Although it has been postulated that being overweight or obese is associated with a greater degree of clinical and physiologic impairment in patients with asthma, our findings do not support the conclusion that there is a clinically-meaningful effect of elevated body mass on markers of impairment in mild-to-moderate persistent asthmatics. In the longitudinal analyses of clinical course in subjects allocated to the placebo arm of treatment trials ranging between 8 and 48 weeks in duration, there were not substantial differences between BMI categories with regard to change in physiologic, inflammatory or clinical outcomes, suggesting that overweight and obese subjects with mild-to-moderate asthma do not necessarily fare worse over time than their lean counterparts. However, with regard to the relationship between elevated BMI and response to controller therapy regimens, our analyses did demonstrate an approximately 55% reduction in the effectiveness of ICS monotherapy in lowering exhaled nitric oxide in overweight/obese subjects, as well as a reduction of the beneficial effect of ICS/LABA combinations on FEV1 and FEV1/FVC ratio in overweight and obese subjects.
Our findings must be viewed in context, as there has been a substantial amount of discussion in the literature about if and how obesity might modify asthma. First, although a statistically-significant and dose-response effect of elevated BMI on asthma risk was demonstrated in a recent meta-analysis,2
there was heterogeneity of effect among included epidemiologic studies, with reported odds ratios for the impact of being overweight or obese on asthma risk ranging between 1.0 and 3.5, suggesting that prospective validation of this hypothesis in carefully-phenotyped cohorts is warranted to confirm these findings. Although our data cannot shed light on the impact of overweight and obesity on asthma risk, they suggest that, at least in adults with mild and moderate persistent asthma, elevated BMI does not substantially increase asthma-related impairment or airway inflammation. These findings are consistent with findings in different populations (e.g.
both in pediatric subjects and in adults subjects with severe asthma); for example, in the Childhood Asthma Management Program cohort, investigators did not find a correlation between BMI and markers of asthma control, and BMI did not modify eosinophil counts or IgE concentrations. While there was a weak inverse relationship between BMI and bronchodilator reversibility (β = −0.003, p = 0.02), there was no impact of BMI on airway hyperresponsiveness.34
In adults, a recent report from the NHLBI-funded Severe Asthma Research Program35
indicated that in approximately 250 subjects with severe asthma,36
obesity was not more prevalent in severe versus moderate asthma.
Our findings do suggest, however, that the small observed effect of elevated body mass in impairment-related domains may have a biological basis, in that there was evidence of a dose-related increase (albeit small and of questionable clinical significance) in the inverse relationship between BMI and lung function, albuterol use and quality of life, a relationship that has been demonstrated in other studies of the obesity-asthma relationship.2,10
Additionally, being overweight or obese might be associated with reduced efficacy of asthma controller therapies, particularly those regimens that contain inhaled corticosteroids, either alone or in combination with long-acting beta-agonists. While this finding may be an in vivo
manifestation of recent data suggesting that overweight and obesity are associated with reduced response to glucocorticoids in vitro
in subjects with asthma,10
prospective validation of this finding is warranted to determine if glucocorticoid insensitivity underlies the reduced effect of ICS observed in these analyses.
These data must be viewed in light of a number of potential limitations: first, these are post hoc analyses of existing clinical trial data, and in none of the studies was BMI an a priori stratification variable. However, there was a relatively symmetric distribution of BMI across the study population, with slightly more than 50% of the study population being overweight or obese, suggesting that randomization resulted in relatively equal distribution of this variable. Second, the effects observed are small, suggesting that despite the large number of subjects evaluated, adequate power might not have existed to detect small differences. However, the finding of small effects of uncertain clinical impact is, in this scenario, an important observation in that it calls into question the assertion that BMI is an important modifier of asthma severity and response to therapy. Third, these observations were made in mild-to-moderate asthmatics and may not be generalizable to individuals with more severe asthma. However, the finding of a minimal impact of BMI in mild and moderate persistent asthma is important and has potential bearing on the large proportion of the asthma population that falls into these two categories, suggesting that weight loss might not yield significant asthma-related clinical benefits in this population. Fourth, BMI alone is a relatively crude technique for characterizing obesity, and we are unable in this dataset to assess other important obesity-related variables such as body fat distribution or degree of systemic inflammation. Fifth, the absence of a obese, nonasthmatic comparator group limits our ability to determine the extent to which obesity alone impacted the outcomes evaluated; it is possible that the observed differences are attributable not to the interaction of overweight/obesity and asthma, but rather to body weight itself. Finally, overweight and obesity may reflect dietary, environmental, or other important factors that might play a role in modifying biological processes relevant to asthma impairment and response to therapy, and these factors cannot be evaluated in this type of study. Therefore, it is important to recognize these findings as requiring prospective validation.
A major strength of these analyses, however, and one which distinguishes it from other contributions to the literature, is the extent to which clinical status, physiology and airway inflammation have been rigorously characterized in a large sample size. One significant concern surrounding epidemiologic studies, on which many of the aforementioned conclusions have been based, is a limited ability to characterize relevant physiologic and inflammatory variables. This could lead to significant misclassification of obesity-related dyspnea, resulting in erroneous conclusions about the nature of the obesity-asthma relationship. Additionally, the analysis population is representative with regard to sex, age and race and ethnicity, all features which enhance the generalizability of our findings to individuals with mild or moderate asthma. Finally, because comorbid illnesses such as clinically-significant obstructive sleep apnea and gastroesophageal reflux disease (both of which are clearly associated with obesity37,38
and which could also influence asthma control39–41
) are typically exclusionary conditions in these trials, our analysis has the benefit of being able to assess the relationship between elevated BMI and asthma in the absence of these potential confounding comorbidities.
In sum, elevated BMI is not a clinically-significant modifier of impairment in patients with mild-to-moderate asthma, but it is associated with a modest reduction of therapeutic effect of ICS-containing regimens with regard to indices of airway inflammation and lung function. Additional prospective studies are needed to further define relevant mechanisms by which obesity impacts response to therapy in asthma.