The Framingham study was the first major epidemiological study in history to attempt to identify risk factors for heart disease — or really any disease. It began in 1948, spurred in part by the premature death of Franklin D. Roosevelt. Probably the most important conclusion from that study was that elevated blood cholesterol seems to be a risk factor for later development of heart disease. Later this was refined to focus on the LDL-cholesterol (the so-called “bad cholesterol”). The identification of cholesterol as a risk-factor led to widespread advice to lower cholesterol by diet. However diets to lower cholesterol are almost always unsuccessful, in large measure because the liver produces much of the cholesterol that is found in the blood in any form. [EDIT ADDED. The previous sentence is probably too strong. But a lot of people will not comply with a diet that might succeed]. The development of drugs that can inhibit the synthesis of cholesterol by the liver promised to put an end to the scourge of cardiovascular mortality and morbidity – at least that was a very prominent view in the 1990s. These drugs comprise a class of agents referred to as statins – atorvastatin, rosuvastatin, pravastatin, lovastatin, simvastatin, fluvastatin, and pivastatin – that all work by inhibiting one of the enzymes the liver uses to produce cholesterol. That enzyme is also needed to produce other metabolites too, such as ubiquinone (Co-Q) and dolichols. So while there is no question whatsoever that statins reduce cholesterol, often a lot, these drugs produce effects said to be “pleiotropic”. As a class, their effects on cell function and metabolism are not limited to liver and they are not limited to cholesterol. (As a cell physiologist, I would certainly worry about disrupting cholesterol in cell membranes to any great extent).
Statins are very very very big business. Even though most of them can now be had as generic equivalents, global sales of statins are somewhere in the neighborhood of $1 trillion. That is not a misprint. Companies have been pushing these drugs hard for quite a while now and if you are reading this there is a very strong likelihood that you are taking a statin, or have discussed taking a statin with your doctor; and if not, your time will come. The suggestion will be that you should take one of these pills daily for the rest of your life and if you do it will make you healthier and stave off cardiovascular disease or stroke. Some have gone so far as to advocating that everyone over the age of 50 should take them.
The big questions are will these drugs protect you? And should you take them? The answer is that it depends and sometimes the answers aren’t obvious.
However there is a good chance that the potential benefits described to you have been exaggerated. About me: My PhD is in pharmacology, I do research on pathophysiology of kidney disease, and I have been wrestling myself with the issue of whether or not to take a statin. Also, I am not an epidemiologist, I don’t design or analyze clinical trials, and I am not a clinician. Finally, in what follows I’m not saying anything that is original at all, actually the ideas I’m presenting are widely debated.
Guidelines from the American Heart Association/American College of Cardiology (and their equivalents in other countries) strongly advocate for widespread use of these drugs in two different scenarios: (1) primary prevention, which means giving the drug to people who have never had any overt cardiovascular disease but who may have some risk factors, and (2) secondary prevention, which means giving the drug to people who already have cardiovascular disease (perhaps a myocardial infarction or a stroke) so as to prevent a repeat occurrence. People in group 2 are at higher risk than most people in group 1 (one exception being people in group 1 with chronic kidney disease, but I digress). Mostly I’m going to talk about people in the first group, who will be advised to take statins for primary prevention.
The use of statins for primary prevention of cardiovascular disease is pushed hard on the basis of seemingly persuasive claims based on legitimate and very large controlled clinical trials lasting several years [1-3]. An example of the type of claim you will see is that statins will reduce your risk of heart disease by some large number – around 30-50% -- and that this effect is directly proportional to how much you can lower your LDL-cholesterol. For example Collins et al.  claimed that lowering LDL-cholesterol would reduce relative risk of cardiovascular events by 45%/year. That sounds amazing and most of these clinical trials can show some statistical effect of statins to reduce cardiovascular disease and deaths from cardiovascular disease. That is really not in dispute. But if you look a little closer, the truth is a lot more nuanced. A big part of it comes down to assessing relative risk (RR) versus absolute risk (AR).
Imagine that you had a 30% chance of a heart attack in the next five years, and taking a statin would reduce that to 15%. The relative risk reduction in the case of the statin is 50%, in the ballpark of Collins et al. . Most people would opt to take the drug. I would. However the absolute risk reduction in this example is 15% (30 -15), but even so, I would consider that a pretty strong reason to take a statin.
But now, let’s suppose that your risk of getting a heart attack in the next five years is 4% and the statin reduces it to 2%. You would still see the relative risk reduction of 50%! Hooray!!! But the absolute risk reduction is only 2%. And somebody might reasonably ask if the relative small incremental reduction in absolute risk would really be worth it. And the answer is that for most people the answer is that it probably isn’t.
So what are the real-world numbers? One of the largest analyses from these kinds of studies was carried out by a large consortium of physicians and scientists known as the Cholesterol Treatment Trialists (CTT) . This consortium is arguably the strongest organized advocate for widespread statin use. They constantly publish in The Lancet (very high visibility, very high prestige in our business). They observed an absolute risk reduction for “major vascular events” of 0.8% and a reduction in the absolute risk for all-cause mortality of 0.4% over a period of five years.
One way that pharmacoepidemiologists will sometimes try to combine thinking about relative and absolute risk is with a statistic known as “number needed to treat” (NNT). Basically, that is the number of people you would need to treat for a specified period of time to prevent even one event from happening. So a five-year NNT value of 50 would mean that you would need to give 50 people a statin for five years in order to prevent even one of them from having a heart attack over that period. There are nuances to NNT but the idea is actually fairly straightforward and really quite shocking. So what are some representative NNT numbers for statins? One study from a group called the US Preventive Services Task Force (USPTF) estimated an NNT of 217 for non-fatal heart attacks and 313 for non-fatal strokes . Again, I emphasize, this is for primary prevention, that is people who have not had prior cardiovascular events. Moreover, they found no reduction in overall mortality over a period of several years (they are not alone in that, the CTT trial concluded the same thing for people in the two lower-risk groups they stratified ). No effect on all-cause mortality you ask??!!! Yep. No effect. And nobody to my knowledge has ever reported a large effect.
Meanwhile we have to consider possible adverse effects of drugs. Statins can cause side-effects, although the extent to which they do this is controversial and very much depends on how you define them, whether you have placebo controls in a trial, and how you view real-world experience. The most common is muscle pain (myalgia) but in very rare cases you can get severe and dangerous muscle breakdown. Everybody agrees from clinical trials that there is a measurable increase in new-onset type-2 diabetes, especially for people who are pre-diabetic at the time treatment is started. You can create a statistic for harmful effects analogous to NNT, which is the number needed to harm (NNH). Again, if for diabetes the NNH is 50, then if 50 people are given statins over some period of time, then you would get 1 new case of diabetes. From my reading of the literature, there seems to be a tendency for the NNT for statins to be more favorable for patients than the NNH from diabetes, but you still have to consider the possibility of harm from statins. That has to factor into your decisions of risk. And there are other adverse effects reports, including elevated liver enzymes, “brain fog”, gastrointestinal disturbances and flatulence, cystitis, even erectile dysfunction. This is by far not a complete list and in my view it is really hard to get good data for how prevalent these are. My sense is that clinicians often understate the adverse effects. In some clinical trials, for example, blood levels of creatine kinase have to be elevated ten-fold before a muscle side effect is counted, but there is reason to believe that statin users can have muscle pathology that affects their lives well before that . Incidentally, a lot of the largest statin clinical trials under-estimated adverse effects because they used a so-called “run-in period” of several weeks. During that period, people who were really having a hard time with the drugs were removed from the study. The justification was because the study was going to go for a long time.
So let’s get back a bit more directly to the question of whether you would benefit from use of statin for primary prevention of cardiovascular disease. It goes back to my first mention of relative vs. absolute risk of getting the disease in the first place. The higher your risk of cardiovascular disease, the more rational it becomes to use statins (and hence I would certainly use them for secondary prevention). But how do you know? To get at this, over the years many “risk calculators” have been devised to make a quantitative prediction of the risk of heart attack or stroke over the next ten years. This was an important outcome of the Framingham study, and risk calculators have certainly been refined since then. These take into account family history, body-mass index, blood lipids, blood pressure, age, sex, etc. Sometimes these are called pooled cohort equations (PCEs). One widely used was revised most recently in 2013 by American College of Cardiology. It is definitely not the only scheme in use. So what happens when you take a bunch of people, predict their risk with PCEs, wait some time, and see how it actually worked out? It turns out that these PCEs have nearly always over-estimated risk, in many cases the PCEs actually predict somewhere around double the risk compared to what actually occurred. Of course, that artificially elevated risk would make you over-estimate that absolute benefit you would get from taking statins.
Now you will certainly hear from statin advocates that these drugs will save thousands and thousands of lives every year. They are not actually lying but the reason is that like I said at the top, annual sales of these things are around $1 trillion. That is a LOT of people. So imagine that the NNT to prevent a death from a heart attack is 150, and that 30,000,000 were taking the drug for primary prevention, then you would save 200,000 people from fatal heart attacks. Very impressive but maybe it shouldn’t weigh that heavily on YOUR decision. On the other hand, if you are a company pushing these drugs to the populace at large, or if you have some financial interests in supporting these companies, that is the message you are going to deliver as loud as you can, and you are not going to appreciate any dissent..
So I’m going to now go on a bit of a rant that may sound a bit like a conspiracy theory but it’s not really. These very large clinical trials on statins were entirely run by the companies who later marketed the drugs while they still had patent rights. Those companies controlled all of the raw data. Large consortia like CTT who advocate so strongly  actually are not allowed to release the raw data and even they don’t have access to the data on frequency of adverse effects. And in spite of numerous calls for transparency so that there could be an independent review of the primary data by other completely independent groups, the people who control the data of the largest clinical studies refuse to make it available. Now in the US, newer regulations mean that primary data from all new trials have to be made public, but new trials on the scale needed to address some open questions are really expensive and drug companies are certainly not going to pay for it at this point. CTT for example says there is no longer any debate. All the same, I would like to point out that people who have been most strongly advocating for statin use receive a LOT of money from drug companies. Not directly into their own pockets, not these days, but it largely funds their professional activities. For example in one of the Lancet articles  we read: JA, CB, LB, RC, JE, RP, DP, and CR work in the Clinical Trial Service Unit & Epidemiological Studies Unit (CTSU) at the University of Oxford. The CTSU has received research grants from Abbott, AstraZeneca, Bayer, GlaxoSmithKline, Merck, Novartis, Pfizer, Roche, Schering, and Solvay that are governed by University of Oxford contracts that protect its independence, and it has a staff policy of not taking personal payments from industry (with reimbursement sought only for the costs of travel and accommodation to attend scientific meetings). The disclosure at the end of the paper is a lot longer than that, this just covered a few of the authors, but you get the idea. Personally I would feel better if these data could be analyzed by people who were in groups that received nothing at all from any drug company. Only government agencies like NIH can really do that, but since the Reagan era, that very rarely happens in the US.
In my own case, I have elevated LDL-cholesterol, mild hypertension very well controlled by a single drug (losartan), and my dad died of a heart attack when he was not a whole lot older than I am (in his mid-60s). He was also completely sedentary, a life-long heavy smoker, and he had an insanely type-A personality. I am not overweight and I ride my road bike 150-200 miles per week. My mom lived to her late 80s. My diet is not awesome, so a couple of years ago I started on atorvastatin. It definitely lowered cholesterol. After a couple of months I felt it was messing with my memory. I stopped. A new primary care doctor convinced me later to try a different one, rosuvastatin. I started in October, and I am convinced it really makes me fuzzy and I hate it. And that is what caused me to take a very deep dive into this literature, and hence to this diary.
Bottom line. I’m not going to take statins anymore. But your decision may be different and rational. You need to be honest with yourself about your actual risks. It is my experience that a lot of physicians are not aware of how these risk numbers are used to create a somewhat misleading impression of the benefits of statins, and they are actually not always well informed on how to critically evaluate clinical trials.
1. Collins R, Reith C, Emberson J, et al. Interpretation of the evidence for the efficacy and safety of statin therapy. Lancet. 2016;388:2532–2561.
2. Silverman MG, Ference BA, Im K, et al. Association between lowering LDL-C and cardiovascular risk reduction among different therapeutic interventions: systematic review and meta-analysis. JAMA. 2016;316:1289–1297.
3. Ference BA, Ginsberg HN, Graham I, et al. Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European atherosclerosis society consensus panel. Eur Heart J. 2017;38:2459–2472.
4. Cholesterol Treatment Trialists’ (CTT) Collaboration. Efficacy and safety of LDL-lowering therapy among men and women: metaanalysis of individual data from. 174 000 participants in 27 randomised trials. Lancet. 2015;385:1397–1405.
5. Chou R, Dana T, Blazina I, Daeges M, Jeanne TL. Statins for Prevention of Cardiovascular Disease in Adults: Evidence Report and Systematic Review for the US Preventive Services Task Force. JAMA. 2016;316(19):2008-2024.
6. Phillips PS, Haas RH, Bannykh S, et al. Statin-associated myopathy with normal creatine kinase levels. Ann Intern Med. 2002;137:581–585.
7. DeFilippis AP et al. An analysis of calibration and discrimination among multiple cardiovascular risk scores in a modern multi-ethnic cohort. Ann Intern Med 2015,162:-175. Also. Yadlowsky S et al. Clinical implications of revised pooled cohort equations for estimating atherolsclerotic cardiovascular disease risk. Ann Intern Med. 2018; 169:20-29.