Side Effects of Inhaled Glucocorticoids for Asthma Treatment

The Challenge: Current Asthma Treatment Has Chronic Side Effects

Asthma is one of the most prevalent noncommunicable diseases attacking both adults and children. According to the World Health Organization (WHO), an estimated 262 million people were affected by the disease in 2019, while 45,000 died from asthma attacks.¹ In the U.S., about 25 million people suffer from asthma, which is equivalent to 1 person for every 13 U.S. residents.²

Some methods of controlling the disease include anti-inflammatory inhaled glucocorticoids (GCs) and smooth muscle-relaxing bronchodilators. Although GCs have been used as the standard care for asthma, inhaled GCs can affect adrenal storage pathways. Chronic use of high-dose inhaled GCs can cause systemic adverse effects such as hypothalamus-pituitary-adrenal (HPA) axis dysfunction, hyperglycemia, skin thinning, bruising, and perturbed energy metabolism.

While GC effects have been studied using the HPA axis or specific organ systems, not much has been done to classify GC effects at a molecular level, and the differences between GC molecules have not been determined.³ A study was conducted to understand how the dosage of glucocorticoids (GCs) impacts side effects experienced by patients. This study sought to determine the systemic effects of inhaled GCs at a molecular level using metabolomics.

The team evaluated the effects of 3 inhaled GC molecules—fluticasone furoate (FF), fluticasone propionate (FP) and budesonide (BUD)—in randomized, escalating-dose, placebo-controlled, incomplete-block study in patients with mild asthma.

Patients were randomly selected and given 1 or 2 of the 4 treatments (FF, FP, BUD, or placebo) with a washout period of 25 to 42 days. Each of the 4 treatment periods lasted 35 days with 5 successive dose escalations lasting 7 days. Plasma samples were analyzed using the Metabolon Global Discovery Panel.

Metabolon Insight: Metabolomics Reveals Pathways Impacted by Glucocorticoids

Small molecule metabolites play a vital role in understanding biological systems and represent an effective and modern approach to understanding the phenotype of diseases such as asthma, but their low molecular weight structure makes analysis a challenging assignment to accomplish.

The Global Discovery Panel enables the separation, detection, characterization, and relative quantification of such metabolites using our proprietary software and unmatched chemical library of more than 5400 metabolites. Following a rigorous quality control process, such a high-precision dataset provides a comprehensive perspective of the underlying biology which can be interpreted by our expert biochemists to provide powerful, actionable insights.

The Solution: Comprehensive Metabolomics Analysis of Glucocorticoid Effects

Results from the study showed that inhaled GCs induce significant changes in several biochemical pathways only at high and supratherapeutic doses, thus supporting the safety of low- and mid-therapeutic doses. These changes include a reduction in metabolites related to adrenal steroids, anti-inflammatory mediators and precursors, and tricarboxylic acid (TCA) cycle intermediates.

As a means to inform precision medicine approaches, metabolomics analysis made it possible to compare different GC types and dosages, thus potentially guiding future therapy decisions for patients who are sensitive to adrenal disruption.

The Outcome: Precision Medicine in Asthma Treatment

Results from this study illustrate how metabolomics can be employed to elucidate the systemic effects of different asthma medications at the molecular level since metabolites directly reveal the underlying biology of cells.