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Tuesday 18 March 2014

Statins side effects are minimal, study argues

reposted from: http://www.nhs.uk/news/2014/03March/Pages/Statins-side-effects-are-minimal-study-argues.aspx
crabsallover highlights, key points, comments / links.

Thursday March 13 2014
Statins are used to lower blood cholesterol levels
“Cholesterol-lowering statins have almost no side effects,” The Guardian reports. A new UK study argues that the majority of reported side effects are actually due to the nocebo effect – symptoms that are “all in the mind”. 
The researchers looked at the combined results of 29 studies and found there was no difference in the incidence of common side effects in the treated group compared to those in the placebo group. However, there was a slightly higher occurrence of diabetes.
Statins slightly reduced the risk of death from any cause, as well as the risk of heart attack and stroke in people with or without vascular disease. 
However,  the research did not include analysis for some reported side effects of statins, such as memory problems, blurred vision, ringing in the ears or skin problems.
The frequently reported side effect of muscle weakness was only considered if there was also a 10-fold rise in a muscle enzyme associated with muscle injury. Muscle aches, in particular, were no more common in the statin group than the placebo group.
This research has provided a novel approach to assessing the risks and benefits of using statins. Arguably, it provides the most comprehensive research yet on the number of people thought to have genuine side effects, and the risks and benefits of taking statins in both low- and high-risk groups for cardiovascular diseases such as heart attacks.
However, some headlines – such as “Statins are safe” – have overstated the case. There is no such thing as an entirely "safe" drug for everyone who takes it. If a drug doesn’t have side effects, it doesn’t work.
If you have any concerns about taking statins, you should discuss this with your GP or health advisor.

The nocebo effect

Most people have heard of the placebo effect – where people see an improvement in symptoms, despite having been given a dummy treatment; this is thought to be down to the power of the own mind.

Well, the nocebo effect is its evil twin. People can develop what they believe are side effects, even though they have been given a dummy treatment.

Ben Goldacre, one of the authors of the study in question, says that if you want to see the nocebo effect in action, when sitting on a sofa with friends suddenly ask: “does this things have fleas in it?”.

Where did the story come from?

The study was carried out by researchers from Imperial College London and the London School of Hygiene and Tropical Medicine. They say they did not receive any grants from any funding agency in the public, commercial or not-for-profit sectors. The authors are supported by the British Heart Foundation, the National Institute for Health Research and the Wellcome Trust.
The study was published in the peer-reviewed medical journal European Journal of Preventive Cardiology.
The media reported that this study shows that statins have no side effects in comparison to placebo.
This is misleading, as the research was aiming to ask a different question: “What proportion of symptomatic side effects in patients taking statins are genuinely caused by the drug?”
And the researchers were more cautious in their conclusion.
It has not comprehensively looked at all side effects, and it gives no indication of the severity or frequency of side effects experienced.
The media also did not report how small the benefits of statins were found to be in this study. This is an important consideration for people who want to make an informed choice when weighing up the risks and benefits of statin treatment.

What kind of research was this?

This was a meta-analysis of double-blind randomised controlled trials. This means the researchers added together and analysed the results of all studies that met their inclusion criteria. Double-blind randomised controlled trials are the gold standard for studies of whether a drug works or not, as they compare a drug directly with a placebo (dummy), and neither the participant nor the clinician knows which one they are taking. This removes any bias that could affect the results.
Studies of safety are often based on long-term observational studies, often without a placebo. The approach of reviewing randomised trials for safety data, as used by these researchers, would be particularly good at checking on differences between a drug and placebo.

What did the research involve?

The researchers found studies comparing statins to placebo and pooled the results to see if statins increase the risk of side effects, compared to rates in the placebo arm.
Two large databases were searched for relevant studies looking at statins being compared to placebo for cardiovascular disease prevention. Studies were excluded if they compared statins with standard therapy or no treatment. They also excluded studies that mainly included people on renal dialysis, those with organ transplants or if other non-statin medication was also started. This was because people in these categories did not represent the majority of people treated with statins.
They separately analysed studies of primary cardiovascular disease prevention (i.e. in people who had not had a heart attack or stroke) and secondary cardiovascular disease prevention (reducing the risk of a further heart attack or stroke in people who have already had one or the other).
They recorded any serious events for each trial and pooled the results, including:
  • mortality of any cause
  • fatal heart attack
  • non-fatal heart attack
  • fatal stroke
  • non-fatal stroke
  • any life-threatening condition
  • any hospitalisation
They also recorded other side effects, but only if they were reported in at least two trials and the sample size was at least 500 people:
  • increased liver enzymes
  • newly diagnosed diabetes mellitus
  • myopathy symptoms (muscular weakness)
  • muscle aches
  • increased creatine kinase (a muscle enzyme that raises during muscle injury) more than 10 times the upper limit of normal
  • back pain
  • newly diagnosed cancer
  • kidney problems
  • insomnia
  • gastrointestinal disturbance, nausea
  • dyspepsia (indigestion), diarrhoea or constipation
  • fatigue
  • headache
  • suicide
They performed internationally recognised statistical analysis to pool the results together. They then calculated the increased risk of experiencing each side effect for participants taking the statins and for participants taking placebo. They subtracted the placebo risk from the statin risk to find the absolute increase in risk for being on statins. By doing this, they worked out the proportion of symptoms that would not have been attributable to taking medication.
The researchers reported risks as “absolute risks” and calculated the reduction in risk by subtracting the risk in one arm from that in the other. This makes a direct comparison of the possible risks and benefits.

What were the basic results?

They found 14 randomised controlled trials, which included 46,262 people without previous heart disease or stroke (primary prevention). They also found 15 randomised controlled trials, including 37,618 people who already had heart disease or stroke (secondary prevention). On average, the trials lasted between 6 months and 5.4 years, and those included were mostly men.
In the studies, on people who had not already suffered from a heart attack or stroke, the rate of new-onset diabetes for people on statins was 2.7% and on placebo was 2.2%.
The difference between rates on treatment and on placebo is 0.5% (95% confidence interval [CI] 0.1 to 1%), meaning there was a small, statistically significant increase in the rate of developing diabetes with a statin.
This means that in 100 people taking statins, 20 cases of newly diagnosed diabetes mellitus could be due to taking this medicine. In people who had already suffered from a heart attack or stroke, there was only one study that reported new onset diabetes, and no significant effect was seen.
In the studies on people who had not already suffered from a heart attack or stroke, the risk of death from any cause on statins was 0.5% (CI -0.9 to -0.2%) less than the risk on placebo. The risk of a heart attack was 1% (CI -1.4 to -0.7%) less and the risk of stroke 0.3% (CI -0.5 to -0.1%) less.
In the studies on people who had already suffered from a heart attack or stroke, the reduction in absolute risk of death from any cause was even more: 1.4% (CI -2.1 to -0.7%) less compared to placebo. Statins also significantly reduced the risk of a heart attack by 2.3% (CI -2.8 to -1.7%) and the risk of stroke was 0.7% (-1.2 to -0.3%) less.
The proportion of people developing symptoms or other blood test abnormalities was as follows:
  • In both study groups, liver enzymes rose in 0.4% of people on statins. No symptoms were reported, and it is unclear if this was harmful.
    There was no significant difference between
  • taking statins or placebo for any of the other adverse events or side effects listed above.
  • With regards to muscle weakness, this was only recorded if the muscle enzyme (creatinine kinase) level was greater than 10 times the upper limit of normal, so was found in just 16/19,286 people on statins and 10/17,888 on placebo in the primary prevention group. A separate category for muscle aches were experienced in 1744/22,058 (7.9%) in people on statins and 1646/21,624 (7.6%) on placebo.

How did the researchers interpret the results?

At the doses tested in these 83,880 patients, only a small minority of symptoms reported on statins are genuinely due to the statins; almost all reported symptoms occurred just as frequently when patients were administered placebo. New-onset diabetes mellitus was the only potentially or actually symptomatic side effect whose rate was significantly higher on statins than placebo; nevertheless, only one in five of these new cases were actually caused by statins.

Conclusion

This meta-analysis pooled results from 29 studies and has shown a very small increased risk of newly diagnosed diabetes mellitus. This is the same as the decreased risk of any cause of death in people taking statins, compared to placebo, to prevent a heart attack or stroke.
The researchers point out some limitations to the meta-analysis:
  • Each study did not report on all of the side effects, meaning that for each category of side effect, the number of participants differed. The side effect categories were only included if at least 500 people had reported suffering from it. This means there may be numerous other side effects that were not covered by this research.
  • New onset diabetes was only documented in 3 of the 29 trials, though the numbers were still reasonably large.
  • Many trials do not state clearly how and how often adverse events were assessed. This is particularly important, as it is not clear from this type of analysis how often the side effects were experienced or the severity.
Side effects not covered by this review include memory problems, blurred vision, ringing in the ears and skin problems.
Anecdotally, muscle aches or weakness is one of the main reasons people stop taking statins. In this review, the category for muscle weakness was only looked at if the person also had a 10-fold increase in creatinine kinase level (indicating muscle damage). Muscle aches were separately recorded, as this is more common and not always experienced alongside muscle weakness. No firm conclusions can therefore be drawn from this meta-analysis regarding whether statins have an effect on the risk of muscle weakness, if there was less than a 10-fold increase in creatinine levels.
This research was limited to studying the side effects reported in the included studies. Although it was not a comprehensive study of all side effects, it has provided a novel approach to assessing the balance of risks and benefits.
It provides extremely useful data on the proportion of people expected to have genuine side effects and the balance of risks and benefits when taking statins in both low- and high-risk groups.
There are other ways you can lower your cholesterol levels, such as eating a healthy diet low in saturated fat and taking regular exercise.

Links to the headlines

Statin side-effects minimal, study finds. The Guardian, March 13 2014

Links to the science

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