This is the first clinical study examining the association of TZDs with asthma exacerbations and steroid prescriptions. Consistent with prior studies showing that TZDs have potent anti-inflammatory effects, we found significant reductions in asthma exacerbations and oral steroid prescriptions among patients who were exposed to TZDs. This study provides new evidence that TZDs may have a role in the future treatment of asthma among patients with diabetes.
Prevention of asthma exacerbations has been a cornerstone of guidelines on asthma management . First line therapies target decreasing airway inflammation through the use of inhaled corticosteroids, which reduce the risk of asthma exacerbation by more than 50% . However, inhaled corticosteroids are not always effective, and despite having less systemic distribution than oral steroids, they are still associated with multiple adverse effects . While many patients in our study were already on inhaled corticosteroids, exposure to TZDs was associated with a further reduction in the risk for exacerbation.
Our findings demonstrating the beneficial effect of TZDs on asthma have a plausible biological mechanism. TZDs are agonists to PPARγ and are involved in a variety of biological functions, including the inflammatory response . Activation of PPARγ inhibits the production and release of cytokines and cell survival factors involved in inflammation . A study on human airway smooth muscle cells found PPARγ agonists were more effective at inhibiting inflammatory cytokine release than corticosteroids . Animal models of asthma that are exposed to TZDs have consistently demonstrated reduced airway inflammation, mucus production, and airway hyperresponsiveness [12–15]. A study of the effect of ciglitazone on a murine model of asthma further demonstrated inhibition of airway smooth muscle remodeling . This body of literature identifies a potential role for TZDs in asthma management.
Ours is the first large study looking at clinical outcomes among patients with asthma, and our findings are consistent with prior studies that showed improvements in pulmonary function and bronchoconstriction among asthmatic patients. Case reports of two diabetic patients with asthma found improvement in respiratory symptoms after initiation of pioglitazone . In one of the patients, spirometry was measured before and after starting TZDs, and there was a significant improvement in both FVC and FEV1. A placebo controlled randomized study of 32 patients also found a modest decrease in late phase asthma reactivity to allergen challenge after four weeks of treatment with rosiglitazone . A separate study of 16 asthmatic patients found a similar decrease in airway bronchoconstriction with methacholine challenge after 12 weeks of treatment with rosiglitazone . Comparing rosiglitazone with inhaled corticosteroid treatment, a randomized trial of 46 patients with asthma showed improvement in FEV1 and FEF25–75% among patients treated with rosiglitazone . Our findings, using a much larger sample of patients, are consistent with these studies and demonstrate a positive impact of TZDs on asthmatic patients.
While there may be a beneficial effect of TZDs in asthma, it is also important to note TZDs have been associated with multiple adverse effects, including weight gain and heart failure, bladder cancer (in the case of pioglitzone) and possible cardiovascular effects (in the case of rosiglitazone) [33–35]. These adverse effects would have to be weighed against any potential gain in asthma management.
Limitations of this study include the non-randomized study design. Though it would also be desirable to perform a new-user study design in order to overcome biases with prevalent-user studies, we did not have a large enough sample size to evaluate new users of TZDs . Furthermore, because these are observational analyses, we cannot infer causality in the association between TZDs and decreased asthma exacerbations, though this does add evidence to support their relationship. We attempted to control for a broad range of potential confounding factors, though unmeasured variables could have impacted the outcome. Notably, we did not have data on tobacco use or obesity, both of which are associated with asthma development and asthma exacerbations [37, 38]. We also did not have information on spirometry or bronchoprovocation testing and could not adjust for the severity of asthma based on these measures. Prescriptions for respiratory medications and prior asthma exacerbations may be a marker of asthma severity and we included these variables in our multivariable analyses, though prescriptions for asthma medications is not a perfect proxy for severity .
Our study population comprised mostly elderly, male veterans, which may limit the generalizability of these findings. Incidence of asthma exacerbations in our study was low. This may be partly due to the population that we studied, as the risk of asthma exacerbation decreases with increasing age and with male gender . In addition, our definition of exacerbations may not have adequately captured all patients experiencing an acute asthma attack. We broadened our analysis to assess the impact of TZDs on the risk for any oral steroid prescription and found similar results, though we could not ascertain the indication for these prescriptions. Despite these limitations, we were able to study a large cohort of asthmatic patients who were taking TZDs and control for a wide variety of potential confounding factors.