Treatment with sodium-glucose cotransporter 2 (SGLT2) inhibitors appears to have the added benefit of reducing the incidence of obstructive airway disease (OAD) in Asian patients with type 2 diabetes (T2D), as shown in a study from Hong Kong.
Compared with dipeptidyl peptidase-4 (DPP4) inhibitors, SGLT2 inhibitors conferred a significant protective effect not only against the risk of incident OAD (hazard ratio, 0.65, 95 percent confidence interval [CI], 0.54–0.79; p<0.001) but also that of exacerbations (rate ratio, 0.54, 95 percent CI, 0.36–0.83; p=0.01). [JAMA Netw Open 2023;6:e2251177]
The observed benefit with SGLT2 inhibitors was seen in both male and female patients, without significant difference.
“One interpretation of these results is that rather than SGLT2 inhibitors being protective against OAD, DPP4 inhibitors may be detrimental. However, published studies showed no associations of DPP4 inhibitor use with OAD outcomes,” according to the investigators. [Pragmat Obs Res 2017;8:231-240; Respir Res 2020;21:319]
“More importantly, our results were in agreement with a recent meta-analysis and a network meta-analysis of cardiorenal randomized clinical trials showing that SGLT2 inhibitor use was associated with a lower risk of [adverse] OAD outcomes … compared with placebo or DPP4 inhibitor use,” they added. [J Cardiovasc Pharmacol 2022;79:655-662; Diabetes Res Clin Pract 2022;183:109080]
The study included 5,696 propensity score–matched SGLT2 inhibitor users and 22,784 DPP4 inhibitor users in the cohort of patients without OAD (mean age 61.2 years, 56 percent men; incidence analysis), as well as 381 SGLT2 inhibitor users and 1,524 DPP4 inhibitor users in the cohort of patients with OAD (mean age 62.2 years, 51 percent men; exacerbations analysis).
Potential role in respiratory disease treatment
How SGLT2 inhibitors reduce the risk of OAD and exacerbations may be attributed to the potential anti-inflammatory property of the drug class. Experimental studies have shown that SGLT2 inhibitors could reduce proinflammatory markers in kidney cells and liver cells of mice, as well as increase anti-inflammatory cytokine in patients with T2D. [Am J Physiol Renal Physiol 2014;306:F194-F204; Ann Transl Med 2019;7:429; J Clin Med 2019;8:1814]
More importantly, SGLT2 inhibitors seem to be capable of inhibiting the NLRP3 inflammasome activation in multiple tissues, including the heart, liver, kidney, and lung. 
“To our knowledge, no experimental studies have directly evaluated the association of SGLT2 inhibitor use with OAD; however, NLRP3 inflammasome activation has been implicated in asthmatic airway inflammation and chronic obstructive pulmonary disease (COPD) exacerbations. Therefore, SGLT2 inhibitors may potentially alleviate OAD symptoms through inhibition of the NLRP3 inflammasome,” the investigators pointed out.
All this has clinical implications, they said. Given that T2D is associated with increased risk of OAD and worsened control, the identification of glucose-lowering agents that harbour protective effects against the respiratory condition carries considerable weight.
However, the findings of the study, while encouraging, are not sufficient to inform clinical practice just yet, as the investigators acknowledged.
“The effects of SGLT2 inhibitors on the cardiorenal systems have been studied extensively, while the role of [the drugs] in the respiratory system remains largely unexplored. This study raises the possibility that SGLT2 inhibitors may play an important role in the treatment of chronic respiratory diseases, such as COPD and asthma, and that further investigation is warranted,” they said.


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