Acute heart failure (AHF) is a clinical syndrome characterized by a sudden onset or exacerbation of left ventricular dysfunction, leading to decreased myocardial contractility and increased cardiac load, resulting in a rapid decline in acute cardiac output [1]. Globally, the prevalence of heart failure (HF) continues to rise and has become one of the most common causes of hospitalization in individuals aged 65 and older. Despite modern treatment options, the in-hospital mortality rate for AHF patients remains at 8–10%, with a 30-day readmission rate reaching 25%, thus posing a significant public health burden [2]. Therefore, recent research has focused on multi-target drugs that can effectively improve prognosis. Sodium-glucose co-transporter 2 inhibitors (SGLT2i) are a novel class of oral hypoglycemic agents that primarily target the SGLT2 receptors in the renal proximal tubules, inhibiting glucose reabsorption [3]. Recent clinical randomized trials have demonstrated that SGLT2i have beneficial effects in cardiovascular and renal diseases, and this effect extends to non-diabetic populations. The 2023 European Society of Cardiology (ESC) guidelines included SGLT2i as one of the four cornerstone therapies for heart failure with reduced ejection fraction (HFrEF (Heart Failure with Reduced Ejection Fraction), left ventricular ejection fraction (LVEF) $\le$40%), alongside angiotensin receptor–neprilysin inhibitor (ARNI)/angiotensin-converting enzyme inhibitors (ACEI), $\beta$-blockers, and mineralocorticoid receptor antagonists (MRA), forming the “new quadruple therapy”. Furthermore, SGLT2i is the only drug currently proven to have prognostic benefits in heart failure with preserved ejection fraction (HFpEF) [4]. Some researchers have shifted the focus of SGLT2i to AHF, although the timing of its application and its corresponding clinical benefits remain controversial. Existing meta-analyses have not provided a comprehensive analysis of clinical benefits at different time points, nor a detailed evaluation of drug safety [5]. Therefore, this study includes 22 studies to investigate the safety and clinical benefits of early SGLT2i application in AHF patients, aiming to provide new insights and evidence-based medicine for the use of SGLT2i in AHF.

This study was designed and conducted under the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines for the systematic evaluation and Meta-analysis.

This may be the largest meta-analysis and systematic review to date in terms of the number of studies included and sample size. It comprehensively explores and demonstrates that the early use of SGLT2i in-hospital can safely and effectively reduce the incidence of composite events, such as all-cause mortality and cardiogenic rehospitalization, both in the short term and within 1 year, in patients with acute heart failure (AHF). This suggests potential benefits in improving patient prognosis.

Initially, SGLT2i were introduced as a treatment for diabetes. However, with the emergence of numerous randomized controlled trials and evidence from evidence-based medicine, the clinical indications for SGLT2i have expanded to include non-diabetic populations and other diseases. The DELIVER study highlighted that SGLT2i significantly reduced the risk of major composite outcomes in patients with chronic heart failure (HF), including 18% of those with HF with improved ejection fraction (HFimpEF) [HR 0.74, 95% CI (0.41–0.96)], and reduced the risk of the first heart failure worsening event by 22% [HR 0.78, 95% CI (0.61–1.14)] [29]. Following this, some researchers hypothesized that SGLT2i might also provide clinical benefits in AHF. The EMPULSE study was the first to confirm this hypothesis, showing that, compared to placebo, administration of dapagliflozin 10 mg within 3 days of hospitalization for newly diagnosed AHF significantly improved 90-day clinical outcomes in AHF patients (stratified win ratio: 1.36; 95% CI: 1.09–1.68; p = 0.0054), including improvements in the Kansas City Cardiomyopathy Questionnaire (KCCQ) total symptom score, time to all-cause mortality, or first heart failure event [24]. However, the DAPA-RESPONSE-AHF study pointed out that within 24 hours of hospitalization, randomization to dapagliflozin reduced rehospitalization within 30 days after discharge, but had no impact on the incidence of heart failure worsening or mortality during hospitalization [20]. Additionally, potential adverse effects of SGLT2 inhibitors may also affect the safety of AHF patients. Due to the complex physiological status of patients in the acute phase, common side effects such as hypoglycemia, dehydration, and further renal function impairment may pose a greater risk to these patients [30]. A study by Voors AA et al. [31] noted that SGLT2 inhibitors may cause early renal impairment in AHF patients, though this damage was no longer significant after 90 days, with similar rates of acute kidney events between groups. However, this has led to concerns regarding the early use of SGLT2 inhibitors in AHF patients. Therefore, SGLT2 inhibitors still require more evidence from randomized controlled trials and further evidence-based studies.

A meta-analysis conducted by Carvalho PEP et al. [32] summarized the treatment effects of SGLT2i within 30 days of acute AHF onset. It found that compared to traditional treatment groups, SGLT2i reduced all-cause mortality (OR: 0.75; 95% CI 0.56–0.99; p = 0.049), heart failure (HF) readmission (OR: 0.54; 95% CI 0.44–0.66; p 0.001), and the composite of cardiovascular death and HF readmission (RR: 0.71; 95% CI 0.60–0.84; p 0.001). In another meta-analysis by Hou J et al. [5], SGLT2i was shown to reduce the number of short-term HF deterioration events, hospital readmissions due to HF, and improve quality of life in AHF patients (standardized mean difference (SMD) = –0.24, 95% CI: –0.40 to –0.09, p = 0.002), without increasing the incidence of adverse events (RR = 0.91, 95% CI: 0.82–1.01, p = 0.06). In the current meta-analysis, we aggregated additional literature that met our inclusion criteria to further verify and expand upon these findings. First, we compared the incidence of MACEs within 30 days, including composite event rates, all-cause mortality, and cardiovascular readmission. We found that early use of SGLT2i provided benefits to patients, consistent with previous studies. However, no significant difference was observed in the incidence of cardiogenic death within 30 days between the SGLT2i and control groups, likely due to the short duration of drug use or the severity of AHF. Subsequently, we compared the overall event rates within one year and found that clinical benefits were sustained through the entire year post-discharge, including reduced cardiogenic mortality, HF readmission, and all-cause mortality. Although the composite event rate within one year was lower in the SGLT2i group compared to the control group, we consider this as a major result, accounting for the high heterogeneity among the included studies. This may also be the first meta-analysis comparing the short- and long-term effects of SGLT2i on AHF patients. Furthermore, our study compared the incidence of adverse drug events during SGLT2i use: common adverse effects such as acute kidney injury (AKI), urinary tract infections, hypoglycemia, and hypotension showed no significant differences between the placebo/control group and SGLT2i group, which is one of the novel aspects of this research.

Although existing evidence confirms that early use of SGLT2i can safely and effectively yield clinical benefits for AHF patients in the short and long term, some issues remain unresolved. First, the mechanisms underlying these benefits are still unclear. Kasperova BJ et al. [33] have pointed out that SGLT-2 inhibitors significantly downregulate pro-inflammatory gene expression in epicardial adipose tissue (EAT) and reduce macrophage and T lymphocyte infiltration in EAT, thereby decreasing oxidative stress and ferroptosis, which protects the myocardium. However, the protective mechanism of SGLT2i in AHF remains uncertain. Second, the optimal timing for early use of SGLT2i is still undefined. Research by Echeverría LE et al. [11] has suggested that administering SGLT2i within 48 hours of AHF hospitalization was associated with a reduction in in-hospital mortality (RR 0.37; 95% CI, 0.17–0.77), shorter hospital stay, and lower 30-day composite mortality/HF readmission rates (RR 0.72; 95% CI, 0.53–0.98). Our study mainly compared the clinical benefits of early inpatient use versus no use or post-discharge use, but the exact timing (immediately, 24 hours, or 48 hours after admission) for optimal benefit in AHF patients still requires further clinical validation. Lastly, more subgroup analyses are needed to investigate the use of SGLT2i in different populations, such as those with or without diabetes, hypertension, renal insufficiency, and gender differences. Currently, the latest guidelines for AHF recommend that SGLT2i treatment should be initiated in AHF patients either before discharge or early after discharge. Additionally, the DAPA ACT HF-TIMI 68 Trial, the largest randomized controlled trial to date, will soon release its follow-up results, and we look forward to its findings, which may provide further evidence for the early use of SGLT2i in AHF patients [34].

(1) Since only one study reported the improvement of quality of life with SGLT2 inhibitors, this study did not perform a comparative analysis on the impact of early use of SGLT2 inhibitors on quality of life.

(2) Due to the differences in the definition of “early” treatment across studies, this research did not define or categorize specific time points for early treatment.

(3) Due to differences in study populations, objectives, and the lack of specific individualized data, this study only performed subgroup analysis based on study type. Future randomized controlled trials targeting specific populations, heart failure classifications, and treatment duration are anticipated.

(4) This study only included relevant English-language literature, which may have excluded studies published in other languages.

In summary, early use of SGLT2i effectively reduces the incidence of all-cause mortality, cardiogenic readmission, and other composite events in AHF patients over the short term and up to one year, without increasing the occurrence of adverse drug events such as hypoglycemia, hypotension, renal impairment, or ketoacidosis. However, further high-quality and large-scale clinical evidence is needed to confirm its hemodynamic effects and clinical benefits in non-diabetic populations.

All data in this study are available from the original cited studies.

YFD is responsible for the organization, verification, and writing of the relevant literature data for this article. YM and HL each completed literature retrieval, data organization, statistical analysis, and revisions of the article. LZ is responsible for the conception of the study, drafting the manuscript, and making substantial revisions to its content. All authors read and approved the final manuscript. All authors have participated sufficiently in the work and agreed to be accountable for all aspects of the work.

Not applicable.

Not applicable.

This study was financially supported by Postgraduate Research & Practice Innovation Program of Jiangsu Province (NO: SJCX24-2350).

The authors declare no conflict of interest.

Supplementary material associated with this article can be found, in the online version, at https://doi.org/10.31083/RCM45590.