Sodium-glucose cotransporter 2 inhibitors and the risk of pneumonia and septic shock: A systematic review and meta-analysis

Abstract Context Individuals with type 2 diabetes mellitus (DM) have an increased risk of pneumonia and septic shock. Traditional glucose-lowering drugs are recently found to be associated with a higher risk of infections. It remains unclear whether sodium-glucose cotransporter 2 inhibitors (SGLT2i), 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 19 May 2022 for randomised, placebo-controlled trials of SGLT2i which 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 risks (RRs) and 95% confidence intervals (CI) across trials. Results Out of 4,568 citations, 26 trials with a total of 59,264 patients (1.9% developed pneumonia and 0.2% developed septic shock) were included. Compared to placebo, SGLT2i 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, and glycaemic control, duration of DM and trial follow-up showed consistent results without evidence of significant treatment-by-subgroup heterogeneity (all Pheterogeneity > 0.10). Conclusions Among DM patients, SGLT2i reduced the risk of pneumonia and septic shock, compared to placebo. Our findings should be viewed as hypothesis-generating, with concepts requiring validation in future studies. PROSPERO registration ID: CRD42021249264