Statins and prevention of infections: systematic review and meta-analysis of data from large randomised placebo controlled trials

In their review and meta-analysis van den Hoek and coworkers [1] show that in large randomised placebo controlled trials statins had no effect on the risk of infections, the accompanying editorial thus concludes that the best evidence now says that statins do not reduce infection [2].

We extensively studied the effects of statin treatment on polymorphonuclear leukocytes (PMNs), which are key players in the innate immune response against infections. Our investigations focussed on dyslipidaemic subjects at increased cardiovascular risk according to the National Cholesterol Education Program—Adult Treatment Panel III (ATPIII) guidelines [3]. According to our initial findings [4], in these subjects PMNs show enhanced production of interleukin (IL)-8, and increased reactive oxygen species (ROS) generation and 4-week simvastatin treatment reduces both IL-8 production and chemotaxis at levels comparable to those observed in healthy subjects. When however we performed a follow-up study after long-term (1 year) statin treatment, results indicated that ROS generation by PMNs from high-risk subjects on simvastatin were comparable to those in cells from healthy subjects [5], however IL-8 production was significantly lower both in resting PMNs (mean difference: -119.1 pg/ml, 25th-75th percentiles: 66.8 to 171.4 pg/ml) as well as after stimulation with fMLP (-280.5 pg/ml , 170.8 to 390.1 pg/ml). It is thus suggested that: (i) the functions of human PMNs are reduced during statin treatment; (ii) distinct functions are affected to different extents (ROS production is just reduced to values found in cells from healthy subjects but IL-8 production is profoundly impaired).

Our studies were performed in small groups of subjects (n= 14-15) and therefore provided no information regarding the possible association between reduced PMN functional responses and increased susceptibility to infections. Nonetheless, results provide some clues about mechanisms potentially contributing to decreased antiinfective defenses during statin treatment. Indeed, statin-induced reduction of the proinflammatory profile observed in subjects at high cardiovascular risk may result in additional benefit for the prevention of vascular events, but also in light of our findings we agree with van den Hoek and collaborators [1] that detailed reporting of infectious outcomes should be mandatory in statin trials. Infectious events should be also carefully monitored an reported during routinary statin treatment in particular in the long term.

Franca Marino, Luigina Guasti, Marco Cosentino

Center for Research in Medical Pharmacology, University of Insubria, Varese, Italy. E-mail: marco.cosentino@uninsubria.it

References
[1] van den Hoek HL, Bos WJ, de Boer A, van de Garde EM. Statins and prevention of infections: systematic review and meta-analysis of data from large randomised placebo controlled trials. BMJ 2011; 343: d7281.
[2] Golomb BA. Do statins reduce the risk of infection? BMJ 2011; 343: d7134.
[3] Expert Panel on Detection Evaluation Treatment of High Blood Cholesterol in Adults. Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001; 285: 2486-2497.
[4] Guasti L, Marino F, Cosentino M, Cimpanelli M, Maio RC, Klersy C, Crespi C, Restelli D, Simoni C, Franzetti I, Gaudio G, Marnini P, Grandi AM, Lecchini S, Venco A. Simvastatin treatment modifies polymorphonuclear leukocyte function in high-risk individuals: a longitudinal study. J Hypertens 2006; 24: 2423-30.
[5] Guasti L, Marino F, Cosentino M, Maio RC, Rasini E, Ferrari M, Castiglioni L, Klersy C, Gaudio G, Grandi AM, Lecchini S, Venco A. Prolonged statin-associated reduction in neutrophil reactive oxygen species and angiotensin II type 1 receptor expression: 1-year follow-up. Eur Heart J 2008; 29: 1118-26.