Statins and The BMJ
BMJ 2014; 349 doi: https://doi.org/10.1136/bmj.g5038 (Published 07 August 2014) Cite this as: BMJ 2014;349:g5038
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Dear Sir,
Another trial needing some scrutinity is SPARCL, a stroke-tia secondary prevention trial demonstrating some effect of atorvastatin 80 mg on the recurrence of ischemic stroke. I never found out why the marginal benefits (NNT > 200) of atorvastatin found their way into guidelines.
Another miracle was, why on earth there was there no overall survival benefit of this kind of statin in mostly above 70 stroke patients who should bear their share of IHD etc.
Is there really no difference between the overall effects of "natural" and "synthetic" statins ?
Kind regards
Joerg Wiesenfeldt
Competing interests: No competing interests
Following a very intense debate in the BMJ concerning the expansion of the use of statins in low risk populations. (1)
An Independent statins review panel have called for the individual patient data to be made available for independent scrutiny. They concluded patients and their doctors need access to all relevant information to make informed decisions about their health.(2) This is never more important concerning the safe prescribing of drugs in pregnancy and those of reproductive age.
The US Food and Drug Administration currently designate statins in pregnancy as category X, or contraindicated.(3). Statins in pregnancy are also contraindicated in Europe and in many other countries worldwide. The FDA declared that the benefits of taking them do not outweigh potential risks.
A new study of statins has examined the teratogenic potential of statins (4) http://www.bmj.com/content/350/bmj.h1035
Bateman et al reason ‘As the prevalence of risk factors for cardiovascular disease, including hypercholesterolemia, diabetes, hypertension, and obesity in women of reproductive age increases (5) and as the indications for statin treatment expand, (6) it is important to understand whether it is safe to use these drugs in patients who may inadvertently become pregnant; about half of all pregnancies in the United States are unintended’. (7)
A subsequent review of the study by Haramburu et al concluded:
‘New safety data are reassuring enough about the side effects but suspension of treatment is still advisable’
Women should not take the medication if they are pregnant or planning on becoming pregnant. (8)
The Bateman statin study conducted in America included data from patients with diabetes (type unspecified) A wealth of evidence has established that cholesterol lowering statin drugs, widely used for the prevention of cardiovascular disease, do increase the risk of new-onset diabetes. (Type 2) (9)Statins have been associated with a 46% rise in type 2 diabetes risk. (10)
Those with type 2 diabetes have to have an appropriate regime to keep healthy; this regime must be immaculate within pregnancy. A good diabetic diet is a nutritious one which would be beneficial in maintaining a good lipid profile. Good health can be achieved within T2DM/gestational diabetes management without resorting to drugs unrecommended for use in pregnancy. Were the women given the option or choice of treatments/protocols which would enhance the chances of a healthy pregnancy supporting both the mother and infant? A nutritious diet is of cause vital in all women to support a healthy pregnancy. Lifestyle measures should be given more consideration as a priority, without the potential harm of barely tested prescribed drugs.
Pregnancies compromised by diabetes (types 1, 2 and gestational) are considered high risk pregnancies requiring diabetes specialist attention. This population should certainly not be a target for any medical experimentation.
Further concerns of statin use have also been highlighted that statins block the endogenous production of co-enzyme Q10 (CoQ10) (11)(12)(13)(14) Studies conducted on CoQ10 levels provide a gathering body of evidence highlighting the importance of CoQ10 in diabetes management.(15)(16)(17) Further studies in the role of co-enzyme Q10 are obviously needed.
It is interesting to note that the Bateman study suggests statins may have a therapeutic effect on pre-eclampsia. A 2009 study suggests Coenzyme Q10 supplementation during pregnancy reduces the risk of pre-eclampsia. (18)
Cholesterol has been portrayed as a villain in cardiovascular health. However it holds an essential role in homeostasis. Vitamin D is Synthesized from Cholesterol and found in Cholesterol-Rich Foods.
Vitamin D is manufactured in the body from cholesterol specifically, from 7-dehydrocholesterol. (19)
Cholesterol is a precursor for other important steroid molecules: the bile salts, steroid hormones, and vitamin D. (20)
Vitamin D is also a regulator of homeostasis of bone and mineral metabolism, but it can also provide nonskeletal actions because vitamin D receptors have been found in various tissues including the brain, prostate, breast, colon, pancreas, and immune cells. (21)
Adverse reactions of statin use include a spectrum of muscle disorders including rhabdomyolysis, a form of severe myalgia. Rhabdomyolysis is a rare but clinically important adverse event of statin therapy. (21)
The FDA has reported serious liver injury with statins to be rare but unpredictable in individual patients. (23)
Past studies urged caution in using statins preconceptually and in pregnancy.
A UK 2009 study stated: “Our study examined the effects that both lipophilic and hydrophilic statins had on a key biological system that is crucial for maintaining the normal function of the placenta, which acts as the nutrient-waste exchange barrier between mother and fetus.”
They concluded: Pregnant women or those hoping to start or extend a family should talk to their physician about avoiding using the cholesterol-lowering drugs statins (24)
Another 2009 study stated ‘Given the essential role of independent cholesterol synthesis, it is not surprising that most of the known genetic defects of cholesterol biosynthesis in fetuses severely impact their development and survival.’ (25)
The cholesterol debate has captivated scientific opinion for decades. Is it not high time that all aspects of cholesterol management are discussed with all facts available to all? Prescribing of statins to pregnant women and those of reproductive age should not happen as per prescribing guidelines. There needs to be more information and awareness of avoidance of harmful substances in pregnancy. The study does not even mention loss of pregnancy through miscarriage or spontaneous abortion. (Loss of a fetus before the 20th week of pregnancy).
Cholesterol is irrefutably essential for a healthy pregnancy. Medical opinion is still divided over the role of statins and cholesterol management in general. Diet and lifestyle must be considered as a matter of priority, particularly in pregnancy. Especially in those considered high risk including those compromised by diseases such as diabetes. Statins cannot replace healthy living.. In effect medicalisation has occurred before the cradle to the grave.
(1) Godlee F. Adverse effects of statins. BMJ 2014;348:g3306
(2). www.bmj.com/content/independent-statins-review-panel-report-0
http://www.bmj.com/campaign/statins-open-data
(3).http://www.fda.gov/downloads/ScienceResearch/SpecialTopics/WomensHealthR... Consistency of Pregnancy Labeling Across Different Therapeutic Classes. Accessed 12th April 2015.
(4) Bateman Brian T, Hernandez-DiazSonia, Fischer Michael A, SeelyEllen W, Ecker Jeffrey L, FranklinJessica M et al. Statins and congenital malformations: cohort study BMJ 2015; 350 :h1035
(5)Hayes DK, Fan AZ, Smith RA, Bombard JM. Trends in selected chronic conditions and behavioural risk factors among women of reproductive age, behavioural risk factor surveillance system, 2001-2009. Preven Chronic Dis2011;8:A120.
(6) Stone NJ, Robinson JG, Lichtenstein AH, Bairey Merz CN, Blum CB, Eckel RH, et al. 2013 ACC/AHA Guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation2014;129(25 Suppl 2):S1-45
(7) Edison RJ, Muenke M. Gestational exposure to lovastatin followed by cardiac malformation misclassified as holoprosencephaly. New Engl J Med2005;352:2759.
(8) Statins in pregnancy. Françoise Haramburu, Amélie Daveluy,Ghada Miremont-Salamé.BMJ 2015;350:h1484
(9) Do statins cause diabetes? Goldstein MR1, Mascitelli L. Curr Diab Rep. 2013 Jun;13(3):381-90. doi: 10.1007/s11892-013-0368-x. http://www.ncbi.nlm.nih.gov/pubmed/23456437
(10) Mayor Susan. Statins associated with 46% rise in type 2 diabetes risk, study shows BMJ 2015; 350:h1222
(11) Ellen CG Grant. Rapid response. Inevitable adverse effects due to blockage of co-enzyme Q10? http://www.bmj.com/content/348/bmj.g3306/rr/698281
(12) David L Keller Rapid response. Discussion of Dr. Grant's point regarding coenzyme Q10 http://www.bmj.com/content/348/bmj.g3306/rr/698414
(13) Sergio Stagnaro. Rapid response. Adverse effects of statins. http://www.bmj.com/content/348/bmj.g3306/rr/698206
(14) Andrew N Bamji. Rapid response. Adverse effects of statins. Http://www.bmj.com/content/348/bmj.g3306/rr/698457
(15) Mitochondrial factors in the pathogenesis of diabetes: a hypothesis for treatment. Lamson, D.W.. Plaza S.M. Altern Med Rev, 2002. 7(2): p. 94-111.
(16) Brownlee, M., The pathobiology of diabetic complications: a unifying mechanism. Diabetes, 2005. 54(6): p. 1615-25.
(17) CoEnzyme Q10:The State of the Science in Diabetes Ryan Bradley, ND, MPHDiabetes Action Research and Education Foundation February 2007 http://www.diabetesaction.org/site/PageServer?pagename=complementary_2_07
(18) Coenzyme Q10 supplementation during pregnancy reduces the risk of pre-eclampsia. Enrique Teran, Isabel Hernandez, Belen Nieto, Rosio Tavara, Juan Emilio Ocampo, Andres Calle International Journal of Obstetrics and Gynaecology. April 2009Volume 105, Issue 1, Pages 43–4
(19) The role of vitamin D in pregnancy and lactation: emerging concepts Carol L Wagner, Sarah N Taylor, Donna D Johnson, and Bruce W Hollis Womens Health (Lond Engl). 2012 May; 8(3): 323–340.
(20) Berg JM, Tymoczko JL, Stryer L. Biochemistry. 5th edition. New York: W H Freeman; 2002. Section 26.4, Important Derivatives of Cholesterol Include Bile Salts and Steroid Hormones. Available from: http://www.ncbi.nlm.nih.gov/books/NBK22339/
(21) Role of Vitamin D in Insulin ResistanceChih-Chien Sung,1 Min-Tser Liao,2 Kuo-Cheng Lu,3and Chia-Chao Wu1 Journal of Biomedicine and Biotechnology Volume 2012 (2012), Article ID 634195, 11 pages
http://dx.doi.org/10.1155/2012/634195
(22) Rhabdomyolysis and HMG-CoA reductase inhibitors. Omar MA, Wilson JP, Cox TS. Ann Pharmacother 2001;35:1096-107
(23) FDA Drug Safety Communication: Important safety label changes to cholesterol-lowering statin drugs. http://www.fda.gov/Drugs/DrugSafety/ucm293101.htm
(24) "Statin Warning For Pregnant Women." University of Manchester. ScienceDaily. ScienceDaily, 10 December 2008.
(25) Maternal–Fetal Cholesterol Transport in the Placenta. W Palinski. Circulation Research.2009; 104: 569-571
Competing interests: No competing interests
As a medical journalist who has been following the statin debate for some years, I'm concerned about the committee's recommendation that the ongoing statin debate "be conducted primarily in medical journals rather than in the lay media".
Quite apart from the issue of how on earth would you enforce such a restriction, it it seems to reflect precisely the sort of thinking that has allowed this situation to arise in the first place. Statins have been around for 20 years and for most of that time there has been a solid medical consensus that these drugs are safe, save lives and should be given to an ever increasing number of people.
There have of course been a few brave dissenting medical voices but opposing the might of NICE, the MHRA, and a range of prestigious Heart charities is not professionally rewarding. In fact the response of Sir Rory Collins to criticism - to take to the press and to accuse his critics of killing people - illustrates just what the costs can be.
It might of course be an example of the kind of public debate the committee wants to avoid but is it really better if that kind of hostility were vented in private? "Don't fund that chap Abramson, very unsound, no grasp of statistics at all." Having it in the press allows people a much better sense of what is going on.
That combined with the open letter to NICE objecting to the proposal to expand statin prescribing that put the issue of the front page. Without the public being able to see both sides of the argument in this way I would argue that many of the issues that have subsequently come have might well have remained comfortably behind closed doors.
Earlier this year I exchanged emails with Dr Godlee in connection with evidence that I had obtained showing that the CTT did not allow any independent researchers access to its data and that it did not hold data on side-effects while researching an article for the Daily Mail (http://dailym.ai/1oukfV5)
Dr Godlee agreed that it was unsatisfactory that the data was not accessible but observed that it was not actually breaking the law.
The findings of the committee have certainly highlighted these two issues but surely they need a lot more public discussion rather than less. The proposal to have the CTT data examined by the likes of Abramson is obviously welcome (not so sure about Collins who has already produced his analysis) but the results will need a lot of public explaining.
The recent round of public discussion of statins involving hidden data, vested interests, and critiques of how benefits and side effect are calculated let a lot of light in on a topic that has remained largely hidden. That is especially important with a new generation of more powerful and far more expensive cholesterol lowering drugs coming down the pipe line.
If all discussion about them were kept behind doors it's likely that once again a more nuanced picture wouldn't t become public for another twenty years. This is one proposal to be be firmly resisted.
Competing interests: No competing interests
Its fascinating to see all these experts, and even Nigel Hawkes, getting sucked into the debate about statin side-effects. But they seem to be missing the wider point........................... do we really want to create a society where we're all on pills to prevent this disease and that, when the same diseases are largely products of a self-abusive lifestyle? We know that those who grew up in periods of shortages, for example between and during the wars, have so much less of the disease which statins seek to compensate for but we're not prepared to address these primary causes and effects.
Just as we've sleep-walked into Orwell's world of almost universal state scrutiny of citizens, we're now sleep-walking into Huxley's world of a pill for everything. (Or if not a pill, then enormously expensive weight-loss surgery). Why aren't all the great and the good of Oxford University, the BMJ and NICE debating this issue instead of bickering about statin-related pains?
Competing interests: No competing interests
I am pleased to see that the review panel requested that further contributions to the statin debate be channelled through medical media and not the lay press. In my view, Professor Collins’ initial unscientific resort to the newspapers disqualifies him from undertaking any further data analysis, something I have already criticised in a rapid response to the BMJ. It would have been ridiculous to withdraw the original article on the basis of one small (in context) error but, just as Roy Meadow was unjustly pilloried for a similar type of error, mud sticks. The Cochrane Collaboration remains the only completely independent potential reviewer that cannot be criticised by one of the existing parties to the debate. Or does it? Nigel Hawkes’ article raises some doubts.
There is no doubt that some muscle “side-effects” are coincidental. I concluded that from an observational study of statin users who contacted me following an article of mine in the "Daily Mail". Neither do I doubt that statins are the only cause of muscle side-effects – other cholesterol-lowering drugs may do it. The principle of re-challenge may be important. In my own case I re-challenged with a whole range of different statins once the apparent side-effect of the previous one wore off. In each case, though with variable intervals, the side-effects recurred and were accompanied by biochemical disturbance (a rise in muscle enzymes). Since stopping all anti-cholesterol therapy they have never recurred. This is a pattern I have had patients report to me also. I confess that when I also developed severe myalgia (and a significantly raised creatine kinase) on ezetimibe I was weary of science and did not re-challenge.
I still maintain that we may be looking through the wrong end of the telescope. Cholesterol levels may be an irrelevant epiphenomenon, or at best a marker for treatment compliance. We should re-define cardiac risk omitting cholesterol levels from the algorithm. The effect of statins may be (indeed in my view is much more likely to be) a function of their anti-inflammatory properties. If it is true, then the C-reactive protein level would be a better biochemical marker. The hypothesis would also explain the apparent paradox of a rise in cholesterol when active rheumatoid arthritis is treated, despite such treatment reducing the already substantially elevated cardiac risk. Likewise the relation between side-effects and coenzyme Q10 levels may be critical in determining whether there is a particular group of people who should not take statins because they are at risk of side-effects, and this requires investigation. Given the current controversy, investigation of these hypotheses may distract folk from hysterical polemic.
Of course, for as in Adam all die, reducing cardiac causes of death increases the deaths from other things…
Competing interests: I have suffered from significant muscle side-effects from cholesterol-lowering drugs
Following the recent controversy on SARs in the BMJ Prof Collins argues the investigation was not independent and came to the wrong conclusion. (BMJ 'right' in statins claims row. By James Gallagher Health editor, BBC News website http://www.bbc.co.uk/news/health-28602155)
“He told the BBC: "It is not surprising the BMJ investigates itself and exonerates itself.
"The BMJ published misinformation and they've withdrawn one major error, but have not corrected several other major errors.
"My concern is that as before, patients and their doctors are misinformed by those papers and the BMJ's failure to correct them."
“their doctors are misinformed by those papers”
Really! and what about his own study, the HPS[1] report where there are hidden data, inaccurate reporting, etc. and massive misinformation about the value of statins? As shown by de Lorgeril in his expose of skullduggery in clinical research on cholesterol and statins (see: de Lorgeril, Michel (2014-03-05). Cholesterol and statins: Sham science and bad medicine Kindle edition[2]) HPS at the Ultimate in Clinical Research: the Heart Protection Study Section) shows that misinformation and other flaws are present in Collins’ own research and by extrapolation all medical clinical research on Big Pharma drugs.
The problems is now “What and who does anyone believe!” The flaws in statin research[2] are such that it brings disrepute on the whole medical profession, the vast majority of whom are genuine hard-working docs doing their best for their patients but are being tainted by Big Pharma and their complicit medical researchers, the medical establishment and Governments with their DIRECTIVES (aka guidelines).
Reminds me of a 150 year-old quote
“Not only are men who are overconfident in their theories or ideas unlikely to discover anything, they are also very poor observers. Indeed, their observation will necessarily be influenced by their preconceived convictions and, when they are the instigator of an experiment, they are most likely to focus on those results that support their theory. Thus, because they do not point in the desired direction, certain essential facts are often neglected."
Claude Bernard: Introduction à la médecine expérimentale 1865
M. J. Hope CAWDERY
References:
1. THE LANCET • Vol 360 • July 6, 2002 • www.thelancet.com
2. Michel de Lorgeril (2014-03-05). Cholesterol and statins: Sham science and bad medicine. Kindle edition
Competing interests: No competing interests
“… asked that the debate be conducted primarily in medical journals rather than in the lay media.. “ Since when has the BMJ or anyone else had the right to tell the lay media what to debate and what not to? This smacks of academic snobbery.
“… such debates will not be satisfactorily resolved in the public interest unless legitimate third parties are given access to the clinical study reports and the anonymised patient level data..;.” who decides who is a LEGITIMATE party. This smacks of academic snobbery. Throw it open to everyone.
Competing interests: No competing interests
Individual level data from big pharma
As an independent researcher and a PhD student who focuses on the statin safety in older adults aged 65 years and older in primary prevention, I have applied two datasets (APSEN & BONE) from Pfizer and one dataset from Astrazenaca (METEOR). Both of them were willing and friendly to share the individual patient data, even the access process took me around 1-2 years.
Thankfully, I also got access to PREVENT-IT data from Dr. Frank. Furthermore, I know that Pfizer are also willing to share other data they have, such as ASCOT-LLA data. I will be very glad to share these unpublished data in my meta-analysis which is estimated to be submitted at the end of this year.
Considering my experience, it seems unfair to claim that big pharma are unwilling to disclose the data from the trial they sponsored.
Competing interests: No competing interests