Sodium-glucose co-transporter 2 (SGLT2) receptors are primarily located in the proximal convoluted tubule of the nephron. These receptors are responsible for almost 90% to 95% of tubular reabsorption of the glucose in the nephron. In patients with diabetes mellitus, due to upregulation of SGLT2 receptors, glucose reabsorption is further increased. The Food and Drug Administration approved SGLT2 inhibitors, such as canagliflozin, empagliflozin, dapagliflozin, and ertugliflozin, for the treatment of type 2 diabetes. In addition to their positive effect on blood glucose, additional cardioprotective and renoprotective functions have been demonstrated in major trials such as EMPA-REG OUTCOME, CANVAS, DECLARE-TIMI-58, and CREDENCE. Unlike other antihyperglycemic drugs, reduction in hospitalization for heart failure (HF) was also seen as a class effect with this group, mechanisms of which are probably multifactorial. Subgroup analysis from these major trials indicated a reduction in progression of nephropathy and HF readmission with SGLT2 inhibitors. Although this unique property of canaglifiozin was further analyzed in the CREDENCE trial, similar trials for empagliflozin (EMPERIAL-Reduced and EMPERIAL-Preserved) and dapaglitiozin (DAPA-HF) are currently underway. Recently released phase HI results from DAPA-HF trial indicate that dapaglifiozin shows significant reduction in death due to cardiovascular causes and hospitalization in HF compared with the placebo, in both diabetics and nondiabetics. In this review article, the authors attempt to explore the possible underlying molecular mechanisms and data from existing trials pertaining to the HF related outcomes associated with SGLT2 inhibitors. (C) 2019 Elsevier Inc. All rights reserved.