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Mar 2, 2012

Behind the latest news on cholesterol medications (the statins issue)

(March 6: An update has been added at the bottom of this post, including a review of the SMH story by Media Doctor Australia. March 8: The Cardiac Society of Australia and


(March 6: An update has been added at the bottom of this post, including a review of the SMH story by Media Doctor Australia.
March 8: The Cardiac Society of Australia and NZ has released a statement urging patients not to stop taking statins without discussing the matter with their doctors. It is available on this website, under the Media/Media releases headings).


The cholesterol lowering medicines known as statins have been in the global headlines this week as a result of the Food and Drug Administration’s revision of safety labelling information.

If the issue is of personal concern to you or yours, it is worth reading the FDA’s information; it is considerably less alarmist than some of the headlines (as always, consult a doctor before taking headlines-based advice).

One of the FDA revisions that did not get much media play is that there has been a downgrading of warning over liver effects. The drug labels have been revised to remove the need for routine periodic monitoring of liver enzymes in patients taking statins. “FDA now recommends that liver enzyme tests should be performed before starting statin therapy, and as clinically indicated thereafter. FDA has concluded that serious liver injury with statins is rare and unpredictable in individual patients, and that routine periodic monitoring of liver enzymes does not appear to be effective in detecting or preventing this rare side effect.”

On the two main issues dominating the headlines (concern about effects on memory and blood sugar levels), the FDA advice says the cardiovascular benefits of statins outweigh these small increased risks.

At a quick glance, however, the FDA does not appear to give any data to help practitioners or their patients weigh up the absolute risks and benefits, tailored to patients at high and low risk of cardiovascular disease.

This is the advice on the memory and blood sugar concerns:

Certain cognitive (brain-related) effects have been reported with statin use. Statin labels will now include information about some patients experiencing memory loss and confusion. These reports generally have not been serious and the patients’ symptoms were reversed by stopping the statin. However, patients should still alert their health care professional if these symptoms occur.

Increases in blood sugar levels (hyperglycemia) have been reported with statin use. The FDA is also aware of studies showing that patients being treated with statins may have a small increased risk of increased blood sugar levels and of being diagnosed with type 2 diabetes mellitus. The labels will now warn healthcare professionals and patients of this potential risk.

As well, specific new recommendations have been made for one particular drug, lovastatin. The FDA says: “Some medicines may interact with lovastatin, increasing the risk for muscle injury (myopathy/rhabdomyolysis). For example, certain medicines should never be taken (are contraindicated) with Mevacor (lovastatin) including drugs used to treat HIV (protease inhibitors) and drugs used to treat certain bacterial and fungal infections.”

Part of the broader context to these issues is ongoing debate about the merits of statins in primary prevention, particularly in people at low risk of cardiovascular disease (more details on this debate are at the bottom of the post, with links to a recent review from the Cochrane Collaboration and a recent article in Australia Prescriber)

Meanwhile, below are articles related to media coverage of the FDA warning:

Professor Stephen MacMahon, Professor of Cardiovascular Medicine, University of Sydney and Principal Director, The George Institute for Global Health, critiques an SMH report

• The SMH’s Amy Corderoy responds to his comments

• Advice to readers from Dr Amanda Wilson of Media Doctor Australia.

(Update: more analysis from Dr Lynn Weekes at the NPS has been added at the bottom of the post)


Sensational headline “puts thousands at risk”

Professor Stephen MacMahon writes:

Earlier this week the United States’ Food & Drug Administration (FDA) updated the information it provides to doctors and patients about the safety of statins, the cholesterol-lowering drugs used by millions of people worldwide for the prevention of heart disease and stroke.

The main new additions concern some rare reports of entirely reversible memory loss and other reports of small increases in blood sugar levels among some people taking statins.

In The Sydney Morning Herald’s leading article on March 1, the first sentence states that as a consequence of these developments: “Thousands of Australians could be taken off cholesterol-lowering medications because of mounting evidence that they increase the risk of diabetes and dementia”.

However, the report from the FDA specifically emphasises that the reports of reversible memory loss “did not appear to be associated with fixed or progressive dementia, such as Alzheimer’s disease.” It also states that these reports “did not suggest that cognitive changes associated with statin use are common or lead to clinically significant cognitive decline”.

The Herald article has, as a consequence, misinformed its readership and, as a result, may well cause some readers to stop taking medication that would otherwise have prevented them having a heart attack, stroke or early death. This is no small mistake.

The other concern noted in the FDA update relates to reports of small increases in haemoglobin A1c, which is an indicator of blood sugar control among people with diabetes.

However, this has not been a universal finding with some very large randomised trials demonstrating no effect of statins whatsoever on blood sugar levels. Additionally, the same studies have shown that statins can improve kidney function, which is one of the principal goals of good blood sugar control.

Most importantly, however, there is now unequivocal evidence that treatment with statins among people with diabetes reduces their risk of heart attack, stroke and the need for coronary revascularization (either bypass surgery of stenting). These benefits vastly outweigh any small increase in blood sugar levels, should such effects actually be proven to exist.

This episode draws into sharp focus the difficulties faced in providing consumers with balanced reliable information about the effects of drugs on health.

Most drugs have some side effects that will affect some patients. However, the risks of such side effects have to be considered in the context of the benefits that are likely to be gained.

Balancing potential benefits and risks is a challenge for both doctors and patients: these can be literally life and death decisions, and inaccurate, exaggerated media reports about drug effects does not make this any easier.

While it might be a way to increase newspaper circulation and advertising, if the result is the inappropriate termination of life-saving treatment for even a few, there is a serious need to question journalistic ethics.

• Stephen MacMahon is the James Martin Professor of Medicine, University of Oxford, Professor of Cardiovascular Medicine, University of Sydney and Principal Director, The George Institute for Global Health

Declaration: The George is involved in NHMRC-funded research on a low-cost “polypill” for the prevention of cardiovascular disease in resource-constrained environments.


My article was fair and balanced

Amy Corderoy from the SMH writes:

My article this week suggested new warnings on the link between statins and diabetes and cognitive impairment could lead to people at low-risk of heart disease going off drugs, and this has upset some people in the medical community.

That’s fair enough – statins are the most commonly prescribed drugs in the country and are of huge public health significance.

This piece from Stephen MacMahon, whose work I respect, sums up well many of the criticisms that have been made.

But it ignores the crucial point of the article, which was repeated several times: these warnings are only of relevance to people who are on statins who are at low-risk of heart disease.

At no point did the article suggest people at moderate to high risk of cardiovascular disease should go off these drugs.

It also included commentary from the director of Baker IDI, Garry Jennings, specifically disputing the point that anyone at all would need to go off their medication, despite the fact that this seems unlikely.

With 2 million Australians currently taking statins, only 0.1 per cent of them would need to be people at low-risk of cardiovascular disease who could potentially be taken off their medication for “thousands” of people to be affected.

In fact, this is likely to be a conservative estimate. While little research has been done into the rate of prescribing of statins to people at low-risk of heart disease in Australia, as several people were quoted saying, our high rates of prescribing compared to the rest of the world indicate this is a problem.

The AusHEART study http://www.mja.com.au/public/issues/192_05_010310/hee10422_fm.html of cardiovascular disease risk factors and their management found 30 per cent of patients who were at low risk of heart disease were being prescribed a statin. If that finding is representative, the numbers would be far higher than suggested by my report.

Are Professor MacMahon and the other cardiovascular researchers and clinicians who have called the article “sensationalist” and “hysterical” saying that it is hysterical or sensationalist to suggest that people at low-risk of heart disease should reconsider their use of statins? I would say that position is mainstream, and a conservative approach. http://www.ncbi.nlm.nih.gov/pubmed/22025650

It’s also worth pointing out that sometimes, as in the case of this Medical Observer article, http://www.medicalobserver.com.au/news/statin-relabelling-sparks-hysterical-overreaction the criticisms are made without the speakers declaring their links to pharmaceutical companies that produce lipid-lowering medications.

Professor MacMahon also focuses heavily on the issue of the link between cognitive impairment and statins, despite my article being primarily about the diabetes link and stating explicitly that the cognitive impairment evidence was not as strong. He emphasises that the cognitive effects are entirely reversible – but they are reversible only in patients who go off the drugs!

He is unconvinced by the suggested link between diabetes and statins. But the finding has been replicated in many studies and was considered serious enough for the FDA to include a warning about it for doctors and patients – and that is the key word here, “patients”.

These warnings are not just for doctors, they are for patients to make their own minds about as well. There seems to be an idea still among some in the medical community that people can’t be trusted to evaluate evidence for themselves, to look at the FDA warnings and to speak to their doctor.

My article was fair, balanced, and clearly explained the issue for a general audience.

The FDA has put these warnings out there and I have a right and a responsibility as a medical reporter to report that, particularly now the internet allows people to find this information easily for themselves.


Weigh up benefits and risks

Dr Amanda Wilson, Media Doctor Australia, writes:

With any story about adverse events or side-effects with a drug, there is the potential to scare people enough to make them stop taking the medication without talking to their doctor about it – never a good idea.

The NPS have put together an accessible response to this story.  It basically says people need to weigh up the risks and benefits of taking statins in consultation with their doctor.  The available evidence shows that risks are relatively low and the benefits of the drug are good.

People who have had cardiovascular events previously have much more to gain in the way of benefit from statins than any potential risk of diabetes or dementia.  People who are at low risk (no history of heart or vascular disease) should discuss the benefits/risk balance with their GP.

Another aspect to consider is that the FDA makes more recommendations about adverse event warnings than Australia does.

• MDA will review media coverage of this story next week


Advice from the NPS

Meanwhile, the NPS is urging people taking statins to continue to take their medicine as prescribed and to see their doctor if they are unsure about the benefit of the medicine for them.

The recommendation comes in light of regulators in the US announcing that the cholesterol-lowering drugs will now carry advice about a small increased risk of diabetes and reports of memory problems.

NPS Head of Programs Ms Karen Kaye says that statins are recommended for people at high risk of cardiovascular events, such as a heart attack or stroke. The risk of developing diabetes with statins is small compared with their benefits for preventing heart attacks, strokes and deaths from such events.

• More information about statins and the risk of diabetes and memory problems is available on the NPS website.


The debate about statins and primary prevention

• An article last year in Australian Prescriber raised concerns about overuse of statins among patients at low risk of cardiovascular disease.

Jane Smith, Associate Professor of General Practice at Bond University in Queensland, concluded that:

“It is likely that we are over-prescribing statins to low-risk patients. A focus on single risk factors such as high cholesterol promotes statin treatment. This will not benefit patients unless they have a high risk of cardiovascular disease, and it could result in harm. It is appropriate to assess absolute cardiovascular risk in people aged over 45 years (or from 35 years if Aboriginal and Torres Strait Islander) using tools that integrate multiple risk factors.”

• The Cochrane Collaboration published a systematic review last year raising concerns about quality of evidence to support statin use in primary prevention, particularly in low risk patients. It said:

“On the basis of our systematic review and these recent meta-analyses, it is clear that any decision to use statins for primary prevention should be made cautiously and in the light of an assessment of the patient’s overall cardiovascular risk profile.  Widespread use of statins in people at low risk of cardiovascular events – below a 1% annual all-cause mortality risk or an annual CVD event rate of below 2% observed in the control groups in the trials considered here – is not supported by the existing evidence. Furthermore, the tendency of trial protocols to remove patients suffering with co-morbidities limits their generalisability to typical patient populations in whom decisions to prescribe statins have to made.

Our review is not able to comment on cost-effectiveness as, surprisingly, few of the trials have published cost-effectiveness data to support their contentions that these drugs are worth using for primary prevention. …

This current systematic review highlights the shortcomings in the published trials of statins for primary prevention. Selective reporting and inclusion of people with cardiovascular disease in many of the trials included in previous reviews of their role in primary prevention make the evidence impossible to disentangle without individual patient data. In people at high risk of cardiovascular events due to their risk factor profile (i.e. 20+% 10-year risk), it is likely that the benefits of statins are greater than potential short term harms although long-term effects (over decades) remain unknown. Caution should be taken in prescribing statins for primary prevention among people at low cardiovascular risk.”


Update:  The mixed impact of media reports

NPS CEO Dr Lynn Weekes writes:

NPS yesterday released information stating that people should continue taking statin medicines unless otherwise advised by their doctor, despite recent media reports that suggest they increase risk of diabetes and memory loss.

Evidence reviewed by the main regulator for medicines in the US – the Food and Drug Administration (FDA) – suggests that for people at high risk of cardiovascular events (heart attack or stroke), the risk of developing diabetes because of statins is small compared with their effectiveness in reducing the risk of cardiovascular events.

Despite statins being widely prescribed world-wide there are a relatively small number of reports of minor memory loss in people taking statins and these have been reversible on ceasing the medicines.

Journalists have a responsibility to report on medicines issues accurately and with consideration of their reports on medicines use in the community.

The Sydney Morning Herald article from March 1 provided good advice for consumers from both Professor David Le Couteur of the Australasian Society for Clinical and Experimental Pharmacologists and Toxicologists and Professor Ric Day of the University of NSW. The article also covered important points about people at low risk of cardiovascular disease.

There is often a fine line between accuracy and achieving newsworthiness. When news reports create controversy and fear for consumers who may only read the headline, people turn to organisations like NPS to clarify information and provide an unbiased view. We also find that such reports generate an increase in calls to services like the NPS Medicines Line.

Sometimes articles like this do have a positive effect because they create a better awareness of issues, and can help the right conversations take place between consumers and their health professionals.

The flipside is when people make their own judgement and cease taking medicines out of fear, which can put their health at risk.

Our consistent advice when medicines come under scrutiny is for people to talk to their prescriber to obtain personalised, evidence-based advice in order to weigh up the risks and benefits of the medicine for them.


Update, March 6

How Media Doctor Australia rated the story in question 

The problem with this story lies mainly in the inaccurate headline and the first sentence. Statins are not ‘miracle’ drugs, they don’t ‘put thousands at risk’ and they do not ‘increase the risk of dementia’. Once we get beyond these initial missteps, the story includes some balanced comments from a range of informants.

First the facts: The Food and Drug Administration has recently updated its advice on problems with statin drugs, reducing the previous warnings about liver damage and clarifying two additional risks. The first is NOT dementia; it is temporary memory loss and a feeling of ‘fuzziness’ reported by some users, which reverses after treatment is stopped. In fact, the large trials of statins show a trend to reduced risk of dementia (permanent loss of memory and cognition).

The second is an increased risk of developing diabetes. A meta-analysis of randomised clinical trials in early 2010 found a 9% relative increase in the risk of diabetes in users of statins compared with control patients. This translated into an absolute increase of 0.4%. In other words for every 250 people treated with statins one extra developed diabetes (the article says 500 but it’s not clear where this came from).

It has been estimated that in people at low risk of heart attacks and strokes, around 250 have to be treated so one will benefit. This underscores the fact that benefit and harm are finely balanced in people at low risk of heart problems. However, in those who are at high risk – those who have a history of heart trouble and those with major risk factors such as diabetes and high blood pressure the benefits clearly outweigh the harms.

The story really represents these facts well and it is a good example of the value of getting comments from a range of informants, who are in pretty good agreement on the benefit to risk ratio, but differ on the extent to which low risk individuals in Australia are being treated unnecessarily. It’s a pity the headline and first sentence got it so wrong.


Querying conflicts of interest

• Croakey was sent information raising questions about Professor Stephen MacMahon’s conflicts of interest, stating:

That he is the Chair of the world-wide Caduet advisory board for Pfizer (Caduet is a combination blood pressure medication and statin); citing a 2008 paper in The New England Journal of Medicine which acknowledged “Dr MacMahon… a member of advisory boards for Servier, Pfizer, and Novartis and receiving lecture fees from Servier and Pfizer and research grants from Servier, Pfizer, and Novartis”; and a 2006 FDA document stating: “With respect to FDA’s invited guest speaker, Dr Stephen MacMahon reports that he has received research grants from Pfizer and Merck. He also receives occasional honoraria from Pfizer, Novartis, Boehringer Ingelheim and Merck.”

However, the George Institute said the Caduet information was out of date and that:
• Professor MacMahon has not received lecture fees from any commercial sponsor since 2009
• Professor MacMahon has not received consulting fees from any commercial sponsor since 2007


Meanwhile, more discussion on this story is at Amy Corderoy’s blog.











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