The Therapeutic Role of SGLT-2 Inhibitors in Acute Heart Failure: From Pathophysiologic Mechanisms to Clinical Evidence with Pooled Analysis of Relevant Studies across Safety and Efficacy Endpoints of Interest

Abstract

(1) Background: Sodium-glucose co-transporter-2 (SGLT-2) inhibitors constitute a novel drug class with remarkable cardiovascular benefits for patients with chronic heart failure (HF). Recently, this class has been utilized in acute HF as an additional treatment option to classic diuretics, which remain the cornerstone of treatment. (2) Methods: We attempted to identify those pathophysiologic mechanisms targeted by SGLT-2 inhibitors, which could be of benefit to patients with acute HF. We then conducted a comprehensive review of the literature within the PubMed database in order to identify relevant studies, both randomized controlled trials (RCTs) and observational studies, assessing the safety and efficacy of SGLT-2 inhibitors in acute HF. (3) Results: SGLT-2 inhibitors induce significant osmotic diuresis and natriuresis, decrease interstitial fluid volume and blood pressure, improve left ventricular (LV) function, ameliorate LV remodeling and prevent atrial arrhythmia occurrence, mechanisms that seem to be beneficial in acute HF. However, currently available studies, including six RCTs and two real-world studies, provide conflicting results concerning the true efficacy of SGLT-2 inhibitors, including “hard” surrogate endpoints. (4) Conclusions: Current evidence appears insufficient to substantiate the use of SGLT-2 inhibitors in acute HF. Further trials are required to shed more light on this issue.

The Prognostic Role of Spot Urinary Sodium and Chloride in a Cohort of Hospitalized Advanced Heart Failure Patients: A Pilot Study

“…Sodium–glucose co-transporter-2 inhibitors (SGLT-2) inhibitors, a novel drug class, inhibit the SGLT-2 receptors predominantly expressed in the proximal tubule of the nephron; thus, they induce glycosuria and natriuresis and have been shown to reduce the combined endpoint of all-cause mortality and HF rehospitalization in chronic HF patients irrespective of the LVEF [ 32 , 33 , 34 , 35 , 36 ]. However, recent studies revealed that these drugs might also be beneficial in hospitalized HF patients.…”

“…Furthermore, the randomized EMPULSE demonstrated that more patients treated with empagliflozin had a clinical benefit compared with placebo (stratified win ratio, 1.36; p = 0.0054), meeting the primary endpoint (a hierarchical composite of all-cause death, number of HF events and time to first HF event, or a 5 point or greater difference in change from baseline in the Kansas City Cardiomyopathy Questionnaire Total Symptom Score at 90 days) [ 38 ]. Nevertheless, an interesting recent meta-analysis of two observational and six randomized studies reported conflicting results concerning the true efficacy of SGLT-2 inhibitors in acute HF patients, including “hard” surrogate endpoints [ 32 ]. Whether the UNa + can be used as a prognostic marker and its potential cut-off values in patients already receiving SGLT-2 inhibitors needs to be investigated in future studies.…”

The Role of Sodium-Glucose Co-Transporter-2 Inhibitors on Diuretic Resistance in Heart Failure

“…SGLT-2 inhibitors exhibit substantial efficacy in HF and have demonstrated clear cardioprotective and renoprotective effects. Nonetheless, the exact underlying pathophysiologic mechanisms resulting in their therapeutic benefits remain incompletely understood [ 67 ]. Further research is needed in this field [ 68 ].…”

The Role of Sodium-Glucose Cotransporter-2 Inhibitors in Heart Failure Management: The Continuing Challenge of Clinical Outcome Endpoints in Heart Failure Trials

“…The application of SGLT2 inhibitors in the treatment of acute heart failure was outside the focus of this review. A recent review concluded that currently available studies including six randomized trials and two real-world studies provide conflicting results concerning the true efficacy of SGLT 2 inhibitors in the setting of acute heart failure [152]. Interestingly, the win ratio was used to evaluate the impact of empagliflozin on the primary composite endpoint in the EMPULSE (Empagliflozin in Patients Hospitalized With Acute Heart Failure Who Have Been Stabilized) acute heart failure trial [153].…”