At a time when the
wider prescription of statins is under renewed public scrutiny, a substantial
analysis of placebo-controlled randomized trials of statins has found that only
a small minority of side effects reported by those taking the cholesterol-lowering
drugs are actually attributable to them. Almost all the side effects reported
in these trials "occurred anyway when patients were administered
placebo," say the investigators.
The study, a
meta-analysis involving more than 80,000 patients and reported today in the
European Journal of Preventive Cardiology, was performed without funding from
any agency in the public, commercial or not-for-profit sectors.(1)
Explaining the need
for such a study, the authors note that evaluation of the efficacy of statins
is always based on the evidence of randomised controlled trials (RCTs) against
placebo, while the evaluation of side effects is not. Adverse events listed for
statins come from many sources, they note, including observational studies, in
which most are unable to differentiate between events caused by the drug or
caused by chance.
"Patients and
doctors need clear reliable information about benefits and risks to make
informed decisions," they write, adding that those reporting symptomatic
side effects during statin therapy need reliable confirmation that a symptom is
truly caused by the drug.
This study analysed
the prevalence of side effects in 29 eligible RCTs performed for the primary
(46,262 participants) and secondary (37,618) prevention of cardiovascular
disease. Data on all adverse effects, cardiovascular events and death were
recorded in both the treatment and control (placebo) arms of the studies. Using
a statistical model, the investigators calculated the increase in risk for each
side effect in the statin and placebo arms.
Among a long list of
side effects assessed -- which included nausea, renal disorder, myopathy and
rhabdomyolysis (muscle breakdown), muscle ache, insomnia, fatigue, and
gastrointestinal disturbance -- only the risk of new onset diabetes mellitus
was increased by statin therapy.
In the 14 primary
prevention trials, randomisation to statins rather than placebo significantly
increased the prevalence of diabetes by 0.5% (and similarly reduced mortality
rate by 0.5%). And across both primary and secondary prevention trials, the
rate of developing diabetes with statins was 3%, against 2.4% with placebo,
thus indicating that around one in five of new cases of diabetes was actually
caused by statins.
Otherwise, the authors
report, the many side effects commonly attributed to statins (notably myopathy,
fatigue, muscle aches, and rhabdomyolysis) were no more common in the statin
arms of these RCTs than in the placebo arms.
Overall, the study
found serious adverse effects in 14.6% of patients receiving statins and 14.9%
given placebo in the primary prevention trials, and in 9.9% of those on statins
and 11.2% on placebo in the secondary prevention trials. Similarly, comparable
numbers of patients withdrew from the trials because of symptomatic adverse
events (around 12-15%).
In their bid to
provide doctors with a clear estimate of the risk of side effects genuinely
attributable to statins, the investigators have calculated a "clear,
understandable metric for everyday clinical use" -- the proportion of side
effects not attributable to their pharmacological action, or PSN.
Thus, in the diabetes
risk noted above, 20% (0.6/3.0) of all new diabetes diagnoses on statins were
directly attributable to the drugs, giving a PSN of 80.
Despite the findings,
the authors acknowledge that many real-world patients do report symptoms with
statins -- which of course contrasts markedly with their results. In explaining
this, the study's first author, Dr Judith Finegold from the National Heart and
Lung Institute in London, says: "We clearly found that many patients in
these trials -- whose patients are usually well motivated volunteers who didn't
know if they were getting a real or placebo tablet -- that many did report side
effects while taking placebo. In the general population, where patients are
being prescribed a statin for an asymptomatic condition, why would it be
surprising that even higher rates of side effects are reported?
"Most people in
the general population, if you repeatedly ask them a detailed questionnaire,
will not feel perfectly well in every way on every day. Why should they
suddenly feel well when taking a tablet after being warned of possible adverse
effects?"
Asked if the study
results add weight to the case for the wider prescription of statins, Dr
Finegold said: " No, we think that our results will help improve the
patient-doctor consultation. We believe that patients should be empowered to
make their own decisions, but we must first make sure they have top quality
unbiased information. This is why we call on drug regulators to highlight in
the long lists of side effects those few whose rate is incrementally greater
than that experienced with a dummy tablet."
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