Sodium-Glucose Cotransporter 2 Inhibitors and the Risk of Pneumonia and Septic Shock

CONTEXT: Individuals with type 2 diabetes mellitus (DM) have an increased risk of pneumonia and septic shock. Traditional glucose-lowering drugs have recently been found to be associated with a higher risk of infections. It remains unclear whether sodium-glucose cotransporter 2 inhibitors (SGLT2is), which have pleiotropic/anti-inflammatory effects, may reduce the risk of pneumonia and septic shock in DM. METHODS: MEDLINE, Embase, and ClinicalTrials.gov were searched from inception up to May 19, 2022, for randomized, placebo-controlled trials of SGLT2i that included patients with DM and reported outcomes of interest (pneumonia and/or septic shock). Study selection, data extraction, and quality assessment (using the Cochrane Risk of Bias Assessment Tool) were conducted by independent authors. A fixed-effects model was used to pool the relative risk (RRs) and 95% CI across trials. RESULTS: Out of 4568 citations, 26 trials with a total of 59 264 patients (1.9% developed pneumonia and 0.2% developed septic shock) were included. Compared with placebo, SGLT2is significantly reduced the risk of pneumonia (pooled RR 0.87, 95% CI 0.78-0.98) and septic shock (pooled RR 0.65, 95% CI 0.44-0.95). There was no significant heterogeneity of effect size among trials. Subgroup analyses according to the type of SGLT2i used, baseline comorbidities, glycemic control, duration of DM, and trial follow-up showed consistent results without evidence of significant treatment-by-subgroup heterogeneity (all P(heterogeneity) > .10). CONCLUSION: Among DM patients, SGLT2is reduced the risk of pneumonia and septic shock compared with placebo. Our findings should be viewed as hypothesis generating, with concepts requiring validation in future studies.