The unintended effects of statins

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PillsThis is a guest post from the authors of a paper on statins published on Saturday in BMC Medicine. Statins have hit the headlines a lot over the last few weeks. Here, the authors take us through the findings of their review and analysis into the unintended effects of these drugs.

Statins are widely used in clinical practice and their efficacy for secondary prevention of cardiovascular diseases (CVD) is well founded, but their expanding use in primary prevention in low-risk individuals has to be balanced against the risk of potential unintended effects. This assumes particular importance since the new draft guidance from the National Institute for Health and Care Excellence (NICE) recommends lowering the 10-year risk threshold for considering statin therapy from 20% to 10% risk of developing CVD.

Evidence on unintended effects reported by randomised controlled trials (RCTs) and their associated meta-analyses is often insufficient. In RCTs not all harmful effects can be easily anticipated, but even if measured their reporting is inadequate. Under-reporting of unintended effects may affect the interpretation of the net clinical benefit, particularly among people at low cardiovascular risk.

A recent meta-analysis of 29 RCTs, involving more than 80,000 patients taking statins, concluded that almost all reported symptoms occurred just as frequently when patients were administered placebo, even for unintended effects commonly attributed to statins such as myopathy. However, for the majority of these events the conclusions were drawn from the analysis of the reports of only 2 of the 14 primary prevention RCTs. Only development of new-onset diabetes mellitus was significantly higher on statins than placebo.

In addition to inadequate reporting of the unintended effects in the statin trials, people who are prescribed statins in general practice are not always similar to trial participants – they tend to be older, to have multiple pathology, and therefore may be more likely to suffer the unintended effects.

In our study, we systematically assessed unintended effects of statins from 90 observational studies in the general population, with comparison of the findings – where possible – with those derived from RCTs. Observational studies are more likely to include a broad representation of the population treated with statins, and provide reliable estimates of the incidence of effects experienced in the general population, important in evaluating the public health impact of an intervention.  

Hand with pillsWe found no increased risk of peripheral neuropathy, depression, common eye diseases, renal disorders, or arthritis associated with taking statins.

Of the studies we looked at, those of higher quality did not show previously reported protective effects of statins on fractures, venous thrombo-embolism, or pneumonia. Lower odds of dementia and cognitive impairment were associated with statin use, but were attenuated in the higher quality studies indicating that these apparent protective effects  may not be robust. There was evidence of an increase in myopathy, raised liver enzymes and diabetes.

In our study, the estimates derived from high quality observational data were consistent with the findings from RCTs for the same outcome, indicating that observational studies can provide reliable and relevant evidence on unintended effects of statins to add to the evidence from RCTs for health care guidance.

The absolute excess risk of the observed harmful unintended effects of statins is very small compared to the beneficial effects of statins on major cardiovascular events in evidence derived from randomized trials and from observational studies.

The new draft NICE guidance and the published American College of Cardiology/American Heart Association (ACC/AHA) guideline may result in increased use of statins among a much wider section of the population.  Inconsistent definitions and non-reporting of unintended effects of statins in randomized trials supported by the pharmaceutical industry reduce confidence in the evidence base, but it is highly unlikely that serious life-threatening hazards attributable to statins have been over-looked.

It is also clear that statins reduce cardiovascular events in people at the risk thresholds defined by NICE and ACC/AHA.  Patients and doctors should be reassured that no major or minor potential unintended effects of statins were found in our review of observational studies, which included patients more typical of those treated in routine medical practice.  In the future it is hoped that the pharmaceutical industry will refine their approach to collection of data and reporting of unintended effects of drugs.

Authors: Ana Filipa Macedo, Fiona Claire Taylor, Juan P Casas, Alma Adler, David Prieto-Merino and Shah Ebrahim from London School of Hygiene and Tropical Medicine.