Do statins prevent or promote cancer? - Current Oncology

Do statins prevent or promote cancer?

Mark R. Goldstein MD FACP, Medical Director, Fountain Medical Court, 9410 Fountain Medical Court, Suite

Keywords: Statins, regulatory T cells, elderly

Copyright 2008 Multimed Inc.

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

The Editor, Current Oncology December 24, 2007

 

In their commentary, Drs. Takahashi and Nishibori¹ discuss putative antitumour effects of statins. However, prospective data suggest that statins actually increase cancer in certain segments of the population. Additionally, new findings regarding the immunomodulatory effects of statins may explain the mechanism by which that increase occurs².

Statins increase the number of regulatory T cells (Tregs) in vivo by inducing the transcription factor forkhead box P3². Although that increase may be beneficial in stabilizing atherosclerotic plaque by reducing the effector T-cell response within the atheroma³, it might impair both the innate⁴ and adaptive⁵ host antitumour immune responses. Not surprisingly, the number of Tregs present in many solid tumours correlate inversely with patient survival⁶.

Indeed, analysis of large randomized statin trials demonstrate a highly significant (p = 0.009) inverse association between achieved low-density lipoprotein cholesterol levels and cancer⁷. Close inspection of statin trials reveal the specific populations at risk for the development of incident cancer with statin treatment. These include the elderly^8–10 and people with a history of breast or prostate cancer^11,12. Furthermore, statin-treated individuals undergoing immunotherapy for cancer may be at increased risk for worsening cancer¹³.

The elderly are relatively immunosuppressed and are more likely to harbour occult cancers¹⁴. In the prosper (Prospective Study of Pravastatin in the Elderly at Risk) trial⁸, a 3.2-year prospective study of pravastatin for cardiovascular disease prevention in the elderly (mean age at trial entry: 75 years) at high risk for cardiovascular disease, cancer incidence was significantly increased in subjects randomized to pravastatin. In fact, the increase in cancer mortality equalled in magnitude the decrease in cardiovascular disease mortality in the statin-treated patients, leaving all-cause mortality unchanged. Likewise, post hoc analysis of the lipid study⁹, a 6-year prospective trial of pravastatin in individuals with cardiovascular disease, revealed a significant increase in cancer incidence in the elderly subjects (age: 65–75 years) randomized to pravastatin. In a secondary analysis of the tnt (Treating to New Targets) study¹⁰, elderly subjects randomized to high-dose atorvastatin (80 mg daily) versus low-dose atorvastatin (10 mg daily) demonstrated a trend toward increased death, largely from an increase in cancer mortality. Therefore, the increase in incident cancer in the elderly might be dose-related. It is highly plausible that the elderly are particularly sensitive to a statin-induced increase in Tregs, further impairing their immune response to cancer.

An alarming increase in breast cancer incidence, some of which were recurrences, was seen in women randomized to pravastatin in the care trial¹¹ Thereafter, cancer was an exclusion criterion in randomized statin trials. In clinical practice, however, it is not infrequent to find an association between recurrence of breast cancer and concurrent statin therapy¹⁵. Long-term follow-up (10 years after trial completion) of woscops (West of Scotland Coronary Prevention Study), a 5-year prospective trial of pravastatin in hypercholesterolemic men, revealed an increase in prostate cancer in the men who were randomized to pravastatin therapy¹². That finding indicates that cancers may become evident a decade or more after treatment with statins. Treg increases have been associated with both breast and prostate cancers^16,17, and therefore, it is highly plausible that the increase in cancers seen with statin therapy is related to a statin-induced increase in Tregs.

Statin therapy has been associated with tumour progression leading to radical cystectomy in patients treated for bladder cancer with bacille Calmette–Guérin immunotherapy¹³. That association may be likewise due to a statin-induced increase in Tregs, resulting in impaired host antitumour immunity.

Statin trials have typically randomized subjects free of prevalent cancers and have been about 5 years in duration. Long-term follow-up data are limited, particularly for the development of cancer. Statins are now promoted for widespread use in adults of all ages and at high doses¹⁸, potentially for decades. Importantly, they are used in individuals with other significant comorbidities such as cancer. Unfortunately, the post-market surveillance of drugs has been poor¹⁹. Because cancer is highly prevalent in the population, particularly in the elderly, a statin-induced increase in cancer incidence will likely go unrecognized.

Long-term prospective data are needed on the feasibility of statin therapy in the very elderly, the immuno-suppressed, and those with prevalent cancer. Furthermore, long-term outcome data are needed in young individuals treated with statins for prolonged time periods. Perhaps a constant increase in Tregs over years, even in the young, will weaken host antitumour immune surveillance and increase the risk for various cancers.

In conclusion, we feel that there is ample evidence that statins may promote cancer in certain segments of the population. Currently, the indications for statin therapy are based on lipoprotein levels, prevalent cardiovascular disease, other vascular risk factors, and family history²⁰. Maybe it is time for a new paradigm that also includes age extremes, prevalent cancer, a past history of cancer, and overall immunocompetence.

Go to:

REFERENCES

1. Takahashi HK, Nishibori M. The antitumour activities of statins. Curr Oncol. 2007;14:246–7. [PMC free article] [PubMed]

2. Mausner–Fainberg K, Luboshits G, Mor A, et al. The effect of hmg-coa reductase inhibitors on naturally occurring cd4⁺cd25⁺ T cells. Atherosclerosis. 2007 [Epub ahead of print] [PubMed]

3. Goronzy JJ, Weyand CM. Immunosuppression in atherosclerosis: mobilizing the opposition within. Circulation. 2006;114:1901–4. [PubMed]

4. Tiemessen MM, Jagger AL, Evans HG, van Herwijnen MJ, John S, Taams LS. cd4⁺cd25⁺Foxp3⁺ regulatory T cells induce alternative activation of human monocytes/macrophages. Proc Natl Acad Sci U S A. 2007;104:19446–51. [PMC free article] [PubMed]

5. Curiel TJ. Tregs and rethinking cancer immunotherapy. J Clin Invest. 2007;117:1167–74. [PMC free article] [PubMed]

6. Yakirevich E, Resnick MB. Regulatory T lymphocytes: pivotal components of the host antitumor response. J Clin Oncol. 2007;25:2506–8. [PubMed]

7. Alsheikh–Ali AA, Maddukuri PV, Han H, Karas RH. Effect of the magnitude of lipid lowering on risk of elevated liver enzymes, rhabdomyolysis, and cancer: insights from large randomized statin trials. J Am Coll Cardiol. 2007;50:409–18. [PubMed]

8. Shepherd J, Blauw GJ, Murphy MB, et al. on behalf of the prosper (Prospective Study of Pravastatin in the Elderly at Risk) study group. Pravastatin in elderly individuals at risk of vascular disease (prosper): a randomised controlled trial. Lancet. 2002;360:1623–30. [PubMed]

9. Hunt D, Young P, Simes J, et al. Benefits of pravastatin on cardiovascular events and mortality in older patients with coronary heart disease are equal to or exceed those seen in younger patients: results from the lipid trial. Ann Intern Med. 2001;134:931–40. [PubMed]

10. Wenger NK, Lewis SJ, Herrington DM, Bittner V, Welty FK. on behalf of the Treating to New Targets Study Steering Committee and Investigators. Outcomes of using high- or low-dose atorvastatin in patients 65 years of age or older with stable coronary heart disease. Ann Intern Med. 2007;147:1–9. [PubMed]

11. Sacks FM, Pfeffer MA, Moye LA, et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial investigators. N Engl J Med. 1996;335:1001–9. [PubMed]

12. Ford I, Murray H, Packard CJ, Shepherd J, Macfarlane PW, Cobbe SM. on behalf of the West of Scotland Coronary Prevention Study Group. Long-term follow-up of the West of Scotland Coronary Prevention Study. N Engl J Med. 2007;357:1477–86. [PubMed]

13. Hoffmann P, Roumeguère T, Schulman C, van Velthoven R. Use of statins and outcome of bcg treatment for bladder cancer. N Engl J Med. 2006;355:2705–7. [PubMed]

14. Gruver AL, Hudson LL, Sempowski GD. Immunosenescence of ageing. J Pathol. 2007;211:144–56. [PMC free article] [PubMed]

15. Winer EP, Harris JR, Smith BL, D’Alessandro HA, Brachtel EF. Case records of the Massachusetts General Hospital. Case 32-2007. A 62-year-old woman with a second breast cancer. N Engl J Med. 2007;357:1640–8. [PubMed]

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Statins Do Not Save Lives - Smith

New Study Confirms Statins Do Not Save Lives

Thursday, August 29, 2013

 

A 'new' study of statin medications has just been published in the Journal of the American College of Cardiology. I say new, but actually its a new manipulation of old data.

The researchers looked at eight previously conducted clinical trials done on statins. The population studied was elderly people without existing cardiovascular disease. After doing their calculations, it was concluded that statins did slightly reduce the risk of heart attack and stroke, but the use of statins did not reduce the risk of death from cardiovascular disease. There was also no reduction in the risk of death from all causes.

The bottom line is that it has once again been established that statins do not extend life expectancy for people without cardiovascular disease.

This is one of the key points that STATIN NATION exposes.  The video excerpt below provides a summary of this issue:



A Bit More Detail
Around 75% of all the people who take a statin, are taking it for  primary prevention. This means they do not have a heart problem but are taking the medication in the hope of preventing a heart problem in the future.  When it comes to primary prevention none of the largest clinical trials have been able to conclusively show any net benefit.

The AFCAPS (1), ASCOT (2), CARDS (3), PROSPER (4) and WOSCOPS (5) clinical trials all failed to show a statistically significant reduction in all cause mortality (deaths from all causes, not just heart disease related deaths).

All cause mortality data, of course, is the only true measure one can use to determine if a statin is going to extend life expectancy or not. Whilst some clinical trials of statins have shown a very slight reduction in heart disease, in primary prevention, this has always been countered by deaths from other causes. The net result is that people do not live any longer after taking a statin.

In 2010, a meta-analysis of 11statin trials was published in the Archives of Internal Medicine. Professor Kausik Ray and colleagues concluded that statins provided no benefit in terms of deaths from all causes, when used for primary prevention (6). This analysis had the “cleanest” dataset of any analysis completed to date - the researchers were able to exclude patients with existing heart disease (known as secondary prevention) and only include data associated with primary prevention.
When we look at the use of statins for people who already have a diagnosed heart problem (the 25% of people, in secondary prevention) the picture becomes less clear cut. Some trials have found significant increases in life expectancy for these people, however, the trials have always been too short for us to assess the long-term impact of being on a statin.

Even if statins do provide a short-term benefit for those with a heart problem, it is debatable that this has anything to do with the cholesterol-lowering effect of statins. Quite simply, the amount of benefit does not match up with the degree of cholesterol-lowering. The potential beneficial affects of statins for people with heart disease is now widely recognised to be associated with a reduction in inflammation. And recent evidence suggests that this is mediated through an improvement in iron metabolism (7).

“Benefits Outweigh Risks” 
Any decision to take a medication should of course involve a clear understanding of the benefits balanced against the risks. Many authorities have repeatedly stated that the benefits of statins far outweigh the risks. Clearly, this is not correct.

First of all, as we have seen above, there is no net benefit for the 75% of people who take a statin in primary prevention. So, for these people, the choice should be abundantly clear, since they will only expose themselves to the significant adverse effects associated with statins.

Statins have been linked with more than 300 different adverse effects. The most common adverse effects include: depression, suicide, sleep disturbances, memory loss, sexual dysfunction, lung disease, muscle-related problems, cognitive loss, neuropathy, pancreatic dysfunction and liver dysfunction. More recent studies have also shown that statins cause type 2 diabetes and acute kidney injury.

In addition, many doctors are concerned about statins and a potential increase in the risk for cancer and heart failure. A recent study found that the long term use of statins doubles the risk of breast cancer in women.

The best estimates suggest that at around 20% of the people who take a statin will experience significant adverse effects. This needs to be considered when thinking about both primary and secondary prevention, since this 20% is a much greater number than the number of people who might benefit, even in secondary prevention.

References: 
1. Downs JR, et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study. JAMA 1998; 279:1615-22.
2. Sever PS, et al. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial. Lancet 2003; 361:1149-1158.
3. Clhoun HM, et al. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atovastatin Diabetes Study (CARDS). Lancet 2004; 364:685-696.
4. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. Lancet 2002; 360:1623-1630.
5. Shepherd J, et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia (WOSCOPS). N Engl J Med 1995; 333:1301-1307.
6. Ray KK, et al. Statins and all-cause mortality in high-risk primary prevention: a meta-analysis of 11 randomized controlled trials involving 65,229 participants. Arch Intern Med. 2010; 170:1024-31.
7. Zacharski, LR et al. The Statin–Iron Nexus: Anti-Inflammatory Intervention for Arterial Disease Prevention. American Journal of Public Health. Published online ahead of print February 14, 2013.
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New Documentary Exposes the Over-Prescription of Statins -Smith

New Documentary Exposes the Over-Prescription of Statins

Posted on: Tuesday, September 18th 2012

Written by: Justin Smith

An estimated 40 million people take a statin to lower their cholesterol levels. These are one of the most widely prescribed medications in history and, of course, one of the most profitable.

We are led to believe that the benefits associated with statins far outweigh any risks. However, when it comes to primary prevention (accounting for around 75 percent of all the people who take a statin), no clinical trial has been able to conclusively show any net benefit.

This is one of the issues discussed in the documentary film STATIN NATION: The Great Cholesterol Cover Up.

If we look at the history of primary prevention clinical trials involving statins, we find that none of the major trials were able to demonstrate a significant reduction in the number of deaths from all causes. The AFCAPS, ASCOT, CARDS, PROSPER and WOSCOPS clinical trials all failed to show a statistically significant reduction in all cause mortality.

This data for deaths from all causes is, of course, important because it is the only measure we can use to determine if the statin is going to extend life expectancy or not.

Whilst some statin clinical trials have shown a very slight reduction in cardiac events, this has always been counter-acted by deaths from other causes. The net result being that people did not live any longer after taking the statin.

In fact, a meta-analysis of primary prevention clinical trials published in 2001 suggested that statins increase mortality when taken over a ten year period for both men and women.

More recently, pharmaceutical companies and much of the world's media have been touting the results of the JUPITER trial. However, if we take a closer look at the data for this trial, we can see that the statin and the placebo group had exactly the same number of cardiovascular related deaths - a fact that is highlighted by Dr Malcolm Kendrick in the new documentary.

In addition, an article published in the Archives of Internal Medicine in 2010 questioned the validity of the data from the JUPITER trial and raised concerns about the role of the company sponsoring the trial. Another article published in the journal Cardiology in 2011 raised similar concerns.

In 2010, a meta-analysis of 11 statin trials was published in the Archives of Internal Medicine. Professor Kausik Ray and colleagues concluded that statins provided no benefit in terms of deaths from all causes. It is worth mentioning that this analysis had the 'cleanest' dataset of any analysis completed to date - the researchers were able to exclude patients with existing heart disease (secondary prevention) and only include data associated with primary prevention.

In 2011, the highly respected Cochrane Collaborative conducted a review of statin clinical trials. Based on this review, lead authors Dr Shah Ebrahim and Dr Fiona Taylor said that they could not recommend the use of statins for primary prevention. The absolute benefit was so small that it could have been down to chance, and even if it was a real benefit, 1000 people would have to be treated for one year to prevent one death.

Thus, even before we start to assess the risks associated with statins, we can see that there is no meaningful net benefit where primary prevention is concerned.

Adverse Effects

We are told that the adverse effects of statins are only experienced by a very small number of people. This is said with confidence despite the fact that many of the trials did not report the adverse effects at all. For example, in the Cochrane review, the researchers noted that eight of the 14 randomized controlled primary prevention trials of statins analyzed did not report on adverse events.

It is very difficult to obtain a realistic overall percentage for the rate of adverse effects, however, GreenMedInfo.com has compiled what is probably the most extensive database of published studies documenting statin adverse effects. This body of evidence shows that there are more than 300 documented adverse effects of statins. This document can be accessed here: Statin Toxicity Research.

In summary, it is clear from the clinical evidence that for at least 75 percent of people who are taking a statin, there is no net benefit; only a strong possibility of significant adverse effects.
In my next article, I will focus on the use of statins for people who already have a diagnosed heart problem.

REFERENCES

• Downs JR, Clearfield M, Weis S, Whitney E, Shapiro DR, Beere PA, Langendorfer A, Stein EA, Kruyer W, Gotto AM Jr,. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study. JAMA 1998; 279:1615-22
• Sever PS, Dahlöf B, Poulter NR et al. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial. Lancet 2003; 361:1149-1158
• Clhoun HM, Betteridge DJ, Durrington PN, et al. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atovastatin Diabetes Study (CARDS). Lancet 2004; 364:685-96
• Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. Lancet 2002; 360:1623-1630
• Shepherd J, Cobbe SM, Ford I, et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia (WOSCOPS). N Engl J Med 1995; 333:1301-7
• http://www.ncbi.nlm.nih.gov/pubmed/7566020
• Jackson PR, Wallis EJ, Haq IU, Ramsay LE. Statins for primary prevention: at what coronary risk is safety assured? Br J Clin Pharmacol 2001; 52:439-46
• http://www.ncbi.nlm.nih.gov/sites/entrez/11678788?dopt=Abstract&holding=f1000,f1000m,isrctn
• Ridker PM, Danielson, E, Fonseca F, et al, for the JUPITER Study Group. Rosuvastatin to Prevent Vascular Events in Men and Women with Elevated C-Reactive Protein. N Engl J Med 2008; 359:2195-207
• http://www.nejm.org/doi/pdf/10.1056/NEJMoa0807646
• de Lorgeril M, Salen P, Abramson J, et al. Cholesterol lowering, cardiovascular diseases, and the rosuvastatin-JUPITER controversy. A critical reappraisal. Arch Intern Med. 2010; 170:1032-1036
• http://www.ncbi.nlm.nih.gov/pubmed/20585068
• Serebruany VL. Extreme all-cause mortality in JUPITER requires reexamination of vital records. Cardiology. 2011; 120:84-8
• http://www.ncbi.nlm.nih.gov/pubmed/22142620
• Ray KK, Seshasai SR, Erqou S, Sever P, Jukema JW, Ford I, Sattar N. Statins and all-cause mortality in high-risk primary prevention: a meta-analysis of 11 randomized controlled trials involving 65,229 participants. Arch Intern Med. 2010; 170:1024-31
• http://www.ncbi.nlm.nih.gov/pubmed/20585067

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Hughes, S. Cochrane review stirs controversy over statins in primary prevention. TheHeart.org
JANUARY 20, 2011
http://www.theheart.org/article/1174743.do

Justin Smith is an experienced personal trainer and nutritionist. He is the author of the book $29 Billion Reasons to Lie About Cholesterol and Producer/Director of the documentary film $TATIN NATION: The Great Cholesterol Cover-Up.
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Do Low Cholesterol Levels Cause Cancer?

Do Low Cholesterol Levels Cause Cancer?

March 26, 2012 Dr. Malcolm Kendrick

We live in a world where a high cholesterol is now considered to be virtually the most terrible and dangerous thing known to man. Everything possible must be done to bring the level down, or else you are going to die of a stroke or heart attack.

The anti-cholesterol propaganda has been so successful that six million people in the UK now take statins each and every day to reduce their risk of heart disease. Something which, I strongly believe, future generations will look back on in amazement. ‘Did they not know that cholesterol is essential for human health….what on earth did they think they were doing?’

Can it really be true that a chemical compound, so important that the liver synthesises at least five times as much as you consume in food, can be disastrous to our health. All cell membranes need it, our brains need it, almost all of our hormones are made out of it, and it is used to make vitamin D in our skin. It has always seemed to me that having too little cholesterol is just as likely to be damaging as having too much – probably more so.

One area I have particular concerns about is cancer. For many years it has been noticed that people with low cholesterol levels are more likely to die of cancer. This has been a consistent finding, for many years, from studies done all around the world^1-9.

The statin ‘zealots,’ as I shall call them, are well aware of the association between low cholesterol and cancer, and they have gone out of their way to dismiss the possibility that low cholesterol may cause cancer.

The primary argument they have used is known as reverse causality. This ‘reverse-causality’ hypothesis suggests that depressed LDL-cholesterol levels are the result of subclinical cancer (not the other way round). This idea has been put forward with absolutely no evidence to support it. Despite this, it has been accepted without question.

It is true that if you have advanced cancer, your cholesterol levels fall. This happens for a number of interconnected reasons, including the fact that large tumours use a lot of cholesterol to divide and grow.

However, the idea that a cancer so small, that it cannot not yet be detected, is using up so much cholesterol that it lowers the total cholesterol level throughout the body, is stretching the boundaries of possibility. I would say breaking the bounds of possibility.

The second argument put forward, which is not really an argument, is the ‘how can a low cholesterol level cause cancer anyway.’ It should always be remembered that a great deal of medical research consists of bumping into effects, without understanding how it could happen in the first place – see under penicillin. See more recently under aspirin protecting against cancer. A finding as yet, without any clearly defined mechanism of action.

In short, just because you can’t easily see a mechanism of action, does not mean that it doesn’t exist. In fact, several possible ways that cholesterol, or to be more accurate lipoproteins, could protect against cancer have been researched in some detail¹⁰.

Anyway, as I have always known must happen, the ‘reverse causality’ hypothesis has finally been laid to rest. A recent analysis of the longest running heart disease research project in the world (the Framingham Study) has shown that low cholesterol levels predate cancer diagnosis by many, many, years. And, to quote:

“Based on these data, it would suggest that lower cholesterol predated the development of cancer by quite a long time. Now, that doesn’t necessarily speak to [low cholesterol] causing the cancer; it could have been related to something else altogether, but it’s not supportive of the hypothesis that cancer caused the low levels of LDL cholesterol. We don’t know why it predates cancer, but it would be premature to attribute it to the cancer itself.” ¹¹

In short, it must now be accepted that cancer doesn’t cause low cholesterol levels. Which leaves the possibility that low cholesterol levels might cause cancer. This, inevitably, leads to the next question. If low levels of cholesterol precede cancer, can statins cause cancer?

The evidence is not conclusive, and I would not claim that it was. But there have been some significant warning signs from statin studies. Just to mention three. In the CARE trial¹², twelve women in the statin group had breast cancer at follow up, compared on only one in the placebo group. In the PROSPER study¹³ there were forty six more cases of cancer in the statin group than the placebo group.

Possibly the most worrying figures come from a Japanese study which looked at nearly fifty thousand people taking statins over six years. They found that the number of cancer deaths was more than three times higher in patients whose total cholesterol was less than 4.0mmol/l at follow-up, compared with those whose cholesterol was normal or high:

‘The patients with an exceptionally low TC (total cholesterol) concentration, the so-called ‘hyper-responders’ to simvastatin, had a higher relative risk of death from malignancy than in the other patient groups.’

The authors then went on to warn:
‘Malignancy was the most prevalent cause of death. The health of patients should be monitored closely when there is a remarkable decrease in TC (cholesterol) and LDL-C (Low Density Lipoprotein ‘bad cholesterol’) concentrations with low-dose statin.’¹⁴

This is not proof of causation, but these are warning signs. Armed with the Framingham data, I believe that the medical profession has to face up to the painful reality that low cholesterol levels could be a cause of cancer, and this needs to be properly researched. We must remember that it took Richard Peto more than thirty years to prove that smoking caused lung cancer, and no statin trial has lasted longer than six.

1. Williams RR, Sorlie PD, Feinleib M, McNamara PM, Kannel WB, Dawber TR. Cancer incidence by levels of cholesterol. JAMA 1981; 245:247–52.
2. Salmond CE, Beaglehole R, Prior IA. Are low cholesterol lvalues associated with excess mortality? BMJ 1985;290:422–4.
3. Schatzkin A, Hoover RN, Taylor PR, Ziegler RG, Carter CL,Larson DB, et al. Serum cholesterol and cancer inthe NHANES I epidemiologic followup study. NationalHealth and Nutrition Examination Survey. Lancet 1987;2:298–301.
4. To¨rnberg SA, Holm LE, Carstensen JM, Eklund GA. Cancer
incidence and cancer mortality in relation to serum cholesterol. J Natl Cancer Inst 1989; 81:1917–21.
5. Isles CG, Hole DJ, Gillis CR, Hawthorne VM, Lever AF.Plasma cholesterol, coronary heart disease, and cancer inthe Renfrew and Paisley survey. BMJ 1989; 298:920–4.
6. Kreger BE, Anderson KM, Schatzkin A, Splansky GL. Serum cholesterol level, body mass index, and the risk of coloncancer. The Framingham Study. Cancer 1992; 70:1038–43.
7. Schuit AJ, Van Dijk CE, Dekker JM, Schouten EG, Kok FJ.Inverse association between serum total cholesterol andcancer mortality in Dutch civil servants. Am J Epidemiol1993; 137:966–76.
8. Chang AK, Barrett-Connor E, Edelstein S. Low plasma cholesterol predicts an increased risk of lung cancer in elderlywomen. Prev Med 1995; 24:557–62.
9. Steenland K, Nowlin S, Palu S. Cancer incidencein the National Health and Nutrition Survey I. Follow-updata: diabetes, cholesterol, pulse and physical activity.Cancer Epidemiol Biomarkers Prev 1995; 4:807–11
10: http://qjmed.oxfordjournals.org/content/early/2011/12/08/qjmed.hcr243.full.pdf?keytype=ref&ijkey=kZGZxqVjYWEOtoc
11: http://www.theheart.org/article/1375049.do?utm_campaign=newsletter&utm_medium=email&utm_source=20120325_ACC_dimanche_2
12: Sacks FM, Pfeffer MA, Moye LA, Rouleau JL, Rutherford JD,Cole TG, et al. Effect of pravastatin on cardiovascular eventsin women after myocardial infarction: the cholesterol and recurrent events (CARE) trial. N Engl J Med 1996;335:1001–9
13: Shepherd J, Blauw GJ, Murphy MB, Bollen EL, Buckley BM,Cobbe SM, et al. Pravastatin in elderly individuals at risk ofvascular disease (PROSPER): a randomised controlled trial.Lancet 2002; 360:1623–30.
14: . Matsuzaki M, Kita T, Mabuchi H, Matsuzawa Y, Nakaya N,Oikawa S, et al. Japan Lipid Intervention Trial. Large scalecohort study of the relationship between serum cholesterol lconcentration and coronary events with low-dose simvastatin therapy in Japanese patients with hypercholesterolemia. Circ J 2002; 66:1087–95.
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The truth about statin drugs - Kresser

The truth about statin drugs

Statins have been almost universally hailed as “wonder drugs” by medical authorities around the world. The market for statins was $26 billion in 2005, and sales for Lipitor alone reached $14 billion in 2006. Merck and Bristol Myers-Squib are actively seeking “over-the-counter” (OTC) status for their statin drugs. Statins are prescribed to men and women, children and the elderly, people with heart disease and people without heart disease.

In fact, these drugs have a reputation for being so safe and effective that one UK physician, John Reckless (I’m not kidding – that’s actually his name!) has suggested that we put statins in the water supply.

That’s a bold suggestion, of course, and it begs the question: are statins really as safe and cost effective as mainstream medical authorities claim? The unequivocal answer is no.

Statins don’t increase survival in healthy people

Statins have never been shown to be effective in reducing the risk of death in people with no history of heart disease. No study of statins on this “primary prevention population” has ever shown reduced mortality in healthy men and women with only an elevated serum cholesterol level and no known coronary heart disease. (CMAJ. 2005 Nov 8;173(10):1207; author reply 1210.) In fact, an analysis of large, controlled trials prior to 2000 found that long-term use of statins for primary prevention of CHD produced a 1% greater risk of death over 10 years compared to placebo.

Statins don’t increase survival in women

Despite the fact that around half of the millions of statin prescriptions written each year are handed to female patients, these drugs show no overall mortality benefit regardless of whether they are used for primary prevention (women with no history of heart disease) or secondary prevention (women with pre-existing heart disease). In women without coronary heart disease (CHD), statins fail to lower both CHD and overall mortality, while in women with CHD, statins do lower CHD mortality but increase the risk of death from other causes, leaving overall mortality unchanged. (JAMA study)

Statins don’t increase survival in the elderly

The only statin study dealing exclusively with seniors, the PROSPER trial, found that pravastatin did reduce the incidence of coronary mortality (death from heart disease). However, this decrease was almost entirely negated by a corresponding increase in cancer deaths. As a result, overall mortality between the pravastatin and placebo groups after 3.2 years was nearly identical.

This is a highly significant finding since the rate of heart disease in 65-year old men is ten times higher than it is in 45-year old men. The vast majority of people who die from heart disease are over 65, and there is no evidence that statins are effective in this population.

Do statins work for anyone?

Among people with CHD or considered to be at high risk for CHD, the effect of statins on the incidence of CHD mortality ranges from virtually none (in the ALLHAT trial) to forty-six percent (the LIPS trial). The reduction in total mortality from all causes ranges from none (the ALLHAT trial) to twenty-nine percent (the 4S trial).

However, the use of statins in this population is not without considerable risk. Statins frequently produce muscle weakness, lethargy, liver dysfunction and cognitive disturbances ranging from confusion to transient amnesia. They have produced severe rhabdomyolysis that can lead to life-threatening kidney failure.

Aspirin just as effective as statins (and 20x cheaper!)

Perhaps the final nail in the coffin for statins is that a recent study in the British Medical Journal showed that aspirin is just as effective as statins for treating heart disease in secondary prevention populations – and 20 times more cost effective! Aspirin is also far safer than statins are, with fewer adverse effects, risks and complications.

The bottom line

1. Statin drugs do not reduce the risk of death in 95% of the population, including healthy men with no pre-existing heart disease, women of any age, and the elderly.
2. Statin drugs do reduce mortality for young and middle-aged men with pre-existing heart disease, but the benefit is small and not without significant adverse effects, risks and costs.
3. Aspirin works just as well as statins do for preventing heart disease, and is 20 times more cost effective.

So what if you are at risk for heart disease and you’d prefer not to take a statin? Other than aspirin, there are many clinically proven ways to prevent heart disease involving simple adjustments to diet and lifestyle. In fact, the recent INTERHEART study which looked at the incidence of heart disease in 52 countries revealed that over 90% of heart disease is preventable by diet and lifestyle modifications.

I’ll discuss these natural methods of preventing heart disease in my next post. Stay tuned!

Recommended links

• Dangers of statin drugs: what you haven’t been told about cholesterol-lowering drugs
• The effect of statins is not due to cholesterol lowering

Cholesterol and Statins: Who’s the Hero? Who’s the Villain?

Read the full article HERE. This is only an exerpt.
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Cancer

It is not easily shown that statins increase risk to cancer, because it takes considerable time for cholesterol to become depleted in the tissues as the supply line to replenish worn out cholesterol is reduced, and then more time for this depletion to lead to cancer due to genetic mutations. However, low cholesterol is a risk marker for cancer [15], and, despite the fact that statin trials are usually too short to reveal the trend towards increased cancer risk, several statin trials have resulted in observable differences between treatment and control groups, with treatment groups faring worse. In the first two trials on simvastatin, non-melanoma skin cancer was more prevalent in the treatment group, a result that becomes statistically significant if the data from the two trials are combined. In the CARE trial, which involved exclusively women, 12 women in the treatment group developed breast cancer, as against only one in the control group, a result that was highly significant (p = 0.002). Two other trials, both PROSPER and SEAS, also showed statistically significant increases in cancer incidence in the treatment group compared to the control group.

The story, in my view, for how statins increase your risk to cancer, involves a number of players and some complexity regarding mechanism. But it’s a very logical step-by-step progression, taking place steadily over an extended period of time. To understand the story, you first have to know something about vitamin B12 (cobalamin), a key player in the story. Vitamin B12 catalyzes a great number of reactions that require methionine, an essential sulfur-containing amino acid, as substrate, extracting the methyl group from methionine and adding it to some other molecule. One of the key molecules that benefits from such reactions is DNA. Methylation of DNA protects it from damage due to exposure to carcinogens or oxidation or radiation.

Methionine can also be degraded via a different pathway, and it’s an either-or situation here. This alternative fate results in the production of homocysteine, which later becomes substrate for the synthesis of sulfate. So, logically, if sulfate is in short supply, then methionine would get side-tracked down the homocysteine pathway, and less of the DNA would get methylated. Eventually, this would manifest as an increased risk to cancer.

Why might sulfate supply be deficient? This is something I have already discussed in previous blog posts, and one way it could happen is if the cells in the epidermis didn’t have enough cholesterol. This is because they need cholesterol in order to produce cholesterol sulfate, upon exposure to sunlight. The cholesterol sulfate is then shipped out via the blood stream to all the tissues, which eagerly take it up to resupply themselves with both cholesterol and sulfate.

The cells in the skin can synthesize their own cholesterol, but statin therapy would interfere with this process. As a result, they would not be able to spare cholesterol to ship out. What happens first is that, due to cholesterol deficiency in their membranes, they start leaking potassium at an excess rate, and an energy burn they can’t afford ensues, to pump the potassium back in. This becomes untenable, so calcium is brought in to replace some of the potassium as a positively charged electrolyte. Being a much bigger molecule, calcium doesn’t leak out nearly so easily. Its presence has a dramatic effect, however, on the eNOS molecules that had been responsible for synthesizing sulfate. They detach from the cell membrane and start making nitric oxide (−→ nitrate) instead. Unfortunately, this also results in some nasty side products like peroxynitrite and superoxide, which are potent oxidizing agents.

One of the first molecules that gets oxidized is cobalamin [1]. This drives the cobalt atom in cobalamin to a +3 charge, which inactivates the molecule, meaning that it will no longer support the methylation of the vulnerable DNA, thus increasing the risk to cancer. This is interesting from a biological standpoint, because it means that the methionine will naturally shift towards producing sulfate, a good idea since the skin is no longer going to be able to keep up with the supply.

One of the other molecules whose synthesis is catalyzed by cobalalmin is coenzyme Q10, probably the most important antioxidant in the mitochondria. The mitochondria are the chambers where sugars and fats are oxidized to produce ATP, the energy currency of the cell. Mitochondria are the organelles in the cell that suffer the greatest exposure to oxidizing agents, because oxidative metabolism takes place there. They contain their own separate mitochondrial DNA, now highly vunerable to attack.

To add insult onto injury, statins also interfere with the synthesis of coenzyme Q10, so this potent antioxidant is now in very short supply in the mitochondria of any cell in the skin that has been hit hard by a statin drug. The cells in the skin are now poised to develop cancer: they’ve got an extra burden of oxidizing agents, an increased vulnerability in their DNA to susceptibility to damage due to the demethylation process, and a decrease in the agents that would mop up extra free radicals. It’s not at all surprising that skin cancer is where the increased risk to cancer with statin therapy was first noted.

Another cancer which I suspect is increasing in incidence directly due to statin therapy is prostate cancer, which is the most common cancer by far in men. A very interesting recently noted observation is that prostate cancer tumors actually are producers of cholesterol sulfate! [3]. It has been suggested that this feature might be useful as a more reliable indicator of prostate cancer than the PSA test. I suspect in fact that this is a positive role they play, to try to correct a severe deficiency in this vital molecule, as cholesterol sulfate plays an essential role in fertilization [6]. Unlike women, men normally remain fertile throughout life, but not if cholesterol sulfate is insufficient. I would predict that surgery to remove a prostate tumor, beyond rendering a man infertile, will lead to an increase in various medical problems related to cholesterol sulfate deficiency.

From:  http://cindy-on-health.blogspot.com/2011/12/cholesterol-and-statins-whos-hero-whos.html

See also: http://stephanie-on-health.blogspot.com/

The author Stephanie is a research scientist at MIT.

From: Oxford University Press Quarterly Journal of Medicine.
http://qjmed.oxfordjournals.org/content/early/2010/11/29/qjmed.hcq230.full

Statin-induced diabetes: perhaps, it’s the tip of the iceberg

The meta-analysis by Mills et al.¹ involving 170 255 patients randomized in 76 trials reported on the efficacy and safety of statin therapy for the prevention of cardiovascular disease (CVD) and found a relative 9% increased risk in the development of incident diabetes (P = 0.001) among subjects randomized to statins compared with placebo in the 17 trials reporting on diabetes development. It is noteworthy that the average age of the subjects in the meta-analysis was 59.6 years, average follow-up was 2.7 years and more than half of the subjects were randomized for the primary prevention of CVD. We feel that the implications of statin-induced diabetes are not trivial, but of major concern, particularly in the primary prevention of CVD when statin therapy might be used for decades in individuals at relatively low risk²; many questions need answering before statin therapy can be safely recommended across broad populations.

Interestingly, a recently published meta-analysis involving 91 140 patients randomized in 13 trials³ specifically looking at the risk of incident diabetes from statin therapy also revealed a significant 9% increased relative risk of the development of diabetes over a mean overall trial period of 4 years. Disturbingly, 2 of the 13 trials demonstrated very high incidence of the development of diabetes among the statin-treated subjects. The Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER),⁴ a primary prevention trial of 1.9-year duration in subjects with a mean age of 66 years, demonstrated a significant relative increase in diabetes incidence of 26% among subjects randomized to rosuvastatin; the absolute rate of incident diabetes expressed in events per 1000 patient-years was 13 and 16 among the placebo and rosuvastatin subjects, respectively. Low-density lipoprotein (LDL) cholesterol was decreased robustly by 50% in the rosuvastatin subjects and the median LDL cholesterol at the end of follow-up was 55 mg/dl. The PROspective Study of Pravastatin in the Elderly at Risk (PROSPER),⁵ a combined primary and secondary prevention trial of 3.2-year duration in subjects with a mean age of 76 years, demonstrated a significant relative increase in diabetes incidence of 32% among subjects randomized to pravastatin; the absolute rate of incident diabetes expressed in events per 1000 patient-years was 16 and 21 among the placebo and pravastatin subjects, respectively. LDL cholesterol was decreased by 31% in the pravastatin subjects. Therefore, it appears that the risk of statin-induced diabetes is more prominent with aggressive LDL cholesterol lowering and among the elderly subjects. It is of concern that thought leaders in the cardiovascular arena strongly suggest that statin use should be increased from 16 to 100 million people in the USA and LDL cholesterol should be aggressively lowered.⁶ This issue takes even more relevance given that the prevalence of diabetes is rapidly increasing in the USA⁷ and worldwide⁸; alarmingly, three-quarters of the elderly in the USA have diabetes or pre-diabetes.⁷

In vivo studies have demonstrated that despite lowering LDL cholesterol levels, some^9–11 but not all statins¹¹ significantly increase fasting plasma insulin levels and significantly decrease insulin sensitivity in hypercholesterolemic patients in a dose-dependent manner. Statins can significantly increase fasting plasma insulin levels and glycated hemoglobin levels in the absence of significant changes in fasting glucose.^9–11 Additionally, some statins have been shown to significantly decrease plasma adiponectin levels.^10,11

In vitro and animal studies^12,13 have shown that statins can significantly decrease the expression of the insulin-responsive glucose transporter 4 (GLUT4) in adipocytes. GLUT4 is distributed in the intracellular compartment in the basal state and relocates to the cell membrane in response to insulin signaling. Moreover, statins increase the expression of GLUT1¹² in adipocytes; GLUT1 is localized in the cell membrane. It is unclear how statins change the expression of GLUT1 and GLUT4; perhaps, it is related to an inhibition of isoprenoid biosynthesis by statins¹² or cholesterol lowering, leading to a change in membrane lipid raft structure resulting in decreased insulin signaling.¹⁴ Since GLUT4 concentrations are not reduced in skeletal muscle in obese subjects and subjects with diabetes, and skeletal muscle is the primary source of insulin-stimulated glucose disposal, it has been argued that whole-body insulin sensitivity cannot be explained by a decrease in the production of GLUT4¹⁵; however, it has been shown that the downregulation of GLUT4 and resulting glucose transport in adipose tissue can cause insulin resistance.¹⁶ It is notable that GLUT4 concentrations are decreased in skeletal muscle in elderly compared with younger subjects,¹⁵ which might explain why the elderly are more sensitive to the diabetes promoting effects of statin therapy. Furthermore, dysregulation of cellular cholesterol may attenuate pancreatic β-cell function, since cholesterol maintains normal function of voltage gated calcium channels and is vital in the mobilization and fusion of insulin granules with the cell membrane.¹⁷ In summation, there are many ways by which statin therapy might lead to hyperinsulinemia, insulin resistance, prediabetes and diabetes.

In addition to the classic complications of diabetes such as CVD, renal failure, blindness and neuropathy, epidemiological studies demonstrate that diabetes is related to the increased risk of many cancers.¹⁸ These include liver, pancreas, kidney, endometrial, colorectal, bladder and breast cancer and non-Hodgkin’s lymphoma. A large European population study with a median follow-up of 15.8 years has shown that compared with individuals with normal glucose tolerance, men and women with prediabetes or diabetes had a significant increase in cancer mortality, irrespective of the body mass index.¹⁹ There is epidemiological evidence that insulin resistance is associated with cancer in Eastern populations.²⁰ Interestingly visceral fat mass, assessed by computed tomography, but not subcutaneous fat mass, correlates positively with cancer²¹; indeed, visceral fat is a strong determinant of insulin resistance and hyperinsulinemia.

There are many ways by which hyperinsulinemia can promote cancer.^18,22 Hyperinsulinemia results in an increase in the biologically active free circulating insulin-like growth factor-1 (IGF-1) by increasing hepatic IGF-1 production²² and decreasing IGF-1 binding proteins.¹⁸ Tumor cells are replete with IGF-1 receptors and two isoforms of insulin receptors (IR-A and IR-B).²³ IGF-1 primarily signals through the IGF-1 receptor resulting in mitogenic effects and, not surprisingly, higher IGF-1 blood levels have been associated with an increased risk of several cancers.^24,25 Insulin signaling through the IR-A and IR-B results in mitogenic and metabolic effects, respectively.²² Hyperinsulinemia can persist for decades in prediabetic states and it is certainly conceivable that this prolonged mitogenic stimulus increases cancer promotion as has been seen in epidemiological studies.

Statin therapy might affect tumor metabolism by insulin independent means. As previously mentioned, some statins decrease adiponectin levels.^10,11 This is potentially problematic over the long-term since adiponectin is anti-proliferative and anti-angiogenic and has other oncostatic properties.²⁶ Furthermore, obesity is associated with lower circulating adiponectin levels and this might partially explain the association of obesity and various cancers. Additionally, the fact that statin therapy might increase GLUT1 expression¹² is of concern since GLUT1 is already overexpressed and is the main glucose transporter in cancer cells.²⁷ Glucose uptake by cancer cells is extremely avid and up to 30 times that of normal cells and utilized by glycolysis for energy and supplying important metabolites for rapid cellular proliferation.²⁸ Indeed, in human studies, increased expression of GLUT1 in cancer cells has been associated with poor prognosis of many cancers.^27,29

The Western diet is permissive to the diabetogenic effects of statin therapy. The prevalence of obesity has been steadily increasing in the USA and more than two-thirds of adults are overweight or obese.³⁰ As mentioned, the prevalence of diabetes has been increasing in the USA and a majority of the elderly subjects in the USA now have pre-diabetes or diabetes.⁷ Interestingly, total cholesterol and LDL cholesterol have been decreasing in the USA likely due to cholesterol awareness and the increased use of lipid-lowering medication, and more than half of the elderly subjects in the USA have reported using lipid-lowering medications.³¹ However, blood triglyceride levels have been steadily increasing despite the increasing use of lipid-lowering therapy.³¹ Intriguingly, it is now believed that abnormalities in fatty acid metabolism are at the root of diabetes, and ectopic lipid accumulation in muscle, liver and pancreatic β-cells leads to the development of insulin resistance by interfering with insulin signaling.^32,33 The increase in blood triglyceride levels is driven by a high carbohydrate diet and partially fueled by the increase in dietary sweetener consumption.³⁴ Unfortunately, fructose consumption, largely from sweetened beverages, has escalated drastically in North America over the past three decades³⁵ and excessive fructose intake leads to increased hepatic de novo lipogenesis resulting in hepatic steatosis, visceral fat accumulation and ectopic lipid deposition in skeletal muscle, thereby all leading to insulin resistance.

We are living in times when there seems to be a much stronger emphasis on the use of drugs over lifestyle change to prevent disease. The food industry has been uncooperative and blames personal responsibility as a cause of the obesity problem.³⁶ There is a belief among many patients that they can eat whatever they want as long as they are on statin therapy.³⁷ This has been amplified by a proposal to offer powdered statin in packets to be sprinkled on hamburgers at fast-food restaurants in order to neutralize the detrimental effect of the food choice.³⁸ Plant-based diets have been shown to decrease both CVD and cancer risk and even result in a rapid change in gene expression in neoplastic tissue, and they are not diabetogenic.^39–41 Moreover, a Mediterranean diet has been shown to counter the insulin raising effects of simvastatin therapy.⁴² It is extremely troubling that a goal has been proposed for decreasing the LDL cholesterol levels of all subjects worldwide to below 100 mg/dl and ideally below 60 mg/dl by statin therapy.⁴³

In conclusion, many important questions need answering before expanding the use of statin therapy, particularly for the primary prevention of CVD. In what proportion of subjects do statins increase plasma insulin levels, even if there is no progression to diabetes? Are some statins more likely than others to cause hyperinsulinemia because of physiochemical differences? Will prolonged statin therapy result in chronic hyperinsulinemia and potentially increase prediabetes, diabetes and/or cancer? Will this risk outweigh any perceived benefits, particularly in the elderly or in aggressively treated patients? Will the Western diet and lifestyle encourage the use of more statin therapy and provide a metabolic substrate to further perpetuate hyperinsulinemia and its subsequent complications? Is the increase in diabetes prevalence in the elderly subjects fueled partially by the increasing use of statins in this age group? What statins decrease blood adiponectin levels, and is it continuous, and, if so, what are the long-term clinical implications? How should physicians monitor patients for the adverse metabolic effects of statin therapy? Should subjects have a plasma insulin level measured prior to initiating and during statin therapy? What diet or diets will mitigate the hyperinsulinemic effects of statin therapy? Will statin therapy used by subjects with a history of cancer increase the chance of hyperinsulinemia increasing the promotion of occult micrometastatic disease? Finally, physicians should realize that statin-induced diabetes, as seen in the relatively short-term clinical trials, might be just the tip of the iceberg, and properly designed clinical trials must be done to determine what else lurks beneath the water in order to ensure the safety of patients on long-term treatment with these drugs.

• © The Author 2010. Published by Oxford University Press on behalf of the Association of Physicians. All rights reserved. For Permissions, please email: journals.permissions@oup.com

Scientists sometimes shift the scientific goalposts

Dr. John Briffa

Scientists sometimes shift the scientific goalposts

Posted on 10 August 2011

It’s easy to believe that statins have dramatic life-saving properties. The reality is, however, that for the majority of people who take them, they don’t. In the biggest and best review published to date, statins were not found to reduce overall risk of death in individuals with no previous history of cardiovascular disease [1]. What this study shows is that for great majority of people who take statins, the chances of them saving their life are, essentially, nil (just so you know).

Of course, you wouldn’t expect everyone to take this finding lying down. A number of people responded to this study with letters to the journal in which it appeared, attempting to cast doubt on its findings. None of it amounted to much, but I thought I would focus on one response, which in my view demonstrates how some scientists and doctors attempt to shift the scientific goalposts to make their point and suit their ends.

The response came from Drs Gabriel Chodick and Varda Shalev [2]. The main thrust of their objections come in the form of three studies that were included in the review referred to above that they claim have ‘major limitations’. Here’s what they say about each of these studies:

“…their meta-analysis included 3 studies with major limitations: a significant decrement in low-density lipoprotein cholesterol levels over the study period in the placebo arm (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial [ALLHAT]), old age at therapy initiation (Pravastatin in Elderly Individuals at Risk of Vascular Disease [PROSPER] Study), and incomplete information on low-density lipoprotein cholesterol levels over the follow-up period (Air Force/Texas Coronary Atherosclerosis Prevention Study [AFCAPS/TexCAPS]). All these studies showed negative results; their inclusion would have biased against finding a benefit to statin treatment.”

With regard to the first study, what Drs Chodick and Shalev seem to be saying is that the control group (the group treated with placebo rather than statin) saw natural reductions in cholesterol, so the benefits of taking a statin did not to show up. However, the impact that statins had on cholesterol levels relative to a control group is not important – the only important thing is the impact statins had on health (and, in particular, overall risk of death). This is also true for the last study highlighted by Drs Chodick and Shalev.

As regard the second study, it’s not clear why the advanced years of participants would be a barrier to determining the effectiveness of statins. Actually, the elderly are known to be at particularly high risk of cardiovascular disease, meaning that if anything, this population would, theoretically, be generally most likely to benefit from statin therapy.

In summary: none of Drs Chodick and Shalev’s objections hold any water at all. But they don’t stop there. Here’s the final paragraph from their letter.

“Also, randomized controlled trials are often characterized by limited follow-up periods. Therefore, all-cause mortality benefits may not be apparent in randomized controlled trials among a primary prevention population. It would be informative in this regard to take into account the results of large observational studies with longer follow-up periods to better capture the benefits of statins in primary prevention patients.”

What they’re saying here is that clinical trials don’t go on long enough to detect benefits. It’s better, in their mind, to revert to longer studies that are observational (also known as ‘epidemiological’) in nature. However, such studies look at associations between things, but can never be used to prove the benefits of statins. Only intervention studies can do this.

So, what the authors of this letter are effectively saying is that we should ignore the best evidence we have in favour of quite-useless epidemiological evidence.

One of the authors of this letter is, in fact, an epidemiologist, and really should know better. But then again, both of the authors work for a company that assists drug companies in, among other things, ‘reducing the time to market’ and the writing and submission of scientific articles for publication.

See here for more details. It’s a clear conflict of interest, of course, and perhaps goes some way to explain why they make apparently spurious objections to existing evidence and appear to be calling for an approach that can never really get to the truth.

References:
1. Ray KK, et al. Statins and all-cause mortality in high-risk primary prevention: a meta-analysis of 11 randomized controlled trials involving 65 229 participants. Arch Intern Med. 2010;170(12):1024-1031
2. Chodick G, et al. Statins and all-cause mortality in high-risk primary prevention: a second look at the results. Arch Intern Med. 2010;170(22):2041-2
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Read the full article here.