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.

Keywords: SGLT-2 inhibitors; acute heart failure; cardiovascular disease; mechanism; outcome; type 2 diabetes mellitus.

Figure 1

Effects of SGLT-2 inhibitors on the cardio–renal axis with potential benefit in acute HF.

Figure 2

(a) Effect of SGLT-2 inhibitors compared to control on the risk for all-cause death: pooled analysis of eligible RCTs. (b) Effect of SGLT-2 inhibitors compared to control on the risk for all-cause death: pooled analysis of eligible RCTs, after exclusion of SOLOIST-WHF trial.

Figure 2

(a) Effect of SGLT-2 inhibitors compared to control on the risk for all-cause death: pooled analysis of eligible RCTs. (b) Effect of SGLT-2 inhibitors compared to control on the risk for all-cause death: pooled analysis of eligible RCTs, after exclusion of SOLOIST-WHF trial.

Figure 3

(a) Effect of SGLT-2 inhibitors compared to control on the risk for worsening HF: pooled analysis of eligible RCTs. (b) Effect of SGLT-2 inhibitors compared to control on the risk for worsening HF: pooled analysis of eligible RCTs, after exclusion of SOLOIST-WHF trial.

Figure 4

Effect of SGLT-2 inhibitors compared to control on the risk for all-cause death: pooled analysis of eligible observational studies.

Figure 5

Effect of SGLT-2 inhibitors compared to control on the risk for worsening HF: pooled analysis of eligible observational studies.

Figure 6

Effect of SGLT-2 inhibitors compared to control on the risk for urinary tract infections.

Figure 7

Effect of SGLT-2 inhibitors compared to control on the risk for diabetic ketoacidosis.

Figure 8

Effect of SGLT-2 inhibitors compared to control on the risk for acute kidney injury or worsening renal function.