The Deadly Danger Of Cholesterol Lowering Drugs
Beatrice A. Golomb, MD, PhD on Statin Drugs
March 7, 2002
On February 1, 2002, CHS posted a Patient Alert about Statin Drugs. According to an article in the Wall St. Journal, doctors and patients have noted several side effects of the most widely prescribed drugs in the U.S. - statins (some brand names are Lipitor, Zocor, and Provachol). Common complaints of patients taking statins include memory loss, personality changes, irritability, and aching muscle pain. The article also noted that the National Institutes of Health is in the midst of an independent study that will subject statin drugs and their side effects to scientific scrutiny.
Dr. Beatrice A. Golomb, MD, PhD, is the Principal Investigator of the NIH study. Dr. Golomb is affiliated with the University of California at San Diego. In this interview, Dr. Golomb answers questions posed to her by Janet Williams, Colorado HealthSite librarian.
Dr. Golomb asks that the users of CHS who are willing to share their experience with statins, or complete a questionnaire regarding their experience, should contact her at statinstudy@ucsd.edu.
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Question: We understand that cholesterol is a nutrient which occurs naturally in the body and is essential for cell functioning. How low should one's LDL-cholesterol level be reduced before this nutrient is depleted? Is the age of the patient relevant in determining the appropriate level of LDL cholesterol?
Dr. Golomb: Cholesterol is indeed vitally important for function of every cell in the body. It is the most common organic molecule in the brain (and only salt and water are more common on a "molar" basis). It is essential to formation of "synapses" that allow nerve cells to communicate. It is the precursor for all the steroid hormones, including estrogen and testosterone, and stress and blood sugar regulating corticosteroids. It regulates function of membranes of all cells, and may have a role in what toxins and nutrients can enter the cell; and regulates function of cell membrane "enzymes" that facilitate key chemical reactions. Nonetheless, high blood levels of cholesterol do bear a relation to heart disease risk; and statin drugs that lower cholesterol reduce the risk of heart disease and stroke, which are primary causes of death and disability, respectively, in the US.
[Karl Note: This terribly false comment, thrown in, shows the predjudice of government scientists. Once they have concluded, as they have, that some claim is true, they can hardly ever admit a falsehood. High levels of cholesterol are NOT associated with a risk of heart disease. This is conclusively proven HERE.]
We don't know that there is any one level that is too low for everyone. Just as low cholesterol protects against heart disease; and lowering cholesterol -- even though it is still high -- reduces the risk of heart disease, it is possible that low cholesterol is associated with certain negative outcomes, and that lowering cholesterol - even though it is still high -- may increase the risk of these. Other factors, like blood pressure and smoking, help to determine how risky a given high level of cholesterol is for the heart. We suspect that other factors also determine the likelihood of getting "low" cholesterol associated problems at a given cholesterol level. We are working to identify what those factors might be -- for instance, is older age associated with greater risk of adverse outcomes, as it is for many drugs? (Older age is also associated with higher risk of heart disease, so the balance of these factors needs to be better sorted out.) Also, of course, the same cholesterol value may not influence risk the same way for all possible side effects of cholesterol reduction.
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Question: What are the common complaints of patients who take statins?
Dr. Golomb: The most common problems we hear reported pertain to muscle pain or weakness, fatigue, memory and cognitive problems, sleep problems, and neuropathy. Erectile dysfunction, problems with temperature regulation (feeling hot or cold, or having sweats), are among the other problems reported.
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Question: We have read that statins can cause an increase in insulin levels. Have you seen evidence of such an increase?
Dr. Golomb: Although some people have contacted us to report dramatic increases in blood sugar levels on statins, that resolve with discontinuing statins, the average reported differences in blood sugar on statins have been modest, and such marked elevations are not among the more common adverse effect reports we have heard. Elevations in insulin (and when they occur, in blood sugar) could relate to reductions in coenzyme Q10, an important body chemical that appears to play a role in insulin sensitivity, and that is reduced with statins. (It also may play a role in statin-associated muscle problems.) Our ongoing randomized trial, in which insulin and glucose levels are measured, may provide additional information on how commonly this occurs.
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Question: Are there tests patients should have done to monitor these side effects?
Dr. Golomb: There are no tests that are considered "standard of care" for monitoring patients on statins, with the exception of liver function tests; and CK levels in the context of muscle problems (but it appears that even severe statin-associated muscle problems can occur with no CK elevation, or with only modest elevation). Currently, measurement of other factors that may be affected, such as coenzyme Q10, or insulin, is not routine, though these tests may be appropriate in some settings; and it is possible that work to identify who is at risk for adverse effects may, in the future, suggest measurement of such additional factors.
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Question: If patients stop taking statins or lower the dose of the statin, will the side effects reverse?
Dr. Golomb: Based on case reports we have received, these problems seem to generally be reversible. However it appears that in some cases recovery is prolonged or incomplete, particularly for muscle symptoms and neuropathy. We are seeking to get more systematic information from people who have experienced adverse effects, of any kind on statins, to provide more definite information on recovery from statin adverse effects (or unexpected benefits). This will help us to know whether certain statin drugs or doses, whether subject age or sex, whether baseline cholesterol or on-treatment cholesterol, increase the chance of problems -- or may recovery more prolonged or less complete. We hope readers who have had statin experiences, favorable or adverse, will contact us with their experience at statinstudy@uscd.edu.
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Question: What advice would you give to elderly people about their cholesterol levels?
Dr. Golomb: Among older elderly persons, for instance those over age 75 or 80, higher cholesterol is actually associated with living longer, rather than with dying earlier. It is a matter of debate whether this is "causal" (whether high cholesterol actually is protective in older elderly), or whether it is the result of "confounding" (e.g., it could occur because some health problems both may lower cholesterol and lead to earlier death). No one has done a randomized controlled trial focusing on this group to let us know for sure. There are factors, though, that might lead higher cholesterol to be of benefit selectively in the elderly, so a "causal" element to this relationship cannot be dismissed. For instance, memory and strength (which may be adversely affected by statins in some) may be more troubling in older elderly, and may affect both quality of life and survival.
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Question: We understand the University of California, San Diego is currently doing a research study on cholesterol and heart disease in order to determine whether the reduction in LDL cholesterol can affect mood and well-being. Is this an accurate summary of your study? When will the study be completed? What cholesterol-lowering medications will be used in the study? Where can we locate more information on the preliminary findings?
Dr. Golomb: We are conducting an NIH-funded randomized controlled trial, the UCSD Statin Study, to examine the effects -- positive or negative -- of statin cholesterol-lowering drugs on noncardiac outcomes -- including cognition (such as thinking ability and memory), mood, quality of life, and biochemistry (such as blood sugar and insulin).
1000 subjects will be assigned with equal likelihood to simvastatin, pravastatin, or placebo. Simvastatin and pravastatin are 2 of the 3 most widely used statins; they were chosen because these drugs are at the extremes of being the most and least able to enter the brain and other cells in the body. Simvastatin most readily crosses the blood brain barrier and penetrates into all cells, in principle blocking cholesterol production in each cell. Pravastatin, in contrast, is selectively taken up into the liver, and does not readily enter other cells or block cholesterol production in those cells. It acts by blocking cholesterol production within the liver.
Over 600 subjects have been enrolled, and the study will be completed in 2004. We will remain blinded to treatment assignment of subjects until that time, and no preliminary findings have been published.
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Question: Are there other issues with statins that would help patients make decisions?
Dr. Golomb: Patients should be aware of possible side effects, so that they can recognize (and address) these promptly if they occur.
These drugs have critically important benefits to heart disease and stroke. Because of these benefits, these drugs extend life (on average) in certain groups of people -- including, particularly, middle aged or moderately elderly men at high risk of heart disease. However benefit to survival with statins or other cholesterol-lowering agents has never been demonstrated in women (even those at high cardiac risk), in the older elderly, or in men at lower cardiac risk, and there are reasons to be concerned that the risk-benefit ratio may be less favorable in these groups.
For this reason attention to possible adverse effects is particularly important in these groups (though it is also important, of course, even in subjects that fit a profile for receiving survival benefit). For older elderly, possible reductions in muscle function or thinking ability must be viewed as not only important to quality of life, but to survival, since even modest reductions in strength or thinking ability may shorten survival in elderly persons.
Whether or not people are candidates for statin treatment to lower cholesterol, there are lifestyle choices they can make to reduce heart risk and extend survival -- such as regular exercise; avoidance of cigarettes; diets rich in fruits, vegetables, nuts, and legumes; and, if they have heart disease (or are at high risk), fish consumption.
Please be sure to let your readers know, again, that we are vitally interested in learning their experiences on statins; if they are willing to share their experience, or complete a questionnaire regarding their experience, they should contact us at statinstudy@ucsd.edu. Thank you!
Related Reading
Questions Raised About Side Effects of Statin Drugs
Cholesterol-Drug Use Soars, Raising Questions About the Side Effects, The Wall Street Journal, Health Journal, February 1, 2002.
The Wall Street Journal reports that doctors and patients have noted several side effects of the most widely prescribed drugs in the U.S. - statins (some brand names are Lipitor, Zocor, and Provachol). Common complaints of patients taking statins include memory loss, personality changes, irritability, and aching muscle pain.
According to the article, cholesterol is the most common organic molecule in the brain. Some researchers theorize that blocking cholesterol production, as statins do, interferes with the brain’s performance and causes muddied thinking and memory loss. The article quotes Dr. Peter Lansjoen, a Tyler, Texas cardiologist as follows: “ You take these fragile elderly people, lower their cholesterol in half and deplete them of this essential nutrient and it makes sense they’re going to have trouble. I think we’re going to see some real trouble if we’re not careful.”
The article notes that the National Institutes of Health is in the midst of an independent study that will subject statin drugs and their side effects to scientific scrutiny. The results of this study will tell us whether the current anecdotal evidence is valid.
CHS has interviewed the physician who is the principal investigator of the National Institutes of Health Study. To read that interview, click here.
Source
Statins and the Risk of Polyneuropathy
Statins and Risk of Polyneuropathy: A Case-control Study, by D. Gaist, MD, PhD; U. Jeppesen, MD, PhD; M. Andersen, MD, PhD; L. A. Garcia Rodriguez, MD, MSc; J. Hallas, MD, PhD; and S. H. Sindrup MD, PhD; Neurology, May 2002.
Definition
Polyneuropathy A disorder that involves the slow progressive (or recurrent) inflammation of multiple nerves. Loss of movement and sensation are common findings. Some symptoms that may be associated with this disease include:
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facial weakness
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difficulty walking
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difficulty using the arms and hands or legs and feet
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sensation changes (usually of the arms and hands or legs and feet), such as pain, burning, tingling, numbness, or decreased sensation
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swallowing difficulty
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speech impairment
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loss of muscle function or feeling in the muscles
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joint pain
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hoarseness or changing voice
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fatigue
Idiopathic polyneuopathy means that the illness has no known cause.
Background
Here is the important background information that the authors give us:
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statins are lipid-lowering (cholesterol) drugs used in the primary and secondary prevention of coronary artery disease when life style changes have failed to achieve such lowering,
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in the U.S. and Denmark (where this study took place) an ever-growing number of patients are receiving long-term treatment with statins,
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although the benefits and relative safety of statins have been documented in large clinical trials, the long-term use of statins may expose previously unrecognized adverse effects,
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one such adverse effect may be polyneuropathy. One study, based on data from British general practitioners, found that the use of statins increased the risk of polyneuropathy, but the study contained only a small number of cases.
Purpose of This Study
The authors undertook this study to identify the relative risk of the occurrence of idiopathic polyneuropathy in a large population of patients taking statins.
Participants and Methodology
The authors used a patient data base from the Funen County hospital registry in Denmark. The patient registry contained information on all outpatient visits, discharges, diagnoses, and prescribed medications from nonpsychiatric hospitals in Funen County. Using that data base, the authors identified all of the patients diagnosed with idiopathic neuropathy in the 5-year period from 1994 to 1998 and. A total of 585 patients were found to meet the study criteria of:
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having received a diagnosis of polyneuropathy after January 1,1994,
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having no predisposition to polyneuropathy because of diabetes, renal failure, or alcohol abuse, and
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having accessible medical records.
For each patient-participant, the authors randomly selected 25 persons from the general population as "controls." The authors then performed statistical analyses to determine the links between statin use and polyneuropathy.
Results
Here is what the authors found:
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166 patients in the study had a diagnosis of idiopathic polyneuropathy,
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9 of these patients had used statins,
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the patients who used statins for 2 or more years were at a 4 to 14-fold increased risk of developing idiopathic polyneuropathy when compared to the general population as measured by the "controls."
Author’s Summary and Conclusions
The authors note that their study showed that long-term exposure to statins may substantially increase the risk of polyneuropathy. These findings suggest that statins may have a toxic effect on peripheral nerves. One possible mechanism may be that by interfering with cholesterol synthesis, statins may alter nerve membrane function.
Despite their findings, however, the authors remind us that statins also have known benefits in protecting against coronary artery disease. In fact, the authors tell us that "the substantial protective effect of statins, particularly on coronary artery disease, is well documented and by far outweighs the potential risk of statin-induced polyneuropathy." Nevertheless, they urge physicians who treat their patients with statins to prevent coronary artery disease to initiate a thorough workup for those patients who have complaints compatible with peripheral neuropathy. In patients who develop neuropathy, the authors recommend considering termination of the use of statins.
CHS Asks: What Should You Do With This Study?
Currently, patients who use statins are told to alert their physicians if they experience muscle pain or muscle cramps or weakness since these symptoms may indicate statin-induced myopathy (a disease of the muscles, which can be progressive, severely disabling, life-threatening, or fatal). This study shows that the risk of statin-induced polyneuropathy is higher than the risk of statin-induced myopathy.
The authors’ findings suggest that patients taking statins should alert their physicians if they experience any of the symptoms of polyneuropathy listed at the beginning of this report.
Article 1 of 2
HEALTH JOURNAL
Cholesterol-Drug Use
Soars, Raising Questions
About the Side Effects
By Tara Parker-Pope
02/01/2002
The Wall Street Journal
Page B1
(Copyright (c) 2002, Dow Jones & Company, Inc.)
SOME OF THE most popular drugs in the country lower cholesterol and dramatically reduce heart-attack risk. But what else do they do?
As new government cholesterol standards could triple the number of people taking the drugs to 36 million, doctors and patients want more-solid information on the side effects. The class of drugs known as statins includes blockbuster brands Lipitor, Zocor and Pravachol, among others.
Like all powerful drugs, statins have side effects. The problem is that some of the alleged side effects, such as muscle aches and memory loss, also are common complaints of the elderly.
"Most people taking these drugs are older people," says physician Paul J. Rosch, professor of medicine and psychiatry at New York Medical College, whose wife developed weakness and temporary memory loss after taking a statin . "They think, `Gee, I'm just having a senior moment,' and it's something doctors don't ask about."
Confusing the issue further is the fact that most of the memory-loss evidence is anecdotal. Little independent research has been done on the topic. And most physicians believe the benefits of statins far outweigh any risks or side effects.
DRUG MAKERS flatly dispute the notion that statins contribute to memory problems and some, ironically, are even studying the use of statins to treat Alzheimer's. "There's a lot of evidence that statins improve memory function and no good evidence that it affects memory function" in a negative way, says Rob Scott, vice president of the cardiovascular and metabolic group at Pfizer, maker of Lipitor.
A spokesman for Merck, maker of Zocor, said the drug "has a proven safety and tolerability record" and prevents coronary deaths.
The University of California at San Diego is in the midst of an independent study assessing statin side effects, good and bad. The study, funded by $4.4 million from the National Institutes of Health, ultimately will follow 1,000 patients taking either Zocor, Pravachol or a placebo. All the results are blinded, so doctors don't know whether a complaining patient is taking a drug or a placebo. Some patients have quit the study because of irritability, clouded thinking, or pain.
Beatrice A. Golomb, the UCSD assistant professor of medicine leading the study, says common complaints from patients taking statins include being unable to remember the name of a grandchild, walking into a room and forgetting why you are there, or starting a sentence and being unable to finish. Some complain of personality changes or irritability.
"Because these are the most widely prescribed class of drugs in the United States, we need to be sure we understand the full spectrum of effects," says Dr. Golomb.
WHAT IS KNOWN about statins is that they can dramatically lower cholesterol, and that may be the problem when it comes to side effects. Although cholesterol has been vilified as a culprit in heart disease, it is also the most common organic molecule in the brain. Some researchers theorize that blocking cholesterol production, as statins do, interferes with the brain's performance and causes muddled thinking and memory loss.
Drug makers say the real risk factors of memory problems are heart disease and stroke.
Muscle pain is an undisputed side effect of statins, although estimates on the incidence range from 5% to 30%. One statin , Baycol, was pulled from the market last year after being linked to 100 deaths from a rare muscle-wasting condition called rhabdomyolysis.
However, the type of aching muscle pain most patients report isn't believed to be life-threatening. Paul S. Phillips, director of interventional cardiology at Scripps Mercy Hospital in San Diego, says his research shows that some of the muscle problems associated with statin therapy aren't detected by the typical enzyme screening method doctors use, and therefore are dismissed as signs of aging.
In his study, neither the doctors nor the patients involved knew whether a statin or a placebo was given, but the majority began feeling pain when they started back on the real drug. "They could tell every time within three weeks of being on the statin therapy," says Dr. Phillips, who presented the findings at an international cholesterol drug meeting in New York last September and is seeking NIH funding for further study. "These drugs unquestionably save lives, but these muscle toxicities are poorly studied."
Nobody recommends that patients with muscle pain or memory problems stop taking statins on their own. They should, however, discuss their concerns with their doctor. Some patients experience fewer side effects if the dose is lowered or the brand is changed.
Other doctors recommend taking the supplement coenzyme Q10 as a way to counteract memory problems. "You take these fragile elderly people, knock their cholesterol in half and deplete them of this essential nutrient and it makes sense they're going to have trouble," says Peter Langsjoen, a Tyler, Texas, cardiologist. "I think we're going to see some real trouble if we're not careful."
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