Recent review on statins ignores body of evidence that suggests these drugs don’t work through cholesterol-reduction

Big cholesterol news emerged last week on the publication (much publicised) of a massive meta-analysis of statin treatment in those at relatively high risk of cardiovascular disease. The idea of this meta-analysis was to assess whether aggressive lowering of cholesterol (specifically LDL-cholesterol) brings additional benefits in terms of cardiovascular disease protection. The meta-analysis included results from a total of 26 trials (involving a total of about 170,000 individuals) [1].

What this meta-analysis found was that more intensive lowering of cholesterol was associated with a reduced risk of ‘vascular events’ such as heart attacks, fatal heart attacks and the most common form of stroke (ischaemic stroke). The authors state that for each 1.0 mmol/L (39 mg/dl) reduction in LDL-cholesterol, risk of vascular events was reduced by about a fifth. They go on to say “reduction of LDL cholesterol by 2-3 mmol/L would reduce risk by about 40-50 per cent.”

Perhaps not surprisingly, this meta-analysis is being used to ram home the conventional view that cholesterol causes cardiovascular disease, and that lower levels of LDL-cholesterol are better. However, there are a number of reasons why this study fails to tell the whole story about statins and cholesterol reduction.

Statin drugs have a number of different mechanisms which might allow them to reduce cardiovascular disease risk in a way which has nothing to do with cholesterol reduction. For example, statins have anti-inflammatory effects, which we would expect to lead to reduced risk of cardiovascular disease. Now, when we intensively lower cholesterol with these drugs, non-cholesterol-related effects (e.g. anti-inflammatory action) will generally be increased too. So, we cannot assume that any additional benefits from more intensive statin therapy have come from more intensive lowering of cholesterol.

In this meta-analysis, the results of a large number of studies was pooled. The problem is, these studies used a range of different drugs at different doses. Sometimes, the drugs were being tested against placebos, and sometimes they were being tested against other drugs. Rarely, two doses of the same drug were tested. Basically, the studies represent a huge hotchpotch of ‘methodologies’ and ‘variables’.

If you really want to take a scientific approach to assessing the role of cholesterol reduction on health, you would ‘control your variables’. This basically means changing only one thing. So, for instance, you could give two groups of people differing doses of the same statin. You could then see if the group on the higher dose had additional benefits, and also see if this appeared to be related to cholesterol reduction or something else. You’d be surprised how rarely such studies are done.

One example of such a study is the so-called TNT study [2]. Here, individuals with heart disease (very high risk of future vascular events) were given either 10 or 80 mg of atorvastatin for an average of about 5 years. The higher dose did lead to lower LDL levels and lower risk of death due to heart-related disease. The absolute reduce in risk was 0.5 per cent, by the way, so nothing to get too excited about. Plus, this study did not report on the non-cholesterol-related effects of the two different dosages, and so it’s impossible to gauge if the relative benefit of the higher dosage was down to LDL reduction and/or something else.

It should also be borne in mind, by the way, that the higher dose of statin in this study (eight times the lower dose, remember) did not lead to a reduction in overall risk of death. In other words, taking 8 times the dose of this drug for five years did not, overall, extend life by a single day, even in individuals at high risk of heart attacks and stroke.

The idea that the anti-inflammatory effects of statins (and not their cholesterol-reducing effects) may be at the heart of their benefits has been bolstered by work focusing on an inflammatory marker known as C-reactive protein (CRP). Statins are known to have the capacity to reduce CRP levels.

In one study [3] assessing the relationship between statin therapy and cholesterol and CRP levels, it was discovered that “Patients who have low CRP levels after statin therapy have better clinical outcomes than those with higher CRP levels, regardless of the resultant level of LDL cholesterol.” (emphasis mine).

In another study [4] published in the same edition of the journal, statin therapy and cardiovascular disease risk assessed using ultrasound scanning of the inside of the coronary arteries. It was found that “atherosclerosis regressed in the patients with the greatest reduction in CRP levels, but not in those with the greatest reduction in LDL cholesterol levels.”

In yet another study [5] it was found that when treating with statins, those with the highest levels of inflammatory markers at the start of the study derived the most benefit, irrespective of initial cholesterol levels.

Evidence that statins don’t work through their cholesterol-reducing effect comes from other evidence, including the findings that:

  • Statins substantially reduce the risk of stroke, despite the fact that raised cholesterol levels are a weak or non-existent risk factor for stroke [6,7].
  • Statins are claimed to reduce CVD risk in individuals who have ‘normal’ or even ‘low’ cholesterol levels [8].
  • More intensive cholesterol reduction does not necessarily lead to improved outcomes [9].

Despite what the authors of the recent Lancet review would have us believe, there is considerable evidence that statins primarily work through mechanism that are independent of their cholesterol-reducing effects.

Stepping aside from the science for a moment, let’s also perhaps inject some common sense. Let us not forget that cholesterol is a natural constituent of the body that is a major component in cell membranes, the brain, steroid hormones (including sex hormones) and vitamin D (which appears to have major disease-protective properties). It simply does not make sense to me that driving levels of this key substance to lower and lower levels if, in and of itself, beneficial to health. We would not make the case for driving levels of, say, sodium to lower and lower levels, would we? Or blood sugar levels?

All rationality and common sense seems to fly out of the window when certain doctors and scientists start talking about cholesterol. And when it comes to the science, it’s clear that many are ignorant of or choose to ignore the stacks of evidence that clearly contradict their stance.

References:

1. Cholesterol Treatment Trialists’ Collaboration. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet 9 November 2010 [epub ahead of print]

2. La Rosa JC, et al. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med. 2005;352(14):1425-35

3. Ridker PM, et al. C-reactive protein levels and outcomes after statin therapy. N Engl J Med 2005;352(1):20-8

4. Nissen SE, et al. Statin therapy, LDL cholesterol, C-reactive protein and coronary artery disease. N Engl J Med. 2005;352(1):29-38

5. Ridker PM, et al. Inflammation, pravastatin, and the risk of coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events (CARE) Investigators. Circulation. 1998;98(9):839-44

6. Cholesterol, diastolic blood pressure, and stroke: 13,000 strokes in 450,000 people in 45 prospective cohorts. Prospective studies collaboration. Lancet 1995;346(8991-8992):1647-53.

7. Imamura T, et al. LDL cholesterol and the development of stroke subtypes and coronary heart disease in a general Japanese population: the Hisayama study. Stroke 2009;40(2):382-8

8. Ridker PM, et al, JUPITER Study Group. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 2008;359(21):2195-2207

9. Kastelein JJ, et al, ENHANCE Investigators. Simvastatin with or without ezetimibe in familial hypercholesterolemia. N Engl J Med 2008;358(14):1431-1443

14 Responses to Recent review on statins ignores body of evidence that suggests these drugs don’t work through cholesterol-reduction

  1. Sue 16 November 2010 at 1:20 pm #

    Did you see this article in Heartwire:
    http://www.theheart.org/article/1145175.do

  2. Sue 16 November 2010 at 1:22 pm #

    That link is an article about that study you talk about.

  3. Lucien 16 November 2010 at 11:16 pm #

    I am very interested in Epidemiology. Except
    when I read the word Meta-analysis : I stop
    reading. How can it be serious science to jumble
    together the results of diverse studies and
    deduce from the sum what is not apparent in the
    individual components ?

    I suspect it occupies the forced leisure of
    university departments who cannot afford the very
    expensive and time comsuming original studies.
    Feed the old ones into the computer instead. Hope
    to come up with a conclusion that satisfies the
    industry and raises a few headlines.

    I accept everyone needs to make a living but I don’t think we need to take any of this seriously.

  4. Justmeint 17 November 2010 at 12:51 pm #

    Lucien I cannot agree more…. I too ‘turn off’ when I note tiz a meta……

    Problem is that many accept it as PROOF etc, and the wretched media will ‘parrot’ the news ad infinitum!

    Perhaps it is time to get them all onto statins with their morning coffee…. when they too begin to suffer the debilitating side effects, perhaps they too will question the status quo!

    Cheer’s.

  5. Feona 19 November 2010 at 8:02 pm #

    Dr Briffa, if I read you aright, it’s more important to lower the inflammation levels in the body than the cholesterol. I understand that high inflammation levels also contribute to diseases such as arthritis. Has there been much research into the causes of high inflammation levels in the body and how they could be reduced via diet rather than anti-inflammatory medication?

  6. David Manovitch 19 November 2010 at 9:19 pm #

    We know that cholesterol levels that are very high, say > 10mmols /L are definitively associated with early onset CHD and if untreated lead men to die in their 40′s and women soon after, as used to be common in hereditary hyperlipidaemias. Thus it follows that there is a safe range of cholesterol levels, though of course one has to break it down into HDL/LDL ratios. We don’t know though what the long term effects are of pushing total levels down to < 4mmols/L. There is the suggestion that statins may cause one to die of something else, as was demonstrated in 1980 with Clofibrate.

    I don't see how people can be so condemnatory of meta analyses. At least they can iron out some of the variance due to design flaws and population variability. This is surely better than just citing the papers that support one's own pre-conceived ideas.

  7. peter dingle 19 November 2010 at 10:16 pm #

    In a comment to David. the levels of cholesterol may be associated with higher risk but that does not mean cause. cholesterol is more of an indicator than a risk factor.
    Elevated cholesterol is an indicator of stress in the liver, where it is produced. Usually as a result of sugar (high GI), stress or low hydration. fix these not the indicator. By contrast C reactive protein is a risk factor and the benefits derived from statin drugs is probably working through the mild anti inflammatory effect they have.something any good health food, or supplement like vitamin C will achieve as well.

    It is also worth noting that the statistics quoted in the study are relative statistics not absolute. that is i a trial of 1000 people if one person dies instead of 2 it is a 50% reduction.The likely figures in the study although touted in the abstract and the media really mean that if you take this drug with serious side effects you may reduce the risk of a heart attack by 0.5% and you would probably need to spend close to half a million pounds to stop this one heart attack. At the same time it is likely to increase the rate of all other cause mortality by the same amount. To sum it up. one person doesn’t die of a heart attach but another will die of some other cause, it will cost millions of pounds and the only one who benefits is the drug company. in the mean time more than 20%(not relative stats here but 20 of 100) of people will have serious side effects from the drugs.

  8. Inger 21 November 2010 at 3:18 pm #

    Could you please advise on where I could find information about Doctors in Norway who support your views on Statins. My dad decided to stop using statins after I informed him about your information and also other sources. He has not used statins for a year, and is feeling better. The problem is that he has no support from his doctor and this is causing a worry for him. I do worry as well as I am not a Doctor – I have just read alot about the subject. I would really appreciate your advise.

  9. Anne Robertson 21 November 2010 at 7:07 pm #

    When my father-in-law, who is taking simvastatin, asked his doctor about whether he should take CoQ10, she said that the group practice had recently had a lecture from an expert research chemist who said that CoQ10 was of value only to the drug companies that manufacture it. Isn’t the real truth that it’s the statins that are only of value to the drug companies that manufacture them? My father-in-law lives in Melton Mowbray so is this NHS policy?

  10. helen 22 November 2010 at 2:41 am #

    Dear Inger if you have read a lot on the subject then you are probably way more knowledgeable than more than half the doctors in Norway, as you will probably find that they do not bother to read up on treatments, research and the like but instead rely on drug company propaganda to form their opinions. Try discussing it with them using only what you know and I bet you don’t get a reasonable discussion from any of them only a bit of condesending blah about how they are qualified and you are not!!!

  11. Maret 23 November 2010 at 12:59 pm #

    The British National Formulary (BNF) “provides UK healthcare professionals with authoritative and practical information on the selection and clinical use of medicines in a clear, concise and accessible manner”.

    NHS GPs normally have a copy of the BNF in their practices and (should) use it as a reference when prescribing pharmaceuticals to patients.

    The BNF indicates that CO Q10 should be prescribed with statins.

  12. Barkeater 25 November 2010 at 3:04 am #

    There is a back story to this meta-analysis, which may have been missed here. Published right next to the meta-analysis was one part of the SEARCH study. In a nutshell: an apparently well-designed study comparing 20mg simvastatin to 80mg simvastatin in very high risk (already had an MI) patients. 12,000 in the study, followed for 6.7 years (a pretty decent length study as these things go).

    As usual, you have to read closely and ignore the spin. The study, ahem, failed. No statistically significant improved outcome for the group taking 4x the low dose. Uh oh. This had to be a shock to the proponents. What to do?

    Well. at the time they announced the results in 2008, they also spelled out the spin strategy. They would say that the results were consistent with previous studies (ignore that lack of statistcal significance) and gin up a meta-analysis with those earlier studies and trumpet that. This is not really all that speculative on my part, just read this heartwire article from 2008 (the title of the article was good: “SEARCH me: Null trial ‘morphed’ into positive meta-analysis”).

    Dr. Briffa, the SEARCH study of low vs. high dose simvastatin is one of the few to compare the same statin, and supports your analysis in the blog. The high dose group did have lower LDL, as you would expect. Many times more side effects occurred in the high-dose group, although the total reported number is suspiciously low.

    By the way, the failed SEARCH study represented nearly 30% of the patients in the studies included in the meta-analysis (one of five studies comparing low vs. high dose of the same statin). The meta-analysis purports to have a p value of .00001 or something like that, which I suppose is true but contrasts starkly with the p of .10 for the new SEARCH study. I am guessing most of the earlier studies were in the pre-2005 bad old days when failed studies like SEARCH would not see the light of day. It is quite telling that most statin trials (not meta-analyses) since 2005 have failed.

  13. Les Ryan 27 February 2011 at 3:11 am #

    In my view, the “results” of the meta analysis are pure rubbish, in common with most publicity given to the supposed benefits of statin therapy.

    What on earth is WRONG with the medical establishment? It seems that most medical professionals are both blind and deaf!

    Five years ago, at the age of 65, I had an MI and underwent quintuple heart bypass surgery, from which my recovery was painfully slow, impeded, I’m now certain, by high dosage Simvastatin therapy prescribed by my cardiologist, along with a cocktail of about eight other drugs. At the time of my MI, my cholesterol was “normal” at around 5.2 – 5.4. CoQ10 was NOT prescribed or recommended at the time of my discharge.(Or since)My GP doesn’t even seem to be aware of its existence! I eventually ceased taking statins (by now changed to Lipitor)against my GP’s advice. I had endured a lot of pain in my upper arms, shoulders and joints but I’m now pain free after a long period of supplementation and natural therapies.The muscle wastage in my upper arms and shoulders is, I fear, permanent and completely the result of unnecessary statin therapy. I’ve done a lot of research in the last five years and I’m 100% satisfied that cholesterol is not the “bogey” it is ‘cracked up’ to be. I’m convinced that inflammation (principally elevated homocysteine levels)is the cause of most heart problems blamed on cholesterol, and the benefits of statins, if any, appear to be restricted to their mild anti-inflammatory effect. There are many safer and more efficient anti-inflammatory agents available, but the drug barons don’t this to become common knowledge. And they certainly don’t want the scales to fall from the eyes of my blinkered and patronising GP, who appears to genuinely believe that I will die shortly due to my not adhering to his advice!

  14. dermot 26 April 2012 at 8:31 pm #

    wow !
    glad i found this page , everything i have read has cheered me up, for a start i am 42 and have been on staitins to control my high chloesterol but due to side effects i have binned them and started on a simple heathly diet and exercise routine and hey presto my cholesterol has shot up to 8.5 but my blood pressure has plummeted ! for example while on drugs and a while after my bp was 128/ 89 average my bp now is averaging 116/77 , and i feel so much better no pains or aches form the side effects, if my bp has fallen to heathly levels does that mean my arteries are in better shape now than before , does anybody know ?

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