Long-term use of thiazolidinediones and the associated risk of pneumonia or lower respiratory tract infection: systematic review and meta-analysis.

INTRODUCTION The peroxisome proliferator-activated receptor-γ agonists rosiglitazone and pioglitazone activate glucocorticoid receptors and have an immunomodulatory effect. The authors aimed to systematically determine the risk of pneumonia or lower respiratory tract infections associated with thiazolidinediones. METHODS Systematic searches of MEDLINE, EMBASE, regulatory documents and trial registries were carried out for randomised controlled trials of thiazolidinediones with no date restrictions through March 2010. The authors selected long-term (≥1 year) randomised controlled trials of thiazolidinediones versus a placebo, metformin or sulfonylurea control for prevention or treatment of type 2 diabetes that reported on pneumonia or lower respiratory tract infection adverse events or serious adverse events (hospitalisation, disability or death). Relative risks (RRs) were estimated using a fixed-effects meta-analysis, and statistical heterogeneity was assessed using the I(2) statistic. RESULTS Thirteen trials (n=17,627, including 8163 patients receiving thiazolidinediones and 9464 patients receiving control therapy) with a duration of follow-up of 1-5.5 years were included after a detailed screening of 58 studies. Thiazolidinediones were associated with a statistically significantly increased risk for any pneumonia or lower respiratory tract infection (n=130/8163 vs 100/9464; RR 1.40; 95% CI 1.08 to 1.82; p=0.01; I(2)=0%) and serious pneumonia or lower respiratory tract infection (n=111/7391 vs 87/8692; RR 1.39; 95% CI 1.05 to 1.83; p=0.02; I(2)=0%). INTERPRETATION Long-term thiazolidinedione use is associated with a modestly increased risk of any pneumonia or lower respiratory tract infection and serious pneumonia or lower respiratory tract infection in patients with type 2 diabetes.