Statins have no side effects? What our study really found, its fixable flaws, and why trials transparency matters (again).

March 13th, 2014 by Ben Goldacre in alltrials campaign, bad science, placebo | 20 Comments »

telesillyHi there, sorry to be absent (dayjob!). I was surprised to see a study I’m a co-author on getting some front page media play today, under the headline “Statins ‘have no side effects'”. That’s not what our paper found. But it was an interesting piece of work, with an odd result, looking at side effects in randomised trials of statins: specifically, and unusually, it compares the reports of side effects among people on statins in trials, against the reports of side effects from trial participants who were only getting a dummy placebo sugar pill. 

Remarkably, people report typical statin side effects even when they are only receiving a placebo: the phenomenon of people getting unpleasant symptoms simply because they expect to is fairly well-documented, and it’s called the nocebo effect, the evil twin of the placebo effect. Here’s a piece I wrote a piece on the nocebo effect a while ago, specifically reviewing some of the earlier studies where people report side effects even when they’re only getting a placebo in a trial. It’s remarkable:

Can a sugar pill have a side effect? Interestingly, a paper published in the journal Pain next month looks at just this issue. They found every single placebo-controlled trial ever conducted on a migraine drug, and looked at the side effects reported by the people in the control group, who received a dummy “placebo” sugar pill instead of the real drug. Not only were these side effects common, they were also similar to the side effects of whatever drug the patients thought they might be getting: patients getting placebo instead of anticonvulsants, for example, reported memory difficulties, sleepiness, and loss of appetite, while patients getting placebo instead of painkillers got digestive problems, which themselves are commonly caused by painkillers.

This is nothing new. A study in 2006 sat 75 people in front of a rotating drum to make them feel nauseous, and gave them a placebo sugar pill. 25 were told it was a drug that would make the nausea worse: their nausea was worse, and they also exhibited more gastric tachyarrhythmia, the abnormal stomach activity that frequently accompanies nausea.

paper in 2004 took 600 patients from 3 different specialist drug allergy clinics and gave them either the drug that was causing their adverse reactions, or a dummy pill with no ingredients: 27% of the patients experienced side effects such as itching, malaise and headache from the placebo dummy pill.

And a classic paper from 1987 looked at the impact of listing side effects on the form which patients sign to give consent to treatment. This was a large placebo-controlled trial comparing aspirin against placebo, conducted in three different centres. In two of them, the consent form contained a statement outlining various gastrointestinal side effects, and in these centres there was a sixfold increase in the number of people reporting such symptoms and dropping out of the trial, compared with the one centre that did not list such side effects in the form.

Now, this has real world implications. If we tell people about side effects, and in doing so, we induce these unpleasant symptoms, then we are inflicting harm on our patients. Inflicting harm isn’t so unusual in medicine, in the process of doing good, but we aim to ensure that overall we do more good than harm, and in particular we aim to produce and share good quality information, so that patients can make informed decisions about the treatments they take.

With that in mind, we have a responsibility to try and establish good quality evidence on side effects, and in particular to nail down how far these side effects are genuinely being caused by the drugs. We certainly shouldn’t give false reassurance; but we also shouldn’t scare people into experiencing side effects; or scare them into avoiding a medication which might help them. (Some people get a bit melodramatic about statins, as if they’re being forced down our throats: the evidence shows they reduce your risk a bit if you’re at high risk of a heart attack; they’re less helpful – but still a bit helpful – if you’re low risk; and if you decide you don’t want to take them, after being appraised of the evidence, well, that’s easy, don’t take them).

newbookAs I explain in Bad Pharma, we are generally pretty imperfect at monitoring side effects, partly because it’s a hard job to do, and partly because there’s still a lot of dismal secrecy around: the WHO Uppsala side effects monitoring centre withholding information from researchers is a particularly disappointing example of this, as is the European Medicines Agency’s silly and rather self-defeating secrecy around the content of full Risk Management Plans.

And that brings me to the central flaw in our study. As we say in the text, the side effects information we were able to work with, from trial publications, is likely to be incomplete: the trial reports varied in what side effects they reported, they often failed to describe their methods for spotting and reporting side effects very well, and companies may not be highly motivated to put a lot of side effects data into their academic papers (to say the least).

Since the last draft of the paper (time moves slowly in academic publishing…) our knowledge of these flaws has deepened. I wrote in Bad Pharma about how side effects information can be buried, and the importance of access to something called the Clinical Study Report about a trial: these are very long and detailed documents that give a huge amount of detail about the methods and results of a trial, and they’re important, because methodological flaws can often be glossed over in the brief report on a clinical trial that appears as an academic journal paper. This is why asking for CSRs to be shared is one of the key asks of the AllTrials campaign, which I co-founded last year.

In a recent paper, we got a much clearer picture of how much information is missing: researchers from IQWiG (the German equivalent of NICE, but more muscular) compared CSRs against academic papers, side by side, and worked out exactly how much was missing from the journal publications. They found that CSRs consistently report much more complete information on methods and results. Table 3 is the money shot, most easily seen in the PDF: the amount of missing information on side effects in journal reports is particularly bad.

When I saw that the statins paper was finally coming out this week I tried to make an amendment, in amongst the many caveats in our discussion section (trial participants are often unrepresentative of everyday patients, as explained in Bad Pharma, etc…) but sadly I was too late. Here’s the small addition I wanted to make (in bold):

Comparison with real-life clinical experience

Many real-world patients report muscle-related symptoms with statins. This contrasts with the low placebo subtracted rate in blinded trials shown in this meta- analysis. Several explanations are possible. First, commercial sponsors of clinical trials may not be motivated to search exhaustively for potential side effects. One pointer towards this is that, although liver transaminase elevation was documented in the majority of trials, new diagnosis of diabetes was only documented in three of the 29 trials. It is also likely that side effects data is collected, but not reported in the academic paper: a recent study by IQWiG, the German government’s cost effectiveness agency, found complete information for 87% of adverse event outcomes in the standard lengthy regulatory document for industry trials (the Clinical Study Report) but for only 26% of adverse event outcomes in the journal publication [Wieseler 2014]. Second, many trials do not state clearly how and how often adverse effects were assessed….

Wieseler B, Wolfram N, McGauran N, Kerekes MF, Vervölgyi V, Kohlepp P, et al. Completeness of Reporting of Patient-Relevant Clinical Trial Outcomes: Comparison of Unpublished Clinical Study Reports with Publicly Available Data. PLoS Med. 2013 Oct 8;10(10):e1001526.

That certainly doesn’t mean I think our paper is wrong. I think it’s a useful illustration of how we could – and should – gather side effects data from trials, and use this alongside other sources of imperfect information. This is especially true for commonly prescribed treatments like statins, because normally trials are too small to spot side effects, whereas here we have large enough numbers of participants in the trials, and a good chance of detecting and documenting rarer adverse events. Lastly, trial participants are subject to a very high level of scrutiny, so it’s a colossal missed opportunity if we fail to exploit that and document side effects as well as benefits.

So, overall, I think our paper uses the right method, on an important question, but our data was flawed.

And there’s an easy way to fix that. I’d like to repeat the study, using the CSRs on the trials as the source data on side effects, rather than the academic journal papers. That is a big piece of work, because companies generally refuse to share CSRs (although GSK have promised to, in signing up to AllTrials), while some like Abbvie and InterMune even sue regulators to keep them secret. Then, once you’ve finally managed to obtain these documents, they are huge and unwieldy, as the Cochrane group who’ve gone through the Tamiflu ones can attest.

But that would be the way to get a proper answer, and it would also have the interesting side effect of showing whether side effects really are obfuscated, in the editing process that happens between a lengthy and complete (but inaccessible) CSR, and a brief academic journal publication for doctors and researchers to read. If there was a big difference, that, I think, would be big potatoes.

If anybody wants to fund that, or has a year of a full time researcher to donate, I’m ben@badscience.net, please get in touch.

Lastly, though, if the findings from our paper are correct – and I’m fairly certain that muscle ache on statins, for example, often is a product of the nocebo effect – then this is yet another illustration of the remarkable power of the mind over the body.

There’s a ton of content about the placebo effect on this site (including a couple of BBC documentaries I did, all here). Lastly, after all that data and talk of ICH-GCP compliant Clinical Study Reports, here’s a video of me shouting on stage at the Hammersmith Apollo about the nocebo effect. See you soon!

 

 

 


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20 Responses



  1. davidrodgers said,

    March 13, 2014 at 10:49 pm

    HI Ben, thanks for this. Out in GP land it’s something I worry about when starting a patient on any treatment – is counselling re side effects triggering them to have the symptoms? Without good data it’s impossible to chart a course between scaring a patient and truly informed consent. It’s one thing consenting a patient for a surgical procedure where we should know the rough odds of serious mishaps, quite another to tease out risks for say an SSRI or a calcium channel blocker. Unfortunately I often resort back to “in my experience” which sticks in my mouth somewhat. There’s no good reason why we don’t have the evidence to work from.

  2. istrich said,

    March 15, 2014 at 5:48 pm

    With all due respect Dr Goldacre, how can you let this paper you sign as a third author be published without your real opinion printed ? You should have thought about it before submission, not during the review process ! Or maybe your co-authors don’t agree.

    In addition (I couldn’t access the full paper), you don’t discuss the run-in phase issue.
    Many RCTs have a run-in phase: all patients not tolerating the drug will be excluded. This theoretically aims at reducing drop outs. Of course it also minimizes the number of side effects in the treatment arm of the RCT, thus ruining external validity. CSRs would be useful here.

    Plus: what about unknown unpublished studies ?

  3. Ben Goldacre said,

    March 15, 2014 at 7:39 pm

    Hi there, the new evidence on relative completeness of CSR vs journal (confirming with figures what everyone has assumed for a long time) came out between final manuscript and publication, and I wasn’t fast enough to get it in. To be clear, the limitation I describe in this post is just one more to add to half a dozen already described in the paper, and is partially covered in the paper since it discusses how side effects may not be reported in journal articles. It is well known and well discussed that trial participants are often not representative of real world patients. In fact I was amused to see senior doctors working in pharma claim that such a thing was outrageous and impossible, when Bad Pharma came out, since it’s covered on basic undergraduate ebm teaching…

  4. stevedc said,

    March 16, 2014 at 4:20 pm

    It appears that the paper is saying that muscle aches/pains may be due to nocebo. I find that unlikely, especially as previous cohort studies have found that statin users, especially physically active statin users, are more likely to experience not just musculosketal pain, but musculoskeletal injuries (sprain/strains) and that statins may delay muscle repair (even post-exercise). There may also be a link between Vitamin D and statin-related muscle pain.

    It would be interesting if this study had not only looked at a 10x increase in CK as the cutoff, and had looked at percentage in each group that had any value increased from normal range. It would also be interesting to see if the people who did report muscle pain and have elevated CK also had decreased VitD. Next it would be interesting to see correlate ubinquinone levels…

  5. Majikthyse said,

    March 18, 2014 at 9:41 am

    istrich, you have misunderstood what a run-in phase is. In my 40 years of experience it has always been a placebo phase, when used, so has nothing to do with excluding patients who don’t tolerate the drug. Patients with known conditions incompatible with the study drug will of course be excluded from the trial, and those exclusions are transferred to the labelling of the drug when it gets to market.

  6. JP Sand said,

    March 18, 2014 at 6:03 pm

    I am replying further to foregoing comments by Istrich and Majikthyse, regarding factors that may skew the population of a Randomized Controlled Trial in a manner that makes the study’s conclusions less applicable, or more applicable, to the general population. BTW, Istrich is correct: RCTs may have a run-in phase whereby all patients not tolerating the drug will be excluded from the study.

    Moreover, there are at least FOUR TYPES OF PRERANDOMIZATION RUN-IN PHASES that may be used; singly, or in various combinations, prior to commencement of a randomized controlled drug trial:

    1) RUN-IN PHASE THAT SCREENS SUBJECTS FOR ADHERENCE

    2) RUN-IN PHASE THAT SCREENS FOR PLACEBO RESPONSE

    3) RUN-IN PHASE USING THE DRUG TO SCREEN CLINICAL RESPONSE

    4) RUN-IN PHASE THAT ENHANCES CLINICAL APPLICABILITY

    See JAMA ARTICLE: “Run-in Periods in Randomized Trials: Implications for the Application of Results in Clinical Practice”, Pablos-Mendez et al, 1998. (Link to free full text pdf: mres.gmu.edu/pmwiki/uploads/Main/RunInTrialsRCT)

    ABSTRACT: Prerandomization run-in periods are being used to select, or exclude, patients in an increasing number of clinical trials, but the implications of run-in periods for interpreting the results of clinical trials and applying these results in clinical practice have not been systematically examined. We analyzed illustrative examples of reports of clinical trials in which run-in periods were used to exclude noncompliant subjects, placebo responders, or subjects who could not tolerate or did not respond to active drug.

    ~ The Physicians’ Health Study exemplifies the use of a prerandomization run-in period to exclude subjects who are nonadherent, while recent trials of tacrine for Alzheimer disease and carvedilol for congestive heart failure typify the use of run-in periods to exclude patients who do not tolerate or do not respond to the study drug. The reported results of these studies are [internally] valid. However, because the reported results apply to subgroups of patients who cannot be defined readily based on demographic or clinical characteristics, the applicability of the results in clinical practice is diluted. Compared with results that would have been observed without the run-in period, the reported results overestimate the benefits and underestimate the risks of treatment, underestimate the number needed to treat, and yield a smaller P value.

    ~ The Cardiac Arrhythmia Suppression Trial exemplifies the use of an active-drug run-in period that enhances clinical applicability by selecting a group of study subjects who closely resembled patients undergoing active clinical management for this problem.

    ~ Run-in periods can dilute or enhance the clinical applicability of the results of a clinical trial, depending on the patient group to whom the results will be applied. Reports of clinical trials using run-in periods should indicate how this aspect of their design affects the application of the results to clinical practice.

  7. Joe Graedon said,

    March 18, 2014 at 6:50 pm

    Ben,

    If you think myopathy is just a nocebo effect of statins…you have not been paying attention. Do you not find it fascinating that in the JUPITOR trial Crestor triggered myopathy in 12.7% of subjects and placebo triggered myopathy in 12.1% of volunteers? In Lipitor RCTs the incidence of “musculoskeletal pain” was 3.2% with drug and 3.6% on placebo. In the Livalo RCTs the incidence of myopathy was 1.9% with 1 mg and 1.4% with placebo. So…digest that data for a moment.

    The placebo incidence of myopathy in the JUPITOR trial was 12.1% but in the Livalo trials it was 1.4% How do you account for the dichotomy?

    Read our blog to get the answer! You will also find our take on the flaws in RCTs:
    tinyurl.com/nokaw78
    Maybe they are not the “gold standard” everyone imagines.

  8. Majikthyse said,

    March 19, 2014 at 9:45 am

    JP Sand, thanks for correcting me. But note that all adverse events detected in any kind of run-in phase must also be reported. They do not simply disappear. If they somehow don’t turn up in a journal publication, that would be unethical and unscientific, but they would have to be in the CSR.

  9. Majikthyse said,

    March 20, 2014 at 6:30 pm

    I just asked some colleagues about run-in periods, and like me they have only very rarely encountered them. They do not feature in most drug development studies, so if they do occur they could not have a significant effect on pooled data.

  10. AndersHernborg said,

    March 22, 2014 at 8:32 pm

    Hi Ben!
    First I´d like to say I admire your work and your energy around these issues. Myself I am a retiring Swedish GP and I have worked a lot of yrs in our local Drugs & Therapeutics Comittee. Your interpretation of the results of your study being caused mainly by nocebo effects I do not buy. I was around seing a lot of elderly people long before statins were in common use. Then, as today, these patients frequntly report a lot of different symtoms from their legs: weakness, muscle cramps, tingeling sensations, dumbness, pains of various types etc. I would rather say that behind the results of your study, in most cases, is a “normal” background frequency of complaints, that of course are reported in both statin ans placebo arms.
    Certainly there are some muscle symtoms caused by statins, symtoms that can worsen quality of life, but are very seldomly serious. So you should interview patients on statin regarding such complaints and if they are not marginal you should stop statins, se what happen over a few weeks and if they disappear, provoke by restarting statins to try to decide whether they cause the symtoms.
    And I totally agree that in low risk patients the small absulute benefit is marginal.

    Anders Hernborg, Halmstad, Sweden

  11. AndersHernborg said,

    March 25, 2014 at 10:06 am

    As my posting from 3 days back has not been published ( myself i can read it when I´m logged in, but no one else…)
    I give it another try:

    Hi Ben!
    First I´d like to say I admire your work and your energy around these issues. Myself I am a retiring Swedish GP and I have worked a lot of yrs in our local Drugs & Therapeutics Comittee.
    Your second time interpretation of your study results being caused mainly by nocebo effects I do not share. I was around, seing a lot of elderly people long before statins were in common use. Then, as today, these patients frequntly report a lot of different symtoms from their legs: weakness, muscle cramps, tingeling sensations, dumbness, pains of various types etc. difficult to give a diagnose. I would rather say that behind the results of your study, in most cases, is a “natural” background frequency of complaints, that of course are reported in both statin arms and placebo arms.

    Certainly there are some additional muscle symtoms caused by statins, symtoms that can worsen quality of life, but are very seldomly serious. So I think you should interview patients on statin regarding such complaints and if they are not marginal you should stop statins, see what happens over a few weeks and if they disappear, provoke by restarting statins to try to decide whether they cause the symtoms.

    And I totally agree that in low risk patients the small absulute benefit is marginal.

    Anders Hernborg, GP, Halmstad, Sweden

  12. JP Sand said,

    March 27, 2014 at 8:25 pm

    Ben, it is Ben right?

    Being of a curious mind, I just clicked on the YouTube video link that you posted above.

    I must say, at first I was delighted to see a rather odd character tottering across the stage in a floral frock and a frizzled head of hair. I thought, oh my, Susan Boyle has come to sing us a song. Then, she balled up her tiny fists and shrieked that she was going to “skull-fuck” us with her “data cock”.

    I rubbed the sleep out of my eyes, and then I saw more clearly: THAT’S NOT SUSAN BOYLE, THAT’S BEN GOLDACRE!

    Still, the resemblance is uncanny.(See here: www.youtube.com/watch?v=RxPZh4AnWyk)

    By the way, if I were an epidemiologist, I’d wash your mouth out with soap.
    ____________________________________________________________

  13. David Bailey said,

    March 29, 2014 at 8:30 pm

    Ben,

    I am not a medical doctor, but I am essentially certain that you are wrong about statin side-effects. I took simvastatin (40 mg) for 3 years before I suddenly got severe cramping pains in my right leg, which was weakened by childhood polio. I thought I had Post Polio Syndrome, but fortunately I remembered that statins could have muscle side effects – though my doctor had assured me that these would happen within a week or two of starting treatment.

    I experimented stopping and starting simvastatin three times, and was amazed that the symptoms eased and reappeared as I stopped and started the drug (with a delay of about 1 week). It took about 9 months of not taking statins to return me to normal vigor.

    I realised that I could have been a rare exception, but as I talked to friends and colleagues about my experiences, I discovered that many had either had bad experiences with statins, or knew others who had. Indeed, a friend had asked me if I took statins, and warned me that they might be responsible for my problems. As she is not a doctor, I had ignored her advice! If statin side effects were really rare, I would not have expected to meet anyone with similar problems.

    Your book describes in excruciating detail the sins of the pharmaceutical industry, and I can’t begin to understand why you endorse the safety of statins based on secret industry data!

  14. Ben Goldacre said,

    March 29, 2014 at 10:00 pm

    Observational data overstates side effects, randomised trial data should give a more accurate estimate, but probably underestimates side effects for the reasons we explain in our paper, and for the extra reason i explain above. You feel you had side effects. As a matter of principle, in a world full of doctors giving readers health advice, I’ve decided not to do that, and to focus on explaining evidence instead. For similar reasons i wouldn’t content on your personal experience of side effects. But as i said above, anyone who has side effects from a treatment, which they feel outweigh the benefits, can simply stop taking that treatment.

  15. David Bailey said,

    March 30, 2014 at 12:16 am

    “But as i said above, anyone who has side effects from a treatment, which they feel outweigh the benefits, can simply stop taking that treatment”

    Obviously I did, but what has somewhat shocked me, is that I could easily have assumed that the statin tablets that I had taken for 3 years without incident were nothing to do with my problem, and probably been diagnosed with PPS (which has no specific test) and been damn nearly crippled! In other words, you are assuming that all the people affected by these problems recognise what has happened and so are able to make an informed choice.

  16. FloxieHope said,

    April 3, 2014 at 11:00 pm

    When examining Statins, it should be noted that they have been shown to damage mitochondria. Article – www.ncbi.nlm.nih.gov/pmc/articles/PMC2849981/. Mitochondrial damage can account for all of the relevant adverse effects of statins – muscle weakness and damage, loss of memory/cognitive function, diabetes, depletion of glutathione, etc. An interesting feature of mitochondrial injury is that a threshold of damage must be reached before a disease state results (as described in this article – www.ncbi.nlm.nih.gov/pmc/articles/PMC2895369/?report=classic). So, if your study period isn’t long enough, statins truly will have the same number of adverse effects as sugar pills because in a short period of time, the subjects have not crossed their tolerance threshold for mitochondrial damage and no disease state (or AEs) have manifested. It is only with prolonged exposure to mitochondrial damaging chemicals, like statins, that adverse effects manifest.

    If you don’t design your study of mitochondrial damaging drugs to take into account how mitochondria react to assaults – with an initial adaptive response followed by a toxic response (as the peroxynitrite cycle is induced), your results don’t actually say anything notable. If you design your study to take into account the tolerance threshold feature of mitochondria, and the odd delayed response to toxic stimuli that they often display, you will likely find that statins are quite a bit more dangerous than sugar pills.

    I certainly understand that many research scientists don’t have the time or funding to do long-term studies. But don’t worry – the long-term studies are being done – they’re just being done on the population at large. Hence the reason that it is so important to listen to patients who experience adverse effects of drugs over a long period of time.

    Unfortunately, mitochondrial damage is very difficult to fix and stopping treatment with the mito damaging drug does not necessarily stop the mitochondria from continuing to produce damaging ROS (like peroxynitrite) that continue to do damage long after the drug is metabolized.

    ROS produced in damaged mitochondria are associated with every chronic disease there is. You, and all the other MDs out there may want to consider that chronic disease may be the result of these drugs that are tossed about like candy because they have no adverse effects in the short term, and the long-term effects are dismissed because patient reports are “anecdotal.”

  17. David Bailey said,

    April 4, 2014 at 4:16 pm

    FloxieHope,

    Thanks for your observations, because I think it is important to try to make sense of the experiences of many statin users. Although statin effects don’t seem to dissipate completely immediately (mine took about 9 months), the stories (anecdotes?) of many people on Dr Kendrick’s site all seem to confirm that thankfully the effects do reverse.

    Moreover, statins block a synthetic pathway that produces more than just cholesterol, and indeed cholesterol is used throughout the body! Dr Kendrick points out that the ‘normal’ level of cholesterol in humans was determined in a very strange way, and using this as a target figure may be quite harmful.

  18. Sanchia said,

    May 2, 2014 at 9:50 am

    When reading this article, I kept referring myself back to the placebo effect. With the author making mention of this effect early on in the article, I found myself questioning the relevance of certain medicines: Whether the power of the mind is sometimes stronger than the actual medication. It is then possible that the statins are said to have to side effects so people will believe it and therefore not experience any side effects, eventhough the drug can be harmful.

    However, different side effects are experienced by different people. An example of the different effects experienced by people from placebos is an experiment that was carried out the show Mythbusters. Two individuals were given the placebo, which was said to help with motion sickness. One responded positively while the other person didn’t. Here again the power of the mind is shown and the relevance of certain medication is tested.

  19. Darren_J said,

    May 15, 2014 at 9:11 pm

    I presume that we can’t harness the Nocebo effect to good use. Side effects include a fuller head of hair, improved skin, a feeling of well being and general all round improvement in health and improved resistance to disease.

    Is it, by any chance, ‘more complicated than that’?

    :)

  20. David Bailey said,

    June 5, 2014 at 11:07 am

    Ben,

    It seems to me that the placebo effect is a real joker in the pack because it can be used to come to any conclusion about statin side effects!

    You use it to conclude (in effect) that statin side effects are vastly over-reported due to the nocebo effect.

    Another interpretation, is that there is by now a folk level understanding that statins have nasty side effects! That means that if you give someone a pill that might be a placebo or a statin, their level of problems is probably affected by all the people they know – directly or indirectly – who have had problems with these drugs!

    I have no doubt that if you gave people placebo cyanide pills, some would collapse, and possibly even die – that would not mean that that cyanide was harmless!

    BTW, I am sure I am not immune to the placebo/nocebo effect, but the fact that my problems came on after 3 years, and that I felt very positive about taking statins until that point, makes be doubt that my reaction was a placebo response! My experience came as a real surprise to me.

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