Cholesterol and Statins: Another physician reviews the Jupiter study

UPDATE: 21 April, 2010 -
Cholesterol Drugs May Lower Men's Sex Drive
Some new studies believe that low testosterone is associated with prostate cancer.
Eating your way to lower cholesterol Note that we do not support the use of plant sterols as they are mainly sourced from GMO soy and canola oil

ORIGINAL POST
In addition to the many posts (136) here on Natural Health News, there is a selection of related articles on our main website.

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

By Dr John Briffa On November 10, 2008

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. [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
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Article printed from Dr Briffa’s Blog: http://www.drbriffa.com
URL to article: http://www.drbriffa.com/blog/2008/11/10/statins-reduce-cardiovascular-disease-in-health-people-and-why-this-study-is-a-poke-in-the-eye-for-the-cholesterol-hypothesis/
URLs in this post:
[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.: http://content.nejm.org/cgi/content/full/NEJMoa0807646

And Now for the Rest of the Story

Just this past Sunday (9 November, 2008) I posted this article on Natural Health News: Boosting Drug Sales with Studies.

I added one follow-up article earlier today, and now I am happy to give you something to think about in terms of why sound nutrition is a better option than wholesale use of drugs. Supplements certainly do edge out the pharmaceuticals in this study.

You'll also see how it is totally possible to fool a lot of the people a lot of the time -

Why treat nutritional deficiency with drugs?
(OMNS, November 13, 2008) A recent study suggested that statins might be used to avoid the effects of nutritional deficiency. Writing in the New England Journal of Medicine, the Jupiter group described a study of statin drugs in people with high C-reactive protein and low cholesterol. (1) High C-reactive protein levels are associated with inflammation and heart disease/stroke. The authors concluded that, in apparently healthy persons with elevated C-reactive protein levels, rosuvastatin (Crestor) significantly reduced the incidence of major cardiovascular events.

Their much-publicized claim, that this statin lowers the risk of heart attack by approximately one half, is technically correct though highly misleading. The reported annual incidence of coronary events was 37 people in 10,000 (controls) and 17 people in 10,000 (treated). Similar results were reported for risk of stroke. When expressed as a proportion, a 46% improvement (17/37) sounds large. However, an improvement of 20 events (37-17) in 10,000 people known to be at risk is less impressive. Such an improvement means that 500 people (10,000/20) with this increased risk would need to take the tablet daily for a year, to prevent one person suffering an event.

The paper does not explicitly report deaths. One reason for this may be that if a person on statins suffered a heart attack, that person was about three times more likely to die than a control who was not on statins.

The cost of rosuvastatin per person is approximately $1000 per year. So, treating enough people to prevent one heart attack costs $500,000 per year. Since about 70% of the heart attacks were not fatal, prevention of a single death from heart attack would cost even more, approximately $1,700,000. Giving the benefit of the doubt, we may allow for a similar reduction in stroke and say that "only" $250,000 is needed to protect one person from a stroke or heart attack. It is hardly surprising that Astra Zeneca's share price increased by $1.3 billion dollars on release of this paper and the corresponding media hype. (2)

The media suggested millions of healthy people could cut their risk of heart disease by taking statins. (3) They also claimed that statins could cut the risk of heart attack for "everyone". (4) This is inaccurate and incorrect. The study did not include normal healthy people, only a sample of a relatively small number of people, suffering from inflammation (increased C-reactive protein) - a known cause of heart disease and stroke. Out of 89,890 people considered for inclusion, 17,802 people (19.8%) met the specific criteria of poor health for the study. Widespread prescription of statins to healthy people is not supported by these findings.

The fact that statins produce a modest improvement is unsurprising, since they are known to lower inflammation, as do many nutritional supplements. It has pointed out that Crestor lowered C-reactive protein by 37%, but vitamin E lowers it (C Reactive Protein) by 32%, (5) and vitamin C by 25.3%. (6,7) These effects are similar to those of statins and would be expected to provide comparable benefits, without side effects and at a lower cost.

Crestor and other statin drugs have serious side effects. The incidence of established side-effects, such as rhabdomyolysis (0.3 per 10,000 per year), myopathy (1.1 per 10,000) and peripheral neuropathy (1.2 per 10,000 per year) seems low, (8) but may be underestimated as it takes time to establish long-term side-effects. (The depletion of coenzyme Q10 by statins is a particular concern.) The figures imply that for every ten people who avoid a cardiovascular event, at least one previously healthy person will suffer a non-trivial side effect of the statin drug.

The doctors reported a statistically significant increase (270) in diabetes in the statin group compared to the placebo group (216). Over the course of the study, this corresponds to an increased risk of approximately 61 in 10,000 people. So, the number of people on statins reported to become diabetic was greater than the number that avoided a heart attack! These people might have shorter lives and be at greater risk of heart disease in the long term.

Notably, the Jupiter study was stopped early, which the authors admit prevents assessment of how side-effects might outweigh reported benefits in the longer term. The study was to last 3-5 years and the criteria for stopping were not included in the original published design. (9) The paper claims that when the study was stopped "these [diabetic] events were not adjudicated by the end-point committee". The committee either knew about the diabetes in which case it was considered, or it did not and the committee was not doing its job properly.

The Jupiter name stands for Justification for the Use of statins in Prevention: an Intervention Trial Evaluating Rosuvastatin; the reader might think this "justification" sounds more like a marketing plan than a scientific endeavor. The researchers did not address the underlying cause of the inflammation and increased C-reactive protein: they simply treated the condition with drugs. In many cases, raised C-reactive protein is a result of nutritional deficiency. (10)

It is worth mentioning that several nutritional supplements inhibit inflammation and lower C-reactive protein, without causing known side effects. Deficiency in vitamins A, (11) B6, C, E, A, folate, carotenoids and lycopene, (12) and selenium (for example) is associated with raised C-reactive protein. (13,14,15) We suggest that the $250,000 cost of preventing a single cardiovascular event with rosuvastatin might be better spent funding a study of such inexpensive alternatives the deficiency of which may be the cause of the problem.

The people at risk could be encouraged to supplement their diet and restore their health without using these expensive drugs to conceal their underlying sickness.

Stick with the supplements!

References:

(1) Ridker P.M. Danielson E. Fonseca F.A.H. Genest J. Gotto A.M. Kastelein J.J.P. Koenig W. Libby P. Lorenzatti A.J. MacFadyen J.G. Nordestgaard B.G. Shepherd J. Willerson J.T. Glynn R.J. for the JUPITER Study Group (2008) Rosuvastatin to Prevent Vascular Events in Men and Women with Elevated C-Reactive Protein, NEJM, 359(21), 2195-2207.

(2) Mail Online (2008) Crestor news helps AstraZeneca market value leap by more than £1.3bn, 9:25 PM, 10th Nov.

(3) Smith R. (2008) Millions could cut heart attack risk by taking statins, study finds, telegraph.co.uk, 7:55AM GMT, 10 Nov.

(4) Hope J. (2008) The new statin drug that cuts the risk of heart attacks and strokes for EVERYONE, Daily Mail, 11th Nov.

(5) Devaraj S. Tang R. Adams-Huet B. Harris A. Seenivasan T. de Lemos J.A. Jialal I. (2007) Effect of high-dose alpha-tocopherol supplementation on biomarkers of oxidative stress and inflammation and carotid atherosclerosis in patients with coronary artery disease, Am J Clin Nutr, 86(5), 1392-1398.

(6) Block G. Jensen C.D. Dalvi T.B. Norkus E.P. Hudes M. Crawford P.B. Holland N. Fung E.B. Schumacher L. Harmatz P. (2008) Vitamin C treatment reduces elevated C-reactive protein, Free Radic Biol Med, Oct 10. [Epub]

(7) Sardi B. (2008) The Headline You Should Be Reading: Statin Drugs Don't Save Lives And May Increase Your Risk For Diabetes, Knowledge of Health Report, Nov 11.

(8) Law M. Rudnicka A.R. Statin Safety: A Systematic Review, The American Journal of Cardiology, 97(8), Suppl 1, S52-S60.

(9) Ridker P.M. JUPITER Study Group (2003) Rosuvastatin in the primary prevention of cardiovascular disease among patients with low levels of low-density lipoprotein cholesterol and elevated high-sensitivity C-reactive protein: rationale and design of the JUPITER trial, Circulation, 108(19), 2292-2297.

(10) Ford E.S. Liu S. Mannino D.M. Giles W.H. Smith S.J. (2003) C-reactive protein concentration and concentrations of blood vitamins, carotenoids, and selenium among United States adults, European Journal of Clinical Nutrition, 57, 1157-1163.

(11) Root M.M. Hu J. Stephenson L.S. Parker R.S. Campbell T.C. (1999) Determinants of plasma retinol concentrations of middle-aged women in rural China. Nutrition 15, 101-107.

(12) Boosalis M.G. Snowdon D.A. Tully C.L. Gross M.D. (1996): Acute phase response and plasma carotenoid concentrations in older women: findings from the nun study, Nutrition, 12, 475-478.

(13) Friso S. Jacques P.F. Wilson P.W. Rosenberg I.H. Selhub J.(2001) Low circulating vitamin B(6) is associated with elevation of the inflammation marker C-reactive protein independently of plasma homocysteine levels, Circulation, 103(23), 2788-2791.

(14) Devaraja S. Jialal I. (2000) Alpha tocopherol supplementation decreases serum C-reactive protein and monocyte interleukin-6 levels in normal volunteers and type 2 diabetic patients, Free Radical Biology and Medicine, 29(8), 790-792.

(15) Upritchard J.E. Sutherland W.H. Mann J.I. (2000): Effect of supplementation with tomato juice, vitamin E, and vitamin C on LDL oxidation and products of inflammatory activity in type 2 diabetes, Diabetes Care, 23, 733-738.

Nutritional Medicine is Orthomolecular Medicine

Boosting Drug Sales with Studies

For quite a number of years many health professionals have been speaking out against the statin class of drugs.

Much of the concern is associated kidney failure secondary to muscle wasting. Other serious effects have been noted, yet the drug giants keep coming up with ways to try to convince absolutely everyone they need to be taking these drugs.

Now even the "healthy".

One of the key investigators busting this myth has been Uffe Ravnskov, MD

And what ever happened to improving health with foods and supplements to reduce or eliminate this problem.

Recall that the homogenization of milk (and lack of access to raw milk) really kicked off the march to atherosclerosis back in the 1950s.

And remember that lecithin or eating plain applesauce mixed in plain yoghurt aids healthy, clean and flexible arteries. And with major cost savings over these drugs.

Other issues are the fact that many of the statin drugs are fluoride based, such as Baychol - now off the market.

Even Red Rice Yeast can have the same side effects of the drugs.

Statins and the problems associated with their use is the result of marketing a class of drugs before it was fully investigated.

The imprecise use of statin medications is one big reason why side effects occur in more than 40 percent of patients and why 60-75 percent of statin users discontinue treatment.

Crestor averages about $2 a pill, with a range from $1.41 to $3.41 at a variety of pharmacies. The drug company profit for these drugs is in the 4000 percent range. If you get 10 mg of Crestor when you only need 1 mg, risks increase drastically. With each doubling of a statin dosage, the risk of liver injury also doubles.

Concerned about the renal effects of Crestor, some people have been openly weighing the options between taking a statin or accepting a higher cholesterol number. (For instance, is high cholesterol "normal"? Have we fallen victim to high-end marketing tactics?)

All the statin drugs can cause rhabdomyolysis and kidney failure. In most cases the kidney failure is secondary to blocking of the tiny kidney tubules by the breakdown fragments of muscle cells. The mechanism of action here is loss of cell wall integrity of the muscle cells due to interference of the statin drugs with the vital role of ubiquinone in our bodies.

Ubiquinone, known also as Co-enzyme Q10, is collaterally damaged during the statin drug effect on the so- called mevalonate pathway of cholesterol biosynthesis. Ubiquinone metabolism is a branch on the mevalonate "tree" inevitably damaged by these statin drug "reductase inhibitor" action and the stronger the statin, the more severe this effect.

Public Citizen filed a Citizen's Petition with the FDA suggesting that Crestor be removed from the market. Though the courts did not pass a judgement in favor of Public Citizen (thus allowing Crestor to remain a legally prescribed medication), the case brought to light the fact that statins like Crestor can and do cause serious problems in many patients who take them.

In May of 2005, a study published in the American Heart Association's journal, Circulation, revealed that kidney problems and muscle weakness were two to eight times more frequent among Crestor users than those taking other cholesterol-lowering drugs.

Read more

more

and more

Study: Wider cholesterol drug use may save lives
By MARILYNN MARCHIONE, AP Medical Writer Marilynn Marchione, Ap Medical Writer
Sun Nov 9, 9:44 am ET

NEW ORLEANS – People with low cholesterol and no big risk for heart disease dramatically lowered their chances of dying or having a heart attack if they took the cholesterol pill Crestor, a large study found.

The results, reported Sunday at an American Heart Association conference, were hailed as a watershed event in heart disease prevention. Doctors said the study might lead as many as 7 million more Americans to consider taking cholesterol-lowering statin drugs, sold as Crestor, Lipitor, Zocor or in generic form.

"This takes prevention to a whole new level, because it applies to patients who we now wouldn't have any evidence to treat," said Dr. W. Douglas Weaver, a Detroit cardiologist and president of the American College of Cardiology.

The study also gives the best evidence yet for using a new test to identify people who may need treatment, according to a statement from Dr. Elizabeth Nabel, director of the National Heart, Lung and Blood Institute. The new research will be considered by experts reviewing current guidelines.

However, some doctors urged caution. Crestor gave clear benefit in the study, but so few heart attacks and deaths occurred among these low-risk people that treating everyone like them in the United States could cost up to $9 billion a year — "a difficult sell," one expert said.

About 120 people would have to take Crestor for two years to prevent a single heart attack, stroke or death, said Stanford University cardiologist Dr. Mark Hlatky. He wrote an editorial accompanying the study published online by the New England Journal of Medicine.

"Everybody likes the idea of prevention. We need to slow down and ask how many people are we going to be treating with drugs for the rest of their lives to prevent heart disease, versus a lot of other things we're not doing" to improve health, Hlatky said.

Statins are the world's top-selling drugs. Until this study, all but Crestor have already been shown to cut the risk of heart attacks and death in people with high LDL, or bad cholesterol.

But half of all heart attacks occur in people with normal or low cholesterol, so doctors have been testing other ways to predict who is at risk.

One is high-sensitivity C-reactive protein, or CRP for short. It is a measure of inflammation, which can mean clogged arteries as well as less serious problems, such as an infection or injury. Doctors check CRP with a blood test that costs about $80 to have done.

A co-inventor on a patent of the test, Dr. Paul Ridker of Harvard-affiliated Brigham and Women's Hospital in Boston, led the new study. It involved 17,802 people with high CRP and low LDL cholesterol (below 130) in the U.S. and 25 other countries.

One-fourth were black or Hispanic, and 40 percent were women — important because previous statin studies have included few women. Men had to be 50 or older; women, 60 or older. None had a history of heart problems or diabetes.

They were randomly assigned to take dummy pills or Crestor, the strongest statin on the market, made by British-based AstraZeneca PLC. Neither participants nor their doctors knew who was taking what.

The study was supposed to last five years but was stopped in March, after about two years, when independent monitors saw that those taking Crestor were faring better than the others.

Full results were announced Sunday. Crestor reduced a combined measure — heart attacks, strokes, heart-related deaths or hospitalizations, or the need for an artery-opening procedure — by 44 percent.

"We reduced the risk of a heart attack by 54 percent, the risk of a stroke by 48 percent and the chance of needing bypass surgery or angioplasty by 46 percent," Ridker said.

Looked at another way, there were 136 heart-related problems per year for every 10,000 people taking dummy pills versus 77 for those on Crestor.

Remarkably, every single subgroup benefited from the drug.

"If you're skinny it worked, if you're heavy it worked. If you lived here or there, if you smoked, it worked," Ridker said.

AstraZeneca paid for the study, and Ridker and other authors have consulted for the company and other statin makers.

One concern: More people in the Crestor group saw blood-sugar levels rise or were newly diagnosed with diabetes.

Crestor also has the highest rate among statins of a rare but serious muscle problem, so there are probably safer and cheaper ways to get the same benefits, said Dr. Sidney Wolfe of the consumer group Public Citizen.

"It is highly unlikely that (the benefits are) specific to Crestor," said Wolfe, who has campaigned against the drug in the past.

Crestor costs $3.45 a day versus less than a dollar for generic drugs.

Drs. James Stein and Jon Keevil of the University of Wisconsin-Madison used federal health statistics to project that 7.4 million Americans, or more than 4 percent of the adult population, are like the people in this study.

Treating them all with Crestor would cost $9 billion a year and prevent about 30,000 heart attacks, strokes or deaths, they calculate.

"That's pretty costly. This would be a very difficult sell" unless a person also had family history or other heart disease risk factors, said Dr. Thomas Pearson of the University of Rochester School of Medicine and Dentistry.

Pearson was co-chairman of a joint government-heart association panel that wrote current guidelines for using CRP tests to guide treatment.

Researchers do not know whether the benefits seen in the study were due to reducing CRP or cholesterol, since Crestor did both.

This study and two other government-sponsored ones reported on Sunday "provide the strongest evidence to date" for testing C-reactive protein, and adding it to traditional risk measures could identify millions more people who would benefit from treatment, Nabel's statement says.

U.S. Crestor prescriptions totaled $420 million in the third quarter of this year, up 23 percent from a year earlier. In the rest of the world, third quarter sales were $520 million, up 33 percent.

Sales have been rising even though two statins — Zocor and Pravachol — are now available in generic form.

On the Net:
New England Journal: http://www.nejm.org
Heart conference: http://www.americanheart.org
Government: http://www.nhlbi.nih.gov/health/dci/Diseases/Cad/CAD_WhatIs.html