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AIMS: Sodium-glucose co-transporter inhibitors (SGLT2i) are emerging as a new treatment for heart failure (HF) after demonstrating favorable clinical outcomes in several randomized controlled trials (RCTs). In this meta-analysis, we assessed the safety of SGLT2i in the trials that prespecified heart failure in their inclusion criteria. MATERIALS AND METHODS: We searched the databases for RCTs comparing SGLT2i to placebo in heart failure patients. The primary outcome was the incidence of serious adverse events (SAEs). A sensitivity analysis according to the class of HF was also performed. RESULTS: The incidence of SAEs was significantly lower in the SGLT2i group (OR, 0.85; 95% CI, 0.77-0.92; P, 0.0002) and SAEs remained significantly lower after performing the sensitivity analysis (OR, 0.82; 95% CI, 0.75-0.89; P, <0.00001). Genital infections, urinary tract infections (UTIs), and hypotension were significantly higher in the SGLT2i group. CONCLUSIONS: SGLT2i remain a safe option for patients with HF with a lower incidence of SAEs. However, since they increase the risk of genital infection, UTIs and hypotension, the risks vs benefits in each patient should be weighed when making a prescribing decision.