Statins for heart disease and stroke, and debunking statin myths

There is no class of medications in the history of the world that has been better studied that statins.

This class of drugs is more properly termed HMG CoA reductase (3-hydroxy-3-methyl-glutaryl co-enzyme A reductase) inhibitors, but with a name like that a terser nickname is almost mandatory (the name statin comes from the suffix of the members of this class: lovastatin, pravastatin, etc.).

Simply speaking, this chemical blocks the metabolic pathway that produces cholesterol, which, of course, is known* to be a chief culprit in the formation of arterial blockages and is a direct risk factor for heart attacks and stroke.  Following are statins currently available in the U.S.:

  • Lovastatin (Mevacor)
  • Pravastatin (Pravachol)
  • Simvastatin (Zocor)
  • Atorvastatin (Lipitor)
  • Rosuvastatin (Crestor)

Since the development of the first widely used statin in 1976 (lovastatin, originally isolated from penicillin fungus) thousands of patients have participated in major research studies assessing the safety and effectiveness of this class of medications and more than 3 billion prescriptions have been filled in the U.S. alone.

The theoretical benefit of widespread statin use has translated into a real effect among the current population of patients at risk for heart disease and stroke.  At present, the prevalence of coronary heart disease is at its lowest in decades, despite an ongoing epidemic of tobacco abuse and obesity.  Many experts in the field of epidemiology feel this is a direct result of the generalized application of the knowledge that has come from these many research studies.  I personally agree that the extensive use of lipid-lowering drugs has actually cut into my cardiology business, and I’m quite pleased with that.

You would think that all this information and scientific certainty would settle any potential controversy surrounding the safety of the statins. You might imagine that doctors and patients alike would feel comfortable using a class of medications for which there is study after study demonstrating the benefit of this type of cholesterol blockade.

Not so.

Virtually every patient who has ever gone on a statin medication has heard stories from family, friends, neighbors, and acquaintances about the dangers this class of drugs harbors: muscle and joint pain, weakness, paralysis, memory loss, depression, cancer, chronic pain, liver and kidney failure.  If you go on the internet and type “truth about statins” into virtually any search engine you will come up with thousands of sites that provide you with nearly everything except the truth.  I tried this last week and was astounded at the misinformation that is heaped upon anyone trying to come to an unbiased opinion on the matter (I also found that for most of these sites the damaging assertions about statins serve as nothing more than a gateway to advertise some other product).

Before I proffer my opinion on the matter, let’s detour for a moment to review the hierarchy of patient-based research.  Medical studies come in a myriad of different designs and span the gamut of quality and reliability.  At one end of the spectrum are anecdotal reports (“As a doctor I observed that Mr. X had adverse reaction to the drug Y”) that are unquestionably the least reliable of all scientific methods in that they involve only few patients, often only one doctor, and are fraught with heavy personal bias.

At the opposite end sits the gold standard research protocol: the prospective, randomized, controlled, double-blinded study.  Definitions:

Prospective: All data are collected after the study is designed.  The opposite of this is the retrospective study which collects data about events that have already happened.

Randomized: Each patient to enter the study is randomly assigned to one of two (sometimes more) therapies.  This differs from some studies where the clinician picks the therapy the patient will receive.

Controlled: More than one therapy is represented in the study.  Generally you compare the treatment in question (such as a new drug) to another treatment that is either placebo (sugar pills that reportedly have no true effect) or the established standard of care (therapy that patients are already receiving).

Double-blinded: A radiologist once told me this means to two orthopedists trying to read a chest x-ray.  It actually refers to a deliberate concealment from both the patient and the doctor/nurse/study coordinator so that neither entity can know whether the patient is receiving the therapy being tested or the control.  With many medications this is relatively easy to do.  With other therapies, such as surgeries, it’s very difficult.

The point of each of these provisions is to remove the effect of bias—on the part of the patient, the doctor, and the study designers—to the greatest degree possible.  Unfortunately this type of study is also the most difficult to run and extremely expensive, but it yields the most reliable information we can obtain.  A researcher who could successfully run such a study with a few hundred participants would be guaranteed a publication in a highly reputable medical journal.

How many patients have been enrolled in statin studies?  At this point over 120,000 patients have participated in prospective, randomized, controlled, double-blinded trials specifically looking at the statin class of medications.  And in every one of these studies the side effects of both the statin and the placebo have been documented with the precision of a Swiss watchmaker with obsessive-compulsive disorder.  Every ache and pain, each rise and fall of dozens of lab markers, and all doctor and hospital visits are painstakingly recorded, tracked, and dissected using a mind numbing array of statistical analyses.

Modern medical science has never (and may never again) so thoroughly dissected the effect—and possible adverse effects—of a class of medication as has been the case with statins.  Here’s what the research teaches us:

  • If you’ve had a heart attack already, or have coronary artery disease, you are at relatively high risk for heart attack, stroke and death.  Those with diabetes or atherosclerosis elsewhere in their circulation (carotid or peripheral) are at similarly high risk.  This group of patients has at least a 20% risk of death or severe cardiac problem over the course of 10 years.  A general rule holds true about risk and therapy: the higher your risk, the greater the magnitude of benefit you get from a therapy.
  • If you average all the studies you will find that you can reduce the risk of cardiac-related death by about 20% among individuals at higher risk.
  • Statins reduce the risk of stroke by about 20-30%.
  • Statins are known to raise liver enzymes in a dose-dependent fashion in around 5 percent of people
  • Statins very rarely lead to dangerous muscle damage (myopathy).
  • Side effects were reported only slightly more commonly in patients randomized to receive the statin drugs (when compared to those on placebo), but the rate of drug discontinuance was similar between both groups.

This last finding is critical.  It means that regardless what you may hear from neighbors and family about the dangerous side effects of statins, the truth of the matter is that among the 120,000 patients studied the side effects of the statins were no different than those of the placebo pill.  Sure, muscle aches occurred, but they were no more prominent among patients randomized to receive the statin.

At least one caveat exists to all this research, however.  There is one form of prominent bias that cannot be excluded from prospective studies such as these, and is in fact inherent in the design of the trial.  This bias occurs when the investigator decides what type of patient should be enrolled in the research and who should be excluded.  A good example is the mammoth Heart Protection Study (HPS), a research endeavor that randomized over 20,000 patients to statin versus placebo.  The enrollment criteria required patients to have some form of vascular disease present (coronary, cerebral or peripheral vascular disease) and therefore excluded patients with no established history of atherosclerosis.  Since healthy individuals weren’t enrolled it stands to reason that the findings of the HPS cannot be applied to the general population.

Also excluded were patients with certain medical problems.  Since muscle aches and liver enzyme abnormalities are a known possible side effect of statins, HPS kept patients with preexisting muscle and liver ailments from enrollment in order to limit the confusion.

Research coordinators are free to exclude these individuals from receiving statin therapy but we clinicians aren’t.  Patients with liver and muscle problems come in with heart attacks as often as anyone else does and we are left trying to decide how safe and advisable it is to start these people on statins.  It’s not known whether people with other complicated medical problems (or complex drug regimens) are at higher risk for statin side effects.

Now, having bored you with my lengthy sermon on the scientific literature supporting statin safety and tolerability, let’s look at real world experience.  Most every physician you talk to will tell you that the rate of statin intolerability among their patients is higher than 5%,  I, too, have seen a higher than expected proportion of patients come back to my office complaining of muscle aches and fatigue after initiating this cholesterol therapy.

What to make of this?  I don’t really know.  I have to believe that statins in the general population result in side effects at a rate not seen in the study groups.  For me to deny this would be ignoring my personal experience with patients whose symptoms improve once they stop the medication and recur if it is restarted.

That said, I also believe that the specter of statin toxicity has so suffused the general population that it has affected the way patients and doctors react such possible side effects arise.  When a person who is not on a statin has joint or muscle aches or fatigue, those complaints are attributed to nothing more than old age, obesity, arthritis, or what have you.  But, these days, when a patient on a statin reports the same symptoms, the statin becomes the culprit and is quickly discontinued.  An example: I saw a patient this week who complained to his pharmacist of muscle aches associated with a cold and was told to stop his Crestor because “it might be killing him.”  Thankfully, the patient—an elderly gentleman at great risk of repeat heart attack—was open to hearing a second opinion.

In summary, if you are unfortunate enough to have had a heart attack, stroke, vascular disease, or diabetes, you are at immense risk of suffering some vascular complication down the road.  Pharmaceutical research has provided us an enormously potent tool to cut the risk of heart attack, stroke and death in such individuals, and more than a hundred-thousand patients donated their bodies to help prove the safety of this therapy.  Each of you has to make your own choice about every medication you introduce into your body, but I would encourage you to put a little faith in the best science that modern medicine has to offer and submit to letting your doctor help you control your cholesterol.

* Remarkably, there are numerous so-called experts who call into question the linkage between cholesterol and heart disease and their websites can be easily found.  The research that implicates cholesterol in vascular disease—starting with the seminal Framingham Heart Study in the 1950s—is about as ironclad as any concept we have in modern medicine.  Those who can’t get on board with the lipid hypothesis would likely have been the same ones to reject the earth-is-round theory.

Eric Van De Graaff is a cardiologist at Alegent Health who blogs at the Alegent Health Cardiology Blog.

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  • Bev McCartt

    I’ve been on statins now for over a year. I was first diagnosed with heart problems when the MDs discovered I had apparently had a heart attack some while ago and lost 70% heart muscle. Originally I was on pravastatin, but then had a couple of TIAs, so now I’m on Crestor. I’ve had no issues at all with pravastatin or Crestor. I read the literature provided as well as research on my own. I know my own body so if something doesn’t seem “right”, then I write down the symptoms, time of day, activity preceding onset of symptoms, and journal it. If symptoms don’t cease within 24 hours, I contact my doctor to see if he believes I need to see him. Usually we can resolve the issue via teleconference, which is nice. Since I don’t have medical insurance, it is imperative that I retain an active partnership with my doctor. I don’t know if statins are the be-all and end-all, but I certainly believe that the statins are part of the medical arsenal that needs to be utilized.

  • http://www.GeriPharmBlog.org Thomas Clark

    The vast majority of the patients who participated in the statin clinical trials were males under the age of 65, leaving questions about the value of statins in women and the elderly. Also, the value of statins for secondary prevention (people with heart disease) has been much better validated than the value of statins to prevent heart attacks in people who have not yet had one (primary prevention). Check this link for more details on statins and primary prevention: http://content.enewslettersonline.com/12293/27460.html

  • Dr Lemmon

    Statins gave their place and I prescribe them, conservatively. There has been a lot of negative and unfounded misinformation put forth about statins. On the other hand, there has been a tremendous amount of hype and positive spin about statins that is undeserved and false. They have their place in secondary prevention. Occassionally statins are useful in primary prevention in certain very high risk patients. Generally speaking they are overprescribed. By the way, the Framingham study found a link between elevations in cholesterol and heart disease for people up to age 50 years, after that age there was no increased risk.

    http://bittersweetmedicine.com/2010/03/26/overrated-medications-series-no-2-statins-for-primary-prevention-of-cardiovascular-diseases/

  • Michael F. Mirochna, MD

    This is a very good commentary by Dr. Van De Graaff. Statins are powerful and important medicines.

    I do believe the earth is flat. The lipid hypothesis is pretty good, but I’m not sure where Zetia, the fibrates and the HDL raising drug (that failed to make it to market) leave us. Zetia will lower your cholesterol but not prevent death. The fibrates were shown not to be benefit mortality in the ACCORD study. I’m not sure what the name of the HDL drug was, but I believe that study was discontinued as it increased death. Furthermore, as the comment above me mentioned, primary prevention data is not as strong as the secondary data and primary prevention data for women I believe is almost non-existent.

    Is cholesterol a surrogate marker for the beneficial effects of the statins? Do we really need to titrate to LDL goals in primary prevention (annals of Int med Jan 2010)? Is the benefit of a statin the statin and not the number behind the cholesterol?

  • http://donna-justme.blogspot.com/ Donna W

    Thanks for this. My husband has been on Lipitor for over four years, since having CABG surgery. It’s good to see something like this in print.

  • http://www.drjohnm.blogspot.com DrJohnM

    Very… very nice work.

    Gosh, patients could learn so much from reading this site.

    And yes, I too am a believer in the benefits of statins for secondary prevention. The ICD clinic experience over the past 15 years has taught me that patients who adhere to the plan: the big four meds (statins, BB, ACE/ARB, anti-coag/anti-platelet) PLUS lifestyle modifications live much longer than their coronary anatomy or LV dysfunction would predict. Of course, this is just an anecdotal observation, but more often than not, compliant ICD patients live long enough to die of something other than heart disease.

    My guess is that of these “big four” drugs, statins are the most important.

    Congratulations on presenting such a useful and well-written piece.

    JMM

  • Anonymous

    Shouldn’t diet, exercise, and loss of body fat be tried first before any drugs? Or do most physicians find the failure rate so high that it seems hardly worth the bother?

    • gzuckier

      Yeah, that’s the thinking these days; that every year spent waiting for the patient to get around to a wishful thinking regime of exercise and improved diet is another year for the cardiovascular system to accumulate damage, so just step in with the pharmacotherapy right away; and if the patient does change lifestyle, then getting off the drug may be tried.

  • Aaron

    What I find alarming is that their is am overwhelming reliance on the use and prescription of medication, rather than actual prevention. Far too often,physicians immediately rely on the use of medication rather than lifestyle change and intervention. We as a society are far too relient on drugs. In my own case I had been on lipitor for 7 years before developing severe muscle pains. I was taken off and the problem resolved in a matter of weeks. I was than placed on another statin, only to quickly end up with the same issues. I told my physician, I wanted to try lifestyle change, via dietary and physical excercise. His response “No that wont work for you, you need to take the medication”. He insisted I should try another station. Instead I began by taking several supplements. Omega 3 fish oil, plant sterols, and panthethine. My cholesterol levels dropped 10 percent in 4 weeks. I than started walking on a treadmill for 20 minutes 4 days a week. 6 weeks later my cholesterol levels had dropped nearly 40 percent. My new physician was estactic and commented that he was tired of hearing how statins and so many other medications are so easily prescribed by physicians. Part of the problem is, too many physicians no little to nothing about natural mediciation, nutrition and the like.

    The problem starts with medical schools that are too focused on training physicians to treat symptoms rather than curing the cause. You want to read a great book detailing what is wrong with healthcare and how to fix it, read Dr. Andrew Weils book “Why health care matters”.

  • Jim Sutton

    Anyone who thinks the Framingham Study ‘proved’ the Lipid Hypothesis of CHD should read the exhaustive analysis by Michael Eades MD. It is located at http://www.proteinpower.com/drmike/cardiovascular-disease/framingham-follies/

    Dr Eades exposes the Framingham researchers for the flat-earthers that they are in these excerpts of their words:

    “When it comes to diet and coronary heart disease, nothing changes.

    In undertaking the diet study at Framingham the primary interest was, of course, in the relation of diet to the development of coronary heart disease (CHD). It was felt, however, that any such relationship would be an indirect one, diet influencing serum cholesterol level and serum cholesterol level influencing the risk of CHD. However, no relationship could be discerned within the study cohort between food intake and serum cholesterol level.

    In the period between the taking of the diet interviews and the end of the 16-year follow-up, 47 cases of de novo CHD developed in the Diet Study group. The means for all the diet variables measured were practically the same for these cases as for the original cohort at risk. There is, in short, no suggestion of any relation between diet and the subsequent development of CHD in the study group…

    The study conclusions:

    With one exception there was no discernible association between reported diet intake and serum cholesterol level in the Framingham Diet Study Group. The one exception was a weak negative association between caloric intake and serum cholesterol level in men. [As to] coronary heart disease–was it related prospectively to diet. No relationship was found.

    So, I would say that the results of this study were pretty clear. These guys tried as hard as they could to show a correlation between diet and serum cholesterol and between diet and the incidence of coronary heart disease, but failed. The data conclusively demonstrated no such correlations.”

    • Anonymous

      In other words, you are saying that Eades says based on that study that cleaning up one’s diet won’t significantly affect ones blood cholesterol levels or heart disease risk? If so, then that would be something in support of those doctors who are quick to prescribe drugs while ignoring the burgers, fries, and sodas that patients consume.

  • Steve Brecher

    Dr. Eades’s comments at the page Jim Sutton links to are about the Framingham Study not showing a relation between diet and either serum cholesterol or heart disease.

    This column says that serum cholesterol is a “chief culprit” in atheriosclerosis and a key risk factor for heart disease and stroke.

    Those are two different subjects. This column is about statins, not diet.

  • Steve Brecher

    P.S. to my prior comment: …And the Framingham Study that this column links to claims that serum cholesterol is a risk factor; it doesn’t discuss diet.

  • Steve Brecher

    “[The high-risk] group of patients has at least a 20% risk of death or severe cardiac problem over the course of 10 years.”

    “If you average all the studies you will find that you can reduce the risk of cardiac-related death by about 20% among individuals at higher risk.”

    That doesn’t seem a strong reduction in view of the lack of reduction in all-cause mortality.

  • http://evolutionarypsychiatry.blogspot.com Emily Deans, M.D.

    I’ve read much of the evidence and I am not convinced. As a psychiatrist, I’ve had three patients with increased paranoia or psychosis that began with starting the statin and resolved with removing the statin. Numerous other “foggy brains” and difficult to treat depressions that became much simpler once the statin was removed. All these are anecdotes, of course, but stumble upon an anecdote often enough… why would our livers try to kill us by making cholesterol? If saturated fat is bad, then why is the primary lipid in breastmilk palmitic acid? Why do autopsy studies of Africans on high fat diets and city of London hospital deaths show that atheroslclerosis and our modern heart disease start with the advent of industrial trans fats? These are important questions that I have not made up just to be ornery. I want to know how humans can be healthy.

  • Tom Williams

    Physicians have a bias toward solving cardio problems with drugs. There are no Double blind, randomized, controlled studies that compare statin use for cardio risk patients to lifestyle (including diet) changes. So there’s no proof that the addition of statins and others (BB, ace, plavix) to lifestyle modification is of any benefit. In fact, it may be worse. The studies only show that patients who are inclined to believe in the value of drugs (why else would they be participating in such a trial) and have had an MI fair better with statins. These, of course, tend to be people who don’t believe as much in lifestyle changes. I’ve made dramatic improvements in my lipid profile and bp with lifestyle (lowered stress, more sleep, much better quality of food, high dose NIACIN) and as a result, even though I had a(n mild) MI, I see no reason to stay on the standard drug therapy. In fact, reason tells me to get off them since there is no evidence that they benefit someone like me, and unlike aspirin they haven’t been around long enough to assure safety in other than those who both have had an MI and can’t change their lifestyle much.

  • http://www.katherinefaradymd.com Katherine Farady, M.D.

    At the age of 46, I started taking Lipitor for familial hypercholesterolemia. I was healthy. Within 6 months, I was suffering from cardiac arrythmias, fatigue, colitis/chronic diarrhea, generalized anxiety and a major depression, as well as severe memory lapses. All these problems cost me thousands of dollars in physician visits and medications (at one count, I was taking seven different meds, besides the Lipitor.) After two years of misery, I finally stopped the Lipitor on my own. The diarrhea and arrythmias stopped within 3 weeks. Now, after 2 and 1/2 years, I feel like I’m almost back to my baseline energy level.

    The ironic thing is that I am a physician. I saw over 8 different specialists during my illness and none of them (even me) suspected the statin as the cause of my ills. I have done a lot of research since then, and now know that there is no overall mortality benefit to taking statins for women, and no real benefit for primary prevention. Even the risk reduction for secondary prevention is rather small, given the cost of treatment. (146 high risk men in the WOSCOPS trial had to be treated with statins for 5 years to prevent one death.)

    I know this is an anecdotal story, but I have seen many patients in my dermatology practice who are on statins for no other reason than that their cholesterol is “a little high”. Many of these patients are women, for whom no mortality benefit has ever been shown. And many of these patients are also on antidepressants, or suffering from various other mysterious ailments. Makes you wonder. I also strongly believe that physicians who prescribe statins tend to dismiss patient complaints. I have seen it and experienced it myself. Every one of my side effects can be found in the PDR. I was falling apart; yet my primary physician was happy because my cholesterol numbers looked good.

    Think about the possible ramifications of dismantling one the the most important enzyme pathways in our bodies. Let’s remember our charge as physicians: first, do no harm.

  • http://www.drjohnm.blogspot.com DrJohnM

    Many of these comments illustrate the widespread misinformation of statin drugs. Dr Van De Graaff did an exemplary job, but yet the statin-misinformation locomotive is hard to stop.

    Yes, these drugs cause side effects, but in high-risk patients they also markedly reduce CV events.

    If a drug was found to substantially reduce the risk of cancer, but occasionally caused sore muscles, would it suffer as much as statins?

    You have motivated me to write yet another post on statins. I thank you for the motivation and topic.

    Statins are not really cholesterol-lowering drugs, they are vascular anti-inflammatory agents that work best in those that have the highest risk.

    JMM

    • Anonymous

      If a drug was found to substantially reduce the risk of cancer, but occasionally caused sore muscles, would it suffer as much as statins?

      Yes.

      Exercise is known to reduce the risk of cancer, particularly gastrointestinal and lung cancer, and can sometimes cause sore muscles. Perhaps the latter is related to the fact that most Americans do not get enough exercise.

  • http://health.groups.yahoo.com/group/Stopped_Our_Statins/ Fran

    Where Do I start? First of all I’d like to thank the physicians who’ve taken the time to comment, especially Dr’s Deans & Farady and you too, Jim Sutton. I manage a support forum for those experiencing statin side effects. We have over 600 active members; many of well researched. Granted it sounds like a small number considering we are an International group, but those are just people with internet access and looking for answers, answers they are not getting from their physicians. I’m just a lay researcher trying to help a husband that is severly impaired by 8 years of statin drugs. The emails I read everyday from those experiencing statin side effects at times, bring me to tears. Granted they are anecdotal, but it’s what’s going on in the “real world”, not some hand picked, long list of exclusionary data trials. Yes, trials are necessary BUT seriously flawed. And don’t get me started on “meta analysis”. One thing not mentioned so far is the difference between relative risk and absolute risk or NNT “number needed to treat”. These are the terms used that most don’t question, but huge when it comes to how much longer people actually “live” (longevity) when taking a specific drug. Those people that live into their 90′s and above? Many have very high levels of cholesterol. Excellent article, “Benefits of High Cholesterol” (referenced) on Weston A Price.org website.
    Also not mentioned is the composition of cholesterol. Re: LDL – is it small dense particle (more likely to penetrate the arterial wall) or large buoyant? How many physicians are routinely measuring A1c and looking for signs of Insulin Resistance? When checking to see if thyroid may be the culprit (a condition often mis-diagnosed or under treated) how many Dr’s are not only checking TSH, but also T4, Free T4, Free T3 ?
    Artificially lowering cholesterol levels with statins does not address underlying conditions. Our body make excess cholesterol for a reason.

  • MarkM

    What I find extrardinary about all this is the readiness with which doctors accept the notion that our bodies are conspiring against us. And that we have to change the way our livers work to ensure our survival. I would have thought that someone with tertiary training in how the body works and some insights into self preservation of the human species would reject this notion out of hand. Instead the mainstream medicine has embraced a concept It is both naive and arrogant.

  • DickyFrank

    Is there an issue with taking a statin like Lipitor only every odd day? or twice a week? Taking it every day gave me muscle aches and feeling down.

    I tried Zetia and my HDL’s fell out of bed. After 6 weeks they fell from 65 to 33. My colesterol numbers fell and my LDL’s fell likewise, but …….

    Dicky

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