Statins reduce cardiovascular disease in healthy people, and why this study is a poke in the eye for the cholesterol hypothesis

It’s been going this way for a while: even healthy people should be on the cholesterol-reducing drugs known as statins. That, in a nutshell, is the verdict of a study published over the weekend which found that even in people deemed to be at low risk of cardiovascular disease, treatment with rosuvastatin (Crestor) at a dose of 20 mg per day almost halved the risk of ‘vascular events’ (such as heart attack, stroke, and death from these conditions) in middle-aged and elderly men and women. Overall risk of death was down too in those taking the rosuvastatin, to the tune of 20 per cent. Average length of treatment was a shade under two years.

These results look impressive, but it does need to be borne in mind that the study population were essentially healthy. And, because of this, the risk of things like heart attacks and strokes is generally low in this population. Just to put this in perspective, the risk of vascular events was 2.2 per cent in the group taking the statin, but 2.8 per cent in those on placebo. In other words, what is known as the absolute risk reduction (as opposed to the relative risk reduction) was a little over half a percent.

It is perhaps also worth reflecting on the fact that treatment with rosuvastatin was associated, compared with placebo, with a significantly increased risk of developing diabetes. Curiously, the authors of the study say this effect could reflect the play of chance. In other words, even though there was a statistically significant enhanced risk of diabetes in those taking the statin, it may have nothing to do with the statin, and everything to do with bad luck. Curiously, the authors are not similarly circumspect about the positive effects of statins seen in this study.

But the reason for writing about this study is not so much to put the results in this context, but more to explore what these results say about the widely accepted context that cholesterol causes cardiovascular disease. On the face of it, this study strengthens this concept. But I’m not so sure.

You see this study was done in individuals whose cholesterol levels were not deemed to be risky. Individuals had to have LDL cholesterol levels of less than 130 mg/L (3.37 mmol/L) to qualify. However, to qualify for the study individuals did have to have elevated levels of a substance known as C-reactive protein (CRP). CRP is a marker for inflammation in the body, and inflammation is believed to be a key underlying process in the development of cardiovascular conditions such as heart disease and stroke.

Significant benefits were seen individuals who had elevated CRP levels, but no other major risk factors for cardiovascular disease (and LDL cholesterol levels of 100 mg/L or less). This inevitably throws up the possibility that in this study, the benefits of rosuvastatin came, at least in part, through its ability to reduce CRP levels. CRP levels actually dropped by 37 per cent on average in this study.

Cholesterol levels dropped too (LDL levels actually halved), but as the authors point out, the clinical benefit associated with this was much larger than expected. This finding also adds weight to the idea that rosuvastatin’s benefits may have been less to do with bringing cholesterol levels down, and more to do with an anti-inflammatory and/or other actions.

Previously on this site I have cited a 2006 review of the evidence regarding the relationship between cholesterol and cardiovascular outcomes such as heart attacks and strokes [2]. Having reviewed a broad range of available evidence, the authors of this review stated that: ‘no clinical trial subgroup analyses or valid cohort case control analyses suggesting that the degree to which LDL cholesterol responds to statin independently predicts the cardiovascular risk reduction.’ In other words, there is no robust relationship between cholesterol levels and degree of risk of cardiovascular disease.

This is not the only review that has found this. In another from the same year, researchers reviewed 13 studies in which statins were used in individuals who had suffered from ‘acute coronary syndrome’ (i.e. heart attack and angina). Statin therapy was found to reduce risk of cardiovascular disease, but this was independent of LDL cholesterol reduction. The authors concluded that there is no significant evidence that reduction in LDL cholesterol level explains the clinical benefits seen with statin therapy on cardiovascular disease risk [3].

And what of studies that have assessed the relationship between CRP and cardiovascular outcomes? The lead author of the recent NEJM paper was also the lead author of a paper published in 2005 that assessed data from another large statin study (the so-called ‘PROVE-IT’ study) [4]. The study concluded: 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.

From the same year, comes another study in which the relationship between LDL cholesterol and CRP levels and development of the process which narrows the coronary blood vessels in heart disease (atherosclerosis) in individuals treated with a statin. Atherosclerosis actually regressed in patients with the greatest reduction in CRP levels, but not in those with the greatest reduction in LDL cholesterol levels [5].

Another way of unpicking the role of cholesterol in health would be to go beyond statins, and look at the effectiveness of other cholesterol reducing drugs or strategies on overall risk of death. This latest study, and others (particularly in those at high risk of cardiovascular disease) found statin therapy is associated with a reduced risk of death. A review from 2005 assessing the impact of cholesterol reducing therapy on overall mortality. Here are the results:

Statins – statistically significant reduction in risk of overall mortality

Fibrates – NO statistically significant reduction in risk of overall mortality

Resins – NO statistically significant reduction in risk of overall mortality

Niacin – NO statistically significant reduction in risk of overall mortality

Diet – NO statistically significant reduction in risk of overall mortality

Some people argue that the failure of other cholesterol-reducing strategies is because they don’t reduce cholesterol enough. I suppose that’s one potential explanation. Here’s another: cholesterol reduction doesn’t have broad benefits for health.

References:

1. Ridker PM, et al. Rosuvastatin to Prevent Vascular Events in Men and Women with Elevated C-Reactive Protein. New England Journal of Medicine. Epub 9th November 2008.

2. Hayward RA, et al. Narrative review: lack of evidence for recommended low-density lipoprotein treatment targets: a solvable problem. Ann Int Med 2006;145:520-530

3. Hulten E, et al. The effect of early, intensive statin therapy on acute coronary syndrome: a meta-analysis of randomized controlled trials. Archives of Internal Medicine. 2008;166:1814-1821

4. Ridker PM, et al. C-reactive protein levels and outcomes after statin therapy. New Engl J Med 2005;352:20-8.

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

18 Responses to Statins reduce cardiovascular disease in healthy people, and why this study is a poke in the eye for the cholesterol hypothesis

  1. Anne 10 November 2008 at 3:07 pm #

    I’m glad you have written about this. I read the study yesterday and, because I have high cholesterol and review with my endocrinolgist next week, got very concerned about the increased pressure he would put on me to take a statin…which I won’t do, but I don’t like being pressurized by doctors.

    I was thinking as I read your review of the study that in a way perhaps this study has proved that having elevated levels of high sensitivity C-reactive protein is the cause of CHD ? And that it also proves it’s nothing to do with cholesterol, since the participants had low levels of cholesterol anyway !

    I copied this from the study:

    “we did not include people with low levels of high-sensitivity C-reactive protein in our trial, since our hypothesis-generating analysis of high-sensitivity C-reactive protein in the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS)12 showed extremely low event rates and no evidence that statin therapy lowered vascular risk among persons who had neither hyperlipidemia nor elevated high-sensitivity C-reactive protein levels. Thus, a trial of statin therapy involving people with both low cholesterol and low high-sensitivity C-reactive protein levels would have been not only infeasible in terms of statistical power and sample size but also highly unlikely to show a benefit.”

    I suppose I should get my levels of high sensitivity C-reactive protein tested.

    Anne

  2. Chris 10 November 2008 at 4:28 pm #

    The BBC were pushing this on the news. It was essentially a free advertisement for the drug companies. As you say it seemed to me that cholesterol is not the problem. Inflammation is. So we need to focus on limiting inflammation.

  3. markus 10 November 2008 at 7:22 pm #

    Relationship Between C-Reactive Protein and Glucose Levels in Community-Dwelling Subjects Without Diabetes
    (http://care.diabetesjournals.org/cgi/content/full/28/5/1211)
    “To our knowledge, this is the first report to indicate a direct, positive relationship between CRP and pre-diabetic glucose levels across the normal range.”

    what – glucose in the blood raises CRP?

    who’d have thought it?

    M

    {;¬)

  4. Neil 11 November 2008 at 12:10 am #

    As predicted by Malcolm Kendrick in 2002

    ” CRP is about to suffer the same fate of other innocent substances in the blood that have the misfortune to rise in people who have heart disease. It is going to be accused of causing heart disease…………….
    As a raised CRP is now a recognised risk factor for heart disease, t’will be a very small step to suggest that by lowering it, you will prevent heart disease. I can already see the CRP lowering agents being lined up by the pharmaceutical companies. Watch for the buzz words IL-6 and hyper(c)-proteinaemia.”

    http://www.thincs.org/Malcolm.htm#CRP

  5. jackie 13 November 2008 at 1:44 pm #

    I don’t think anyone has accused CRP of causing heart disease – it seems to merely be a marker for certain types of inflammatory reactions, so is an indirect measure of cardiovascular risk. The aetiology of atheroma is multifactorial, and both cholesterol and inflammation play a part.

  6. Kristine Franklin-Ross 14 November 2008 at 4:55 pm #

    I was put on a statin (simvastatin) after a stroke 6 months ago, I took it for 3 months and just could not get my blood sugar to normalise despite eating a low carb diet. The last 3 months my blood sugars have been perfect, no need for any drugs, just a proper diet.

    Kristine

  7. Margo 14 November 2008 at 5:16 pm #

    Yet another medication or test that I feel I don’t need being pushed. I had a “discussion” with a female friend the other day about the fact that I was the only woman of my age in my circle who was not on thyroid pills. She thought I should go and be checked. How many doctors’ surgeries are full of people, I won’t say patients, with no symptoms yet receiving medication or checks they don’t want or need?

  8. Gordon 14 November 2008 at 5:57 pm #

    Ann’s comment about the pressure doctors put on patients to take statins is very pertinent. I am morally certain that this was in part at least the cause of the decline in my recently deceased wife’s health. I expressed my misgivings both to her and to the doctor. In the event she chose to take the doctor’s advice rather than mine. After all, I’m a layman, while he could say “trust me, I’m a doctor.”

  9. Cathy Bell 14 November 2008 at 10:35 pm #

    So, is there a natural way of keeping inflamation out of the body and RP levels low?

  10. Carmen 15 November 2008 at 12:00 am #

    Interesting article to read, I was told that I had inflammation
    (the result of a blood test), could someone give me some
    advice on how to treat this as the Doctor just gave me the
    results but no treatment.

  11. Liz 15 November 2008 at 12:45 am #

    Your verdict in a nutshell?

    From this anlysis it sounds as if we’d all be better off eating the nuts!

    Why (apart from the profits of the pharmacueitcal companies) is heart diease always presented in a linear cause-and-effect way? If statins are that good why do people who do not have high cholesterol get heart attacks?

    And is anyone monitoring the possible link between statins and diabetes?

  12. Robin 15 November 2008 at 10:56 am #

    This whole statins/cholesterol/hearth disease issue and the pressure GPs are now putting on their patients to take statins is well exposed in the books by Dr. Malcolm Kendrick and Dr. Uffe Ravnskov. These two scholarly – but readable – books should be on your Amazon Christmas list.

    There are some great videos on YouTube of Dr Kendrick speaking at last year’s BMJ Conference.

    Dr Briffa’s last sentence above hits the spot.

  13. James H 15 November 2008 at 12:57 pm #

    To clarify whether CRP is a bystander or active participant in atherogenesis, a 2008 study compared people with various genetic CRP variants. Those with a high CRP due to genetic variation had no increased risk of cardiovascular disease compared to those with a normal or low CRP
    (http://www.ncbi.nlm.nih.gov/pubmed/18971492)

  14. Cybertiger 15 November 2008 at 1:41 pm #

    In a news article about the JUPITER study the BMJ gave this quote,

    “Peter Weissberg, medical director at the British Heart Foundation, said that the results strongly support the “lower is better” approach to cholesterol management.”

    http://www.bmj.com/cgi/content/full/337/nov12_1/a2523

    Let us pray … for such dopey doctors as Peter Weissberg …

    PS. Never minding the appalling-science, our esteemed friend Dr Benjamin Goldacre has just poured a little tepid water over the statistical garbage broadcast by the media whores of the pharmaceutical industry. Let us pray for Dr Ben …

    http://www.guardian.co.uk/science/2008/nov/15/1

  15. David MacPhail 15 November 2008 at 11:17 pm #

    “So, is there a natural way of keeping inflammation out of the body and CRP levels low?”

    Hi Cathy, I think you mean to say “keeping inflammation levels low”.

    Sure, reducing your carbohydrate intake to <60 grams/day for starters will help a lot. There has also been research that shows that supplementing with magnesium will reduce CRP levels. Magnesium deficiency is common in our Western society.

    After a lot of experimenting with different forms of magnesium I am getting the best results with magnesium chloride hexahydate in a concentrated liquid solution. I take about 600-800 mg a day of elemental magnesium from magnesium chloride (which yields 12% of magnesium) in divided doses. You can usually order magnesium chloride in bulk from a chemist. My CRP levels is at the very lowest end of the scale.

  16. Carmen 16 November 2008 at 11:50 pm #

    Thank you so much David. I will certainly try the Magnesium Chloride.

    Many thanks,

  17. Jenny Roberts 4 June 2010 at 5:42 pm #

    Have recently bought Waist Disposal for my husband – it is great – we love the diet – it’s working. I have hypercholesterolaemia – and am on Simvastatin 40. Untreated, my combined levels waver between 10 and 12 (whatever they ares!) LDL between 9.7 and 8.5. I’m 5′, under 8 stone, healthy, don’t smoke – do I need statins – and what about the risk of stroke? A couple of years ago I had a mini-mini incident, funny vision and speech for 20 mins or so, and everyone got very worried, so I agreed to take the drugs.
    Very puzzled by it all, and would love another opinion! Thank you.

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