Add-On SGLT2 Inhibitors: New Era of Diuresis in Acute Heart Failure

Background: Fluid overload is the primary reason for hospitalization of patients with acute heart failure (AHF). Intravenous loop diuretics (LD) remain the mainstay of therapy in this setting, with a significant subset of patients showing suboptimal response. The efficacy of combination diuretic therapy, a widely applied strategy to counter renal sodium avidity, is compared against LD-based regimens that are considered the standard of care. We sought to explore the impact of adding a sodium-glucose cotransporter-2 (SGLT2) inhibitor to LD in contemporary trials of AHF. Methods: The PubMed database was searched for articles cited therein using the keywords “acute heart failure”, “diuretic”, and “SGLT2 inhibitor”. Available data from clinical trials performed between January 2015 and March 2025 were included. The studies were selected if 1) they were randomized controlled trials that explored the role of SGLT2 inhibitors in the management of AHF and 2) included LD as their control arm. Pertinent data on clinical and laboratory parameters (e.g., diuresis, weight change, and renal function) were extracted and reviewed. Results: A total of 11 studies with 8,900 participants were included, with a mean age of 71 years. They consisted of a variety of HF populations with a mean ejection fraction of 39% and an estimated GFR of 53 ml/min. The add-on agents were Dapagliflozin (6 trials), Empagliflozin (4 trials), and Sotagliflozin (1 trial). While there was substantial variation across studies in reporting decongestion markers (e.g., diuresis and weight change), adding SGLT2 inhibitors was generally associated with significantly greater weight loss and diuresis. Incidence of acute kidney injury (AKI) was reported from 0 to 34.4% (mean 14.9%) in the LD arm and from 2.5% to 20% in the intervention arm (mean 9.7%). Conclusion: While the current guidelines of AHF recommend intensifying LD therapy prior to adding a second agent to enhance the decongestion process, there is no consensus on an optimal diuretic strategy. This study shows that 1) there is significant inconsistency in reporting of the decongestion markers and their timing in the studies of AHF, 2) while adding SGLT2 inhibitors to LD seems to be an intriguing option, a reliable comparison of their efficacy is challenging, and 3) these agents do not seem to increase the rate of AKI despite efficient decongestion in AHF.