Sodium glucose cotransporter 2 inhibitors in the management of heart failure: Veni, Vidi, and Vici

Heart failure (HF) is a chronic disease associated with high morbidity and mortality rates. Renin-angiotensin-aldosterone system blockers (including angiotensin receptor/neprilysin inhibitors), beta-blockers, and mineralocorticoid receptor blockers remain the mainstay of pharmacotherapy for HF with reduced ejection fraction (HFrEF). However, despite the use of guideline-directed medical therapy, the mortality from HFrEF remains high. HF with preserved ejection fraction (HFpEF) comprises approximately half of the total incident HF cases; however, unlike HFrEF, there are no proven therapies for this condition. Sodium glucose cotransporter-2 inhibitors (SGLT-2is) represent a new class of pharmacological agents approved for diabetes mellitus (DM) that inhibit SGLT-2 receptors in the kidney. A serendipitous finding from seminal trials of SGLT-2is in DM was the significant improvement in renal and cardiovascular (CV) outcomes. More importantly, the improvement in HF hospitalization (HHF) in the CV outcomes trials of SGLT-2is was striking. Multiple mechanisms have been proposed for the pleiotropic effects of SGLT-2is beyond their glycemic control. However, as patients with HF were not included in any of these trials, it can be considered as a primary intervention. Subsequently, two landmark studies of SGLT-2is in patients with HFrEF, namely, an empagliflozin outcome trial in patients with chronic HF and a reduced ejection fraction (EMPEROR-Reduced) and dapagliflozin and prevention of adverse outcomes in HF (DAPA-HF), demonstrated significant improvement in HHF and CV mortality regardless of the presence of DM. These impressive results pitchforked these drugs as class I indications in patients with HFrEF across major guidelines. Thereafter, empagliflozin outcome trial in patients with chronic HF with preserved ejection fraction (EMPEROR-Preserved) and dapagliflozin evaluation to improve the lives of patients with preserved ejection fraction HF (DELIVER) trials successively confirmed that SGLT-2is also benefit patients with HFpEF with or without DM. These results represent a watershed as they constitute the first clinically meaningful therapy for HFpEF in the past three decades of evolution of HF management. Emerging positive data for the use of SGLT-2is in acute HF and post-myocardial infarction scenarios have strengthened the pivotal role of these agents in the realm of HF. In a short span of time, these classes of drugs have captivated the entire scenario of HF.