GLP-1 receptor agonists, DPP-4 inhibitors and SGLT-2 inhibitors are commonly prescribed antihyperglycaemic drugs, which are known for their favourable cardiovascular effects. However, according to Pradhan et al (2022), emerging research suggests that they may also benefit the respiratory system. There has been interest therefore in exploring whether or not these drugs could benefit the large amount of people who are living with the disabling lung condition, chronic obstructive pulmonary disease (COPD).
The study
A new study published in the British Medical Journal has 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 patients living with COPD and type 2 diabetes (Pradhan et al, 2022). This cohort was chosen as those with type 2 diabetes are at high risk of COPD-related morbidity and mortality (Castañ-Abad et al, 2020).
Pradhan et al (2022) carried out a population based cohort study set in the UK, using data from the UK Clinical Practice Research datalink, which is linked with the Hospital Episode Statistics Admitted Patient Care and Office for National Statistics databases.
The researchers created three active comparator group cohorts. The first cohort involved 1252 patients commencing on GLP-1 receptor agonists and 14 259 starting sulfonylureas, the second cohort involved 8731 patients beginning treatment with DPP-4 inhibitors and 18 204 starting sulfonylureas, and the third cohort included 2956 patients starting SGLT-2 inhibitors and 10 841 starting sulfonylureas. The sulfonylurea cohorts served as a comparator for the group receiving the study drug.
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).
Study findings
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.
Explaining the results
The researchers discussed that there are 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 discuss 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 COPD (Rogliani et al 2019). In shorter trials the researchers note that GLP-1 receptor agonists were observed to help surrogate measures of lung function, such as through improving forced vital capacity. In recent years, COPD has been known as the respiratory manifestation of chronic systemic inflammation, which happens as a result of a vast array of complex underlying risk factors which include smoking, obesity and hypertension (Pradhan et al, 2022). Therefore, 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) discuss that abdominal obesity raises the risk of COPD exacerbations by causing a physical reduction in lung capacity, through pushing the diaphragm against the thorax. GLP-1 receptor agonists may reduce COPD exacerbations as they have been seen to be linked to causing significant weight loss. This in turn reduces pressure on the airways and reduces 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, although to a lesser degree than using the GLP-1 receptor agonists, which are more potent than endogenous GLP-1. The team also discuss that the glucosuric effect SGLT-2 inhibitors is able to cause a reduction of serum concentrations of glucose available for tissue metabolism, which causes a decrease in endogenous carbon dioxide production. Pradhan et al (2022) hypothesise this may be beneficial for patients with chronic obstructive pulmonary disease who have difficulties with getting rid of carbon dioxide from the body. The team also comment that other studies have suggested SGLT-2 inhibitors to be good for those with COPD, having positive effects on COPD outcomes. For example, the team note 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, which in turn could be associated with lower COPD exacerbation risk due to pneumonia being a known causal factor of a COPD exacerbation. 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 showed a reduction in airway hyperresponsiveness by local anti-inflammatory effects, in previous research. Airway hyperresponsiveness is a common feature found in asthma and COPD patients and therefore a patient who has both COPD and asthma, is at increased risk of airway hyperresponsiveness, which thus may potentiate the effects of incretin based drugs in this subpopulation. Therefore, Pradhan et al (2022) think 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.
Limitations
Pradhan et al (2022) observed some limitations that are worth mentioning. One was exposure misclassification, due to the CPRD being a general practice database which does not record prescriptions written by specialists. However, the researchers note that this is unlikely to be an important source of misclassification, as general practice is normally responsible for the management of type 2 diabetes in the UK. The CPRD does not record patients' adherence to the treatment regimens, which again may potentially be a source of exposure misclassification. Using an on-treatment exposure definition whereby patients were followed while continuously exposed to the study drugs was however likely to reduce the impact of this bias. Pradhan et al (2022) also note that some outcome misclassification may have happened, but the definition of severe COPD exacerbation requiring hospital admission has been validated, showing a high specificity.
Conclusions
Overall, the researchers concluded that their large study found that specifically GLP-1 receptor agonists and SGLT-2 inhibitors were associated with a lower risk of severe exacerbations among patients living with type 2 diabetes and COPD compared with sulfonylureas, whereas a risk reduction associated with DPP-4 inhibitor use, if any, was minor. The team commented that 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.