A systematic review of observational studies of sodium-glucose cotransporter 2 inhibitors and COVID-19 outcomes: a methodological assessment

OBJECTIVES: To conduct a systematic review of observational studies examining the association between sodium-glucose cotransporter 2 (SGLT2) inhibitors and the risk of mortality and of hospitalization compared with the use of other antidiabetic medications in patients with type two diabetes and COVID-19, with a focus on the methodological quality. We also describe how such studies can be improved when addressing a public health emergency. STUDY DESIGN AND SETTING: We conducted a systematic review by searching Embase, MEDLINE, and the WHO COVID-19 research article databases up to March 2025. Observational studies reporting on the risk of mortality and of hospitalization with the use of SGLT2 inhibitors among patients with type two diabetes and COVID-19 were included and study quality was assessed using the ROBINS-I tool. Our systematic review focused on the methodological assessment of the literature. RESULTS: We included 20 cohort studies, with 18 reporting on all-cause mortality and eight on COVID-19-related hospitalization. Five studies reported a decreased risk of all-cause mortality (range of effects estimates: 0.25 to 0.82), compared with nonuse or use of other drugs, and four studies reported a decreased risk of hospitalization (range: 0.79 to 0.92); the others reported no association. Overall, 14 studies were at serious risk of bias and six were at critical risk. We identified several methodological issues related to the selection of participants, inadequate control of confounding, and assessment of exposure and outcomes. No meta-analysis was conducted due to the low quality and heterogeneity of the included studies. CONCLUSIONS: The observational studies examining the effectiveness of SGLT2 inhibitors among patients with type two diabetes and COVID-19 outcomes have important methodological issues that limit the conclusions that can be drawn from this knowledge base. Although public health emergencies require rapid responses, methodological rigor remains essential to generate actionable evidence.