Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have recently entered the heart failure (HF) treatment arena as a promising drug class, with multiple clinical trials underscoring their benefit in reducing adverse cardiovascular outcomes and improving survival, regardless of diabetes status or the ejection fraction.1–3 Consequently, contemporary clinical practice guidelines now prioritize SGLT2i as a first-line option for HF treatment, awarding them a class I recommendation.4 Yet, the ideal timing for commencing SGLT-2 inhibitor therapy remains debated. In this regard, the EMPULSE trial revealed the benefits and safety of initiating SGLT2i treatment during acute HF hospitalizations. Notably, the median time of randomization in this trial was 3 days [IQR: 2-4 days].5 This timeframe, largely dictated by patient stabilization requirements in the initial stages of hospitalization, leaves a gap in our understanding regarding the potential benefit of early SGLT2i continuation or initiation during acute episodes regarding survival and rehospitalization. Additionally, there is currently scarcity of real-world evidence on the safety and benefit of early in-hospital SGLT2i prescription in patients with acute decompensated heart failure (ADHF). Therefore, we aimed to explore the association between early in-hospital initiation of SGLT2i and clinical outcomes in patients presenting with ADHF at a tertiary cardiovascular center.

Among 3042 ADHF admissions at the Fundación Cardiovascular de Colombia during the evaluated period, 2016 eligible patients (mean age: 68.0 years; 29.2% females) were included in the present analysis (table 1, figure 1, and figure 1 of the supplementary data and figure 2 of the supplementary data). Patients receiving early SGLT2i presented with distinct clinical characteristics compared to those receiving late or no SGLT2i. The early SGLT2i group had lower systolic blood pressure (119 versus 123 versus 128mmHg, P<.001), lower left ventricular ejection fraction (29% versus 33% versus 40%, P<.001), and higher prevalence of New York Heart Association class III-IV symptoms (67.1% versus 59.5% versus 60.0%, P=.004). These patients also had a higher prevalence of prior SGLT2i use (44.5% versus 30.6% versus 26.6%, P<.001) and better baseline optimization of guideline-directed medical therapy, including angiotensin-converting enzyme inhibitor/angiotensin receptor blocker/angiotensin receptor-neprilysin inhibitor (55.3% versus 43.1% versus 44.1%, P<.001), beta-blockers (52.2% versus 41.9% versus 45.8%, P=.001), and aldosterone receptor antagonists (46.5% vs 34.1% versus 31.6%, P<.001) (table 1). No episodes of ketoacidosis were reported.

Figure 1.

Central illustration. This prospective cohort study aimed to compare the clinical outcomes of adults with ADHF receiving either early in-hospital SGLT2i (≤ 48hours post-admission, n=1275), late in-hospital SGLT2i (> 48hours post-admission, n=346), or no in-hospital SGLT2i (n=395). Results are presented as RR with 95%CI for dichotomous outcomes and MD for continuous outcomes. Comparisons shown include: early versus late SGLT2i (green versus orange icons), early versus late/no SGLT2i (green versus combined orange/red icons), and any versus no in-hospital SGLT2i (yellow versus red icons). In-hospital outcomes include length of stay and mortality, while post-discharge outcomes encompass MLHFQ score improvement, 30-day mortality, and the combined endpoint of 30-day mortality/heart failure rehospitalization. 95%CI, 95% confidence intervals; ADHF, acute decompensated heart failure; HF, heart failure; MD, mean differences; MLHFQ, Minnesota Living with Heart Failure Questionnaire; RR, relative risks; SGLT2i, sodium-glucose cotransporter 2 inhibitors.

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Regarding comorbidities and laboratory values, the no-SGLT2i group showed notably higher prevalence of chronic kidney disease (19.5%) compared to both early (11.9%) and late (9.5%) SGLT2i groups. Similarly, renal function was significantly worse in the no-SGLT2i group (median eGFR 54.9mL/min/1.73 m2) compared to both early (64.2mL/min/1.73 m2) and late (66.5mL/min/1.73 m2) SGLT2i groups (table 1). When specifically comparing early versus late SGLT2i initiation groups, several notable differences emerged. Patients receiving early SGLT2i therapy had more severe HF symptoms, with a higher proportion of New York Heart Association class III-IV (67.1% versus 59.5%, P=.009) and lower left ventricular ejection fraction (29.0% versus 33.0%, P<.001). The early group also showed distinct HF etiologies, with higher prevalence of Chagas disease (18.3% versus 11.8%, P=.005) and dilated cardiomyopathy (21.8% versus 15.6%, P=.011), but lower ischemic etiology (37.8% versus 48.3%, P<.001). Notably, renal function parameters were comparable between groups, with similar eGFR values (64.2 versus 66.5mL/min/1.73 m2, P=.720) and proportion of patients with eGFR<30mL/min/1.73 m2 (6.3% versus 8.4%, P=.165). Finally, the early initiation group showed better baseline optimization of guideline-directed medical therapy, including higher rates of angiotensin-converting enzyme inhibitor/angiotensin receptor blocker/angiotensin receptor-neprilysin inhibitor (55.3% versus 43.1%, P<.001), beta-blockers (52.2% versus 41.9%, P<.001), and aldosterone receptor antagonists (46.5% versus 34.1%, P<.001), differences that were prioritized for adjustment in the multivariate models (table 2 of the supplementary data).

In-hospital management and clinical outcomes

Early SGLT2i use was associated with significantly lower in-hospital mortality compared to late SGLT2i use (adjusted RR, 0.37; 95%CI, 0.17-0.77). This benefit was consistent when comparing early versus late/no in-hospital SGLT2i (adjusted RR, 0.25, 95%CI, 0.14-0.44) and any in-hospital SGLT2i versus none (adjusted RR, 0.24, 95%CI, 0.14-0.42) (table 2 and figure 2).

Table 2.

Regression models evaluating the effect of in-hospital SGLT2i prescription regarding primary and secondary outcomes

In-hospital mortality	Crude effect (95%CI)	Adjusted effect (95%CI)
Early (< 48 h) versus late (> 48 h) SGLT2i prescription	0.41 (0.21-0.79) *	0.37 (0.17-0.77) *
Early (< 48 h) versus late (> 48 h) or no SGLT2i prescription	0.25 (0.15-0.41) *	0.25 (0.14-0.44) *
In-hospital SGLT2i prescription versus no SGLT2i prescription	0.23 (0.15-0.37) *	0.24 (0.14-0.42) *

Length of stay	Crude effect (95%CI)	Adjusted effect (95%CI)
Early (< 48 h) versus late (> 48 h) SGLT2i prescription	−5.70 (−7.05 to −4.34) *	−5.70 (−7.05 to −4.34) *
Early (< 48 h) versus late (> 48 h) or no SGLT2i prescription	−2.99 (−4.05 to −1.92) *	−2.99 (−4.05 to −1.92) *
In-hospital SGLT2i prescription versus no SGLT2i prescription	0.63 (−0.67 to 1.93)	0.63 (−0.67 to 1.93)

30-day mortality	Crude effect (95%CI)	Adjusted effect (95%CI)
Early (< 48 h) versus late (> 48 h) SGLT2i prescription	0.60 (0.29-1.23)	0.49 (0.23-1.04)
Early (< 48 h) versus late (> 48 h) or no SGLT2i prescription	0.44 (0.26-0.77) *	0.42 (0.23-0.77) *
In-hospital SGLT2i prescription versus no SGLT2i prescription	0.43 (0.24-0.76) *	0.44 (0.23-0.84) *

30-day HF rehospitalization	Crude effect (95%CI)	Adjusted effect (95%CI)
Early (< 48 h) versus late (> 48 h) SGLT2i prescription	0.76 (0.51-1.12)	0.72 (0.47-1.08)
Early (< 48 h) versus late (> 48 h) or no SGLT2i prescription	0.87 (0.63-1.18)	0.80 (0.57-1.12)
In-hospital SGLT2i prescription versus no SGLT2i prescription	1.02 (0.69-1.50)	0.98 (0.64-1.50)

30-day combined mortality/HF rehospitalization	Crude effect (95%CI)	Adjusted effect (95%CI)
Early (< 48 h) versus late (> 48 h) SGLT2i prescription	0.79 (0.54-1.13)	0.72 (0.49-1.06)
Early (< 48 h) versus late (> 48 h) or no SGLT2i prescription	0.77 (0.58-1.02)	0.72 (0.53-0.98) *
In-hospital SGLT2i prescription versus no SGLT2i prescription	0.79 (0.56-1.11)	0.63 (0.47-1.93)

30-day MLHFQ improvement ≥ 20 points	Crude effect (95%CI)	Adjusted effect (95%CI)
Early (< 48 h) versus late (> 48 h) SGLT2i prescription	0.90 (0.71-1.14)	0.89 (0.69-1.14)
Early (< 48 h) versus late (> 48 h) or no SGLT2i prescription	1.07 (0.89-1.28)	1.06 (0.87-1.29)
In-hospital SGLT2i prescription versus no SGLT2i prescription	1.26 (1.01-1.57) *	1.28 (1.01-1.63) *

95%CI, 95% confidence interval; HF, heart failure; MLHFQ, Minnesota Living with Heart Failure Questionnaire; RR, relative risk; SD, standard deviation; SGLT2i, sodium-glucose cotransporter 2 inhibitors.

*

Represents a statistically-significant effect.

Figure 2.

Short-term clinical outcome rates stratified by timing of in-hospital SGLT2i initiation.

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Length of hospital stay was significantly shorter with early SGLT2i use compared to late initiation (adjusted mean difference −5.70 days, 95%CI, −7.05 to −4.34) and compared to delayed/no SGLT2i (adjusted mean difference −2.99 days, 95%CI, −4.05 to −1.92). Notably, there was no significant difference in length of stay between any in-hospital SGLT2i use versus none (adjusted mean difference 0.63 days, 95%CI, −0.67 to 1.93) (table 2).

Among hospital survivors, early SGLT2i use showed a trend toward lower 30-day mortality compared to late initiation (adjusted RR, 0.49, 95%CI, 0.23-1.04) and significantly lower mortality compared to delayed/no SGLT2i (adjusted RR, 0.42, 95%CI, 0.23-0.77). Similarly, 30-day HF rehospitalization rates tended to be lower with early SGLT2i use (adjusted RR, 0.72, 95%CI, 0.47-1.08 versus late initiation; adjusted RR, 0.80, 95%CI, 0.57-1.12 versus delayed/no SGLT2i); however, this difference was not statistically significant. Finally, the composite endpoint of 30-day death or HF rehospitalization showed a consistent potential benefit with early SGLT2i use (adjusted RR, 0.72, 95%CI, 0.49-1.06 versus late initiation; adjusted RR, 0.72, 95%CI, 0.53-0.98 versus delayed/no SGLT2i) (table 2).

The present study evaluated the impact of in-hospital prescription of SGLT2i in patients with ADHF, being, to our knowledge, the first to explore the benefit of early continuation/initiation of SGLT2i during the first 48hours of hospital admission in a real-world setting. Our results support the benefit of early SGLT2i prescription in terms of in-hospital mortality reduction and reduced hospital stay compared with late prescription, despite early initiation patients having more severe HF manifestations, as evidenced by higher New York Heart Association class and lower ejection fraction. Additionally, early prescription was associated with lower in-hospital mortality, a shorter hospital stay and a reduced 30-day combined mortality/HF rehospitalization rate when compared with late or no in-hospital SGLT2i prescription. Finally, in-hospital use of SGLT2i was associated with increased ambulatory prescription rates of these drugs at discharge. Our results contribute to the previous high-quality evidence from clinical trials by including different groups of patients not considered in previous randomized studies, reflecting the real-world trends related to SGLT2i use.

Following the confirmation of the outstanding benefit of SGLT2i in chronic HF in the outpatient setting by multiple well-known clinical trials, there has been increasing interest in evaluating its potential benefit in patients with ADHF.1–3,6 On one side, SGLT2i-related natriuresis in the proximal tubules represents a promising mechanism aiding patient decongestion in the acute setting, considering that the majority of Na+ reabsorption (65%) occurs at this level, compared to the Henle loop (35%) and the distal tubules (5%), being proximal Na+ reabsorption proportionally higher in the ADHF patient.7 In addition to increasing diuresis and natriuresis, pleiotropic effects mediated by SGLT2i on oxidative stress can also provide additional benefits in light of the complex pathophysiology of ADHF.8–11 Finally, SGLT2i are characterized by a rapid effect (which can be observed only days after initiation) in addition to an adequate safety and tolerability profile, especially considering the need to preserve renal function in the ADHF patient.6

This potential has been reflected in the results of clinical trials in patients with acute HF. On the one hand, the EMPAG-HF confirmed the diuretic potential of these medications by observing a 25% increase in urine output 5 days after starting empagliflozin (25mg o.d.) compared to conventional management, a finding observed in the absence of impaired renal function and accompanied by a significant reduction in N-terminal pro-B-type natriuretic peptide levels.12 Moreover, the SOLOIST WHF, in which the dual SGLT inhibitor sotagliflozin was compared to placebo, showed for the first time that initiation of an SGLT2i at hospital discharge or during the first 3 days post-discharge was associated with a reduction in hospitalizations for HF and an improvement in quality of life regardless of ejection fraction. However, no statistically significant difference in mortality rates was observed in this trial.13 The benefit of in-hospital use of SGLT2i in terms of survival would be identified more recently in the EMPULSE trial, in which in-hospital use of 10mg empagliflozin o.d. was associated with lower all-cause mortality and incidence of HF events, as well as better quality of life compared to placebo. Additionally, this study confirmed the robust safety profile of these medications, highlighting the absence of ketoacidosis events and a lower incidence of acute renal failure and urinary tract infections in the treated group.5

Despite these findings, real-world evidence about the benefit of in-hospital use of SGLT2i in relation to clinical outcomes such as mortality and rehospitalizations is scarce, which limits the extrapolability of the beneficial results observed in populations not considered in the pivotal clinical trials of ADHF, such as end-stage chronic kidney disease patients. In this regard, the study by Okoroike et al. evaluated the effect of in-hospital initiation of these drugs in patients with HF and reduced left ventricular ejection fraction, analyzing 2663 patients of whom 177 received SGLT2i during hospitalization.14 The authors reported a significantly lower 30-day rehospitalization rate in the SGLT2i group (9.3% versus 22.7%), as well as lower all-cause mortality (4% versus 22.7%). However, the differences in outcomes reported were not adjusted for relevant covariates that differed between the 2 study groups, as for example, patients who received SGLT2i were younger and had lower N-terminal pro-B-type natriuretic peptide levels on admission, among other differences. Additionally, the time from hospital admission to drug prescription was not reported, which limited the possibility of evaluating the effect of this relevant factor on outcomes. Similarly, the study of Mizobuchi et al. reported real-world results of the potential benefits of in-hospital SGLT2i prescription in a third-level center in Tokyo, Japan. Their analysis of 1108 patients revealed that SGLT2i prescription during ADHF had a significantly lower rate of the composite endpoint of all-cause death and HF hospitalization compared to those that were not prescribed these medications, regardless of left ventricular ejection fraction categories.15 Finally, the study of Singh et al. which analyzed the Veterans Affairs health care system data of acute care hospitalizations, reported a significant benefit of SGLT2i continuation during the transition from the outpatient to the inpatient setting in patients with diabetes mellitus, highlighting lower mortality and length of stay, and no increased risk of acute kidney injury.16

In a single-center real-world study including patients hospitalized with ADHF, in-hospital continuation/initiation of SGLT2 inhibitors, particularly within the first 48hours of admission, was associated with improved clinical outcomes. Specifically, early in-hospital SGLT2i prescription was associated with reduced in-hospital mortality, as well as shorter length of stay, higher SGLT2i prescription rates at discharge and a lower risk of mortality compared to late or no in-hospital prescription. These exploratory results require further validation in multicenter studies and clinical trials, which should also focus on special populations present in the real world setting such as end-stage chronic kidney disease patients and individuals with high frailty scores, among others.

The present study did not require funding.

The Institutional Committee on Research Ethics approved the study protocol (CEI-2022-05104). Written informed consent was waived due to the registry-based nature of the study, the use of de-identified data, and the absence of any direct patient contact for research purposes beyond standard clinical care. The sex and gender equity in research (SAGER) guidelines were followed for the design of the study.

No generative artificial intelligence was used in this study.

S.A. Gómez-Ochoa, L.Z. Rojas, and L.E. Echeverría had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: L.E. Echeverria and S.A. Gómez-Ochoa. Acquisition, analysis, or interpretation of data: L.E. Echeverria, A.Y. Serrano-García, D.R. Botero, M. Cantillo-Reines, A.M. Jurado, K.A. García-Rueda, A. Torres-Bustamante, D.I. Cañón-Gómez, C. Idrovo-Turbay, R. Sánchez-García, J.A. Rodríguez, and S.A. Gómez-Ochoa. Drafting of the manuscript: L.E. Echeverria, L.Z. Rojas, A.Y. Serrano-García, and S.A. Gómez-Ochoa. Critical revision of the manuscript for important intellectual content: L.E. Echeverria, L.Z. Rojas, A.Y. Serrano-García, D.R. Botero, M. Cantillo-Reines, A.M. Jurado, K.A. García-Rueda, A. Torres-Bustamante, D.I. Cañón-Gómez, C. Idrovo-Turbay, R. Sánchez-García, J.A. Rodríguez, and S.A. Gómez-Ochoa. Statistical analysis: L.Z. Rojas and S.A. Gómez-Ochoa. Study supervision: L.E. Echeverria, J.A. Rodríguez, S.A. Gómez-Ochoa.

S.A. Gómez-Ochoa, L.Z. Rojas, and L.E. Echeverría received funding from Boehringer Ingelheim S.A. for the development of an Investigator-initiated study. The other authors have no conflict of interest.

We would like to thank the epidemiology unit of the Instituto Cardiovascular, Fundación Cardiovascular de Colombia for their support in the management of the ICARUS.