Do Statins Cause Memory Loss? The Science, The Media, The Statin-Denialist Cult, and The Nocebo Effect

The Skeptical Cardiologist was recently contacted by a television reporter  working on a segment about statins. and looking for a cardiologist to interview who “is concerned about the cognitive side effects of these drugs.”

Since I regularly prescribe statin drugs to my patients to reduce their risk of heart attack and stroke,  I am very concerned about any possible side effects from them, cognitive or otherwise. However, in treating hundreds of patients with statins, I have not observed a consistent significant effect on brain function.

When the U.S. Food and Drug Administration (FDA) issued a statement in 2012 regarding rare postmarketing reports of ill-defined cognitive impairment associated with statin use it came as quite a surprise to most cardiologists.

The FDA made a change in the patient information on all statin drugs which stated:

Memory loss and confusion have been reported with statin use. These reported events were generally not serious and went away once the drug was no longer being taken

This FDA statement was surprising because prior observational and randomized controlled trials had suggested that patients who took statins were less likely to have cognitive dysfunction than those who didn’t.

Early studies implied that statins might actually protect against Alzheimer’s disease.

In fact these signals triggered two studies testing if statins could slow cognitive decline in patients with established Alzheimer’s disease  One study used 80 mg atorvastatin versus placebo and a second 40 mg simvastatin versus placebo and both showed no effect on the decline of cognitive function over 18 months.

More recently, multiple reviews and meta-analyses have examined the data and concluded that there is no significant effect of statins on cognitive function. Importantly, these have been written by reputable physician-scientists with no financial ties to the pharmaceutical industry.

 

Data Show No Evidence of Causality Despite Case Reports

The FDA added the warning to statin patient information based on case reports  Occasional reports of patients developing memory loss on a statin do not prove that statins are a significant cause of cognitive dysfunction.

Case reports have to  be viewed in the context of all the other scientific studies indicating no consistent evidence of negative effects of the statins. Case reports are suspect for several reasons:

First, patients receiving statins are at increased risk for memory loss because of associated risk factors for atherosclerosis and advancing age. A certain percentage of such patients are going to notice memory loss independent of any medications.

Second. The nocebo effect: If a patient taking a statin is told that the drug will cause a particular side effect,that patient will be more likely to notice and report that particular side effect.

A recent study in The Lancet looked at reported side effects in patients taking atorvastatin versus placebo and found substantial evidence for the nocebo effect.

Analysis of the trial data revealed that when patients were unaware whether they were taking a statin or a placebo, the number of side effects reported was similar in those taking the statin and those taking placebo. However, if patients knew they were taking statins, reports of muscle-related side effects in particular increased dramatically, by up to 41 per cent.

Third, a review of the FDA post-marketing surveillance data showed the rate of memory loss with statins is not significantly higher than for other non-statin cardiovascular medications (1.9 per million prescriptions for statins , 1.6 per million prescriptions for losartan) and clopidogrel (1.9 per million prescriptions for clopidogrel.)

What Most Media Prefer: Controversy And Victims

I thought my experience and perspective on statins and cognitive function might be useful for a wider audience of patients to hear so I agreed to be interviewed. After I expressed interest the  reporter responded:

I would like to interview you and also a person who has experienced memory and/or thinking problems that they attribute to statin use.  
 I responded with “let me see what I can find,”  although I was concerned that  this reporter was searching for a cardiologist to support attention-grabbing claims of  severe side effects of statins rather than seeking a balanced, unbiased perspective from a knowledgeable and experienced cardiologist.
If I produced a “victim” of statin-related memory loss this would boost ratings.
I then began racking my brain to come up with a patient who had clearly had statin-related memory loss or thinking problems. I asked my wonderful MA Jenny (who remembers details about patients that I don’t) if she could recall any cases. Ultimately, we both came up without any patients for the interview. (Any patient of mine reading this with definite statin memory loss please let me know and I will amend my post. However, I won’t be posting anecdotes outside of my practice.)
I have had a few patients relate to me that they feel like their memory is not as good as it was and wonder if it could be from a medication they are on.  Invariably, the patient has been influenced by one of the  statin fear-mongering sites on the internet (or a friend/relative who has been influenced by such a site.)
I wrote about one such site in response to a patient question a while back:
The link appears to be a promotional piece for a book by Michael Cutler, MD. Cutler’s website appears to engage in fear-mongering with respect to statins for the purpose of selling his books and promoting his “integrative” practice. I would refer you to my post entitled “functional medicine is fake medicine”. Integrative medicine is another code word for pseudoscientific medicine and practitioners should be assiduously avoided.
The piece starts with describing the case of Duane Graveline, a vey troubled man who spent the latter part of his life attempting to scare patients from taking statins. Here is his NY Times obituary.
You can judge for yourself if you want to base decisions on his recommendations.
There is no scientific evidence to suggest statins cause dementia.
An Internet-Driven Cult With Deadly Consequences
Steve Nissen recently wrote an eloquent article which accuses statin deniers of  being  an “internet–driven cult with deadly consequences.”  Nissen has done extremely important research helping us better understand atherosclerosis  and is known for being a patient advocate: calling out drug companies when they are promoting unsafe drugs.
I have immense respect for his honesty, lack of bias, and his courage to be outspoken .  He writes:

“Statins have developed a bad reputation with the public, a phenomenon driven largely by proliferation on the Internet of bizarre and unscientific but seemingly persuasive criticism of these drugs. Typing the term statin benefits into a popular Internet search en- gine yields 655 000 results. A similar search using the term statin risks yields 3 530 000 results. One of the highest-ranking search results links to an article titled “The Grave Dangers of Statin Drugs—and the Surprising Benefits of Cholesterol”. We are losing the battle for the hearts and minds of our patients to Web sites de- veloped by people with little or no scientific expertise, who often pedal “natural” or “drug-free” remedies for elevated cholesterol levels. These sites rely heavily on 2 arguments: statin denial, the proposition that cholesterol is not related to heart disease, and statin fear, the notion that lowering serum cholesterol levels will cause serious adverse effects, such as muscle or hepatic toxicity— or even worse, dementia.”

He goes on to point out that this misinformation is contributing to a low rate of compliance with taking statins. Observational studies suggest that noncompliance with statins significantly raises the risk of death from heart attack.

The reasons for patient noncompliance, Nissen goes on to say, can be related to the promotion of totally unproven supplements and fad diets as somehow safer and more effective than statin therapy:

“The widespread advocacy of unproven alternative cholesterol-lowering therapies traces its origins to the passage of the Dietary Supplement Health and Education Act of 1994 (DSHEA). Incredibly, this law places the responsibility for ensuring the truthfulness of dietary supplement advertising with the Federal Trade Commission, not the U.S. Food and Drug Administra-tion. The bill’s principal sponsors were congressional representatives from states where many of the companies selling supplements are headquartered. Nearly 2 decades after the DSHEA was passed, the array of worthless or harmful dietary supplements on the market is staggering, amounting to more than $30 billion in yearly sales. Manufacturers of these products commonly imply benefits that have never been confirmed in formal clinical studies.”

Dealing With Statin Side Effects In My Practice

When a patient tells me they believe they are having a side effect from the statin they are taking (and this applies to any medication they believe is causing them side effects), I take their concerns very seriously. After 30 years of practice, I’ve concluded that in any individual patient, it is possible for any drug to cause  side effects.  And, chances are that if we don’t address the side effects the patient won’t take the medication.

If the side effect is significant I will generally tell the patient to stop the statin and report to me how they feel after two to four weeks.

If there is no improvement I have the patient resume the medication and we generally reach a consensus that the side effect was not due to the medication.

If there is a significant improvement, I accept the possibility that the side effect could be from the drug. This doesn’t prove it, because it is entirely possible that the side effect resolved for other reasons coincidentally with stopping the statin. Muscle and joint aches are extremely common and they often randomly come and go.

At this point, I will generally recommend a trial at low dose of another statin (typically rosuvastatin or livalo.)  If the patient was experiencing muscle aches and they return we are most likely dealing with a patient with statin related myalgias. However, most patients are able to tolerate low dose and less frequent administration of rosuvastatin or Livalo.

For all other symptoms, it is extremely unusual to see a return on rechallenge with statin and so we continue statin long term therapy.

Today a patient told me he thought the rosuvastatin we started 4 weeks ago was causing him to have more diarrhea. I informed him that there is no evidence that rosuvastatin causes diarrhea more often than a placebo and had no reason based on its chemistry to suspect it would. (Although I’m sure there is a forum somewhere on the internet where patients have reported this). Fortunately he accepted my expert opinion and will continue taking the drug.

If the symptoms persist and the patient continue to believe it is due to the statin, we will go through the process I described above. And, since every patient is unique, it is possible that my patient is having a unique or idiosyncratic reaction to the statin that only occurs in one out of a million patients and thus is impossible to determine causality.

Since statins are our most effective and best tolerated weapon in the war against our biggest killer, it behooves both patients and physicians to have a high threshold  for stopping them altogether. Having such a high threshold means filtering out the noise from attention-seeking media and the internet-driven denials cult thus minimizing the nocebo effect

Antinocebonically Yours

-ACP

N.B. It turns out the reporter had an open mind about the issue of statin-related memory loss. We had a good discussion  and at some point you may see the skeptical cardiologist on TV being interviewed on the topic.

I could bring to the interview one of  my many patients who since starting to take statins have  not had a heart attack or stroke and who have taken statins for decades without side effects.

Now that would make for some compelling and exciting TV!

For a nice discussion of Nissen’s article see Larry Husten’s excellent piece at Cardiobrief.org here (/nissen-calls-statin-denialism-a-deadly-internet-driven-cult/)

 

14 thoughts on “Do Statins Cause Memory Loss? The Science, The Media, The Statin-Denialist Cult, and The Nocebo Effect”

      1. Jeff,
        When I wrote about how exciting and entertaining interviewing a patient who had not had a heart attack this was verbal irony. The interview would, in fact, be the opposite. Verbal irony is frequently used for humorous effect. Sometimes it is taken seriously at which point the humorous effect is lost. I fear this is the case in my post.
        Your future in the cubic lottery of primary prevention is best judged by determining your level of y subclinical atherosclerosis

    1. Indeed. My statement about bringing a patient who was taking statins and had not had a heart attack and how exciting that would be for TV viewers was actually intended as humorous. Readers and viewers are going to be far more entertained and influenced by the patient to whom something dramatically bad has happened. My unremarkable patient with no dramatic story would be quite boring.
      I see the interview as a Monty Python sketch in which John Cleese plays the TV interviewer desperately trying to get patient Terry Jones to admit to any event of interest in his life that could be related to the statin drug he has been taking.
      Your patient with the heart attack on statins, on the other hand would provide tremendous human interest and stick in the mind of viewers. From then on if discussing the effectiveness of statin drugs with friends or their doctor they could say that they saw a man on TV who had a heart attack on statins therefore they clearly don’t work.

  1. I AM 72 Y.O. AND WAS ON CRESTOR FOR 4 YEARS AND NOW ON
    ATORVASTATIN FOR THE LAST 2 YEARS AFTER HAVING AN AORTIC DISSECTION IN 2011. NO COGNITIVE PROBLEMS AT ALL
    ONLY SOME MUSCLE PAIN ON THE 1ST STATIN COMING OUT OF
    THE HOSPITAL ,BEFORE SWITCHING TO CRESTOR AND THEN
    ATORVASTATIN .

  2. My biggest concern would be less with cognitive decline over a short period (18 months), but what more with what occurs over very long periods of taking statins. What piqued my interest in statins was my father in law’s remarkable recent decline in memory and cognition at age 73 or so. Two PhD’s, three time Jeopardy winner, annoyingly knowledgeable about virtually everything, and now he’s enrolled in a memory study at UCLA due to severe memory difficulties. As you would note, it’s anecdotal and impossibly confounded by aging and other processes, but I am concerned that interrupting what I see as a fundamental biological process might have broad-ranging effects. The duration of most studies I’ve seen would not likely be sensitive to such changes over time. I worry that statins have gotten a free pass in regard to immune function and cognitive challenges due to expectations of dementia, muscle pain, diabetes and cancer in elderly populations. Just seems odd to me that a disruption in cellular function would be as benign as has been shown in industry studies.

    1. I don’t think statins have gotten a “free pass” with respect to immune function or cognitive effects. They have been intensively studied in large numbers of patients in randomized, double-blinded trials. Although funded by industry these trials are run by docs of high-integrity with data safety and monitoring boards. The double-blinding means that nobody knows what is going on until the data are unblinded. Nothing suggests even a hint of increased infections with statins . Likewise for cognitive problems.
      Of course, the trials haven’t gone on for decades so it is possible that a side effect could emerge way down the line. Post-marketing surveillance helps address this possibility.
      And my approach of considering drug withdrawal for any symptom that is otherwise unexplained would hopefully add another layer of confidence.

  3. “I then began racking my brain to come up with a patient who had clearly had statin-related memory loss or thinking problems. ”

    I value the topic of this article because there is not much on the Internet about cognitive dysfunction with statins. I think I am the patient you are looking for. I’m an engineer and have to make extensive use of my mind to make a living.

    After off-pump CABG at age 52 with 100%/70%/40% coronary blockage I started taking statins along with a good diet and exercise. I noticed unexplained short term memory losses (I would go into the other room to retrieve something and forget why I went into the room – 4 times for the same thing; finally I wrote down the item on a post-it note so I wouldn’t forget it on the fifth time). It didn’t occur to me that the short-term memory losses could be due to the statin. The normal dosages weren’t adequate so the dosage was increased. 80mg Vytorin.

    I would make a business call to a co-worker and after a short introduction could not remember why I called him 30 seconds into the phone call. Embarassing. Stopped taking statins for a couple of days and my memory came back. Changed statin dosage.

    My wife would call my cell and ask what my location was in the grocery store, and I couldn’t find the words to explain where I was in the store. Searching for but couldn’t find the word. Apashia? Stopped taking statin and memory returned in a couple of days. Changed statin type.

    Would go to the store and become disoriented. Couldn’t remember where I parked my car in the lot, couldn’t really remember the events leading up to how I got to the store. Never did find my car my memory –
    I walked the parking lot and looked for the distinctive bike rack on the car. Stopped taking statin and memory returned in a couple of days. Changed statin again. Try CoQ10.

    Was working on an engineering project and couldn’t remember basic technical information (which is not only very embarassing but death to an engineer’s career). Stopped taking statin and memory returned in a couple of days. Changed statin.

    Missed an appointment my wife had with me “don’t you remember the conversation from yesterday?”. Stopped taking statin and memory returned in a couple of days. Changed statin. Exhausted all the prescription statins so I tried Red Rice Yeast. Same memory retrieval problem. Running out of statins to try. Try again with lower doses. Same effects. Try statins I’ve used earlier, but at greatly reduced doses. Same effects.

    Doctor insists it isn’t the statins (his Continuing Medical Education (CME) told him so), but I don’t take any other drugs. This “step therapy” has been going on for 10 years now, multiple trials with mutiple statins in many dosages – I’ve tried all the the statins and they have the same memory effect for me, even at very low doses (the memory problems occur before the therapeutic level can be achieved), all the time my cholesterol is really not under control. I’d like to get statins to work for me, but I become useless as an engineer and am effectively “disabled” by taking statins – it’s just not a solution for me. I cring every time I have to start taking them again because in a couple of days the symptoms start showing up. Fortunately the memory loss from statins is easily and quickly reversible (unlike some cases of myopathy).

    For the last year I’ve been taking PSCK9 inhibitors and there is no memory loss at all and my cholesterol has never been better. (LDL before was 230, down to 95 on the last test – best I can do). Insurance company doesn’t want to pay for it, so I just pay cash. $$$, but that is another conversation.

    I’ve talked to many other patients taking statins and nobody else I know has this precise memory loss effect – I imagine the group of patients is quite small, less than 1% – but it’s not zero. I certainly wouldn’t condemn the 95% of the patients who benefit from the drug (less the 4% who suffer from myopathy) – the NNT isn’t that good, but what else is there? I’ve tried the sequestrants and they aren’t nearly powerful enough.

    The fundamental problem with statin-induced memory loss is: how to do test for it? I’ve looked at the “cognitive tests” and there are structural problems with the testing: their patient pool is random and large (5804), none were particularly selected for memory loss, I suspect the population with this exact problem would be small in this group (less than 1%: <58) split between placebo and drug, the population was elderly, perhaps not actively using their minds, and possibly in decline whether or not they take statins (I'm young and active), and this group did not report that they experience memory recovery in a couple of days like I do. The "cognitive tests", once you examine at them, bear little resemblance to my experience with cognitive memory loss.

    From the report "It is important to note that these trials were small and of short duration and used different tests to assess cognitive function. This is important because some cognitive tests appear to be more sensitive to the effect of statins (43)" I've looked at the substance and details of the tests, and the test would not detect the short-term memory loss problem I've experienced. I makes me wonder how hard they were looking, or if they were going through the motions, or if they just didn't understand the problem, or didn't have actual patients with reported memory problems to test.

    Recently the test for "neurocognitive disorders (including amnesia, memory impairment, and confusional state) occurred in 1.2% of patients treated with alirocumab for 78 weeks (mean LDL-C 48 mg/dL), a nonsignificant difference from the control group (57)." So the small population of PSCK9 users also appears to have a small percentage of cognitive disorders too, which is coincidentally the size of the statin memory loss group. Certainly not enough to hold up release of the drug, but I don't think these tests have gotten us to any better understanding of the problem, just that there is a problem – and that is an improvement.

    Fine. I am fortunate to have found a solution to lowering LDL without memory loss. What bothers me is that the statin-induced memory effect was there from the beginning of the introduction of statins, yet it took 20 years for the FDA to make an declaration that there might be something to it. Why? I think it was known from the very beginning, but the decision to go forward was simply based on the belief that benefits far outweighed the risks. Besides, at the time, what other alternative was there? Niacin?

    1. Jim,
      I appreciate your detailed and thoughtful comments. This is why I listen closely to patients who describe unusual potential side effects and why I have a low threshold for stopping statins to look for improvement.
      My understanding of the PCSK9 neurocognitive studies was that the greatest and latest techniques were being utilized because of concerns going in.
      dr p

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