The optimal time of initiation of SGLT2 inhibitors in the treatment of AHF is crucial but widely discussed. In the clinical trials investigating the use of SGLT2 inhibitors in patients with HF, these drugs were initiated in stable patients with chronic HF. However, there is a growing interest in using SGLT2 inhibitors in the setting of AHF. Consequently, the benefit of SGLT2 inhibitors in patients with AHF has been evaluated in the EMPagliflozin in patients hospitalized with acUte heart faiLure who have been StabilizEd (EMPULSE) trial [8]. This randomized, double-blind, placebo-controlled trial included 530 patients with AHF irrespective of their left ventricular function. In this trial, 10 mg empagliflozin showed a clinical benefit compared to placebo at 90 days for the hierarchical composite endpoint of all-cause death, HF events (HF hospitalization, urgent HF visits, unscheduled HF-related outpatient visits), time to first HF event, and change in baseline Kansas City Cardiomyopathy Questionnaire Total Symptom Score (KCCQ-TSS) (≥ 5 point difference) [8,9,10]. The empagliflozin group demonstrated a clinical benefit rate of 53.9%, whereas the placebo group displayed a rate of 39.7% (p = 0.0054). This translated into notable reductions in mortality (4.2% vs. 8.3%), heart failure events (10.6% vs. 14.7%), and a more pronounced change in KCCQ-TSS from baseline to a 90-day mean of 36.19 vs. 31.73, when compared to the placebo arm [9]. Hence, empagliflozin has also improved symptoms and quality of life measures in patients with AHF. The safety profile of SGLT2 inhibitors in patients with AHF appears to be favorable, with no incident of ketoacidosis and no increase in the risk of adverse renal events [8]. Moreover, acute renal failure was less prominent in the empagliflozin group (7.7% vs. 12.1%), along with fewer rates of urinary tract infections (4.2% vs. 6.4%). These findings suggest that there is clearly a role for early initiation of SGLT2 inhibitors in patients with AHF [8].

SGLT2 inhibitors mediate pleiotropic effects, particularly diuresis and natriuresis, and the reduction of oxidative stress may be relevant in AHF [7]. The SGLT2 inhibitor-related natriuresis in the proximal tubules, in conjunction with not reabsorbed intratubular glucose, may provide considerably improved diuretic volume and earlier decongestion. These effects may be particularly beneficial in the setting of AHF, where rapid removal of excess fluid and reduction of congestion are critical. In this context, during the 90-day follow-up period of EMPULSE, patients treated with empagliflozin demonstrated a notably greater and persistent reduction in congestion (adjusted mean difference of − 1.53 kg, p = 0.0137) [8]. This likely represents the causal connection between a lower occurrence of HF events observed in the treatment group, with 26 events compared to 52 [8].

Additionally, evidence from the Effect of Sotagliflozin on Cardiovascular Events in Patients with Type 2 Diabetes Post Worsening Heart Failure (SOLOIST WHF) trial also suggests the benefit of early therapy initiation [11]. This randomized controlled trial demonstrated that sotagliflozin, a dual SGLT1 and 2 inhibitor, led to a significant decrease in the primary endpoint of cardiovascular death, hospitalizations for HF, and urgent visits for HF (HR 0.67, p < 0.001) when administered either at the time of patient discharge or within 3 days following discharge [11]. However, the risk reduction was mainly driven by hospitalizations for HF and urgent visits for HF (0.64, p < 0.001), since mortality rates did only slightly differ between the groups (10.6% sotagliflozin vs. 12.5 placebo, p = 0.36) [11]. This effect was observed, regardless of the patients’ ejection fraction. Furthermore, the treatment arm demonstrated a notable improvement in quality of life as measured by the mean change in KCCQ-12 score at month 4, with scores favoring the treatment group (17.7 vs. 13.6). It may be hypothesized that only the SGLT2 component of the drug contributed to better decongestion since SGLT1 is mainly expressed within the gastrointestinal tract and inhibition of it results in reduced postprandial glucose levels [11].

Thus, SGLT2 inhibitors have emerged as a promising class of drugs in the treatment of AHF, since these drugs have shown to improve cardiovascular outcomes, reduce HF hospitalizations, and improve symptoms and quality of life measures in patients with AHF.