Aims: This study aimed to investigate the association between the use of
sodium-glucose transporter 2 inhibitors (SGLT-2i) and the risk of
diabetic ketoacidosis (DKA), lower limb
amputation (LLA),
urinary tract infections (UTI),
genital tract infections (GTI),
bone fracture, and
hypoglycemia in cohort studies. Methods: A systematic search was conducted in the PubMed and Embase databases to identify cohort studies comparing the safety of SGLT-2i versus other
glucose-lowering drugs (oGLD) in patients with
type 2 diabetes mellitus (T2DM). The quality of the studies was assessed using the Newcastle-Ottawa Scale. Primary endpoints were DKA and LLA, while secondary endpoints included UTI, GTI,
bone fracture, and
hypoglycemia. Hazard ratios (HR) with 95% confidence intervals (CI) were calculated. Results: A total of 9,911,454 patients from 40 cohort studies were included in the analysis. SGLT-2i use was associated with a higher risk of DKA (HR: 1.21, 95% CI: 1.07-1.38, p = 0.003) and GTI (HR: 2.72, 95% CI: 2.48-2.98, p < 0.01). However, it was not associated with an increased risk of LLA (HR: 1.06, 95% CI: 0.92-1.23, p = 0.42), UTI (HR: 0.99, 95% CI: 0.89-1.10, p = 0.83), or
bone fracture (HR: 0.99, 95% CI: 0.94-1.04, p = 0.66). Furthermore, SGLT-2i was associated with a reduced risk of
hypoglycemia. Furthermore, compared to
dipeptidyl peptidase 4 inhibitors, SGLT-2i as a class and individually was associated with an increased risk of DKA.
Canagliflozin specifically increased the risk of LLA (HR: 1.19, 95% CI: 1.04-1.36, p = 0.01). The subgroup analysis suggested that SGLT-2i increased the risk of LLA among patients with a history of
cardiovascular disease. Conclusion: SGLT-2i versus oGLD was associated with a similar occurrence of LLA, UTI, and
bone fracture. However, SGLT-2i was associated with a higher risk of DKA and GTI than oGLD. These findings provide valuable information on the safety profile of SGLT-2i in patients with T2DM and can help inform clinical decision-making.