon is also reduced by green tea supplementation.  Unfortunately, countless previous research studies in rats and mice have failed to show comparably favorable results in humans.  One could imagine a similar study being performed in humans, with the collection of small biopsies of the colon and rectum performed during routine screening colonoscopy.  The role of green tea supplements in the prevention of colon and rectal cancer could then be evaluated objectively in humans.  Meanwhile, I will continue to take my own daily supplements of green tea in liquid and capsule form.
 

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Send your feedback to Dr. Wascher at rwascher@doctorwascher.net
 

Copyright 2008.  Robert A. Wascher, MD, FACS.  All rights reserved.

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