How Statins Make Some People Crazy

–Intelligent discussion about statins is threatened by zealous partisans.

What is it about statins that causes so many people to go crazy?

I’m not talking about any pharmacological effect of the drugs. Instead my focus here is on the zealous partisans— both against and in support of statins— who go off the deep end. Unfortunately this creates the appearance of a vast and empty wasteland of the sane middle ground, like the ocean rushing out in the moments before a tsunami. There’s plenty of room for an intelligent debate about both the risks and benefits of statins, but unfortunately extreme participants on either side make a thoughtful discussion impossible. Instead we get a professional wrestling match.

The Anti-Statin Lynch Mob

I don’t want to commit the sin of false equivalency: the biggest offenders are the anti-statinistas. Every time I write a story about a study supporting statins comments pour in from the anti-statin forces accusing me of being a shill for the statin-industrial complex or of crassly ignoring the drugs’ side effects, which range from mild muscle pain to, they allege, instant dementia. These knee jerk responses are difficult to answer, because they are based on pure emotion, and these critics are not willing to consider facts that don’t agree with their predetermined narrative.

Two important facts are nearly always ignored by these critics. First, although statins were once an enormous source of revenue to the pharmaceutical industry, this is no longer the case, since all the major statins are now available in generic formulations. The commercial interests have not entirely disappeared, of course, but it is hard to seriously support a narrative in which financial forces play a big role in the story. (In fact, as savvy observers know, the financial interests are now aligned against statins, since the real money to be made is in new, very expensive cholesterol drugs like the PCSK9 inhibitors that are more likely to be used when people don’t take statins.)

Second, although there are many important questions remaining about the side effects of statins, all the data from studies that have carefully explored this issue point in the same general direction: statin side effects are real but they occur at dramatically lower levels than is popularly believed. The studies have not been perfect— no studies are!— but they are consistent and persuasive. But when these studies are mentioned or reported on they provoke a violent response of rejection from the statin antagonists, who insist that they have suffered side effects and these effects are real.

Of course it’s impossible to argue with a personal anecdote. The larger perspective is always lost in this type of discussion: anecdote is not data. Unless these people have participated in an n-of-1 placebo-controlled trial (in which they alternatively receive a statin and placebo in a blinded fashion) there is no way to know what their symptoms really mean. No one wants to believe that his or her muscle pain isn’t real, or is related to other factors (like routine aging, diabetes, obesity, arthritis, or lack of exercise, to name just a few), but the best evidence indicates that the “nocebo” phenomenon, in which reading or hearing about side effects increases the likelihood of complaining about these side effects, is real. (And let’s not forget, the entire scientific enterprise is premised on the observation that human beings have a near infinite capacity to deceive themselves.)

I want to make an additional point relating to side effects. It’s important to recognize that for some side effects, like cognitive impairment, sleep disturbance, sexual dysfunction, and depression, there is virtually no good or convincing evidence. Another side effect, the increased risk of new-onset diabetes, has been the subject of even more confusion. The anti-statin forces claim that there is a huge increase in risk. For instance, when the diabetes issue first gained widespread attention one prominent cardiologist wrote an attack on statins in the New York Times: “We’re overdosing on cholesterol-lowering statins, and the consequence could be a sharp increase in the incidence of Type 2 diabetes.” In fact, there’s no evidence that this is the case, but there’s also no evidence to dismiss all risk. Patient advocate Marilyn Mann takes the sensible middle ground— otherwise lost in these battles— that “what really needs to be done is to individualize the risk. People who don’t have prediabetes or risk factors for diabetes are not really at risk. People who have prediabetes or risk factors for diabetes may have a much larger increase in risk than is shown by the average effect.”

Then there are larger, well-organized anti-statin forces, starting with the supplement manufacturers and alternative medicine purveyors, who encourage “statin denial,” which Steve Nissen recently assailed in an editorial. These forces undermine the idea that cholesterol is related to heart disease and encourage “the notion that lowering serum cholesterol levels will cause serious adverse effects.” I don’t think Nissen entirely exaggerates when he writes that this is “an internet-driven cult with deadly consequences.”

Nissen didn’t discuss them in his editorial but there is also a small but vocal group of cholesterol skeptics in the academic community. They often indulge in scare-mongering tactics in their use of anecdotal evidence and cherry-picked data. Mann points to one tactic they have employed and which appears to have started to gain some traction in the more general medical community. “There is a group of people who keep saying that the lack of a clear mortality benefit in primary prevention means there is no benefit. It just makes no sense to put no value on avoiding nonfatal MI or stroke. (Has anyone in their family had a stroke??) Yes, the benefit is small for most, but some people have high baseline risk and some have a preference for avoiding small risks. That’s putting to one side the argument over whether statins lower mortality in primary prevention or not.”

The Blithe Indifference of Statin Supporters

Don’t place all the blame on the anti-statin side. Statin supporters generally don’t engage in the kind of extreme tactics regularly used by their opponents, but they are guilty of lesser evils and these also deserve to be called out.

Most notably they overstate the benefits, or, put another way, gloss over the moderate effects, of statins, particularly in low risk populations. This often comes down to an insistent emphasis on the apparently large and impressive reduction in relative risk while failing to mention the much less impressive reduction in absolute risk. By not fully discussing the modest absolute risk benefits the statin supporters inadvertently supply ammunition to the statin opponents, who can then ridicule them by pointing out the large number-needed—to-treat (NNT) for statins in the low risk primary prevention setting.

Behind this attitude there is often an underlying paternalism or a similar assumption of superior knowledge. They will often talk about the need for patient “compliance.” Their idea of talking with a patient is to convince them to do what they think is best. This perspective may make some sense in a very high risk population. But in a low risk population the values of the patient— here we are talking about “pill disutility” and the aversion to “medicalization”— deserve to be valued and treated with full respect and consideration. But, when I asked him to comment on the concept of “pill disutility,” Steve Nissen said that he found “incredulous the claim that ‘pill disutility’ somehow negates the net benefit of statins. No reasonable public health advocate would equate the burdens of taking a single pill daily to the benefits of avoiding a myocardial infarction, coronary intervention or stroke.” But here I part with Nissen. For low risk people the small absolute reduction in risk may not be worthwhile. This perspective should not be discounted.

As anyone who has met him can tell you, Rory Collins, a leading clinical trial researcher and statin supporter, appears to be the perfect model of a British academic physician. But a few years ago he came out in favor of censorship, though that is probably not how he would describe his actions. He demanded the retraction of two anti-statin BMJ papers, which caused an enormous public spectacle. Ultimately the papers were corrected but not retracted.

The BMJ papers were pretty bad. But they were not any worse than a host of other papers that are published in the medical literature every day, and that no one demands be retracted. (When was the last time you saw a statin supporter demand the retraction of a paper overstating the benefits of statins?) The interesting thing here is that Collins’ actions actually drew far more attention to the two rather mediocre papers than they would otherwise have received, and helped motivate the anti-statin forces. The whole imbroglio became headline news, particularly in the UK, generating a whole lot of heat but very little light. This is what I mean when I say that statins drive some people crazy.

Collins is a serious scientist. But his arguments would be stronger if he were more forthcoming about their limitations. As the leading figure in the Cholesterol Treatment Trialists’ (CTT) Collaboration, Collins is the guardian and gatekeeper for nearly all the clinical trial evidence for statins. The data clearly show the benefits of statins, but they are less useful— but not of course entirely useless— when it comes to side effects. Many of the clinical trials excluded people who were unable to tolerate a statin in the run-in period of the trial. Further, although the trial’s were extremely rigorous in their assessment of the major endpoints such as mortality, stroke, heart attack, etc, they were much less rigorous and consistent in their assessment of side effects. These flaws don’t negate the worth of the trials, but they need to be fully considered when assessing the evidence. So, once again, a moderate and balanced perspective is needed. It’s also worth pointing out that Collins could bolster the credibility of the CTT by making patient-level data available to outside researchers for independent analysis.

A Boring and Sane View of Statins

Can there be any doubt that our understanding of cholesterol and the development of statins represents one of the great achievements of modern medicine? Just consider the early research implicating cholesterol in atherosclerosis, then the Nobel-prize winning research of Brown and Goldstein unraveling the genetics and physiology of LDL cholesterol, the consequent development of statins, and more recent advances in genetics and the development of new drug classes. But it’s also important to remember that every silver lining has a cloud and sometimes consequences are unintended. Most notably, as we now know, the obsession with cholesterol, and fats resulted in the war on dietary cholesterol and fat that was entirely unwarranted and contributed to the diabetes and obesity epidemics. And there are still very important questions to answer about the proper role of statins in primary prevention and now the proper role for newer (and more expensive) drugs that can be given in addition to or instead of statins.

Statins are not miracle drugs. For some people they are life saving, for others they are not. They come at a cost. The economic cost is no longer a dominant consideration, but there are other sorts of costs. We shouldn’t discount the discomfort some people feel about taking a pill for the rest of their life. And there may well be additional unintended consequences: some people may  feel that because they are taking a statin they are free to skip the gym or scarf down an order of fries. The human mind works in funny ways.

One moderate and sane perspective was offered recently by Harlan Krumholz. He certainly does not reject statins, but he acknowledges that there is not a one size fits all universal approach. “Lipid-lowering therapy for primary prevention, that is, for patients with no previous cardiovascular event, can be a complex decision.” A key point for Krumholz is that “shared decision making is particularly important when the risks and costs of an intervention are immediate and the benefits are in the future. Moreover, patients vary considerably in their views about what amount of benefit from a prevention drug is meaningful enough to merit taking a pill every day.”

Another boring and sane view comes from Richard Lehman, who earlier this year wrote the following on his BMJ blog:

“Statins are a pain in the mind. The worst migraine I’ve ever had came from trying to write an editorial about them for The BMJ. I gave up the attempt in the interests of personal survival. As a GP, I prescribed statins liberally and with conviction for nearly two decades. If people came complaining about muscle pains, I would reassure them, stop the drug for a while, and then try a different one at low dosage.”

These perspectives won’t make headlines and they won’t appeal to those who want a simple and definite answers. They are boring, complex, practical, and sane. That is why I like them.

I would like to acknowledge the assistance of Marilyn Mann in writing this post. As always, her contributions are invaluable.

Related reading:

Comments

  1. Statins – Side effects vs Fatal Outcome

    Hyperlipidemia in the pathogenesis of atherosclerosis and its risk reduction by use of statins are the most significant achievements in medicine in the last half a century to prevent cardiovascular events and mortality. Newer statins with their powerful effects on LDL-C reduction and their pleiotropic benefits can’t be ignored in high risk patients with strong family history for atherosclerotic cardiovascular disease (ASCVD) for primary and secondary prevention.

    Almost 50% of the adult U.S. population have either pre-diabetes or diabetes now. Coronary heart disease (CHD) often develops before the onset of clinical diabetes. More than half of first heart attacks are fatal and half of these occur in persons not previously known to have CHD. And more over, 2/3rd of the coronary events occur in people with less than 50% coronary occlusion. Secondary prevention is possible only for those who survive the first event!

    From my personal and professional experience of treating thousands of high risk patients with statins, the first one being Lovastatin, marketed in 1987, I have no hesitation to continue to use them, following the standard recommendations regarding its side effects. Of course, I do use common sense and customize my treatment with full involvement of the patient in the decision making process. Any “minor“ adverse effects are better than the “fatal” alternative.

    As for the nay sayers of statins, it is true that we are getting confusing and contradictory results from our clinical trials on ASCVD in the last few decades!

    T2DM, dyslipidemia, hypertension, obesity, inflammatory reaction, vulnerability of plaque rupture and thrombus formation and other numerous known and unknown risk factors and risk markers are involved in the pathogenesis of cardiovascular events and not withstanding the genetic factors.

    Until and unless we develop genomic therapy, total residual risk reduction, to prevent atherosclerosis and cardiovascular events, will be impossible because almost 40% to 60% of the cardiovascular disease (CVD) risks are inherited genetically in varying degrees. Surrogate risk markers like Carotid Intima-Medial Thickness (CMT), coronary lumen narrowing or atheroma plaque volume are not reliable predictors of impending or future events, as there are distinctly separate genetic factors involved in atherosclerosis and rupture of the vulnerable plaque leading to atherothrombosis and clinical events.

    No wonder we are confused on the statin issue as well!

  2. As per your category of anti-statins, I am someone you are referring to as an “instant dementia” patient. I have excellent records along my illness and I very calculatedly came to the discovery that a statin was the reason for this. With out a doubt. I challenge you to meet me and go over these records and graphs, opinions and psudo-diagnosises. Then write a story of truth WITHOUT emotion biasing your opinions in your editorials. People are dying… including me.

  3. Valerie Brockwell says

    I had the most terrifying side effects from Lipitor which came on after 14 days……I was crippled in agony,couldn’t finish a sentence.couldn’t remember names of common things.calling a book a cauliflower………..sharp pains in arms and legs, cramp night and day..nosebleeds……..chills and fast heartbeat……..took me 2 years to get through it……YEAH statins the wonder drug.——–deadly poison.

  4. Nowhere in my travels of reading and researching statins over the past month or more have I seen any article written by an MD or cardiologist stating that they themselves have personally taken statins for X amount of time and have not suffered any side effects. Why is that? Certainly there MUST be doctors in the world who have family histories of heart attack and/or stroke and need to be on this medication for the rest of THEIR lives. Is it only the rest of us crazy people who need statins? I want to see that double blind clinical study, where 5,000 doctors participate and half have to be on statins indefinitely. Oh, and the trial should NOT be paid for by pharmaceutical companies, nor should the trial be run by pharmaceutical company employees, and outcomes should only be reported as absolute risks.

    • My GP persuaded his father to take statins. The old boy got unpleasant side effects so the dose had to be reduced.

  5. Cholesterol-mania has caused us to focus all our attention around a fairly innocuous molecule with a marginal relationship to heart disease, while totally ignoring the real cause of heart disease. The pharmaceutical companies that fund research have a vested interest in certain results, so conclusions may be based on data that supports a preconceived hypothesis. Many of these studies are biased and flawed, but it is the research on which our doctors base our treatment. A study published in the American Heart Journal found that nearly three out of four patients hospitalised for a heart attack had total cholesterol levels in the “normal” range of 200 or less. In other words statins were not preventing heart attacks from happening, and neither was low cholesterol. Add to that the side effects caused by “cholesterol lowering” and you have a very serious and troubling situation. I am a member of a Facebook Group (Side Effects of Lipitor & Atorvastatin), and we have 3,000 members. The majority of members wish they could turn back the clock, because the effects of lowering cholesterol with statins had a profound effect on their life. Many ‘side effects’ are irreversible, and members have lost their livelihood and quality of life as a result of statin drugs. Dr Michael Rothberg of the Cleveland Clinic is the author of “Coronary Artery Disease as Clogged Pipes: A Misconceptual Model”. It was written in response to a provocative health advertisement he had seen in the NY Times magazine, which had used the clogged-pipe imagery as a way to promote a cardiac catheterisation lab. Yes, the imagery is “simple, familiar, and evocative, he noted in the article. Unfortunately, he added “it is also wrong”. I think it is time we focussed on the ramifications of having too low cholesterol levels. Evidence is mounting that low cholesterol may be a far more serious health concern than anyone, your doctor included, even realizes. Why are we ignoring studies that show half of the people with ‘normal’ levels of LDL cholesterol are having heart attacks. Nobody researches the problems associated with low cholesterol (there is no money to be made), but we do know that those who have low cholesterol tend to have a higher risk for cancer, and a higher propensity for violent and suicidal tendencies, plus all the other very serious, life changing ‘side effects’ which I see on the FB forum on a daily basis.

    • Marion, you can find the response to the points you have raised at the article “Coronary Thrombosis Theory of Heart Attacks: Science or Creed?. published at http://www.positivehealth.com/article/heart/coronary-thrombosis-theory-of-heart-attacks-science-or-creed
      Its introduction:
      “The thrombogenic theory, that advocates the myocardial infarction as consequence of coronary thrombosis, was introduced by the American Dr. James Bryan Herrick in 1912,[1] being entrenched worldwide in the medical culture in spite of important clinical, pathological and cardiac images studies showing discrepancies in their findings, basically conflicting with the conceived pathophysiology for this theory”.

  6. George McWhirter says

    You say: ” statin side effects are real but they occur at dramatically lower levels than is popularly believed.” Would you say that ‘statin benefits are real but occur at dramatically lower levels than is popularly believed?. If so perhaps you’d be kind enough to link to any study that shows that for people without advanced CHD/CVD there is any benefit at all? You also say the anti-statin brigade use scare tactics. If researchers publish data that says ‘taking a statin reduces your risk of a stroke by 25%’ and somehow OMIT to put that this is RRR, then do you think the layman might think NOT taking the statin does NOT reduce your risk by a whopping 25%?If so would you say that was a scare tactic?Your reply will be interesting.

  7. dearieme says

    I’m an anti-Stalinist. Oops, anti-statinist. Nonetheless I found myself arguing recently against a chap who although statins were being pushed because they were an enormous source of revenue to the pharmaceutical industry. I pointed out that this was no longer the case. He wouldn’t have it. I suggested he google to see the dates of the expiries of the patents. He still wouldn’t have it.

    I am always made uncomfortable by people on my side of the debate who produce lousy arguments.

    (P.S. Mr Husten, thank you for your recent courtesy. I’m grateful.)

  8. Larry Husten, as you agree, there are many harmful side effects from statins like diabetes, etc.., But my main criticism is that statin fails on secondary prevention (avoiding infarctions, etc) in more than 98% of the patients. In primary prevention much more than that.. Am I wrong?

  9. Transparency with the data – Sir Rory (the keeper of the data) certainly has not been very forthcoming wrt to the raw numbers. I humbly submit if this (the raw data) was available for all to review then this would be a great step in quelling the ‘statinistas’. However, his blithe ‘trust me, I’ve analyzed the numbers and this is what they always reveal’ attitude is not good for medical science and leads to today’s skepticism as to the dubious benefit of statins.

  10. I am not confused on the statin issue at all.

    You said “Any “minor“ adverse effects are better than the “fatal” alternative.” I am a stroke survivor (1/3/17 caused by afib) and was put on atorvastatin 80mg while in the hospital. I left rehab after 30 days, after relearning to walk and had recovered about 90%. I felt good! I was looking forward to resuming my walking and horse activities.

    Then the statin side effects kicked in. I no longer can even exercise because the muscle pain is too great. I can only walk for short distances. In 2 months, I went from being an active 64 year old, to feeling like a bedridden 90 year old. In my eyes, the adverse effects are FAR from “minor”.

    The statin that was prescribed to me by a cardiologist, someone who I am expected to trust, has pretty much taken my life from me. NOT the stroke, but the statin. Some days I almost think the “fatal” alternative would have been better…it certainly would be less painful! Most days I am grateful to be alive, but certainly no thanks to that “life-saving” statin.

    Why isn’t CoQ10, vitamin D and other essential nutrients that are depleted at the same time this miracle statin works be prescribed at the same time? Nowhere along my recovery path did any doctor even mention that. Maybe they don’t even know of the destruction they may cause when they prescribe, because they are only told what the drug companies want them to know?

    • Magnesium deficiency is linked to all 4 conditions: afib, muscle cramps/pain, low energy, heart disease and stroke. It may help in your recovery. Sadly, being deficient in it may have been a major factor in your current state of disease. You should be aware many people experience the laxative effect long before they reach therapeutic levels. Read “Magnesium Miracle” by Dr Carolyn Dean. She does peddle her line of products but also backs her claims with countless studies.

      Besides, the worst you can say about magnesium therapy is its “unproven”. That’s a semantic slight of hand that would make Houdini jealous. And it’s the same snake oil peddlers mentality. Unproven does NOT mean irrelevant. It just means someone can’t make a quick buck because there’s no patent to be had. Patent medicine used to be a dirty word.

  11. Richard Kones MD says

    This post is one of the best ever. It calls for common sense and sanity in the approach to statins. In all things, balance, moderation, and prudence is best, and statins are included. This includes individualization and shared decision making using absolute risk and NNT/NNH). Not to mention the old-fashioned and oh, so archaic practice of listening to the patient…. Only 11 words are needed: statins are valuable agents but side effects, sometimes serious, do occur. Generalizations based upon anecdotes are, as usual, perilous. But when ADE occur, pay attention.

  12. “Statin supporters generally don’t engage in the kind of extreme tactics regularly used by their opponents,”

    You’re kidding, right? Bellowing “YOU’RE KILLING PEOPLE!!!” whenever anyone suggests statins are not the best thing to happen to medicine ever is not extreme?

    I draw a line in a slightly different place to you. Personally I never got any side effects, but I have little doubt that the level of side effects is at least an order of magnitude worse than the manufacturers admit, and the benefits are at least an order of magnitude less than the manufacturers claim. Look at some of the differences between industry-sponsored studies and independent studies.

    • suspect the reality is that while they may be useful drugs for some people with some conditions, they are marketed to everyone else as well. Anyone who questions this marketing is promptly tarred and feathered.

      My main, major beef, not only with statins but the diet-heart hypothesis, cholesterol hypothesis and the whole works is this: now I am an Old Fart surrounded by my fellow Old Farts, I see many of their symptoms, like mine, as symptoms of, let’s say, a dysfunctional insulin/glucose system, but doctors insist on looking only at “cholesterol” which I’m becoming less and less convinced is actually causal of anything, and looking AWAY from anything else which actually MAY be causal or at least MORE causal. They are looking where they are told to look, under the street light where the cholesterol is, not over there where the Ancel Keys, I mean car keys, were actually dropped.

      • Real Science is not about “proving” and more about “probing”. People who call for things to never be studied, or never again be studied, are NOT scientists, they are dogmatists, and frankly a lot of the dogma has never worked and continues to not work decades after it was invented, but it makes a metric shedload of money (the polite version) some of which goes straight back into marketing it while suppressing anyone or anything that pokes holes in it. I am often amazed by what was once “known” and has since been ignored, and the vituperation expressed against those researchers who are currently refinding this, let alone finding actual genuine new information.

  13. I don’t consider myself an anti-statinist but because I’m not 100% behind them I think many of my colleagues think I am.
    I remember the early days of the statin push, and in discussing who should get statins with an internist, according to recommendations it turned out every patient on the floor should be receiving one. We both knew this was not likely true. So perhaps the strong anti-statin push is just a result of what happens when you over-market something. People don’t like being told one thing and having something different play out before their eyes – they feel manipulated and angry, and it doesn’t help that the medical community holds up pages of studies to dismiss/devalue their experiences.
    And as far as the drug companies not cashing in on statins anymore, you miss the big picture: Any good salesman knows that your chances of re-inventing the market are slim, but putting a new spin on an old product is usually successful. Cholesterol is still the industry’s bread and butter (excuse the pun) for the future.

  14. Anecdotal – Definition: “(of an account) not necessarily true or reliable, because based on personal accounts rather than facts or research.” Hmmm… So when a person is prescribed a statin, and shortly there after, experiences muscle pain, TGA (transient global amnesia) observed by others as “they” themselves can’t remember the incident, fatigue, etc., is that anecdotal or fact? Does a person have to be under the watchful eye of a research team to “prove” they are experiencing what they are experiencing? “Marion” has over 3,000 members in her support group. I have 1,400 and more joining daily. Do these people not matter? Are their complaints any less meaningful than those experienced by participants in a clinical study? Has it really come to that? I feel anecdotal is what’s happening in the “real world”. Post marketing side effects are added to the DPI. Who ever sees this information? The prescribing physician? Patient? I will continue to encourage people to do their research so they can make informed decisions about their heart health. Am I part of the “anti statin cult”? Cult is a very derogatory term meaning “people having religious beliefs or practices regarded by others as strange or sinister”. I’m neither strange or sinister.

  15. Well, with that link list, no-one could call you prejudiced. ;/

    And weasel words. “zealous partisans”, “completely unreliable”, “scary headlines”. We’re crazy, naive and oh, childish.

    But not dead. In spite of. How inconvenient for you.

    http://www.ti.ubc.ca/2014/05/28/ti-podcast-letter-89-statins-proven-and-associated-harms/

  16. Bobette Bryan says

    I was on one last year, and it almost killed me. It felt like my lungs were full of glass and surrounded by tight bands. I couldn’t walk from the dining room table to the kitchen sink without being horribly short of breath. Luckily, I missed a dose and noticed some improvement, but it took months for me to recover. I’ll never take one again. I was put on them initially because I have high triglycerides–my cholesterol is normal. I’m currently trying the fish oil method to lower them.

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