We found no increased risk of peripheral neuropathy, depression, common eye diseases, renal disorders or arthritis associated with taking statins. Studies 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 higher quality studies indicating that they may not be robust. There was evidence of an increase in myopathy, raised liver enzymes and diabetes. The pooled observational findings were heterogeneous which might reflect differences in study quality, the populations studied and how statin exposure and effects were measured.
Observational studies of effects of drugs are beset with problems of ‘confounding by indication’ which results in people on treatment often having worse outcomes than those not on treatment simply because they are sicker. In the studies reviewed here, investigators attempted to obtain comparable groups by a range of methods including simple matching, controlling for potential confounders and propensity score matching. None of these methods are as efficient as randomization in controlling for selection bias and confounding but for rare outcomes and to study typical patients using drugs in the general population, observational studies provide the only means of making assessments. Moreover, population-based observational studies provide reliable estimates of the incidence of effects experienced in the general population, important in evaluating the public health impact of an intervention, as this usually cannot be done reliably using randomized trial data (because of limited power and differences between trial samples and general populations).
Comparison of results with randomized trials
For unintended effects that had been reported in RCTs, the effect estimate derived from observational studies was compared with RCT findings to determine the extent to which observational studies were capable of obtaining robust findings. This approach has been used previously [
94]; and a recent study found no difference in the risk estimate of adverse effects of interventions derived from meta-analyses of RCTs and meta-analyses of observational studies, suggesting that these may be estimated reliably from observational data [
115]. For this comparison we used results from published data from the CTT collaboration, systematic reviews from the Cochrane collaboration or recent systematic reviews on specific unintended effects that superseded either of these sources. Pooled or single RCT estimates are presented below the observational pooled estimates for the higher quality studies and indicate that in the RCT and observational findings were broadly similar (Figure
3), although RCT estimates tended to be more conservative. Consistency between observational and RCT findings suggests that confounding by indication is unlikely to invalidate the observational results, particularly for estimates obtained from large, better quality observational studies.
Evidence from recent systematic reviews and meta-analyses of randomized trials showed no differences in risk of psychological outcomes [
116], fractures [
117], acute renal failure [
118], arthritis [
1] or venous thromboembolism [
119]. A recent meta-analysis of randomized trials and prospective cohort studies concluded that long-term data may support a beneficial effect of statins in the prevention of dementia [
120] and another review of statins and cognitive impairment found no strong evidence of an association with Alzheimer disease or cognitive function [
121].
A recently published meta-analysis of observational studies also found a similar reduction in the likelihood of pneumonia associated with statin use [
122], in line with randomized findings from the Justification for the Use of Statins in Primary Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) trial [
123]. Statin use may be a surrogate marker for better health which may confound the observed association with pneumonia [
124].
RCTs in both primary and secondary prevention found an increased risk of T2DM (OR 1.18; 95% CI 1.01 to 1.39 and OR = 1.09; 95% CI 1.02 to 1.17) [
1,
12]. This association appears to be higher with intensive-dose statin therapy and among elderly subjects [
125], and is strongly associated with baseline fasting blood glucose and co-existing CVD risk factors, suggesting that statins raise blood glucose by a small amount, moving people from below to above the diagnostic threshold [
126]. In a recent observational cohort study, atorvastatin and simvastatin compared with pravastatin were associated with an increased risk of new onset diabetes [
127]. In a new analysis of the JUPITER primary prevention trial, the cardiovascular and mortality benefits of statin therapy exceeded the risk of developing diabetes even in people at high risk of developing diabetes [
128]. Although the mechanism underlying the increase in new onset T2DM in patients treated with statins is unknown, it is possible that statins interfere with insulin signaling, leading to hyperinsulinemia, insulin resistance, metabolic syndrome, pre-diabetes and diabetes [
129‐
131].
The apparent protective effect of statin use on cognitive function was linked with ApoE4 genotype in one study among individuals <80 years [
68]. Further research is needed to assess the possible interaction of statin use and ApoE genotype on risk of AD or dementia.
Our analysis gave higher estimates than RCTs for myopathy which may reflect differences in the diagnostic criteria used and the populations studied. Myopathy is more likely to occur with higher doses of statins and in situations that raise statin blood levels, including advanced age, frailty, deterioration of renal function and the presence of interacting drugs [
132], all common exclusions for RCTs. A blinded, controlled trial among healthy statin-naïve people showed that high-dose atorvastatin for six months had no effect on muscle strength or exercise performance but confirmed that statins increase muscle complaints and increased average creatine kinase, suggesting that statins produce mild muscle injury even among asymptomatic subjects [
133]. An observational study using military personnel records found that musculoskeletal conditions, arthropathies, injuries and pain were more common among statin users than among propensity score-matched nonusers [
134].
No increased risk of renal disease attributable to statin treatment was found in our review. Recent systematic reviews of trials have demonstrated lower mortality and cardiovascular events in persons with early stages of chronic kidney disease (CKD) on statins, but little or no effect in persons receiving dialysis, and uncertain effects in kidney transplant recipients [
135,
136].
We found an increased risk of liver disorders, although outcome definition was heterogeneous across studies. With the exception of statin-induced transaminase elevation, large statins trials have not shown an increase in the incidence of liver diseases. In a systematic review of 21 randomized trials, elevated transaminases occurred with an excess rate of 7 per 10,000 person-years but liver disease was rare (0.05 per 10,000 person-years) [
137]. This was confirmed in a larger network meta-analysis [
138]. Routine monitoring of liver function after starting a statin is no longer recommended [
14].
Limitations and strengths
One major strength of our systematic review is the inclusion of a large number of observational studies in general populations and a wide range of potential unintended effects of statins. Therefore, our analysis is more likely to include a broad representation of the population at-risk, and may reflect better the nature and frequency of unintended effects experienced in clinical practice.
Despite the many positive aspects, observational research is prone to bias and confounding. The results from the studies included in this meta-analysis could be influenced by a “healthy-user” effect and closer monitoring. We explored the robustness of our results across three dimensions: study design, sample size and quality of the studies but heterogeneity of the pooled observational findings could not be explained by them, and may reflect the different populations studied, how the statin exposure was measured or different outcome definitions. It was not possible to assess the consistency of outcome definitions between studies which is an inherent limitation of systematic reviews based on published data. We also recognize the limitation of having a single reviewer assessing all data extraction and validity; although no discrepancies were identified in a random sample of 10% of the titles and the numbers extracted. Publication bias is a particular threat to the validity of meta-analysis of observational studies. Although we contacted authors asking for unpublished studies, publication bias is possible since observational studies with significant outcomes are more likely to be published and, therefore, over-represented in our meta-analysis. The pooled effect sizes may potentially be exaggerated by this bias.
A further limitation is the difficulty in keeping this review up to date given the high level of publication on statins. In recognition of this we conducted a rapid update search of Medline (January 2012 to February 2014, terms: statins, humans, core medical journals, 141 hits) and have incorporated substantive new findings in relevant sections of our discussion.
Some unintended effects (for example, ventricular arrhythmia, intracerebral hemorrhage) were not covered in this meta-analysis as they were not reported in population-based studies, but from case reports and clinical case series which provide weaker evidence of causal association. A recent meta-analysis including RCTs and observational studies (mainly secondary analysis of RCTs and small studies in subgroups of patients with atrial fribrillation or acute ischemic stroke) found no association between statin exposure and intracerebral hemorrhage, consistent across study designs [
139].
Implications for clinical practice
Statins are widely used in clinical practice and their efficacy for secondary prevention of CVD is well founded, but their expanding use in primary prevention in low-risk individuals has to be balanced against the risk of ‘overmedicating’ the general population [
140]. This assumes particular importance since findings from a recent cohort of 3.8 million general population patients of UK Clinical Practice Research Datalink (CPRD) showed substantive overuse of statins in low CVD risk and underuse in high CVD risk [
141]. Given that several trials are currently evaluating the effects of a polypill on risk factor levels, the use of statins is likely to increase to a much wider section of the population (whether by age or by cut-off on absolute risk) [
142]. Thus, accurate evidence on the potential unintended effects of statins is of public health relevance.
The observed unintended effects, most importantly myopathy and elevated liver enzymes, are rare and more likely to occur with higher doses of statins. The possible increased risk of developing T2DM has resulted in surveillance recommendations.