Drugs known for their favourable cardiovascular effects may also benefit the respiratory system. There has been interest in exploring whether such treatments could therefore provide relief for the estimated 1.2 million people living across the UK with chronic obstructive pulmonary disease (COPD)—a disabling lung condition.
Commonly prescribed antihyperglycaemic drugs
Pradhan et al (2022) examined whether the use of the receptor agonist glucagon-like peptide 1 (GLP-1), dipeptidyl peptidase 4 (DPP-4) inhibitors, and sodium-glucose co-transporter-2 (SGLT-2) inhibitors, separately, are associated with a lower risk of COPD exacerbations among a patient cohort with COPD and type 2 diabetes.
The researchers assessed factors such as whether each drug was linked with, for example, a decreased risk of developing a moderate exacerbation (the researchers defined this as a co-prescription of an oral corticosteroid and an antibiotic, along with an outpatient diagnosis of acute COPD exacerbation that same day). The results showed that when compared with sulfonylureas, GLP-1 receptor agonists were found to be associated with a 30% reduced risk of a severe exacerbation (3.5 v 5.0 events per 100 person years) and moderate exacerbation. DPP-4 inhibitors were also observed to be associated with a modestly decreased incidence of severe exacerbation (4.6 v 5.1 events per 100 person years) and moderate exacerbation. The team also observed that SGLT-2 inhibitors were associated with a 38% lower risk of severe exacerbation (2.4 v 3.9 events per 100 person years), but these were not seen to have any effect on the risk of developing moderate exacerbation.
The team discussed several ways that the risk of COPD exacerbation could have been decreased with GLP-1 receptor agonists. This drug can reduce local inflammation and airway hyperresponsiveness in murine models, as shown by previous research (Rogliani et al, 2019). Pradhan et al (2022) also discussed that other studies have shown this same effect but in isolated human airways, and this effect was also observed in patients with type 2 diabetes and chronic obstructive pulmonary disease (Rogliani et al, 2019). In shorter trials, the researchers noted that GLP-1 receptor agonists were observed to help surrogate measures of lung function, such as by improving forced vital capacity. COPD has been known in recent years as the respiratory manifestation of a chronic systemic inflammation, which occurs as a result of a vast array of complex underlying risk factors—including smoking, obesity and hypertension (Pradhan et al, 2022). It is seen as a disease that manifests from inflammation on a system-wide basis, surpassing the respiratory system alone.
GLP-1 receptor agonists have been observed to have systemic anti-inflammatory effects. Pradhan et al (2022) discussed that abdominal obesity raises the risk of COPD exacerbations by causing a physical reduction in lung capacity by pushing the diaphragm against the thorax. GLP-1 receptor agonists may reduce COPD exacerbations as they have been linked to causing significant weight loss. This, in turn, reduces pressure on the airways and inflammation at the same time.
Any small effect of DPP-4 inhibitors may be due to the raised concentration of endogenous GLP-1, which in turn may produce a local and systemic anti-inflammatory effect. However, these effects may be to a lesser degree than using the GLP-1 receptor agonists, which are more potent than endogenous GLP-1. The team also discussed that the glucosuric effect SGLT-2 inhibitors are able to cause a reduction of glucose serum concentrations available for tissue metabolism that cause a decrease in endogenous carbon dioxide production. Pradhan et al (2022) hypothesised that this may be beneficial for patients with COPD who have difficulties getting rid of carbon dioxide from the body. The team also commented that other studies have suggested SGLT-2 inhibitors are good for those with COPD, having positive effects on COPD outcomes. For example, the team noted a large study that observed SGLT-2 inhibitors to be associated with a trend of a reduced risk of new onset COPD. Other studies found this drug to be linked to a lessened incidence of pneumonia (a causal factor of COPD exacerbation), which in turn could be associated with lower COPD exacerbation risk. The way that the drug can prevent severe but not moderate exacerbations would require further research.
Pradhan et al (2022) were intrigued that the findings show GLP-1 receptor agonists and DPP-4 inhibitors to be associated with a lower risk of severe COPD exacerbations among patients who had asthma, yet not among those without a history of asthma. The lab analyses found benefits of an up-regulated GLP-1 pathway in airway diseases, which, in previous research, have shown a reduction in airway hyperresponsiveness by local anti-inflammatory effects. Airway hyperresponsiveness is a common feature found in asthma and COPD patients and therefore, a patient who has both is at an increased risk of airway hyperresponsiveness, which may potentiate the effects of incretin-based drugs in this subpopulation. Therefore, Pradhan et al (2022) believe they have uncovered a role of GLP-1 receptor agonists and DPP-4 inhibitors in the asthma-COPD overlap syndrome, a major phenotype of the older generation living with COPD. Further RCTs would be required to measure the efficacy of the use of GLP-1 receptor agonists and SGLT-2 inhibitors as a therapeutic option in patients with type 2 diabetes and COPD.