Dr John Briffa's response to the BMJ's withdrawal of comments.

My reaction to the BMJ’s withdrawal of statements relating to the safety of statins

By Dr John Briffa on 21 May 2014

 

You may have noticed that there’s a bit of a ‘fight’ going on over the cholesterol-reducing class of drugs known as ‘statins’. I am simplifying here, but there are essentially two opposing camps. In one corner, there are those doctors and researchers who hold the view that the statins should be given to pretty much all adults from middle-age, and there is little to be concerned with regarding their safety. In the other corner, there are those who believe that statins do no good at all for the vast majority of people who take them, and that the side-effects are more common that ‘official statistics’ suggest.
The fight went up a notch last week when the editor of the British Medical Journal announced that remarks made in two BMJ articles about the side-effects of statins had been withdrawn [1]. One of the articles was written by Dr John Abramson from Harvard Medical School and colleagues, and principally questioned whether extending statin use to those at lower risk (as has been suggested by the National Institute of Health and Care Excellence) will save lives [2].  According to their analysis, it won’t. The other piece was written by UK cardiologist Dr Aseem Malhotra, and principally questioned the role of saturated fat in heart disease [3].

In both articles, the authors referred to a study [4] that found that 17.4 per cent of people taking statins had adverse effects as a result attributed to statins. In the articles this figure was expressed as 18 per cent or ‘about 20 per cent’ which, apparently, was the first error. However, other issues, according the BMJ, was that the authors claimed that the 17.4 figure related to the percentage of people who stopped statins (at least temporarily) due to side-effects – this is not correct (it represented the percentage of people who had adverse effects). Also, the study in question was ‘observational’ in nature, which means that we don’t know if the adverse effects are due to statins or are the result of the ‘nocebo’ effect (like a placebo effect, only with negative effects rather than positive). The Editor of the BMJ, Fiona Godlee, tells us in her editorial that the caveats concerning the observational nature of these findings should have been made.

Both the articles made it through the peer-review process, so how did these errors come to be picked up? Well, apparently, they were brought to the attention of Fiona Godlee by Professor Sir Rory Collins, who heads up what is known as the Cholesterol Treatment Trialists (CTT) collaboration based in Oxford, UK. The CTT holds data on statin studies and periodically assesses it to tell us that statins are safe and very effective.

However, the CTT has in the past made grand claims about the effectiveness of statins that are based on the extrapolation of data (rather than actual data). Plus, as some have pointed out, the CTT refuses to release its data for independent inspection. The CTT can basically say what it likes about the effectiveness and safety of statins, but no-one can challenge what it says because no-one else has access to its data.

Apparently, Professor Sir Collins was invited by Fiona Godlee to put his concerns in writing for publication but he refused. He and Fiona Godlee met, and this set the ball rolling which culminated in the withdrawal detailed above. However, apparently this is not enough for Professor Sir Collins: he is demanding retraction of both articles, even though he has not challenged the main points raised in the articles. Fiona Godlee has set up an investigation to determine whether or not the articles should be retracted.

I have written to the BMJ in the form of an online ‘rapid response’ that was posted yesterday. You can read my response here.

In my response I accept that errors were made, but ask if a simple correction might have done.
Professor Sir Collins bases his assertions regarding the safety of statins on data from randomised controlled trials, like the ones analysed by the CTT. However, there are many reasons why randomised controlled trials may not adequately identify and report adverse effects from statins. Fiona Godlee acknowledges this herself and lists some of the issues, and I add to that list in my response. In all, there are about a dozen reasons why randomised trials stand to ‘miss’ adverse effects.

I also raise the issue of a recent study which appeared to confirm the safety of statins [5]. The study also detailed many reasons why results from clinical trials are an unreliable assessor of side effects. The study was reported in the BMJ [6], but the report included none of the caveats listed in the paper (or any other ones). As I explain to the Editor, these omissions may lull individuals into a false sense of security, and put people at unnecessary risk of adverse effects of statins, some of which can be serious.

One might argue that the ‘crime’ committed by the BMJ is roughly equivocal to the ones perpetrated by Drs Abramson and Malhotra. I point this out to Fiona Godlee in my response, and request a meeting with Fiona Godlee to discuss my concerns. After all, why should I not be afforded similar privileges as Professor Sir Collins”

You can read the response in full here. If you agree with the sentiments expressed in it, please click on the ‘thumbs up’ symbol to the right of the response to log your agreement.

References:
1.    Godlee F. Adverse effects of statins. BMJ 2014;348:g3306
2.    Abramson JD, Rosenberg HD, Jewell N, Wright JM. Should people at low risk of
cardiovascular disease take a statin? BMJ2013;347:f6123
3.    Malhotra A. Saturated fat is not the major issue. BMJ2013;347:f6340
4.   Zhang H, et al. Discontinuation of statins in routine care settings. Ann Intern Med 2013;158:526-34
4.    Finegold JA, et al. What proportion of symptomatic side effects in patients taking statins are genuinely caused by the drug? Systematic review of randomized placebo-controlled trials to aid individual patient choice. European Journal of Preventive Cardiology 2014;21(4):464-74
5.    Wise J. Statins may have fewer side effects than is claimed, meta-analysis finds BMJ 2014; 348:g2151
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Read the complete article here.

It’s not about statins – it’s about censorship - Zoë

It’s not about statins – it’s about censorship

Written by Zoë on May 19, 2014

Two very serious things happened last week – one in Australia and the other in the UK, although both are about information on line, so they have global impact…

Catalyst – Australia
Last October, two programmes aired on ABC television under the “Catalyst” banner (Catalyst is like Horizon – a science/investigation kind of programme). The first programme was called “Heart of the Matter Part 1 – Dietary Villains” and it aired on 24th October 2013. A transcript and copy has been preserved by someone on line. You can currently see it here, but I’m not sure for how long. The transcript of the programme is also available on this link. In essence – this programme challenged the widely held view that saturated fat causes heart disease.

The second programme aired on 31st October 2013 and, again, it can currently be seen here (video and transcript). This programme was called “Heart of the Matter Part 2 – Cholesterol drug war.”
Those who stand to gain from the diet-heart-cholesterol hypothesis did not want these programmes aired. There were calls for the second programme to be cancelled, after the first programme had been shown. The person making these demands, professor Emily Banks, admitted that she “didn’t have a lot of detail” about the cholesterol programme, but wanted it pulled anyway.

Both programmes aired. Catalyst is the only science show on Primetime Australian TV and it pulled in approximately 1.5 million viewers. That’s approximately half the number of people who take statins in Australia, by the way.

Barely had the closing credits run before the pro-statin brigade swung into action. A formal complaint was lodged with the body that reviews “Audience and consumer affairs” and a few months later, the findings were published in a 49 page document. In between airing and publication, Catalyst – producers and presenter (Maryanne Demasi) – were pretty much paralysed from doing further work by the demands placed upon them by the investigation.

You can read the full report. You may like to wait for a Dr Malcolm Kendrick blog – due any time now – where he summarises all the complaints made against the two programmes and those rejected and upheld. Nothing was upheld against the first programme on dietary fat and yet this has been pulled. For the second programme on cholesterol, I lost count of the judgements that recorded “no breach” of any of the codes – 16 I think. There was 1 breach upheld – and 1 alone. This is on P46 of the 49 page report.

The investigation concluded that in one part of one programme the presentation favoured an anti-statin view more than a pro-statin view. The report did not recommend that the programme be removed from the ABC web site and condemned to the scrap heap. You can see the recommended remedy on p4 of the report “We suggest it would be appropriate for additional material to be made available on the special ‘Heart of the Matter’ program website.” And that’s about it. Yet this programme has also been pulled – ABC have caved in to the pressure placed upon them by statinators. The intention of those who promote statins was no doubt to ensure that a programme like this is never aired, touched or conceived of again. They didn’t want this one to air. Tragically, they have almost certainly achieved their aim.

I tweeted the irony of the judgement – that the pro-statin bias prevails 365 days a year and yet 1 hour of a TV programme, where one small part was slightly less than balanced towards both pro and anti-statin views, is silenced – for bias! This isn’t about statins. It’s about censorship.

UK – BMJ
In the UK, in the same week, same drug, we also experienced censorship. Only this time, thanks to the robustness of BMJ editor-in-chief Fiona Godlee, we experienced only a small censorship – for now anyway.

On 15th May, Fiona Godlee published this editorial in the BMJ Godlee noted that, in October 2013, the BMJ “published an article by John Abramson and colleagues that questioned the evidence behind new proposals to extend the routine use of statins to people at low risk of cardiovascular disease. Abramson and colleagues set out to reanalyse data from the Cholesterol Treatment Trialists’ (CTT) Collaboration. Their contention was that the benefits of statins in low risk people were less than has been claimed and the risks greater.”

Godlee continued, “In their conclusion and in a summary box they said that side effects of statins occur in 18-20% of people. This figure was repeated in another article published in the same week in The BMJ by Dr Aseem Malhotra. The BMJ and the authors of both these articles have now been made aware that this figure is incorrect, and corrections have been published withdrawing these statements. The corrections explain that although the 18-20% figure was based on statements in the referenced observational study by Zhang and colleagues—which said that “the rate of reported statin-related events to statins was nearly 18%”. The BMJ articles did not reflect necessary caveats and did not take sufficient account of the uncontrolled nature of Zhang and colleagues’ data.”
Godlee had been alerted to ‘the error’ by Rory Collins, head of the Cholesterol Treatment Trialists (CTT) Collaboration, whose data were reanalysed by Abramson and colleagues. Godlee says in her editorial that Collins visited her at The BMJ in early December and then took the matter up in the UK media towards the end of March 2014.

The Guardian article references Collins as follows: “The Oxford academic said the side-effect claims were misleading and particularly damaging because they eroded public confidence. “We have really good data from over 100,000 people that show that the statins are very well tolerated. There are only one or two well-documented [problematic] side effects.” Myopathy, or muscle weakness, occurred in one in 10,000 people, he said, and there was a small increase in diabetes.”

The challenges that the Guardian should have made:
The Guardian should have ascertained how independent/conflicted their source was. These are the two pertinent questions:

1) How much, Professor Collins, have you/your department/your charity/your family – whatever outlets you have – received directly and/or indirectly from the pharmaceutical industry during your lifetime?

2) You head the CTT. Why will the CTT not release Serious Adverse Effect data (and raw data generally) from clinical trials so that researchers, doctors and patients can fully understand the side effects of statins? How can you claim that statin side effects are negligible when you won’t share the data?

The Guardian should have done their own (simple) research into statin side effects. Here are two pertinent questions:

1) If side effects are as rare as you say, why does the patient leaflet for Lipitor – the most lucrative statin, indeed the most lucrative drug ever in the history of mankind, state the following:

“Common side effects (may affect up to 1 in 10 people) include:
• inflammation of the nasal passages, pain in the throat, nose bleed
• allergic reactions
• increases in blood sugar levels (if you have diabetes continue careful monitoring of your blood sugar levels), increase in blood creatine kinase
• headache
• nausea, constipation, wind, indigestion, diarrhoea
• joint pain, muscle pain and back pain
• blood test results that show your liver function can become abnormal“

2) If diabetes is to be dismissed so lightly, why is the diabetes statins lawsuit gathering pace in the US? (Google diabetes statins lawsuit) and why is “increases in blood sugar levels” listed as one of the common side effects in the patient warning leaflet?

Funding
The web of funding around Collins, CTT, CTSU (Clinical Trial Service Unit) has proved astoundingly difficult to get to the bottom of. I had a bit of a breakthrough recently and came across a declaration of interest for Colin Baigent – CTT secretariat and close senior colleague of Collins. Check page five for current and recent grants. The following have been awarded to Colin Baigent and Rory Collins, (with other names mentioned alongside):

Merck & Schering	£39 MILLION (2002-2011)
Merck	£52 MILLION (2005-2013)
British Heart Foundation	£9 MILLION (2005-2013) (Where does the BHF get that kind of money?) & then another grant from the BHF for £2.7 MILLION (2004-2013) & then a couple more for several hundreds of thousands of pounds.
Medical Research Council	£13.8 MILLION (2008-2013) (Check the most recent appointees to the MRC - a Senior Vice President of Pfizer and Executive Vice President of Astra Zeneca).
Bayer	A mere £965,000
John Wyeth Ltd	£500,000
Novartis	£350,000

That’s £114 MILLION before you get into the small change.

Censorship
ABC has caved in, despite no judgement requiring them to do so. Godlee has asked a third party to review both articles to see if the current revisions are sufficient, or to decide if the two articles should be pulled. Collins wants both articles to be retracted. As Godlee points out: Malhotra’s article is primarily about saturated fat – it merely references the Zhang article, which Collins is not happy about and the Abramson article is primarily about the fact that the CTT data failed to show that statins reduced the overall risk of death in people with a <20 10="" an="" available.="" be="" cardiovascular="" disease.="" fact="" important="" is="" of="" openly="" p="" risk="" this="" to="" which="" year="">I have no doubt that Collins would like these two articles deleted from the records forever. For him it may be about the statins that have funded him/his department/wherever to the tune of over one hundred million pounds. For the rest of us it’s about censorship.
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Read the complete article here.

Statins Flop in Sepsis and COPD - MedPage

Statins Flop in Sepsis and COPD

By Crystal Phend, Senior Staff Writer, MedPage Today Published: May 18, 2014

 

SAN DIEGO -- Statins don't prevent chronic obstructive pulmonary disease exacerbations or improve outcomes in sepsis-related respiratory failure, a series of trials showed. For patients with acute respiratory distress syndrome (ARDS) from sepsis in the ICU, rosuvastatin (Crestor) didn't cut 60-day in-hospital mortality compared with placebo (28.5% versus 24.9%, P=0.21) or boost ventilator-free days (mean 15.1 in both groups, P=0.96).

Putting patients on the lipid-lowering drug actually contributed to hepatic and renal failure, Jonathon D. Truwit, MD, of the Medical College of Wisconsin in Milwaukee, and colleagues found in the ARDS Clinical Trials Network study.

In the STATCOPE trial, simvastatin (Zocor) didn't prevent COPD exacerbations compared with placebo (1.36 versus 1.39 mean per person-year, P=0.54) or delay them (median 223 versus 231 days to first exacerbation, P=0.34), Gerard Criner, MD, of Temple University in Philadelphia, reported at the meeting.

Both National Heart, Lung, and Blood Institute-sponsored trials were reported at a late-breaking clinical trials session here at the American Thoracic Society meeting and released simultaneously online in the New England Journal of Medicine.
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Read the complete article here. See also NEJM article here.

CTT the house of statin secrets - Burne

SOS: Sanity over Statins – CTT the house of statin secrets

by Jerome Burne

Should a professional body, however eminent, be allowed to keep information about the safety of products they are supplying to public hidden so no one else can run tests on them?

That is the question raised by HealthInsightUK’s finding that a large and respected organisation whose job it is to analyses the findings of statin trials – The Cholesterol Treatment Trialists’ (CTT) Collaboration in Oxford – has an agreement to keep secret much of the information contained in its huge database which holds results from 27 trials of these drugs, nearly each of which was run by a drug company.

Questions about the secrecy of the CTT have been put in the spotlight following the recent recommendation by NICE to change the guidelines on statins. If the proposals are accepted, millions more healthy people in the UK who have no sign of heart disease will be prescribed these drugs. A key part of the evidence supporting this proposal was a study by CTT published in the Lancet in 2012.

HealthInsightUK has also established that the CTT do not hold data on the side-effects of statins. A spokesman confirmed that they base their estimate of risk on the published results of trials conducted by the drug companies. He dismissed claims that side-effects such as muscle pain and depression were wide spread, saying they were only “hypotheses”.

Denied access to data

This could explain why the CTT has regularly reported a much lower rate of side-effects than trials run by independent researchers. Knowing the true rate of side-effects is particularly important with statins because many patients have to take them for one to benefit. If the estimate of side effects is too low the benefits may not outweigh the risks.

Concern about the secrecy surrounding CTT’s data is not new. Dr Jim Wright editor of the highly respected and independent journal Canadian Therapeutics Initiative which analyses drug studies has described how several years ago he had tried and failed to get access to statin data held by CTT.
“They had agreed someone from my team could have access to their data, although the researcher would have to go to Oxford to see it. However after travelling 6000 miles, they were told that the data was not available.”

This is just an anecdote but many others have since reported the same thing. The latest concern about access to CTT data was triggered last year when the Cochrane Collaboration – famed for its rigorous assessment of the benefit of drugs and other treatments – produced a report saying that statins should be more widely used on people without heart disease. The report was heavily based on the CTT Lancet study. Was it actually possible to check their findings?

Everyone wanted the data

A number of senior researchers approached by HealthInsight have supported Dr Wright’s claim that the data held by CTT hasn’t been available. Professor Rita Redberg cardiologist and editor of the journal JAMA Internal Medicine, has stated in an email that: “CTT will not make their data available to any colleagues and other researchers who wish to study risks and benefits of statins. The CTT data is not accessible publicly.”

“I have not requested access to the CTT data,’ says Dr David H. Newman, Director of Clinical Research, Mount Sinai School of Medicine, New York.

‘However, I’m not aware of anyone who has gained access to these data, which speaks volumes since everyone has wanted it. For the science to be considered even potentially credible, another independent group will have to replicate their analysis.”

Professor Harriet Rosenberg of the Health and Society Program at York University in Toronto commented that: “many scholars have asked the CTT for data without success” in a formal reply to the Cochrane review last year.

The response by the CTT when such individual claims are made is to say that anyone with a well formulated proposal can get access to their data. But emails seen byHeathinsightUK throw doubt on that. They were exchanged between one of CTT’s top researchers Professor Colin Baigent and an Australian TV journalist researching a story about statins.
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Read the complete article here.

Statins, Statistics and Statinistics - Sigurdsson

Statins, Statistics and Statinistics

12, May, 2014 by Axel F. Sigurdsson MD

Current medical knowledge is to a large extent based on results from scientific studies. Traditionally, these results are published in peer-reviewed medical journals. Before being accepted, a scientific paper has to go through critical assessment by expert reviewers who will assess the paper’s suitability for publication. The peer review process is intended to guarantee standards of quality and provide credibility. The highest ranked medical journals only accept a small fraction of papers submitted to them for publication.

Clinical medicine relies on the scientific literature. For a clinical cardiologist like myself, this is a key issue. The procedures I decide to perform, and the therapy I recommend is, and should be, based on scientific evidence. For the clinician, evidence based medicine is the holy grail.

But what if  scientific studies are flawed? What if evidence based medicine relies on erroneous data? Then, obviously, clinical medicine is broken.

Unfortunately, the scientific community is not free from dishonesty and greed. Scientific fraud is hard to deal with. Faked data exists and is often difficult to expose. However, we should be able to rely on high quality medical journals when it comes to wrong use of statistics, erroneous calculations and wrong conclusions. These journals should guarantee that papers plagued with such problems are not accepted for publication. But, are they up to the task?

The Statins and the Elderly Saga
One of the most important questions facing clinical cardiology today is when to use statin drugs for individuals who have not been diagnosed cardiovascular disease (CVD). Clinical trials have shown that these drugs lower mortality and reduce the risk of future cardiovascular events among people with CVD. However, in those without established CVD, the magnitude of effect is less clear end it is uncertain when the benefits of therapy outweigh the risks.

Age itself is independently associated with the risk of CVD, and risk factors such as high blood pressure, lipid disorders and diabetes are common among the elderly. However, limited clinical research is available addressing statin treatment among healthy people above 65 years old.
Four months ago I read with interest a paper by Gianlugi Savarese and colleagues, published in the Journal of the American College of Cardiology (JACC) presenting a meta-analysis of the  benefits of statins in elderly subjects without established CVD. The authors concluded that their “meta-analysis provided the first-time evidence that the benefits of statins on major cardiovascular events extended to people above 65 years old”.

In the paper, the authors came to the conclusion that statins significantly reduce the incidence of myocardial infarction (MI) and stroke, but do not significantly prolong survival in the short term.
Their numbers show that 83 patients have to be treated with statins to prevent one case of MI and 142 patients have to be treated with statins to prevent one stroke, for a mean follow-up of 3.5 years. However, they did not present these numbers in their paper. Instead they claimed that 24 patents needed to be treated for 1 year to prevent one MI and that 42 patients needed to be treated for one year to prevent one stroke.

I guess anybody with some statistical knowledge will see that the Number Needed to Treat (NNT) for one year should be a higher number than the NNT for 3.5 years. If one is performing a clinical trial in order to test an effect of a drug, a higher number of patents is needed if the study is planned to run for 1 year than if it is supposed to run for 3.5 years. There will be fewer events in one year than in 3.5 years, therefore the NNT for 1 year is a higher number than the NNT for 3.5 years. If you’re still doubtful, read my earlier blog post on the issue.

My Letter to the Editor of JACC
After discovering the error in the paper by Savarese and colleagues I wrote a letter to the editor of JACC which has been published online before print. I pointed out that the authors appeared to have made an erroneous calculation when reporting the NNT for a period of one year. By using data from their paper I had calculated that the NNT for one year to prevent one MI and one stroke was approximately ten times higher than reported in the paper, given that NNT is constant over time. In other words, the statin effect was exaggerated by a factor of ten.

I also suggested that the most appropriate approach would have been to report the NNT for the mean follow-up of 3.5 years, instead of calculating the NNT for one year.

A correction was published by the authors in JACC on March 25. It’s not very substantial:

“The authors report the number needed to treat (NNT) for the entire mean follow-up of studies was 83 and 142 for myocardial infarction and stroke, respectively. The authors apologize for this error.”

 

Strangely, not a word about the erroneous calculation. The wrong NNT numbers per year are left uncorrected.

Two of the authors of the paper, Gianlugi Savarese and Pasquale Perrone-Filardi, responded to my letter. Their response was published online together with my letter. They agreed that it was more appropriate to report the NNT for the mean follow-up of 3.5 years than presenting the NNT for one year. Furthermore they write:

“As previous authors did (citation) using the same formula adopted in our meta-analysis, our aim was to calculate the NNT per year dividing the overall NNT calculated for the entire trial duration by the length of the follow up. We agree with dr Sigurdsson that this may represent an oversimplification, since this calculation assumes that the effect of the treatment (relative risk reduction) is constant over time and that events occur at a constant rate over time”

Oversimplification is not the right word. Simply put, this is a completely wrong approach. But to my surprise, Savarese and colleagues don’t seem to realize or understand it. In fact dividing, when you should multiply will provide numbers that are very far from the truth.

Repeating an Error Won’t Make it Right 
Of course I was curious to see the paper cited by Savarese and Perrone-Filardi in their response to my letter. It turns out that it’s a paper published in Circulation 2008; “Lipid Management to Reduce Cardiovascular Risk: A New Strategy is Required“, written by H. Roberto Superko and Spencer King III. Dr. King is a world-famous senior cardiologist, a pioneer in cardiac catheterization and coronary angiography.

These two renowned cardiologists address the NNT from a number of statins trials in primary and secondary prevention. Interestingly, they also calculate the NNT per year. The results are published in Table 2. The table shows that the NNT per year is always a higher number than the NNT for the whole study period (which is always longer than one year). For example the NNT to prevent one MI in the famous 4S (SSSS) trial was 11.7 for the whole study period, but the NNT per year of the study was 63.2. The NNT for the WOSCOP trial was 44.2 for the whole study period, but 216.6 per year of the study. In fact, this all looks very reasonable and correct.

But the strange thing is that in the paper’s text, Superko and King use a different approach which is in complete disagreement with the table. They write:

“… such as the Scandinavian Simvastatin Survival Study (SSSS), which achieved an NNT of 11.7 and an NNT per year of 2.2″

And they do this again and again, as if they never saw the table in their own paper. So, Superko and King are dividing the overall NNT by the length of follow-up in order to find the NNT per year. If they continue to do this they will find that the NNT per six months in the 4S-trial was 1.1. This would mean that only one patient had to be treated for six months to prevent one event. Completely absurd.
I wonder, do these renowned scientific authors don’t understand what they’re talking about, or is this just a slight oversight. Whatever it is, it’s serious and unprofessional. How can a respected peer-reviewed paper such as Circulation publish such rubbish? And, five years later Savarese and colleagues decide it’s time to repeat the error. And now it’s accepted by JACC, another highly respected medical journal.

Surprisingly, Savarese and Perrone-Filardi don’t acknowledge their error. Instead, they cite the old paper where the same error was made, and believe that’ll make it right. Furthermore, despite the real NNT being a tenfold higher number than the one they reported (meaning the drug effect is ten times less), they have no intention to reconsider the main conclusion of their study.

I must admit I’m deeply disappointed. The medical community expects much more responsibility from the editorial boards of these medical journals. If the medical literature is full of such errors, our knowledge is worthless? Maybe, in this particular context, lying with numbers, whether it’s done on purpose or not, could be called statinistics instead of statistics. Statinistics could be the new word for badly treated statistics.
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Read the complete article here.

Also see "Statins For Elderly People – A Deceptive Message" by Axel F. Sigurdsson MD

Preventing and Reversing Heart Disease - DACH

Preventing and Reversing Heart Disease, Part Three

Preventing and Reversing Heart Disease
Part Threeby Jeffrey Dach MD
This Article is Part Three.
For Part One Click Here,
and for  Part Two Click Here.

A Man with Progressive Coronary Artery Disease Unresponsive to Statins
62 year old Jim came just had his third cardiac stent.  A year ago, Jim noticed a “tight feeling” in his chest radiating to his throat, was rushed to the ER, and doctors found he was having a heart attack. A coronary angiogram showed extensive coronary artery disease with irregular plaque formation.

Progressive Coronary Artery Plaque in Spite of Low Cholesterol
For 12 years now, Jim’s cholesterol level had been driven down into the 140 area by the “top cardiologist in the area”, who prescribed a hefty dose of a statin anti-cholesterol drug.  In spite of the lowest cholesterol level on the planet,  Jim’s heart disease progressed relentlessly with worsening calcium scores, worsening angiograms, and worsening symptoms of chest pain.   His disease progression was obviously not caused by an elevated cholesterol level.  For a discussion of how elevated cholesterol is NOT the Cause of Heart Disease, see my article on patients with familial hypercholesterolemia who have very high cholesterol, yet have no heart disease, proving the hypothesis that cholesterol levels are not necessarily a risk factor for heart disease, and reducing cholesterol levels with drugs may be a fruitless endeavor.

Doctors advise Jim to Stop Testosterone
Jim had been taking topical testosterone for the past 5 years, and recently stopped it because of advice from his cardiologist who pointed a finger and said, “You should stop the testosterone….The testosterone is bad for your heart and probably caused your heart attack“.  Jim came to see me for a second opinion.

Jim’s Doctor is Right About That
Jim’s doctor is right in that a number of recent studies have shown a small increase in heart attack rate in men starting testosterone.   This is caused by increased hematocrit (red blood cell count) and increased iron stores which thicken the blood and make it more susceptible to blood clot formation, all risk factors for heart attack.  See  my article on this.  The simple solution is to monitor blood count and iron levels, and donate blood at the blood bank every 4 to 6 weeks to reduce iron and red cells.

Our Approach to Preventing Heart Disease
I must preface these remarks with our approach to prevention and reversal of heart disease which is outlined in Part One  and Part Two  of this series.  We credit and rely heavily on the  “Track Your Plaque Program ” by William Davis MD.  We also use the Linus Pauling Protocol.

Bioidentical Hormones For Prevention and Reversal of Heart Disease
In this article we will revisit the role of the testosterone and estradiol in prevention and reversal of heart disease, looking at the latest research.  Firstly, let’s try to answer the question:

” Is low testosterone a risk factor for heart diease, and is normal testosterone level protective of heart disease?” 

 

Here we assume red cell count and iron levels are kept under control with monthly trips to the blood bank, so there is no short term increase in heart attack rate from hypercoagulability, as noted in a few recent studies of men started on testosterone.

Low Testosterone is Predictive for Increased Mortality from Heart Disease
If testosterone was causative of heart disease,  one would expect men with high testosterone to have more heart disease, and men with low testosterone to have less heart disease.  This is exactly opposite of four major studies showing men with low testosterone have both increased all-cause mortality and increased heart disease mortality.(1-4)

Testosterone Levels in Men With Heart Disease
A recent study by Malkin looked at Testosterone levels in men with known underlying heart disease.  He showed that low Testosterone is common in men with underlying heart disease, and this is associated with almost double the mortality rate.(5)  Again these findings suggest that higher Testosterone is protective and prevents progression of heart disease.  The assumption that Testosterone causes progression of atherosclerosis plaque has been shown false.(6-9).
Above image: Cross section of arteries (left to right) showing development of fatty streak which enlarges into the atherosclerotic plaque.   Animal Studies on Mechanism of Protection
A number of elegant animal studies have been done to elucidate the mechanism by which testosterone is protective of heart disease.  A 1999 study by Alex Andersen in rabbits showed that testosterone reduced aortic atheroscleosis.(10)  Castrated rabbits had low testosterone levels and doubled the  aortic atherosclerosis plaque formation, suggesting that testosterone has a strong preventive effect on male atherosclerosis. In the groups receiving testosterone or DHEA they found marked inhibition of atherosclerosis compared with placebo. The mechanism was not clearly defined.  They speculated on a non-lipid mediated mechanism, possibly related to aromatase conversion of testosterone to estrogen.(10 )

Mouse Model- It’s Really the Estrogen That’s Protective
In an elegant 2001 study published in PNAS, Nathan et al used a mouse model of accelerated atherosclerosis to show that testosterone inhibits atherosclerosis by its conversion to estradiol by the aromatase enzyme.  Similar protection from atherosclerosis was obtained by administering estradiol.  In addition, blocking conversion of testosterone to estradiol with the aromatase inhibitor, anastrazole, eliminated the protective effect, and these animals had progressive atherosclerosis.(11)  Dr Nathan says:

“Testosterone attenuates early atherogenesis most likely by being converted to estrogens by the enzyme aromatase expressed in the vessel wall”.(11)

 

This information suggests that men with heart disease should NOT take arimidex (anastrazole) along with their testosterone replacement therapy.

Genetically Altered Mouse Model Provides Answers
These findings were confirmed  by Nettleship  in a 2007 study published in Circulation using the Tfm genetically modifired mouse.  This is a mouse genetically altered to have a defective androgen receptor.  In these mice,  testosterone cannot work through its normal pathway, since there is no receptor.  In spite of the lack of androgen receptor, Nettleship found that testosterone replacement in these mice attenuated atherosclerotic changes (fatty streak formation), suggesting the protective effect of testosterone was independent of the testosterone receptor.  The authors concluded that the protective benefits of testosterone were through aromatase conversion to estradiol, and then via the estrogen receptor pathways.(12)

Dr Nettleship’s findings were confirmed by Bourghardt  in a Nov 2010 study published in Endocrinology which using ”ARKO” mice, genetically modified to “knock out” the Androgen Receptor, modified to be Apo-E deficient (to accelerate atherosclerosis).  The authors showed that testosterone therapy administered to the ARKO mice inhibited atherosclerosis.  However inhibition of atherosclerosis was more profound in the wild type mice that still had intact androgen receptors.  The authors concluded the mechanism of protection of testosterone was due to both mechanisms, through the Androgen Receptor as well as through aromatase conversion to estradiol.(13 )

Conclusion:
These genetically modified mouse studies suggest that testosterone’s cardio-protective benefits are due to conversion to estrogen, and that estrogen is the cardioprotective agent.  Both estrogen and testosterone are bioidentical hormones.   Clearly the message here is Testosterone Replacement Therapy should be an important part of any heart disease prevention program,  in those patients who have low Testosterone levels.

Why Do Men Have More Heart Disease Than Women ?
Men and women are quite different when it comes to heart disease.  Men have more than twice the risk of dying from coronary disease than women. (14)  In women, coronary artery disease (CAD) develops on average 10 years later than in men.(15)  Could higher levels of estrogen (estradiol) in women explain the protection enjoyed by women?

Estrogen is Protective
Dr Xing from the University of Alabama would say, yes of course.  In a 2009 article, Dr Xing names a number of mechanisms by which estradiol protects both men and women from heart disease. He says:

“Estrogens have antiinflammatory and vasoprotective effects.  Natural endogenous estrogen 17β-estradiol (bioidentical) has been shown to cause rapid endothelium-independent dilation of coronary arteries of men and women, to augment endothelium-dependent relaxation of human coronary arteries, and improve endothelial function…Observational studies have shown substantial benefit (50% reduction in heart disease) of hormone therapy in women who choose to use menopausal hormones.”(15 )

 

Estrogen is Protective of Heart Disease
A 2010 study in European Heart by Kitamura et al  compared males to female heart attack rates. They found 61% fewer heart attacks in women of reproductive age with high estrogen levels compared to males of the same age.  The authors conclude that estrogen confers cardioprotective benefits.(16)
A review of the Nurse Health Study published in the 2000 Annals  showed 40% reduction in heart disease in hormone replacement users and that “postmenopausal hormone use decreases risk for major coronary events.” (17-18)

See my article on how estrogen protects women from heart disease: Bioidentical Hormones Prevent Heart Disease.

Comparing Three Treatment Modalities
There are three mainstream treatment modalities for coronary artery disease.
1) Surgery with coronary artery bypass.
2) Balloon angioplasty with stenting.
3) Medical Therapy with drugs such as calcium channel blockers and beta blockers.
Which one of these treatment modalities confers the most benefit? The answer is:  None of Them.
Medical Management with Drugs Provides the Same Benefit as Cardiac Angioplasty, Stenting or Bypass
Eleven randomized studies reviewed 3,000 patients with stable coronary artery disease.  Treatment with  angioplasty and stenting showed the same mortality and heart attack rate as drug treatment (also known as medical management).  They both offer the same benefit.(19)(20)
The MASS II study  published in the 2007 Circulation showed medical managment with drugs to have similar outcome to stent or bypass. (21)    A troubling fact remains that after all these studies have been completed,  there is no conclusive evidence that intervention with CABG (coronary artery bypass graft) or coronary stent  is superior to medical therapy (drugs) for treating multivessel coronary artery disease with stable angina and preserved ventricular function.(21 )  Sorano attempts to sort out the fine points of selecting between treatment modalities in her 2009 report. (22)

How Can Drugs Provide the Same Outcome as Surgery or Stenting?
The EPC, the Endothelial Progentor Cell.
Now we have an important question to ask.  How is it possible that the humble country doctor with a few drugs can provide similar outcomes when compared to the high and mighty cardiac surgeon and the interventional cardiologist?  How can drug treatment do as well or better than the cardiac stent or surgical bypass procedure?

I suggest the answer resides in the phenomenon known as “collateral vessel formation”.  The heart has the ability to grow new blood vessels which provide blood flow around the blocked artery.  Medical treatment gives the heart time to grow new collateral vessels. The key to understanding this new vessel formation is the endothelial progenitor cell, also known as the EPC. The EPC is a special type of stem cell found in the bone marrow that circulates to injured myocardium where they promote local angiogenesis, making new blood vessels. (23)

Turning On The Endothelial Progenitor Cell – How to Do It?
A previous article on telomeres and anti-aging discussed the role of estrogen as an activator of telomerase which serves as an anti-aging therapy.  Recent research shows that estrogen  activates the telomeres on endothelial progenitor cells and improves the EPC functional capacity. (24)  Another study showed reduced numbers of EPC cells in the peripheral blood of men with low testosterone levels. (25)

Estradiol Enhances Recovery After Myocardial Infarction – Collateral Vessels
An elegant mouse study was published by Isakura in 2006 Circulation .  They used a mouse model in which myocardial infarction (heart attack) was induced by ligation of the left coronary artery.  The estradiol treated mice showed increased circulating EPC’s and greater capillary density in the recovering myocardium.  This indicates enhanced recovery in the estradiol treated mice by regrowth of collateral vessels. (26)(27)(28)

A study from Bolego in Italy showed that the cardio protective benefits of estrogen could be duplicated with an estrogen receptor drug called PPT. They found that:

“myocardial ischemia-reperfusion injury was exacerbated by ovariectomy (which reduced estrogen levels).   This injury returned to baseline following treatment with estrogen-like drug PPT.”

The protective effects were linked to increased levels of endothelial progenitor cells (EPCs).(29)

Conclusion
Recent research shows the cardioprotective benefits of the bioidentical hormones, testosterone and estrogen.  Testosterone benefit appears mediated by conversion to estradiol via the aromatase enzyme.  Estradiol’s benefits appear related to activation of Endothelial Progenitor Cells which invoke new collateral circulation in areas of injury.

Another treatment modality called EECP also creates new collateral vessels.  Read my article on EECP here.
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Patients Managed to Target LDL Particle Number Experience Fewer Cardiovascular Events

Patients Managed to Target LDL Particle Number Experience Fewer Cardiovascular Events Than Patients Managed to Target LDL Cholesterol, According to Study

Data demonstrates that the NMR LipoProfile® test provides clinically reliable information to help reduce cardiovascular events, especially in patients with diabetes and those on statin therapy

 

WASHINGTON, March 31, 2014 /PRNewswire/ -- LipoScience, Inc. (NASDAQ: LPDX), a diagnostic company pioneering a new field of personalized nuclear magnetic resonance (NMR) diagnostics to advance the quality of patient care in cardiovascular, metabolic and other diseases, today announced data showing that patients managed to a target LDL particle (LDL-P) number, as measured by LipoScience's NMR LipoProfile test, achieved a 22 to 25 percent greater reduction in the risk of cardiovascular (CV) events over a three-year period compared to patients who attained LDL cholesterol (LDL-C) targets.

 

These data, presented in a poster session at the 63^rd American College of Cardiology (ACC) Scientific Sessions in Washington, D.C., are derived from a real-world sample of commercially insured patients who were at a high risk of CV events, including patients with Coronary Heart Disease and Diabetes Mellitus. The investigators found that patients who achieved target LDL-P levels (<1000 aggressive="" concentrations="" dl="" ldl-c="" lipid-lowering="" mg="" more="" nmol="" p="" reaching="" received="" target="" than="" those="" treatment="">

 

Those treatment differences were associated with better outcomes (as measured by the reduction in CV event rates) over one to three years of follow-up. The study was sponsored by LipoScience and jointly designed by LipoScience and HealthCore, with clinical input from Terry A. Jacobson, MD, Professor of Medicine at Emory University, Atlanta, and Peter P. Toth, MD, PhD, Director of Preventive Cardiology at CGH Medical Center in Sterling, Ill.

 

"These new data add to the growing body of evidence suggesting that NMR measurement of LDL particle number, when used in conjunction with other lipid measurements, is a valuable cardiovascular risk management tool," commented Dr. Jacobson, the lead author of the study. "Due to the wide variance in the cholesterol content of LDL particles among individuals, measurements of LDL cholesterol and LDL particle number frequently disagree, especially in patients with insulin resistance and those treated with lipid-lowering therapies. When a disagreement between LDL-P and LDL-C is present, quantification of LDL particle number is a more clinically reliable measure of LDL and of treatment outcomes than measurement of LDL cholesterol."

 

Dr. Jacobson and colleagues analyzed data from more than 4,000  high-risk patients (over 2,000 with LDL-P < 1000 nmol/L and over 2,000 with LDL-C < 100 mg/dL) selected from the HealthCore Integrated Research Database^SM who were followed for as long as three years. Those who achieved LDL-P target <1000 100="" 22="" 25="" a="" above="" achieved="" as="" at="" baseline="" below="" but="" compared="" concentrations="" cv="" dl.="" event="" follow-up.="" group="" higher-potency="" in="" ldl-c="" ldl-p="" levels="" likely="" lower="" measured="" medications="" mg="" more="" nmol="" not="" noted="" of="" one="" over="" p="" patients="" percent="" receive="" risk="" statin="" target="" than="" the="" three="" to="" was="" were="" who="" whose="" years="">

Dr. Jacobson's poster, "Comparison of cardiovascular events between patients achieving low-density lipoprotein particle targets and patients achieving low-density lipoprotein cholesterol targets," will be presented Monday, March 31 from 9:30 a.m. to 12:30 p.m. in Hall C of the Washington Convention Center. The poster number is 150.

 

"The HealthCore data add an important, real-world, analysis to the ongoing discussion of how best to optimize individual patient management. These findings are consistent with the recommendations of various expert panels and organizations such as the National Lipid Association, the American Association for Clinical Chemistry, and the American Association of Clinical Endocrinologists, each of which advocates the use of LDL-P as a target of therapy in managing at-risk patients," stated William C. Cromwell, MD, Chief Medical Officer of LipoScience.  "We hope the findings encourage greater adoption by clinicians to manage their patients to an LDL-P target to reduce CVD events."

The ACC Scientific Session also includes the following poster presentations that support the clinical utility of NMR-based lipoprotein particle measurement:

• Poster #143: May HT, et al. Utility of high-density lipoprotein cholesterol, particle concentration, and size in predicting future major adverse cardiovascular events among patients undergoing angiography: The Intermountain Heart Collaborative Study.
  • Saturday, March 29, 9:30am to 12:30pm, Hall C
• Poster #146: Muhlestein JB, et al. GlycA and GlycB, novel NMR biomarkers of inflammation, strongly predict future cardiovascular events, but not the presence of coronary artery disease (CAD), among patients undergoing coronary angiography: The Intermountain Heart Collaborative Study.
  • Sunday, March 30, 9:30am to 12:30pm, Hall C
• Poster #128: Koren MJ, et al. Effects of alirocumab, a fully human monoclonal antibody to proprotein convertase subtilisin/kexin type 9, on lipoprotein particle concentrations determined by nuclear magnetic resonance: Substudy of a randomized double-blind phase II clinical trial.
  • Sunday, March 30, 9:30am to 12:30pm, Hall C
• Poster #134: Xu R, et al. Effects of evolocumab on lipoprotein particles and subclasses in hypercholesterolemic and heterozygous familial hypercholesterolemia subjects on statin therapy
  • Sunday, March 30, 9:30am to 12:30pm, Hall C
• Poster #141 Alexander V, An antisense inhibitor of apolipoprotein C-III significantly decreases apolipoprotein C-III, triglycerides, Very-Low-Density Lipoprotein cholesterol and particle number, and increases High-Density Lipoprotein cholesterol and particle number in hypertriglyceridemic patients on a fibrate.
  • Monday, March 31, 9:30am to 12:30pm, Hall C

 

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Ezetimibe Prescribing Fails to Keep Up With Evidence - JAMA

Ezetimibe Prescribing Fails to Keep Up With Evidence     

Mike Mitka, MSJ 

             

JAMA. Published online March 19, 2014. doi:10.1001/jama.2014.2896

          

 

Although physicians like to think they practice evidence-based medicine, that appears to not be the case with prescribing the cardiovascular drug ezetimibe. And some critics say that use of surrogate markers to guide practice rather than clinical outcomes such as occurrence of myocardial infarction, stroke, or death has likely played a role.

 

Ezetimibe is an intestinal cholesterol absorption inhibitor found to reduce low-density lipoprotein cholesterol (LDL-C) levels by about 20% when given alone. It also further reduces LDL-C levels when added to statin therapy, which blocks cholesterol synthesis in the liver by inhibiting HMG-CoA reductase.

 

The Food and Drug Administration approved ezetimibe in 2002 for use in the United States primarily because it lowered LDL-C levels, a surrogate marker for prevention of cardiovascular disease. Whether ezetimibe improved clinically meaningful outcomes remained a question.

 

That question was somewhat answered in January 2008, with the announcement that the Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression (ENHANCE) trial, sponsored and conducted by industry, found that the addition of ezetimibe failed to reduce atherosclerosis progression compared with simvastatin alone, despite lowering LDL-C levels. Atherosclerosis progression was determined by a change in the intima-media thickness of the walls of the carotid and femoral arteries—yet another surrogate end point (Kastelein JJP et al. N Engl J Med. 2008;358[14]:1431-1443).

Place holder to copy figure label and caption

Graphic Jump Location

US and Canadian physicians continue to prescribe ezetimibe even after a study found giving the drug with a statin failed to reduce atherosclerosis progression compared with the statin alone.

 

 

The ENHANCE result prompted some leaders in the cardiology community to question ezetimibe’s place in cardiovascular disease treatment. Harlan Krumholz, MD, professor of medicine and epidemiology and public health at Yale University in New Haven, Connecticut, said the study should change practice. “Although not definitive, [ENHANCE] increases our uncertainty about the clinical value of this novel drug. Without some evidence of improved outcomes associated with its use, ezetimibe should be relegated to a last option for patients who need medication for hypercholesterolemia, and even in these cases, it is reasonable for clinicians and their patients to wait for further information before considering it,” he wrote in NEJM Journal Watch (http://tinyurl.com/pk9xr29).

 

So did the ENHANCE results change practice? In the United States, the answer is “somewhat,” while in Canada, the answer appears to be “no.”

 

In a study published in the American Heart Journal, researchers looked at ezetimibe prescription trends before and after ENHANCE, using data collected from CompuScript in Canada and IMS Health in the United States from January 1, 2002, to December 31, 2009. The researchers found the monthly number of ezetimibe prescriptions per 100 000 population rose from 6 to 1082 in the United States from November 2002 to January 2008 and then declined to 572 per 100 000 population by December 2009, a decrease of 47.1%. In Canada, however, use continuously increased from 2 to 495 per 100 000 from June 2003 (when the drug was approved in Canada) to December 2009 (Lu L et al. Am Heart J. doi:10.1016/j.ahj.2014.01.014 [published online February 27, 2014]).

 

Coauthor Cynthia A. Jackevicius, PharmD, MSc, a professor of pharmacy practice and administration at Western University of Health Sciences in Pomona, California, and an adjunct scientist, Institute for Clinical Evaluative Sciences, in Toronto, said her team was initially surprised by the Canadian results.

 

“Previous findings showed ezetimibe use in Canada experienced a more conservative uptake, so we expected to see a decrease in use in response to the ENHANCE study,” Jackevicius said. “So we looked for different factors, and one is the Canadian lipid guidelines, which specifically said ezetimibe could be added to statins, and that didn’t change after ENHANCE came out.”

A study of ezetimibe use in Saskatchewan, the only Canadian province that lists the drug for open formulary access, even though guidelines say it’s a second-line agent for lowering cholesterol, reflects Jackevicius’s team’s findings. Using data from provincial health administrative databases, the Saskatchewan researchers found that ezetimibe prescriptions were 2.5% of cholesterol-lowering dispensations in 2004 and 8.8% of such dispensations in 2011 (Alsabbagh WM et al. Can J Cardiol. 2014;30[2]:237-243). The authors concluded that allowing unrestricted use of ezetimibe in Saskatchewan may have led to a large number of inappropriate prescriptions, at odds with Canadian clinical guidelines.

 

And although ezetimibe use declined in the United States, its use per 100 000 population is still greater than Canada’s, generating US expenditures of more than $2.2 billion in 2009.

 

Krumholz, one of the coauthors on the study with Jackevicius, remains perplexed as to the continuing popularity of ezetimibe. “The drug continues to defy gravity, and that’s probably a result of really strong marketing and the singular focus on cholesterol numbers,” he said.

 

Krumholz said heart health campaigns urging patients to “know your numbers” and treatment goals based on cholesterol measurements, such as getting asymptomatic individuals’ LDL-C levels below 130 mg/dL, have worked in ezetimibe’s favor at the expense of evidence-based medicine. “Is this the drug that lowers your LDL-C and helps you? We don’t know that,” he said. “The comfort of hitting a target offers little benefit if you don’t know that it is really protecting you.”

 

Although ENHANCE has not derailed ezetimibe prescribing, the newest cholesterol management guidelines just might. The guidelines, issued late last year by the American College of Cardiology and the American Heart Association, abandon the idea of reaching a target level for LDL-C, instead recommending the use of statins to reduce LDL-C levels only for certain types of patients.

Will this change in the guidelines affect ezetimibe prescribing? “It will be interesting to see what the guidelines will do,” Krumholz said.

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Researchers pronouncing ‘statins are safe’ are undermined by their own observations - Briffa

Researchers pronouncing ‘statins are safe’ are undermined by their own observations

By Dr John Briffa on 13 March 2014

 

Listen to most ‘key opinion leaders’ talk about statinsand you will hear soothing reassurances about their safety. Yet, my experience as a doctor suggests that adverse effects such as fatigue and muscle pain occur more commonly than ‘official statistics’ suggest. However, a study published this week claims to provide evidence that, for the most part, statin side effects are ‘imagined’ [1].

In this research, the adverse effect rates from statins was compared with those seen in individuals taking placebo (dummy) pills in a total of 29 studies. The conclusion was that apart from increasing the risk of diabetes, statins don’t generally have any more adverse effects than placebo. The actual words the authors use in their conclusion are: “Only a small minority of symptoms reported on statins are genuinely due to the statins: almost all would occur just as frequently on placebo.”

This is confident, seemingly ‘evidence-based’ stuff, indeed. However, these findings do appear to me to be at odds with what I and many other doctors observe in real life: that a significant number of people who take statins have side-effects that resolve (sometimes slowly) on discontinuation of their medication. Of course, as the authors of this most recent study allude to, these side-effects may be nothing more than a negative placebo response – sometimes referred to a ‘nocebo’ response.
However, is there anything about the way statin trials may be designed and conducted that could jeopardise our ability to get accurate data on the adverse effects of these drugs?

Several explanations are possible. First, commercial sponsors of clinical trials may not be motivated to search exhaustively for potential side effects. One pointer towards this is that, although evidence of liver damage is documented in the majority of trials, diabetes diagnoses were only documented in three of the 29 trials assessed in the recent study.

Second, many trials do not state clearly how and how often adverse effects were assessed. Because of this, it far from certain that all adverse events were ‘caught’ and logged appropriately.

Third, some trials’ exclude patients with severe diabetes, kidney failure or high blood pressure. In reality, though, these individuals may come to be prescribed and take statins.

Fourth, trial volunteers tend to be enthusiastic, and may therefore be less likely to report side effects than patients in routine clinical practice.

Fifth, many trials have a ‘run-in’ period where individuals are given a placebo to help ensure adequate compliance with medication. This can cause studies to be ‘enriched’ with highly motivated individuals who, again, may be less likely to complain of side-effects.

Finally, many trials excluded patients on medication sharing the same liver metabolic pathway as statins (e.g. fibrates and macrolide antibiotics). Patients on such drugs, in the real world, might well suffer higher rates of pharmacologically mediated effects.

I make no secret of the fact that I think the benefits of statins are over-hyped and that the adverse effects are generally downplayed. As a result, a cynical observer might read my reservations here and think ‘well, he would say that’.

But, here the kicker: those six issues I detail above were plucked from the very same study that trumpets the safety of statin [1]. Much of what is written in this section of the post was actually lifted verbatim from the study.

So, by the authors’ own admission, there are many reasons why the adverse effect rates seen in statin studies may not accurately reflect the rates seen in the real world. But then how can the authors conclude that: “Only a small minority of symptoms reported on statins are genuinely due to the statins: almost all would occur just as frequently on placebo.”

The reality is the deficiencies of the studies do not allow the authors (or anyone) to conclude that at all. The authors’ pronouncement on safety is utterly undermined by their own admissions about the incompleteness and untrustworthiness of the study data.

The opening line of the study is this: “Patients and doctors need clear reliable information
about benefits and risks to make informed decisions.” The only clear thing about the risks of statins, to my mind, is that there isn’t much clarity. Making bold pronouncements on the safety of statins without us having the facts is potentially misleading, and may cause many to come to considerable harm, needlessly.

References:
1. Finegold JA, et al. What proportion of symptomatic side effects in patients taking statins are genuinely caused by the drug? Systematic review of randomized placebo-controlled trials to aid individual patient choice. European Journal of Preventive Cardiology March 12, 2014

Early atherogenesis and visceral fat in obese adolescents

 

Early atherogenesis and visceral fat in obese adolescents

A H Slyper, H Rosenberg, A Kabra, M J Weiss, B Blech, S Gensler and M Matsumura

Abstract

Background/Objectives:

 

Little information is available as to the cause of increased thickening of the intima-media of the carotid artery (cIMT) in the pediatric population. Therefore, cIMT was compared in obese adolescents and normal-weight controls, and associations between cIMT and lipid and non-lipid cardiovascular risk factors were assessed.

Subjects/Methods:

 

Subjects included 61 obese non-diabetic male and female volunteers aged 12–18 years inclusive with a body mass index (BMI) >95th percentile for age and 2-h blood glucose <200 class="mb" span=""> 

mg dl⁻¹ matched to 25 normal-weight control volunteers with normal glucose levels. Each subject underwent a 2-h glucose tolerance test and measurement of hemoglobin A1c, ultrasensitive C-reactive protein, fasting insulin, blood lipids, visceral, subcutaneous abdominal and hepatic fat, and cIMT.

Results:

 

Maximum cIMT was 0.647±0.075 mm in the obese subjects versus 0.579±0.027 mm in normal-weight controls (P<0 .001="" 2-h="" and="" assessment="" between="" bmi="" cholesterol="" cimt="" correlations="" difference="" fasting="" female="" glucose="" hdl="" high-density="" homeostasis="" in="" insulin="" ldl="" lipoprotein="" low-density="" male="" maximum="" model="" no="" significant="" sub="" subjects.="" there="" total="" very="" was="" were="" z-score="">2

cholesterol, HDL₃ cholesterol, triglycerides, remnant lipoprotein cholesterol, intermediate-density lipoprotein cholesterol, lipoprotein(a), apoprotein B100, abdominal subcutaneous fat volume, visceral fat volume and hepatic phase difference. On multiple regression analysis, visceral fat was the most significant predictor of maximum cIMT. Two-hour blood glucose, HOMA and systolic blood pressure were also significant predictors of maximum cIMT.

Conclusions:

 

cIMT was increased in the obese adolescents compared with the normal-weight-matched controls. Visceral fat was a key predictor of arterial wall thickening in these subjects. The results suggest that the focus of cardiovascular disease prevention in the adolescent obese should be visceral obesity, and not blood lipids or lipid subclasses.

To read this article in full you may need to log in, make a payment or gain access through a site license (see right).

 

International Journal of Obesity (23 January 2014) | doi:10.1038/ijo.2014.11

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