Risk of sepsis and pneumonia in patients initiated on SGLT2 inhibitors and DPP-4 inhibitors

Aim: The organ protective effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors may be beneficial against infectious complications.This real-world study aims to compare the risk of pneumonia and sepsis between SGLT2 inhibitors and dipeptidyl peptidase 4 (DPP-4) inhibitors in patients with type 2 diabetes.Methods: Using a territory-wide clinical registry in Hong Kong (Clinical Data Analysis and Reporting System [CDARS]), we included patients initiated on SGLT2 inhibitors or DPP-4 inhibitors between January 01, 2015 and December 31, 2019 through 1:2 propensity score matching.The primary outcomes were incident events of pneumonia, sepsis and the related mortality.Cox proportional hazards analysis was used to compare the risk of incident pneumonia and sepsis for SGLT2 inhibitors versus DPP-4 inhibitors.Results: After propensity score matching, 10,706 new users of SGLT2 inhibitors and 18,281 new users of DPP-4 inhibitors were included.The mean age of all eligible subjects were 60 years (SD 11.07) and 61.1% were male.There were 309 pneumonia events [incidence rate per 1000 person-years (IR) = 11.38]among SGLT2 inhibitors users and 961 events (IR = 20.45)among DPP-4 inhibitors users, with lower risk of pneumonia among SGLT2 inhibitors users (adjusted HR 0.63 [95%CI 0.55-0.72],p<0.001).Similarly, SGLT2 inhibitors users had lower incidence of sepsis [164 (IR=6.00) vs. 610 (IR=12.88)events] as well as associated risk of incident sepsis (HR 0.52 [95% CI 0.44-0.62],p<0.001), compared to DPP-4 inhibitors users.Outcome analyses showed that SGLT2 inhibitors were associated with lower risk of pneumonia-related death (HR 0.41 [95%CI 0.29-0.58],p<0.001), sepsis-related death (HR 0.39 [95%CI 0.18-0.84],p<0.05), and infection-related death (HR 0.43 [95%CI 0.32-0.57],p<0.001), compared to DPP-4 inhibitors users.Results were consistent when stratified by age, sex, pre-existing cardiovascular disease, and type of SGLT2 inhibitors. Conclusion:We provide real-world evidence that irrespective of age, sex, prior-existing cardiovascular disease, or type of SGLT2 inhibitors used, patients with type 2 diabetes initiated on SGLT2 inhibitors have lower incidence of pneumonia and sepsis as well as mortality risk associated with pneumonia, sepsis, and infectious diseases, compared with those initiated on DPP-4 inhibitors.