Long-term use of thiazolidinediones and the associated risk of pneumonia or lower respiratory tract infection: systematic review and meta-analysis
- 1Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- 2Clinical Pharmacology, School of Medicine, Health Policy and Practice, University of East Anglia, Norwich, UK
- 3Division of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA
- Correspondence to Sonal Singh, Department of Medicine, Johns Hopkins University School of Medicine, 1830 E Monument St, Suite 8063, Baltimore, MD 21287, USA;
Contributors Dr Singh had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Singh and Loke. Acquisition of data: Singh and Loke. Analysis and interpretation of data: Singh, Loke, Furberg. Drafting of the manuscript: Singh, Loke, Furberg. Critical revision of the manuscript for important intellectual content: Singh, Loke, Furberg Statistical analysis: Singh and Loke. Administrative, technical, and material support: Singh and Loke. Study supervision: Furberg and Loke.
- Received 4 October 2010
- Accepted 6 January 2011
- Published Online First 15 February 2011
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 I2 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; I2=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; I2=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.
- type 2 diabetes
- serious adverse events
- clinical epidemiology
- drug-induced lung disease
- drug reactions
- systemic disease and lungs
SS and YKL contributed equally.
Funding SS is supported by the Johns Hopkins Clinical Research Scholars Program. This publication was made possible by Grant Number 1KL2RR025006-03 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH), and NIH Roadmap for Medical Research. Its contents are solely the responsibility of the authors and do not necessarily represent the official view of NCRR or NIH. Information on NCRR is available on the website (http://www.ncrr.nih.gov/). Information on Re-engineering the Clinical Research Enterprise can be obtained from the website (http://nihroadmap.nih.gov/clinicalresearch/overview-translational.asp). The design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript was independent of any other sources of funding. Other Funders: NIH.
Competing interests Dr Furberg reports that he is a senior investigator and steering committee chair of the National Health, Lung, and Blood Institute–sponsored Cardiovascular Health Study (CHS), a cohort study to examine risk factors of coronary heart disease and stroke in the elderly. In 2004, the study received a grant for $280 000 from GlaxoSmithKline to determine the relationships between LpPLA-2 and various vascular diseases. The grant was primarily for the CHS central laboratory and the CHS coordinating center. Funding was channeled through Wake Forest University and Dr Furberg was the CHS principal investigator, but he received no salary support and the funding period ended 30 June 2006. Dr Furberg did not benefit personally from the grant and has no funding from any other manufacturers of antidiabetic medications. No other financial disclosures were reported. No specific financial interests and relationships and affiliations relevant to the subject of their manuscript were reported by Sonal Singh and Yoon Loke.
Provenance and peer review Not commissioned; externally peer reviewed.