UCSF researchers led a study that found insulin resistance (IR) is common in patients with severe asthma and is associated with lung function impairment and suboptimal responses to asthma medications. These findings suggest that reducing IR may improve lung function in this patient population.
“Therapies that target insulin resistance and metabolic dysfunction may improve lung function in the subset of patients that are not responsive to current medications,” said lead author Michael Peters, MD, assistant professor of medicine in the Division of Pulmonary and Critical Care Medicine and the Department of Medicine at UCSF.
Findings from the Severe Asthma Research Program
The researchers performed metabolic phenotyping on 307 participants enrolled in the Severe Asthma Research Program 3 (SARP-3), which is a five-year longitudinal cohort study. UCSF is one of the leading academic medical centers participating in this program. The metabolic phenotyping incorporated measures of obesity and obesity-related metabolic dysfunction, including the homeostatic model assessment of insulin resistance (HOMA-IR). This method estimates steady-state beta-cell function and insulin sensitivity by multiplying the fasting plasma glucose (mg/dl) value by the serum insulin (mIU/ml) value, divided by 405.
HOMA-IR was categorized as without (<3.0), moderate (3.0–5.0) or severe (>5.0) IR. The team assessed the association between HOMA-IR and cross-sectional measures of lung function, lung function responses to beta-adrenergic agonists and intramuscular triamcinolone (TA), as well as annualized declines in lung function.
Among study participants, 55% were obese and 46% had IR. Compared with patients without IR, those with IR had significantly lower values for forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC). These lower values were not attributable to obesity effects.
“The standard thinking in pulmonary medicine has been that obesity impacts lung physiology,” Peters said. “But our study found that lung function decline occurs independent of obesity and is specific to insulin resistance itself.”
Compared with patients without IR, those with IR had lower FEV1 responses to beta-adrenergic agonists and intramuscular TA. The annualized decline in FEV1 in patients with IR was approximately 25–30 ml per year greater than in those without IR.
“The patients’ lung function declined at a rapid pace—almost twice that of patients who didn’t have insulin resistance,” Peters said.
The researchers concluded that IR is common in patients with severe asthma and is associated with decreased lung function, blunted responses to beta-adrenergic agonists and intramuscular TA, and that increases in the rate of lung function decline over time.
“Insulin resistance is underappreciated and overrepresented in this population,” Peters said. “Around 50% of the patients had insulin resistance, which is a much higher number than would be expected in the general population.”
A different disease process
In addition, the researchers found that the participants with IR had a low sputum eosinophil percentage, which is a marker of airway type 2 inflammation and has been used to predict responses to beta-adrenergic agonists and TA. The relative absence of type 2 inflammation in patients with IR makes it unlikely that they will be good candidates for therapeutic proteins that target the type 2 pathway. These findings provide a rationale to investigate whether treatments for IR can prevent accelerated loss of lung function in patients with severe asthma.
“The disease process is different,” Peters said. “The cause or causes of their asthma are not the same as those for which current drugs were developed. We need to understand what those causes are.”
Investigating precision medicine for asthma
For decades, UCSF has been a leader in the care and research of asthma-related airway disease. UCSF research led to the development of the asthma medications available today. “Our next step is discovering how to treat patients who don’t respond to current therapies,” Peters said.
Clinical trials are underway at the UCSF Airway Clinical Research Center, including:
Impact of Metabolic Dysfunction and Mucus Plugging on Asthma Physiology, which is a single-center study of 80 participants with asthma.
The PrecISE (Precision Interventions for Severe and/or Exacerbation-Prone Asthma) Network Study, sponsored by the U.S. National Heart, Lung, and Blood Institute (NHLBI), which is designed to evaluate precision medicine approaches to treat different types of severe asthma.
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