16 June 2011
This meta-analysis of 13 RCTs (n=17,627) found the use of glitazones was associated with an increased risk of pneumonia or lower respiratory tract infection (LRTI) in patients with type 2 diabetes. Based on the average control event rate in the included trials, the number needed to harm [NNH] over 3.7 years was 239.
Level of evidence:
Level 1 (good quality patient-oriented evidence) according to the SORT criteria.
Healthcare professionals should continue to follow NICE guidance on type 2 diabetes, which places glitazones generally as a third-line hypoglycaemic option for patients following metformin and a sulfonylurea. However, prescribers should be aware of several safety concerns with this class of drugs, notably heart failure, ischaemic heart disease, fractures, and now, possibly, pneumonia.
Rosiglitazone was withdrawn from clinical use across Europe because of concerns over excess cardiovascular (CV) risk. Pioglitazone▼ remains an option but prescribers should note that pioglitazone is contraindicated in patients with heart failure or a history of heart failure. Furthermore, NICE advises that pioglitazone should not be commenced or continued in people with a higher risk of fracture, because it may increase this risk further. In addition, the Summary of Product Characteristics states that pioglitazone should be avoided in hepatic impairment, and liver function should be monitored before treatment and periodically thereafter, or if the patient develops symptoms suggesting hepatic dysfunction.
A European review to investigate the signal of a possible increased risk of bladder cancer with pioglitazone is also ongoing. Pioglitazone remains a black triangle drug and any suspected adverse reactions should be reported through the Yellow Card system.
What is the background to this?
Glitazones have immunomodulatory and glucocorticoid-like properties that could potentially induce susceptibility to infections, including respiratory infections. Two long-term trials of glitazones in patients with type 2 diabetes (RECORD with rosiglitazone and PROactive with pioglitazone) raised concerns about a possible increased risk of pneumonia with these drugs. The authors of this paper aimed to investigate these concerns further by conducting a systematic review and meta-analysis of published and unpublished randomised controlled trials (RCTs) which compared glitazones with controls (placebo, metformin or a sulfonylurea) in patients with type 2 diabetes. For inclusion, trials needed to be of at least one year’s duration and report data on pneumonia or LRTI via routine monitoring of adverse events.
What does this study claim?
In a meta-analysis of 13 RCTs involving 17,627 patients, glitazone treatment for between one and five and a half years was associated with a significantly increased risk of pneumonia or LRTI compared with controls (1.59% vs. 1.06%; relative risk [RR] 1.40, 95% confidence interval [CI] 1.08 to 1.82, P=0.01). In a further meta-analysis of seven RCTs involving 16,083 patients over the same time frame, glitazones were associated with a significantly increased risk of serious adverse events caused by pneumonia or LRTI compared with controls (1.50% vs. 1.00%; RR 1.39, 95% CI 1.05 to 1.83, P=0.02).
The number needed to harm (NNH) was estimated to be 239 (95% CI 117 to 1191) based on the average control event rate in the included trials i.e. 239 patients treated with a glitazone rather than placebo, metformin or a sufonylurea for an average of 3.7 years would result in one extra case of pneumonia or LRTI. However, based on an estimate of the incidence of pneumonia of 4,919/100,000 person-years from a Canadian population-based study in patients with type 2 diabetes, the authors of this meta-analysis estimated that the NNH for pneumonia or LRTI associated with glitazone use could be lower than this, at 55 (95% CI 28 to 269).
When pioglitazone and rosiglitazone were considered separately, the associated increased risk of pneumonia or LRTI compared with controls was statistically significant with pioglitazone (RR 1.63, 95 CI 1.09 to 2.46, P=0.02) but not with rosiglitazone (RR 1.26, 95% CI 0.90 to 1.76, P=0.23). However, such subgroup analyses need to be viewed with caution because they may be underpowered to detect a difference.
This meta-analysis raises concerns about an association between glitazone use and pneumonia or LRTI in patients with type 2 diabetes. Like all meta-analyses, it has limitations, mainly reflecting the quality of the reported data. Pneumonia and LRTI event rates were low in the included trials, and there was no specific mortality data for these events. The detection of pneumonia or LRTI in the included trials was via the routine monitoring of adverse events. Therefore, there was no objective pneumonia definition and no radiographic confirmation. However, the authors suggest that their finding of an increased risk is robust and requires detailed investigation in further trials. There was no statistical heterogeneity among the trials, and the increased relative risk of pneumonia or LRTI was similar across varying severities of events and on sensitivity analysis.
This meta-analysis provides a safety signal about glitazones and a possible association with an increased risk of pneumonia and LRTI. This is in addition to previous concerns with this class of drugs relating to increased risks of heart failure, ischaemic heart disease and fracture.
Rosiglitazone was withdrawn from clinical use across Europe in September 2010 because of concerns over excess cardiovascular risk. Pioglitazone remains an option but prescribers should be aware that this drug is not without safety issues. These were discussed in some detail in a previous MeReC Rapid Review No. 2199.
Briefly, there is consistent evidence that pioglitazone can cause weight gain and fluid retention, and lead to new or worsening heart failure. This is not a rare occurrence, and it can be serious and sometimes fatal. Pioglitazone is contraindicated in patients with heart failure or a history of heart failure. With regard to ischaemic heart disease, the majority of published studies do not suggest that there is an increased risk of ischaemic heart disease with pioglitazone, like there is with rosiglitazone. However, as head-to-head comparisons from prospective RCTs comparing the cardiovascular safety of rosiglitazone and pioglitazone are not available, we should still be cautious with pioglitazone use.
With regard to fracture risk, NICE advises that pioglitazone should not be commenced or continued in people with a higher risk of fracture, because it may increase this risk further. This was discussed in more detail in MeReC Rapid Review No. 524. In addition, the Summary of Product Characteristics states that pioglitazone should be avoided in hepatic impairment, and liver function should be monitored before treatment and periodically thereafter, or if the patient develops symptoms suggesting hepatic dysfunction.
On 9th June 2011, the European Medicines Agency (EMA) published a press release about pioglitazone and bladder cancer, following the French Medicines Agency decision to suspend the use of pioglitazone-containing medicines in France. This decision by the French authority followed results of a retrospective cohort study carried out in France which appeared to suggest an increased risk of bladder cancer with pioglitazone.
The EMA’s Committee for Medicinal Products for Human Use (CHMP) started a European review of pioglitazone-containing medicines in March 2011 to investigate the signal of a possible increased risk of bladder cancer with pioglitazone, and will discuss this issue at their next meeting on 20-23 June 2011 and recommend appropriate actions as necessary. While this review is ongoing the CHMP is not recommending any changes to the use of pioglitazone-containing medicines.
Study details –
Singh S, et al. Long-term use of thiazolidinediones and the associated risk of pneumonia or lower respiratory tract infection: systematic review and meta-analysis. Thorax 2011;66:383-388
Design, patients, intervention and comparison
Systematic review and meta-analysis of published and unpublished RCTs of at least one year’s duration comparing glitazones with controls (placebo, metformin or a sulfonylurea) in patients with type 2 diabetes, reporting data on pneumonia or LRTI via routine monitoring of adverse events. 13 RCTs (n=17,627), including 8,163 receiving glitazones and 9,464 receiving controls with a duration of follow-up of 1 to 5.5 years were included after a detailed screening of 58 studies.
Outcomes and results
The author of the study was supported by the John Hopkins Clinical Research Scholars Program. The publication was supported by a grant from the National Center for Research Resources, a component of the National Institutes of Health (NIH) and NIH Roadmap for Medical Research.
More information on glitazones can be found in the type 2 diabetes elearning materials on the NPC website.
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