Background: SodiumÀglucose cotransporter 2 (SGLT2) inhibitors reduce the composite of heart failure (HF) hospitalizations or cardiovascular mortality among patients with HF. However, the efficacy of SGLT2 inhibitors in secondary endpoints of randomized trials and in subgroups of HF patients is not well known. Methods: We performed a systematic review and meta-analysis of placebo-controlled, randomized trials of SGLT2 inhibitors in patients with HF. PubMed, Embase, and Cochrane databases were searched for trials published up to January 21, 2021. Data were extracted from published reports and quality assessment was performed per Cochrane recommendations. Hazard ratios (HRs) with 95% CI were pooled across trials. The primary endpoints of interest were all-cause and cardiovascular mortality. Results: Out of 3969 database results, 15 randomized trials and 20,241 patients were included; 10,594 (52¢3%) received SGLT2 inhibitors. All-cause mortality (HR 0¢86; 95% CI 0¢79À0¢94; p = 0¢0007; I 2 =0%) and cardiovascular mortality (HR 0¢86; 95% CI 0¢78À0¢96; p = 0¢006; I 2 =0%) were significantly lower in patients treated with SGLT2 inhibitors compared with placebo. The composite of cardiovascular mortality, HF hospitalizations, or urgent visits for HF was significantly reduced with SGLT2 inhibitors in all the following subgroups: male, female, age < 65, age 65, race À Black and White, estimated glomerular filtration rate (eGFR) <60, eGFR 60, New York Heart Association (NYHA) class II, NYHA III, and HF with preserved ejection fraction. Interpretation: In patients with HF, SGLT2 inhibitors significantly reduce all-cause and cardiovascular mortality compared with placebo. In addition, the composite of cardiovascular mortality or HF hospitalizations/ urgent visits is reduced with SGLT2 inhibitors across subgroups of sex, age, race, eGFR, HF functional class, and ejection fraction.