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

Hang-Long Li; Yi-Kei Tse; Chanchal Chandramouli; Nicole Wing-Lam Hon; Ching-Lung Cheung; Lok-Yee Lam; Meizhen Wu; Jia-Yi Huang; Si-Yeung Yu; Ka-Lam Leung; Yue Fei; Qi Feng; Qingwen Ren; Bernard M. Y. Cheung; Hung-Fat Tse; Subodh Verma; Carolyn S. P. Lam; Kai-Hang Yiu


J Clin Endocrinol Metab. 2022;107(12):3442-3451. 

In This Article

Abstract and Introduction


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 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.


The increasing prevalence of type 2 diabetes mellitus (DM) poses a significant public health burden worldwide.[1] Patients with diabetes have an increased risk of pneumonia: in the United States, the overall incidence rate of pneumonia in 2014 was 1.78-fold higher in patients with diabetes than in individuals without diabetes (34 vs 19 per 1000 person-years).[2] Among patients admitted for pneumonia, those with pre-existing DM or acute hyperglycemia had approximately 80% higher risk of mortality than normoglycaemic individuals,[3–6] particularly so in the presence of septic shock.[7] Paradoxically, glucose lowering using conventional anti-DM drugs, including metformin,[8] dipeptidyl peptidase-4 inhibitor,[9] and combination therapy of metformin plus thiazolidinediones,[10] did not lower the risk of pneumonia, and might in fact be associated with higher risk of pneumonia.[8–10] Moreover, in patients with DM complicated with sepsis and pneumonia, metformin use was associated higher sepsis severity.[11] This suggests that glucose lowering per se may not address the excess risk of pneumonia in patients with diabetes.

In recent years, sodium-glucose cotransporter 2 inhibitors (SGLT2is) have emerged as anti-DM drugs with key cardiorenal benefits beyond glucose lowering.[12–16] SGLT2is exert pleiotropic and anti-inflammatory effects[17]—both with plausible benefits in patients with pneumonia. Findings from individual cardiovascular outcome trials on SGLT2is reporting pneumonia or septic shock as secondary outcomes are inconsistent.[12,18] Compared with placebo, the incidence of pneumonia appeared to be lower with empagliflozin and higher with ertugliflozin in the Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients Removing Excess Glucose (EMPA-REG OUTCOME)[12] and Ertugliflozin Treatment in Type 2 Diabetes Mellitus Participants With Vascular Disease (VERTIS-CV)[19] trials, respectively. Preliminary findings from "off-label" SGLT2i usage in subjects infected with severe or critical severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia suggest benefits in subjects with diabetes,[20] and no effects in subjects without diabetes.[21] These may be attributed to the more pronounced anti-inflammatory effects in the context of hyperglycemia, where inflammation is more severe (evidenced by the higher levels of interleukin-6, C-reactive protein, and erythrocyte sedimentation rate) than in the normoglycemic state.[22–24] We performed a systematic review and meta-analysis of randomized controlled trials to comprehensively evaluate whether SGLT2is reduce the risk of pneumonia and septic shock in patients with DM.