A pilot randomized controlled trial of pioglitazone for the treatment of poorly controlled asthma in obesity

Abstract

BackgroundObese asthmatics tend to have poorly controlled asthma, and resistance to standard asthma controller medications. The purpose of this study was to determine the efficacy of pioglitazone, an anti-diabetic medication which can alter circulating adipokines and have direct effects on asthmatic inflammation, in the treatment of asthma in obesity.MethodsA two-center, 12-week, randomized, placebo-controlled, double-blinded trial. Treatments were randomly assigned with concealment of allocation. The primary outcome was difference in change in airway reactivity between participants assigned to pioglitazone versus placebo at 12 weeks.ResultsTwenty-three participants were randomized to treatment, 19 completed the study. Median airway reactivity, measured by PC20 to methacholine was 1.99 (IQR 3.08) and 1.60 (5.91) mg/ml in placebo and pioglitazone group at baseline, and 2.37 (15.22) and 5.08 (7.42) mg/ml after 12 weeks, p = 0.38. There was no difference in exhaled nitric oxide, asthma control or lung function between treatment groups over the 12 week trial. Participants assigned to pioglitazone gained a significant amount more weight than those assigned to placebo (pioglitazone group mean weight 113.6, CI 94.5-132.7 kg at randomization and 115.9, CI 96.9-135.1 at 12 weeks; placebo mean weight 127.5, CI 108.4 – 146.6 kg at randomization and 124.5, CI 105.4 – 143.6 kg at 12 weeks; p = 0.04).ConclusionsThis pilot study suggests limited efficacy for pioglitazone in the treatment of poorly controlled asthma in obesity, and also the potential for harm, given the weight gain in those assigned to active treatment, and the association between increased weight and worse outcomes in asthma.Trial RegistrationClinicaltrials.gov (NCT00634036)

Haem oxygenase‐1 up‐regulation by rosiglitazone via ROS‐dependent Nrf2‐antioxidant response elements axis or PPARγ attenuates LPS‐mediated lung inflammation

“…Treatment with rosiglitazone at 2-4 weeks was associated with a modest improvement in pre-bronchodilator FEV 1 (forced expiratory volume in 1 s), peak expiratory flow and FEF (forced expiratory flow between 25 and 75% of the forced vital capacity) of asthmatic reaction (Spears et al, 2009;Richards et al, 2010). Compared with rosiglitazone, administration of pioglitazone in mild asthma failed to improve any markers of airway inflammation, although it produced significant weight gains in asthmatic who were obese (Dixon et al, 2015;Anderson et al, 2016). Rosiglitazone has been reported to be associated with an increased risk of congestive heart failure, acute myocardial infarction and mortality in the patients during treatment for Type 2 diabetes.…”

Obesity and severe asthma

“…However, a randomized controlled trial of treatment with another type 2 diabetes therapeutic, pioglitazone, indicated little benefit in obese asthmatics. Moreover, pioglitazone treatment caused additional weight gain in these patients (74). …”

Mechanisms of Asthma in Obesity. Pleiotropic Aspects of Obesity Produce Distinct Asthma Phenotypes

“…Leptin, an adipokine increased in obesity, can also affect the parasympathetic regulation of airway tone (27). It is difficult at this time to understand the clinical significance of these observations relating to insulin resistance and cholinergic signaling, because studies of antidiabetic medication in obese mice (28) and humans (29) have not shown efficacy in the treatment of obesity-associated asthma, and a retrospective subgroup analysis of obese patients with asthma found that body mass index (BMI) did not predict response to the anticholinergic medication tiotropium (30). Clinical studies to date have not specifically targeted the late-onset asthma of obesity.…”