Using a previously validated definition of HCF-onset C difficile
we found that the use of statins decreases the risk of HCF-onset C difficile
infection. This is consistent with the outcomes of other studies investigating correlations between statins and infections. The large sample size enabled by the UHC data permitted medication-specific estimates, and is a key strength of this study. The protective association held when looking at individual statin formulations, not just the overall statin class. No association between non-statin cholesterol-lowering drugs was observed, further strengthening the support for our hypothesis. While our study suggests that statin use decreases the risk of HCF-onset C difficile
infection, a number of alternative explanations must be considered.
Residual confounding could have distorted our estimates, although it is unclear what variables might have introduced the level of confounding required to explain the strength of these findings. While matching was based on age, hospital and year of admission, information was not available on other characteristics of the population, such as socioeconomic status, which may have skewed our effect measures. Administrative claims data are based on hospital charges, and hospital charges are driven by what is reimbursable for insurance purposes; laboratory data and other patient-level records were not available. In addition, dosing information was not available, and as such we were unable to perform evaluations of possible dose–response relationships. Another potential limitation is the lack of information available on the patient location within a given hospital (eg, specific floor or ward). An important risk factor for C difficile
infection, like other infectious diseases, is exposure to and transmission from C difficile
infection patients or carriers.31
Unfortunately, the database does not contain information as to ward or patient room sharing, so we are unable to infer potential C difficile
infection transmission from these sources. We did, however, match on hospital and year/quarter and adjust for hospital rate of C difficile
infection. In addition, previous gastrointestinal surgery was not considered a potential confounder. However, the authors believe that surgical procedures would not have significantly confounded the association due to the lack of papers citing gastrointestinal surgery as a potential risk factor.
It is possible that preventive medications such as statins may have been discontinued on admission to the hospital. Indeed, statin use in our study was lower than in the typical US population. Nevertheless, prevalence estimates of statin use based on UHC data are comparable with statin use in other hospitalised populations.32
In this population, monotherapy of statins was used by 16.4% of cases and 20.3% of controls compared with 23% usage in previous studies.32
One possible explanation for the lower use of statins in hospitalised populations is that some drugs may be discontinued when patients are admitted to hospital. However, if this misclassification occurred, it would have diluted the estimate of effect.
Statins have been cited to have multiple protective effects including reducing the risk of cataract,33
improving outcomes in community acquired pneumonia,35
reducing the risk of renal cell carcinoma,36
and particularly relevantly, reducing mortality due to sepsis and other infections.37
Recently, the JUPITER trial demonstrated the role of statins for primary prevention in apparently healthy men and women.38
All of these effects of statins may be considered pleiotropic side effects of the drugs, and many are due to the anti-inflammatory and immunomodulatory properties of the drugs.15,39
One of the mechanisms proposed for statins to affect the immune system is by increasing the phagocyte's ability to create extracellular traps.39
The multitude of observed pleiotropic side effects contributes to the possibility that more unknown effects of statins are present and have yet to be explored. Few studies have been adequately powered to provide individual estimates of effect for statins and other cholesterol-lowering medications due to small sample size and the low frequency of non-statin medication use. In one study exploring the association between statin use and colorectal cancer,40
a possible protective effect of statins on colorectal cancer was observed; however, trends towards risk reductions were also observed for non-statin cholesterol-lowering drugs. How elevated cholesterol may create adverse conditions for C difficile
infection remains unclear.
While statins have been shown to reduce the risk of a number of different infections12,41–44
and other morbidities that could potentially involve inflammatory pathways, other studies and reviews suggest that this observation could be due to a healthy user effect.12
However, without a randomised controlled trial, an observational study will not be able to eliminate all potential elements that could be contributing to the healthy user bias.
Unexpectedly, we found that resins (bile acid sequestrants) were positively associated with the development of HCF-onset C difficile
infection. Resins, including cholestyramine, colestipol and colesevelam, have previously been recommended in combination with statins to reduce lipid levels further.45
Notably, resin users had more comorbid conditions (indicated by a Charlson score of 4 or higher) than non-resin-taking participants. To explain this result, we also considered (and ruled out) confounding due to the diagnosis of pancreatitis, bile obstruction, or liver jaundice. We were unable to disentangle whether confounding by some unmeasured factor remained or if physicians initiated resins to deal with emerging symptoms associated with C difficile
infection. Resins are used in the treatment of diarrhoea and irritable bowel disease. These uses could lead to a possible protopathic bias, or confounding by indication. These results showing increased risk among resin users warrant further investigation, as findings could be clinically meaningful for patients at high risk of C difficile
To the best of our knowledge, this study is the first to consider the role of statins in the risk of hospital-acquired C difficile
infection; however, other studies have considered the impact of statins on the outcomes of other infectious diseases.44,45
Our findings are not generalisable to those with community-associated C difficile
infection, or patients outside of academic health centres. However, our results are consistent with a recent study demonstrating the protective effect of statins for community-associated C difficile
The large size of our study is a strength, as we were able to analyse individual statins and other drugs used in the treatment of hypercholesterolaemia. However, we were unable to evaluate the role of the length of statin therapy on the development on C difficile
infection. In summary, statins, but not other cholesterol-lowering medications, are associated with a decreased risk of HCF-onset C difficile
infection. No differences were observed by individual statin medication. This study adds to the accumulating evidence of the unintended beneficial effects of statins on infections. However, only a randomised controlled clinical trial can determine the causal role of statins in preventing infections.