Category Archives: Medication Side Effects

Statins And Memory Loss: The Latest Findings

In 2017 I wrote a post  entitled “Do Statins Cause Memory Loss? The Science, The Media, The Statin-Denialist Cult, and The Nocebo Effect” which concluded that there was no scientific evidence for cognitive side effects of the widely-utilized statin cholesterol lowering drugs.

Despite this, a common concern of my patients when we discuss potentially utilizing statin drugs to reduce their long term risk of heart attack and stroke is that the drug will rob them of their memory.

More studies have been published in this area and they continue to show absolutely no evidence for adverse association between statins and cognition.

A recent summative review found no beneficial or detrimental associations between statins and cognition in elderly cohorts with normal baseline cognition, impaired cognition or with incident dementia.

Finally, and most recently we have reassuring evidence from Australian researchers who meticulously studied  over a thousand participants aged 70-90 years in the Sydney Memory and Ageing Study.

Over 6 years the study found

-no difference in the rate of decline in memory or global cognition between statin users and never users.

-Statin initiation during the observation period was associated with blunting the rate of memory decline.

-Exploratory analyses found statin use was associated with attenuated decline in specific memory test performance in participants with heart disease and apolipoprotein Eε4 carriage.

-There was no difference in brain volume changes between statin users and never users.

For those who see statins as part of a conspiracy please note that there was absolutely no connection between the researchers and the statin pharmaceutical industry.

  • This study was supported by the Australian Government’s National Health and Medical Research Council (Dementia Research Grant 510124). Dr. Brodaty has served on the Nutricia Australia Advisory Board. Dr. Sachdev has served on the Australian Advisory Board of Biogen. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

My 2017 post was triggered by a call from a reporter who wanted to discuss the “cognitive side effects” of statins. It goes into a fair amount of detail about media and internet fear-mongering and how this contributes to the nocebo effect which makes it more likely patients will experience adverse side effects from medicine.

At the end I discuss how we handle potential side effects in my practice.

I’ve copied it below as it remains highly relevant 2 years later.


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

You Should Stop Taking Zantac (Ranitidine) Now

On September 13 of this year Valisure, an online pharmacy, submitted a  Citizen Petition to the FDA and urged it to  pull all ranitidine (brand name Zantac) from the market. Ranitidine, an H-2 blocker, is widely utilized both by prescription and over the counter for gastric acid suppression in the treatment of acid reflux and peptic ulcer disease.

According to CEO, David Light, based on Valisure’s testing and review of the scientific literature, ranitidine is an inherently unstable molecule which degrades directly and with high efficiency to the known carcinogen N-nitrosodimethylamine (NDMA).

The FDA issued a notice that same day “alerting patients and health care professionals that NDMA had been found in samples of ranitidine.” but did not call “for individuals to stop taking ranitidine at this time” stating:

Although NDMA may cause harm in large amounts, the levels the FDA is finding in ranitidine from preliminary tests barely exceed amounts you might expect to find in common foods.

By September 17, Health Canada asked companies to stop distributing the drug and at this time 30 countries have stopped sales of the drug. The FDA has yet to tell Americans not to take the drug indicating that it is awaiting more definitive studies.

In the meantime all major drug store chains and Amazon have voluntarily removed the drug from their shelves.

After listening to interviews with David Light of Valisure I’m convinced that everyone should stop taking ranitidine in any form because:

  1. The NDMA is not a contaminant but a breakdown product of an unstable ranitidine molecule and will be present regardless of which company makes it.
  2. NDMA is a highly significant carcinogen. Although not proven to cause cancer in humans it very reliable at causing it in mice. The levels Valisure detected are way above the levels the FDA considers acceptable.

Fortunately, there are many alternatives to ranitidine for acid suppression including PPIs (prilosec/omeprazole, pantoprazole, etc.) and an H2 receptor antagonist which does not have NDMA problems, famotidine.

Famotidine , according to this review:

is approximately 7.5 times more potent than ranitidine and 20 times more potent than cimetidine on an equimolar basis. Therapeutic trials indicate that famotidine 20 mg b.i.d. or 40 mg at bedtime is as effective as standard doses of cimetidine and ranitidine for healing duodenal ulcers. A dose of 40 mg at bedtime appears to heal benign gastric ulcers.

Skeptically Yours,

-ACP

N.B. I recommend this Peter Attia podcast interview with David Light (#75 – David Light: Zantac recall due to cancer concerns – what you need to know) if you want more details on Valisure and NDMA.

Also, check out Valisure’s description of the NDMA problem here.

Valisure is a unique pharmacy which per its website:

“sells the same meds that all American pharmacies use, but first put the batches through rigorous chemical analysis so the bad batches are screened out. We summarize our analytics in an easy-to-understand certificate of analysis specific to that batch. We are the only pharmacy to do this.”

 

Very Cool Cartoon On Side Effects Of Proton Pump Inhibitors (PPI) For GERD

The skeptical cardiologist not uncommonly recommends OTC Prilosec (omeprazole), a proton pump inhibitor for cardiac patients with chest pain that is from acid reflux (GERD).

Lately, however, some studies have raised concerns about the long term side effects of taking PPIs.

I came across a very cool cartoon which reviews one patient’s history with respect to PPIs in today’s Annals of Internal Medicine.

I’ve been meaning to delve more deeply into the literature on PPI side effects but until then I think this cartoon does a great job of summarizing what patient’s should be considering.

You can view the entire cartoon for free on the Annals website here

Here is the first panel which describes a patient who has been taking the PPI pantoprazole for decades:

And this is the last panel

It’s ironic that at one point in this patient’s treatment he is put on Zantac (ranitidine). In recent weeks the FDA has issued warnings about a possible carcinogen in generic ranitidine and CVS and Walgreens have pulled it from their shelves.

Antirefluxively Yours,

-ACP

Is An Unneeded Beta-Blocker Making You Feel Logy?

The skeptical cardiologist saw a patient recently who  had undergone stenting of a 95% blocked right coronary artery. Mr Jones had presented  a year ago to our ER 2 days after he first began experiencing a light pressure-type discomfort in his left shoulder and scapular region. This pain persisted, waxing and waning, without a clear relationship to exertion or position or movement of his shoulder.

Upon arrival in the ER, his ECG was normal but his cardiac enzymes were slightly elevated (troponin peaking 0.92), thus he was diagnosed with a non-ST elevation myocardial infarction (MI).

He’s done great since the stent procedure fixed the coronary blockage that caused his infarct and chest pain, but during our office visit he related that since his hospitalization he had been feeling “logy.” 

Being a lover of words, my ears perked up at this new-to-me adjective, and I asked him to describe what he meant by logy. For him, loginess was a feeling of fatigue or lacking energy.

Indeed, the online Merriam-Webster dictionary defines logy as sluggish or groggy. It is pronounced usually with a long o and a hard g.

The origin is unclear but has nothing to do with rum:

Based on surface resemblance, you might guess that “logy” (also sometimes spelled “loggy”) is related to “groggy,” but that’s not the case. “Groggy” ultimately comes from “Old Grog,” the nickname of an English admiral who was notorious for his cloak made of a fabric called grogram – and for adding water to his crew’s rum. The sailors called the rum mixture “grog” after the admiral. Because of the effect of grog, “groggy” came to mean “weak and unsteady on the feet or in action.” No one is really sure about the origin of “logy,” but experts speculate that it comes from the Dutch word log, meaning “heavy.” Its first recorded use in English, from an 1847 London newspaper, refers to a “loggy stroke” in rowing.

Fatigue is a common, nonspecific symptom that we all feel at times. It is more common as we age and it can be challenging for both patients and physicians to sort out when it needs to be further evaluated.

Occasionally, fatigue is the only symptom of a significant cardiac condition, but more frequently in the patient population I see it is either noncardiac (low thyroid, anemia, etc.) or iatrogenic

When a patient tells me they are feeling fatigued I immediately scan their med list for potential logigenic drugs.

In this case, my patient had been started on a low dosage of the beta-blocker carvedilol (brand name Coreg) after his stent, and I suspected this was why he had felt logy for the past year.

In cardiology, we utilize beta-blockers in many situations-arrhythmias, heart failure, and heart attacks to name a few, and they are well-known to have fatigue as a common side effect. There was a really good chance that Mr. Jones’s loginess was due to the carvedilol.

It’s important to review all medications at each patient visit to check for side effects, interactions and benefits, and in the case of Mr. Jones’ carvedilol, loginess.

Do All Patients Post-Revascularization or Post-MI Need To Take Beta-Blockers

Beta-blockers (BBs) are frequently started in patients after a stenting procedure or coronary bypass surgery, and continued indefinitely. However, the evidence for their benefit in such  patients with normal LV function long term is lacking.

If any post-revascularization population benefits from BBs, it is those, like Mr. Jones who have had a myocardial infarction (MI, heart attack) prior to the procedure, however the smaller the infarct, the less the benefits.

And with the widespread use of early stenting to treat MI, infarcts are much smaller and dysfunction of the left ventricle (LV) less likely.

In those patients with minimal damage and normal LV function, the benefits appear minimal. For this reason in the last 5 to 10 years I’ve been stopping BBs in this population if there are any significant side effects.

An “Expert Analysis” published in JACC in 2017 noted that:

A 2015 meta-analysis of 10 observational acute MI studies including more than 40,000 patients showed that beta-blockers reduced the risk of all-cause death  However, the benefit of these agents was not found in all subgroups and seemed confined to the patients with reduced LVEF, with low use of other secondary prevention drugs, or NSTEMI.

In a study of almost 180,000 patients post MI with normal LV systolic function in the UK between 2007 and 2013 there was no difference in mortality at one year in patients discharged with or without beta-blockers.

The only way to answer this question definitely would be with a randomized controlled trial and, to my surprise and delight, such a study (CAPITAL-RCT (Carvedilol Post-Intervention Long-Term Administration in Large-scale Randomized Controlled Trial) was published in PLOS One in August of 2018.

I’ll save readers the details, but the bottom line is that patients treated with optimal contemporary therapy for acute MI, whose LV function was not significantly impaired, did not benefit in any way from treatment with carvedilol, the beta-blocker my patient was taking.

It’s rare that we get such definitive evidence for a change in treatment that reverses what is in current guidelines. This has the potential to affect tens of thousands of patients and improve their quality of life. It should be trumpeted far and wide. The cynic in me suspects that if it were a study demonstrating the benefits of a new drug, physicians would be bombarded with the new information.

Helping Patients Feel Less Logy

We will be ordering an echocardiogram on Mr. Jones, and if his LV function is normal we will stop his carvedilol and see if he feels significantly better.  

I feel like stopping a drug that is not beneficial and that is causing a lifetime of loginess is an incredibly important intervention a cardiologist can make. It’s not as life-saving as stenting for acute MI, but saving quality of life is something this non-invasive cardiologist can do every day for every patient.

Skeptically Yours,

-ACP

N.B. The summary of the recent CAPITAL-RCT:

STEMI patients with successful primary PCI within 24 hours from the onset and with left ventricular ejection fraction (LVEF) ≥40% were randomly assigned in a 1-to-1 fashion either to the carvedilol group or to the no beta-blocker group within 7 days after primary PCI. The primary endpoint is a composite of all-cause death, myocardial infarction, hospitalization for heart failure, and hospitalization for acute coronary syndrome. Between August 2010 and May 2014, 801 patients were randomly assigned to the carvedilol group (N = 399) or the no beta-blocker group (N = 402) at 67 centers in Japan. The carvedilol dose was up-titrated from 3.4±2.1 mg at baseline to 6.3±4.3 mg at 1-year. During median follow-up of 3.9 years with 96.4% follow-up, the cumulative 3-year incidences of both the primary endpoint and any coronary revascularization were not significantly different between the carvedilol and no beta-blocker groups (6.8% and 7.9%, P = 0.20, and 20.3% and 17.7%, P = 0.65, respectively). There also was no significant difference in LVEF at 1-year between the 2 groups (60.9±8.4% and 59.6±8.8%, P = 0.06).

 

 

 

 

Is there a Yelp for Medications and should you be using it?

The skeptical cardiologist recently prescribed ezetimibe to a patient who was leery of taking statin drugs for her elevated cholesterol. In the past she had taken red yeast rice in the belief that this was a safe and natural way to lower her cholesterol. I told her that I had looked into and researched red yeast rice (and wrote about it here), and that it was neither safe nor effective.

When I saw her back at our next office visit, she informed me that she had done her own research. She had gone on the internet and Googled ezetimibe and based on its “reviews” she felt it was an unsafe and dangerous drug.

It occurred to me at that point that patients like Ms X may actually believe that they can get reliable information on drug side effects and efficacy by going to a website where patients leave reviews on drugs they have taken.

Yelp For Medications

Such sites would be the equivalent of Yelp, which the wife of the skeptical cardiologist utilizes extensively to determine which restaurants we should patronize.

Lo and behold, if one Googles “reviews Zetia” a whole host of websites pop up offering you the opinions of random individuals on the drug.

On Everday Health Zetia gets 2 stars from 34 reviews with the most recent review being quite negative;

I hadRated Zetia for Rheumatoid Arthritis Report BEWARE. My husband took Zetia along with stantin, Crestor. Within a week, his leg muscles inflamed and shut down his kidneys and liver. He has been in the hospital for over a month and his condition has not improved. He’s on dialysis and can not walk. He is an alcoholic and his liver failed with Zetia.

The 234 reviews of Zetia on WebMD (another site I don’t recommend) are also pretty negative. Here’s a typical one;

Low dose of Zetia ….After just first days had severe diarrhea, halfed the dose. After a month I started seeing flashes in my right eye. Lots of eye fatigue, now a lot of ‘floaters’ in my right eye. Got checked by eye doctor to make sure it wasn’t optical nerve damage. Scarey. Coincidence? Don’t think so. 

Limitations of The Yelp Concept In Assessing Medications

I empathize with and totally respect my patient’s desire to do her own independent research on the potential side effects of a drug that she will be putting in her body.

However, the Yelp approach just does not work well for medications.

There are three problems with relying on these kinds of patient-reported medication side effects.

The first is that the patients who leave comments on these sites are not representative of the overall pool of patients receiving the drug. Patients who feel they have been harmed in some significant way are much more likely to be motivated to spend the time recording what happened to them than are the individuals who felt fine after taking the drug.

There were 4 million prescriptions for ezetimibe written in 2015 and the number of patients leaving comments on these patient-review websites at most number in the hundreds. Thus, 99.9% of those taking ezetimibe are being silent, most likely because they are doing fine with the drug.

Secondly, most of the side effects reported by patients after taking ezetimibe occur at about the same frequency in those who take a placebo.

Although the package insert for ezetimibe lists various “common” side effects of the drug (such as diarrhea and upper respiratory infection), this table from the same package insert shows that such ailments are about as common in the group taking placebo.

The manufacturer, following FDA guidelines, reports out adverse reactions that are more common than 2% and numerically greater than placebo, but these are not necessarily significant differences.

Thus, we see that 4.1% of patients taking Zetia had diarrhea, but also that 3.7% of patients taking placebo had diarrhea.

If you take any group of several thousand individuals and follow them for a couple of months, probably 4% will get diarrhea whether or not they are taking ezetimibe.

The Nocebo Effect

Finally, we have to take into account the nocebo effect. The opposite of the placebo effect, in which inert substances make patients feel better, the nocebo effect makes patients who believe a drug will have side effects much more likely to experience those side effects.

The nocebo effect is quite common in patients who have read very negative comments on the internet about statin side effects. It is clear to me that this statin-related nocebo effect has also influenced patients taking non-statin cholesterol lowering medications like ezetimibe.

This is such an important factor in how patient’s tolerate ezetimibe that I spend considerable time during office visits emphasizing that ezetimibe works in a totally different way than statins, and is not associated with muscle aches/myalgias.

Alas, my patient has chosen to rely on the Yelp approach to deciding which medications to take. I’ve given her the best information I could on the safety and efficacy of ezetimibe based on my years of prescribing it and studying it. At this point it is her decision to make, and I accept it and we move forward managing her cardiovascular disease with the other tools in my toolkit.

Unlike an inaccurate restaurant review, however, a single individual describing inaccurately horrific side effects of a medication has the potential to steer thousands of patients away from potentially life-saving therapy.

Skeptically Yours,

-ACP

How Important Are Grapefruit (OR CBD Oil)-drug Interactions? David Bailey vs The Florida Dept. of Citrus

Previously, the skeptical cardiologist described a patient  with atrial fibrillation who was taking the blood thinner apixaban (Eliquis ) and developed a nose bleed after consuming a large amount of grapefruit (see here.)

In researching the whole subject of grapefruit-drug interactions I came across a fascinating intellectual battle between David Bailey, the researcher who first identified a significant grapefruit-drug interaction, and clinicians and researchers, some of whom are supported by the Florida Citrus Board, who feel this interaction is not significant.

What Does The Internet Tell Us?

It’s always interesting to see what patients doing a Google search will see on important medical topics. When I Googled  “grapefruit Eliquis interaction” I saw the following:

Screen Shot 2018-06-22 at 9.56.04 PM

The first item is an ad from the company that makes Eliquis which takes you to their patient-oriented Eliquis site and immediately presents you with important patient safety information. Nowhere on the site is the word grapefruit listed (as of July, 2018).

The second item is what Google calls a snippet and which they will present to you as what they think is the best answer to your Google search question. In this case the snippet  (and the first 4 hits) is lifted from Web MD an absolutely unreliable source of information (see my post on entitled Web Md:Purveyor of bad health information and snake oil) but one which Google (and thus millions of unsuspecting Googlers) relies on for answers to medical questions . Web MD advises you to avoid grapefruit if you’re taking eliquis.

Close inspection of the WebMD article proffering this advice reveals the sole reference that actually bears on this topic: (Bailey et al , 2012 , CMAJ).

The main author of this paper (which has  the oddly phrased title Grapefruit–medication interactions: Forbidden fruit or avoidable consequences? ) is David Bailey.

David Bailey: Rapid Runner and Grapefruit Alarmist

David Bailey may be  better  known as the first Canadian to run a mile in under 4 minutes. His Wikipedia entry spends equal time on his running career and on his major claim to fame: grapefruit drug interactions (GDI).

Bailey serendipitously discovered that grapefruit increased levels of the antihypertensive drug felodipine in his own body in 1987,  information which was pretty much ignored until he published a research paper in the Lancet in 1991 showing a doubling of felodipine levels in 6 volunteers who consumed grapefruit.

Since then studies have shown that grapefruit juice  acts by reducing presystemic felodipine metabolism through selective post-translational down regulation of cytochrome P450 3A4 (CYP3A4) expression in the intestinal wall.

Bailey has taken the grapefruit (and Seville orange) ball and run with it. His publications emphasize the broad scope and potential dangers of multiple grapefruit-drug interactions.  A 2012 Bailey paper  lists 85 drugs with the potential to interact with grapefruit juice including, you guessed it, apixaban.

Despite these potential interactions the actual number of clinically significant interactions or harm reported is minuscule. This has not deterred Bailey from emphasizing the importance of the interaction he discovered.

He is  quoted in a 2012 NY Times article as saying:

“The bottom line is that even if the frequency is low, the consequences can be dire,” he said. “Why do we have to have a body count before we make changes?”

“For 43 of the 85 drugs now on the list, consumption with grapefruit can be life-threatening, “

Articles, like the NY Times article typically  buy into Bailey’s fear-mongering and spend multiple paragraphs describing a single case report suggesting that ingestion of grapefruit juice was responsible for a dangerous  interaction but such cases are rare and strong evidence that grapefruit juice was responsible is not present.

What Can We Learn From The Florida Department of Citrus?

In fact, in a letter to the editor in response to Bailey’s 2012 review, two researchers point out that their is little solid evidence to suggest that the grapefruit-drug interactions are important

We know of no validated evidence that coadministration of grapefruit juice with a drug has caused a dangerous interaction, resulting in serious adverse effects or actual harm to a patient’s health. We point readers to 2 extensive review articles on grapefruit juice–drug interactions that have appeared in peer-reviewed medical literature.2,3 These articles provide a review of primary research literature, a compilation of the extent of interactions with specific drugs, and an evaluation of their clinical importance; however, neither of these publications is cited in the CMAJ article.

Whereas David Bailey has a bias to promote and exaggerate an interaction that is his claim to scientific fame most of the research and reviews that counter his claims come from researchers who are likely heavily biased to minimize the importance of the interaction: they are funded by the Florida Department of Citrus.

Are We Missing Important Grapefruit Medication Interactions?

David Bailey would like  us to believe that the GFDI he identified in 1998 is hugely important. If only doctors would spend more time investigating the grapefruit consumption of their patients we would realize this.  He writes

But how big a problem are such interactions? Unless health care professionals are aware of the possibility that the adverse event they are seeing might have an origin in the recent addition of grapefruit to the patient’s diet, it is very unlikely that they will investigate it. In addition, the patient may not volunteer this information. Thus, we contend that there remains a lack of knowledge about this interaction in the general health care community. Consequently, current data are not available to provide an absolute or even approximate number representing the true incidence of grapefruit–drug interactions in routine practiceThe chemicals in grapefruit involved in this interaction are the furanocoumarins.7

Bailey, goes on to warn us that all forms of grapefruit consumption can lead to dangerous interactions and other citrus fruits are to be feared as well

Because these chemicals are innate to grapefruit, all forms of the fruit (freshly squeezed juice, frozen concentrate and whole fruit) have the potential to reduce the activity of CYP3A4. One whole grapefruit or 200 mL of grapefruit juice is sufficient to cause clinically relevant increased systemic drug concentration and subsequent adverse effects.11,12 Seville oranges, (often used in marmalades), limes and pomelos also produce this interaction.1315 Varieties of sweet orange, such as navel or valencia, do not contain furanocoumarins and do not produce this interaction.2

You can follow his references but they are not to patients who were harmed by grapefruit-drug interactions. Indeed, I am unaware of any of my patients reporting such harm until my patient with the nose bleed. I tend to agree with this unbiased editorial from BMJ in 2013

In our experience, and in that of our experienced colleagues, we have yet to come across clinically meaningful interactions of drugs and GFJ. This is despite our day to day experience of managing patients on statins, calcium channel antagonists, anti-platelet agents and anti-arrhythmics, which covers over 10,000 patients in the last 10 years alone. Likewise, there is little formal evidence of an impact, even from large scale clinical trials, with adjudicated and well documented endpoints.

After considerable research and communication with Pfizer, the maker of Eliquis, I ended up agreeing with Pfizer’s conclusion that the grapefruit-Eliquis interaction was unlikely to be significant:

When consumed in usual dietary volumes, grapefruit juice is considered a moderate inhibitor of CYP3A4. Therefore a dose adjustment of apixaban is not expected to be required.

CBD Oil, Grapefruit And Drug Interactions

I was reminded of the grapefruit-drug interaction in the last few weeks as several of my patients have started using CBD oil for various problems and have asked if it is safe to use with their cardiac medications.

I haven’t fully researched the CBD oil-drug interaction but the top Google search (“grapefruit and CBD oil”) result (from CBD school)  states the following:

CBD interacts with other medications in your body in the same way as grapefruit, only even stronger.

However, the site that CBD school references (Project CBD) is not that definitive about grapefruit-drug interactions being a guide to CBD-grapefruit interactions.

And a recent scholarly article on the topic (see here) concludes

The drug-drug interactions between cannabinoids and various drugs at the CYP level are reported, but their clinical relevance remains unclear.

Which sounds very similar to where we are at with grapefruit-drug interactions in general.


I had my patient perform an experiment to see if the grapefruit actually caused her nose bleed. She repeated her consumption of large amounts of grapefruit and had no nosebleed this time.

Nonepistaxisly Yours,

-ACP

Is Pitavastatin (Livalo) A Better Statin For You?

The skeptical cardiologist recognizes that perhaps 10% of patients he starts on a statin drug will develop symptoms that are felt to be due to the drug.

Most often the symptom is myalgia-muscle ache.

But other symptoms may develop after the patient starts the drug and given widespread statin fear-mongering on the internet it is common for these symptoms to be attributed to the statin.

Recently a reader left comments on my post on statins and memory problems describing in detail what appears to be a statin side effect:

My doctor had me on a daily 40mg Lipitor. After about 1 month, I noticed that my short term memory was very bad*. (Not a nocebo effect… I had no idea at the time that statins were linked to memory effects.) I did an experiment on myself. I suspected that my memory problems were the result of the statin. (Nothing else seemed to be different besides the fact that I had started taking Lipitor the previous month.) After 2 weeks off of Lipitor, my memory problems went away. Whew. I put myself back on Lipitor (I didn’t want to die of a heart attack, and my “experiment” could have been a victim of confirmation bias + 100 other faults.) After about a month, crappy short term memory returned. Took myself off Lipitor again. AGAIN, after about 2 weeks, by memory was fine again.
Perhaps my experiment wasn’t scientific. Just one subject (me). 100% anecdotal. Perhaps statins are good for your heart. However, I don’t know about you, but I program computers for a living. Try doing that with crappy short term memory. Hint: you can’t do it.

I’ve outlined my approach to these potential statin associated symptoms (PSAS) previously (see here) and if a patient has resolution of the PSAS we typically try another statin to see if the PSAS recurs.

For my reader, it would make sense to try a statin like rosuvastatin or pitavastatin that is hydrophilic and therefore doesn’t cross the blood-brain barrier and enter the brain.

For the more common myalgias I typically try rosuvastatin at lower dosage. If symptoms recur on rosuvastatin I try pitavastatin.

Pitavastatin (Livalo)

Pitavastatin (Livalo) is the seventh statin. It is minimally affected by the cytochrome P450 system (meaning less drug-drug interactions),  water soluble (so it doesn’t enter the brain,) and does not lower Co-enzyme Q10.  These special biochemical characteristics raise the possibility that  among patients who have not been able to tolerate other statins it might be both usable and efficacious.

It has been used in Japan since 2003 and was approved by the FDA for US use in 2010. The Medical Letter was pretty negative about it in 2010 and feels the same way about the recently approved zypitamag (pitavastatin magnesium.)

The Medical Letter’s review of pitavastatin calcium concluded that recommended doses of the drug had not been shown to decrease LDL-C more than other statins with longer safety records and there was no good reason to use it. That conclusion applies to pitavastatin magnesium as well.

Tom Dayspring, the “national treasure” and lipidologist disputes this and has written of the Medical Letter conclusions

Any statin that has been tested in an outcome trial has been successful and there is no reason why pitavastatin would not also reduce events. Most providers used every statin for years before there were outcomes! Pitavastatin was as successful in
regressing plaque volume as was atorvastatin in an IVUS trial called JAPAN-ACS ((J Am Coll Cardiol 2009;54:293–302). The claim regarding LDL lowering is erroneous as pitavastatin is actually more efficacious than fluvastatin, pravastatin, lovastatin, and 10 & 20 mg doses of simvastatin and the last sentence in the Medical Letter using the word “worrisome” is both ridiculous and 100% false – The pharmacokinetics of pitavastatin are extremely clean, better than all of the more lipophilic statins now on the market except fluvastatin (read the reference cited above which compares pitavastatin to all other statins using published data not invective). I cannot remember the last branded drug that was not first in its class to be released that the Medical Letter found any use for including Crestor which is why personally I find little use whatsoever for recommendations of the medical letter.

The Medical Letter does provide a nice summary of statins effectiveness and cost. As you can see Livalo (and any brand name statin) costs a lot more than generic rosuvastatin (276$ versus 8$) and is less effective

statins.png

 

Thus, there is no reason to use any brand name statin unless you have developed side effects on two generic statins with the second one being low dose rosuvastatin.

Anecdotal Pitavastatin Success

Four years ago I identified by vascular screening in one of my patients, a 65 year old woman a >50% blockage in the left  carotid artery.

We started her on 40 mg atorvastatin and she developed a rash. She was switched to rosuvastatin 10 mg and began waking up in the middle of the night with a headache and feeling light-headed. I thought it unlikely this symptom was due to the statin.

She requested that we go back to atorvastatin because she felt it likely the rash was from something else.one month later, complains of arms and legs are very sore and hard time getting dressed in the morning due to soreness. also constipated

We stopped the atorvastatin and a month later she called back indicating that she could feel her arteries clogging.

At this time we started Livalo at 2 mg twice weekly. LDL dropped by 50% to 71 mg/dl and she has tolerated it without side effects ever since.

Supporting Data

Beyond anecdotal support for pitavastatin in the statin intolerant patient we have one abstract presented at the ACC meetings in 2013.

A total of 40 consecutive patients with documented intolerance to any dose of at least two different statins were prospectively enrolled into a protocol whereby they received a trial of pitavastatin therapy at a dose of 2 mg per day.

Forty patients were enrolled and 27 of them (68%) were able to tolerate pitavastatin. LDL cholesterol was reduced from 147±27 mg/dL to 93±25 mg/dL, resulting in an average LDL-cholesterol reduction of 34%. Patients who could best tolerate pitavastatin tended to be males and those with no history of coronary artery disease or diabetes.



Despite what the Medical Letter says about pitavastatin I tend to agree with Tom Dayspring and I and most progressive preventive cardiologists will give pitavastatin at least a trial in our high risk patients with PSAS before giving up on statins in them.


Hydrophilicly  Yours,

-ACP

N.B. Pitavastatin was discovered in Japan by Nissan Chemical Industries and developed further by Kowa Pharmaceuticals, Tokyo. It has been extensively studied in Japanese studies.

The Livalo website tries to hint that their drug might be better/safer for those of Japanese ethnicity but the science on this is not clear. A review on the topic concludes

Pharmacokinetic investigations have noted higher plasma levels of statins in Asians compared with Caucasians, although postmarketing data for all statins have not identified any particular safety issues, even when statins are given at equivalent doses. The potential mechanisms of heightened response to statins in Asians are related to genetically based differences in the metabolism of statins at the level of hepatic enzymes and drug transporters. Studies indicate that lower statin doses achieve lipid improvements in Asian patients comparable with those observed with higher doses in Caucasians. In conclusion, prescribing lower starting doses of statins in Asians appears warranted while research on this subject continues.

Becoming Enlightened About More Stringent Blood Pressure Goals: Sapere Aude!

The skeptical cardiologist and many of his patients with hypertension have a decision to make: what should our BP goal be?

Given that we have data now on over 1 million patients one might think that the answer would be clear and that there would be a consensus amongst all the experts.

Messerli and Bangalore, writing in a recent special hypertension issue of JACC, however, clearly articulate the “blood pressure landscape schism” that currently exists.

This figure from their paper (subtitled “Schism Among Guidelines, Confusion Among Physicians, and Anxiety Among Patients”) shows the marked difference in BP goal and treatment recommendations for the same patient in recent American and  European Cardiology and American Family Practice Guidelines.

The 2017 American College of Cardiology (ACC)/American Heart Association (AHA) guidelines—which aide approximately 25,000 cardiologists in the United States—indicate that her BP should be <130/80 mm Hg (1). The 2018 European Society of Hypertension (ESH)/European Society of Cardiology (ESC) guidelines—which aide approximately 75,000 physicians—indicate that her BP should be <140/90 mm Hg (2). The 2017 American College of Physicians (ACP)/American Association of Family Physicians (AAFP) guidelines—which aide approximately 250,000 family practitioners and internists in the United States—indicate that her BP should be <150/90 mm Hg

 

 

 

 

 

 

 

 

 

 

 

Messerli and Bangalore use a second figure to graphically illustrate the potential consequences of the differing guidelines.

Stroke Mortality for Upper Limit of On-Treatment Systolic Target BP as per Various Guidelines Absolute risk of stroke mortality is 5% for the suggested on-treatment target BP of the ACC/AHA guidelines, 8% for target BP of the ESH/ESC guidelines, and 14% for target BP of the ACP/AAFP guidelines. Abbreviations as in

Cardiovascular death rates thus may vary three-fold depending on what BP goal we choose.

This marked variation in treatment recommendation highlights that they

are not only an evaluation and interpretation of evidence in question, but also a judgment weighted by personal, regulatory, and organizational preferences that can vary from physician to physician within a country and across geographical regions.

Physicians and patients (hopefully through shared decision making) are going to have to do some thinking on their own.

Messerli and Bangalore quote Immanuel Kant in this regard:

Enlightenment is man’s emergence from his self-imposed nonage. Nonage is the inability to use one’s own understanding without another’s guidance. This nonage is self-imposed if its cause lies not in lack of understanding but in indecision and lack of courage to use one’s own mind without another’s guidance. Dare to know! (Sapere aude.) “Have the courage to use your own understanding,” is therefore the motto of the enlightenment.

As a 64 year old who has emerged from his nonage with hypertension, I have carefully examined the latest American hypertension guidelines especially in light of the SPRINT study and elected to add a third anti-hypertensive agent to get my average BP below 130/80. It’s worked for me with minimal  side effects but I carefully monitor my BP.

If I notice any symptoms (light-headed, fatigued) suggesting hypotension associated with systolic BP <120 mm Hg I tweak my medical regimen to allow a higher BP.

Like all of my patients I would prefer to be on less medications, not more but when it comes to enlightenment about the effects of hypertension, it is now clear that lower is better for most of us in our sixties down to at least 130/80*.

Sapere Audaciously Yours,

-ACP

*N.B. In the SPRINT study the BP was obtained using an automatic BP cuff after 5 minutes of rest with the patient unobserved and averaging 3 recordings one minute apart.

This “research grade BP” averages about 12 mm Hg less than a routine single clinic obtained BP (see here.)

The BP Schism

What’s The Best Treatment For Seasickness? Part I, What Won’t Work Well

While stocking up on key items for our Galapagos cruise, the eternal fiancée of the skeptical cardiologist (EFOSC) bought an item that set off the skeptical cardiologist’s (extremely sensitive) BS detector.

Once I began looking into the seasickness treatment options and science I soon realized that the vast majority of OTC medications, patches and devices offered are snake oil.

There is one highly effective treatment which requires a prescription, one possibly effective OTC treatment which will likely put you to sleep, and one very slightly effective treatment which will also likely put you to sleep.

First let’s look at the totally bogus patch Jen purchased.

It calls itself a “motion sickness patch.” It is manufactured in China. (Somebody should put a tariff on this junk!)

It also carries the allure of being natural which people (mistakenly) assume means free of side effects.

Since most people have heard of an effective motion sickness patch, they naturally assume that this is legitimate. 

It appears to be highly rated on Amazon with 80% of over a thousand reviewers giving it 4 or 5 stars. However, 10% of reviewers give it 1 star, usually commenting that the MQ patches were useless  and were purchased as they were cheaper than the prescription patch that worked for them before.

And it is no surprise that it doesn’t work for many because the ingredients would not be expected to have any effect on motion sickness.

The main Ingredient are listed as

safflowertall,gastrodia,tuber,sanchi,hairy datura flower,borneol,pinellia tuber,obtuseleaf cinnamon bark,frankincense,dahurian angelica root,etc.

Yes, in these patches you get the added bonus of “etc.” in the formulation!

In case you needed more explanation of how this works, check out the bizarre “working theory” of the mysterious ingredient’s efficacy:

Working theory
1. Adjust the control of the vagal nerve to gastrointestinal tract, inhibit the motility of the gastrointestinal, thus preventing nausea and vomiting.
2. By expanding the capillaries of the skin, to improve the microcirculation of body and increase the amount of oxygen to brain, thus comes to the effect of refreshing your brain.

All I can say about those who have experienced relief with this MQ nostrum is “the placebo force is strong with you!”

After reading the reviews for the MQ patch and  listening to an NPR story on paid Amazon product reviews  my faith in Amazon product reviews is at an all time low.

Similarly, most of the sites on the internet which promise to give you the top 10 products in a certain area I have found to be bogus. For example, the amazingly useless MQ motion sickness patch is ranked #5 on the “Best Reviews” Guide to Motion Sickness.

Bonine

The second product the EFOSC purchased online was the oddly-named Bonine.  Bonine is the brand name for meclizine, a first-generation antihistamine with anti-cholinergic properties which is often prescribed for benign positional vertigo.

There is not much evidence supporting meclizine for sea sickness but it is widely used owing to its accessibility and marketing. Like all first-generation antihistamines, it will make you drowsy. Before the second generation, non-sedating antihistamines were introduced, I would walk around in a zombie-like state when my allergies required an antihistamine.

Keep in mind you can get a prescription for 30 tablets of meclizine 25 mg for about 12$.

Acupressure

More evidence that the placebo force is particularly strong in the motion sickness world is the widespread marketing, sales and testimonials to “acupressure”  devices.

The EFOSC with her Sea Band. She likes to wear it because it is blue and white, her favorite colours.

The EFOSC suffers from car sickness and several years ago purchased something called the  Sea Band.

Wrist bands like the Sea Band claim to reduce nausea and other symptoms of seasickness through stimulation of the “P6/Neiguan” acupuncture point by applying acupressure or electrical acustimulation.

These work primarily through placebo effect and studies have shown a “sham” acupressure band works as well as a real one.

One fascinating study examined  a self-fulfilling prophecy (SFP) approach to combating seasickness:

the authors experimentally augmented the self-efficacy of naval cadets by telling them that they were unlikely to experience seasickness and that, if they did, it was unlikely to affect their performance at sea. Naval cadets (N = 25) in the Israel Defense Forces were randomly assigned to experimental and control conditions. At the end of a 5-day training cruise, experimental cadets reported less seasickness and were rated as better performers by naive training officers than were the control cadets

The EFOSC is gravely concerned about debilitating seasickness during our 8 days on the Samba. To maximize the placebo force in her I should have emphasized how well the Sea Band and the MQ patch work. Hopefully she won’t read this post.

In Part 2 of the Best Seasickness Treatment I’ll discuss transdermal scopolamine and dramamine, the treatments with the best evidence for efficacy, safety and tolerability.

I’ll also examine the evidence for ginger.

What’s been your experience with sea sickness and treatments for sea sickness?

Vertiginously Yours,

-ACP

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/)