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. Author manuscript; available in PMC: 2026 Feb 18.
Published in final edited form as: Circulation. 2025 Aug 29;152(20):1411–1422. doi: 10.1161/CIRCULATIONAHA.125.076575

Dapagliflozin in Patients Hospitalized for Heart Failure

Primary Results of the DAPA ACT HF-TIMI 68 Randomized Clinical Trial and Meta-Analysis of Sodium-Glucose Cotransporter-2 Inhibitors in Patients Hospitalized for Heart Failure

David D Berg 1,2, Siddharth M Patel 1,2, Paul M Haller 1,2,3, Abby L Cange 1,2, Michael G Palazzolo 1,2, Andrea Bellavia 1,2, Julia F Kuder 1,2, Akshay S Desai 2, Silvio E Inzucchi 4, John JV McMurray 5, Eileen O’Meara 6, Subodh Verma 7, Jan Bělohlávek 8, Jarosław Drożdż 9, Béla Merkely 10, Modele O Ogunniyi 11, Tomáš Drasnar 12, Joseph L Izzo 13, Balazs Sarman 14, John E McGinty 15, Krishnan Ramanathan 16, Angel J Mulkay 17, Andrzej Przybylski 18, Christian T Ruff 1,2, Michelle L O’Donoghue 1,2, Sabina A Murphy 1,2, Marc S Sabatine 1,2,*, Stephen D Wiviott 2,19,*, for the DAPA ACT HF-TIMI 68 Trial Committees and Investigators
PMCID: PMC12910484  NIHMSID: NIHMS2134685  PMID: 40884036

Abstract

Background:

Sodium-glucose cotransporter-2 inhibitors (SGLT2i) reduce the risk of cardiovascular death or worsening heart failure (HF) in outpatients with HF. Data are limited regarding initiation in patients hospitalized for HF.

Methods:

We conducted a randomized, double-blind, placebo-controlled trial evaluating the efficacy and safety of in-hospital initiation of dapagliflozin (10 mg daily) in patients hospitalized for HF. The primary efficacy outcome was a composite of time to cardiovascular death or worsening HF through two months. Key safety outcomes included symptomatic hypotension and worsening kidney function. A prespecified meta-analysis was performed of randomized trials evaluating initiation of SGLT2i in hospitalized HF patients.

Results:

Of 2401 patients (median age 69 [Q1-Q3, 58–77] years, 815 [33.9%] women, 448 [18.7%] Black race, 1717 [71.5%] LVEF ≤40%, 1074 [44.7%] newly diagnosed), randomized between 09/2020 and 03/2025, 1218 were assigned to dapagliflozin and 1183 to placebo. The primary outcome occurred in 133 patients (10.9%) in the dapagliflozin group and 150 (12.7%) in the placebo group (hazard ratio [HR], 0.86; 95% CI 0.68–1.08; p=0.20). A worsening HF event occurred in 115 (9.4%) and 122 (10.3%) patients in the dapagliflozin and placebo groups, respectively (HR, 0.91; 95% CI, 0.71–1.18). Cardiovascular death occurred in 30 (2.5%) and 37 (3.1%) patients (HR, 0.78; 95% CI, 0.48–1.27), and death from any cause occurred in 36 (3.0%) and 53 (4.5%) patients in the dapagliflozin and placebo groups, respectively (HR, 0.66; 95% CI, 0.43–1.00). The rates of symptomatic hypotension were 3.6% and 2.2%, and the rates of worsening kidney function were 5.9% and 4.7% with dapagliflozin and placebo, respectively. In a meta-analysis of patients hospitalized for HF, SGLT2i reduced the early risk of cardiovascular death or worsening HF (HR, 0.71; 95% CI, 0.54–0.93; p=0.012) and of all-cause death (HR, 0.57; 95% CI, 0.41–0.80; p=0.001).

Conclusions:

In-hospital initiation of dapagliflozin did not significantly reduce the risk of cardiovascular death or worsening HF through two months in hospitalized HF patients. However, the totality of randomized clinical trial data suggests that in-hospital initiation of SGLT2i may reduce the early risk of cardiovascular death or worsening HF and of all-cause mortality.

Registration:

URL: https://www.clinicaltrials.gov; Unique identifier: NCT04363697.

Keywords: randomized clinical trial, hospitalization, sodium-glucose cotransporter 2 inhibitors, worsening heart failure

Introduction

Hospitalization for heart failure (HF) is the leading cardiovascular reason for hospital admission globally,1 and rates have continued to climb over the last decade.2 Patients hospitalized for HF have a high risk of death and other adverse outcomes during hospital admission and in the early post-discharge period,2 highlighting the need for effective treatment strategies focused on this phase of care.3, 4 Evidence from randomized trials suggests that initiating and optimizing disease-modifying chronic heart failure therapies, including angiotensin receptor-neprilysin inhibitors, beta-blockers, and mineralocorticoid receptor antagonists, during heart failure hospitalization and in the early post-discharge period may improve both short- and long-term outcomes.3, 4

Sodium-glucose cotransporter-2 inhibitors (SGLT2i), including dapagliflozin, are indicated for the treatment of HF regardless of left ventricular ejection fraction (LVEF).5, 6 However, there are limited data regarding the efficacy and safety of initiating SGLT2i during HF hospitalization.7, 8 In the SOLOIST-WHF trial (n=1222), which enrolled patients with type 2 diabetes and a recent episode of worsening chronic HF, sotagliflozin significantly reduced total cardiovascular deaths and worsening HF events over a median follow-up of 9 months;9 however, only 596 patients were randomized on or before their date of discharge (76% on the date of discharge).8 In the EMPULSE trial (n=530), in-hospital initiation of empagliflozin in patients hospitalized for HF significantly improved a hierarchical composite outcome that included clinical events and HF-related health status as measured by the Kansas City Cardiomyopathy Questionnaire-23 item (KCCQ-23) through 90 days, though the result was driven by improvements in the latter.7

Data from trials of outpatients with HF suggest that the cardioprotective effects of SGLT2i emerge early, supporting prompt initiation of these therapies.10–12 Nevertheless, hospitalized HF patients may be more susceptible to therapy-related complications due to hemodynamic and rhythm instability, fluctuating kidney function, and concomitant addition or intensification of other HF therapies.13 We, therefore, designed the DAPA ACT HF-TIMI 68 (Dapagliflozin Effect on Cardiovascular Events in Acute Heart Failure – Thrombolysis in Myocardial Infarction 68) trial to test the hypothesis that in-hospital initiation of dapagliflozin, as compared with placebo, can safely and effectively decrease the early risk of cardiovascular death or worsening HF among patients hospitalized for HF. In addition, we aimed to combine data from DAPA ACT HF-TIMI 68 with other placebo-controlled trials of in-hospital initiation of SGLT2i in hospitalized HF patients to generate pooled estimates of the treatment effects of SGLT2i on early efficacy outcomes in this clinical setting.

Methods

Trial Design and Oversight

The DAPA ACT HF-TIMI 68 trial design has been reported previously.14 Briefly, DAPA ACT HF-TIMI 68 was an investigator-initiated, multinational, randomized, double-blind, placebo-controlled trial of in-hospital initiation of dapagliflozin in patients hospitalized for HF. The trial was designed by the TIMI Study Group at Brigham and Women’s Hospital and Harvard Medical School (Boston, MA), in collaboration with the trial steering committee (Supplemental Material). Worldwide Clinical Trials (contract research organization) provided data management services. The safety of patients in the trial was overseen by an independent data monitoring committee. The protocol and amendments were approved by the relevant institutional review board or ethics committee at each participating site, and all participants provided written informed consent. All statistical analyses were conducted by biostatisticians at the TIMI Study Group in accordance with the statistical analysis plan (Supplemental Material). The first draft of the manuscript was written by the first author, and all authors participated in subsequent revisions. The steering committee made the decision to submit the manuscript for publication and assumes responsibility for the accuracy and completeness of the data and analyses. The manuscript adhered to the 2025 CONSORT reporting guidelines. Data will not be made publicly available; however, we encourage parties interested in collaboration and data sharing to contact the corresponding author directly for further discussion.

Participants

Eligible patients were at least 18 years of age and were currently hospitalized with a primary diagnosis of HF, including signs and symptoms of fluid overload. The trial was originally designed to enroll only patients with LVEF ≤40%; however, following publication of the EMPEROR-Preserved trial,15 which demonstrated the efficacy of the SGLT2i empagliflozin in ambulatory patients with HF and LVEF >40%, the protocol was amended in November 2021 to include patients with LVEF >40%. Patients were required to have elevated natriuretic peptide levels (either N-terminal pro-B-type-natriuretic peptide [NT-proBNP] or B-type-natriuretic peptide [BNP]) during the index hospitalization with varying thresholds for inclusion according to LVEF and cardiac rhythm. Patients were randomized while still hospitalized, at least 24 hours and no later than 14 days after hospital admission, and as early as possible following initial stabilization. Stabilization criteria included no intensification in the dose of intravenous diuretics during the 12 hours prior to randomization and no use of intravenous vasodilators or inotropes during the 24 hours prior to randomization. A complete list of eligibility criteria is provided in the Supplemental Material.

Procedures

Eligible patients were randomly assigned in double-blind fashion to receive dapagliflozin 10 mg once daily or matching placebo, in accordance with a sequestered, fixed randomization schedule, with the use of balanced blocks by site to ensure an approximate 1:1 allocation ratio. Randomization was stratified based on diagnosis of type 2 diabetes and history of HF prior to the index hospitalization. Open-label use of SGLT2i was prohibited during the randomized treatment period; use of all other pharmacological HF therapies at baseline and throughout the trial was at the discretion of the treating physician. Randomized treatment was administered for 60 days, with follow-up visits scheduled at 7, 30, and 60 days after randomization. HF-related health status using the KCCQ-12 item (KCCQ-12) was assessed at randomization and the final study visit.

Outcomes

The primary efficacy outcome was a composite of time to cardiovascular death or first worsening HF event. A worsening HF event was defined as any event meeting one of the following criteria: (1) worsening signs or symptoms of HF during the index hospitalization resulting in treatment with intravenous inotropes, mechanical circulatory support, invasive ventilatory support, or heart transplantation; (2) unplanned rehospitalization for HF; or (3) urgent ambulatory HF visit resulting in treatment with intravenous diuretic therapy. A clinical events committee (CEC) led by the TIMI Study Group, whose members were blinded to randomized treatment, adjudicated all components of the primary outcome (Supplemental Material).

Secondary efficacy outcomes included a composite of time to cardiovascular death, rehospitalization for HF, or urgent HF visit; a composite of time to cardiovascular death or rehospitalization for HF; a composite of time to rehospitalization for HF or urgent HF visit; each individual component of the primary efficacy outcome; and time to death from any cause. An additional secondary outcome included a hierarchical composite of time to cardiovascular death, number of worsening HF events, time to first worsening HF event, and change from baseline in KCCQ-12 total symptom score (TSS).

Key safety outcomes included symptomatic hypotension leading to hospitalization or study drug discontinuation and worsening kidney function resulting in at least a doubling of serum creatinine, hospitalization, study drug discontinuation, dialysis, or renal death. Other prespecified safety outcomes included major hypoglycemia, diabetic ketoacidosis, adverse events leading to study drug discontinuation, and serious adverse events considered related to study drug by the investigator.

Statistical Analysis

The primary efficacy analysis was based on time from randomization to the first occurrence of any element of the primary composite outcome. We estimated that a sample size of 2400 patients would provide the trial with 80% power to detect a relative reduction of 27% in the risk of the primary outcome with dapagliflozin as compared with placebo at two months. The estimated treatment effect was based on the DAPA-HF trial of dapagliflozin in ambulatory patients with HF with reduced ejection fraction (HFrEF) as well as a subgroup analysis of DAPA-HF patients who had been hospitalized for HF in the preceding year; the relative risk reductions were 26% and 36% in the overall trial and subgroup analysis, respectively.10, 16 The sample size calculation assumed an event rate of 16% in the placebo group, a dropout rate of 0.5%, and a two-sided alpha level of 0.05. All efficacy analyses were conducted on an intention-to-treat basis.

The primary outcome was assessed using the log-rank test, with stratification based on diagnosis of type 2 diabetes and history of HF prior to the index hospitalization. The cumulative incidence of the primary outcome was estimated using the Kaplan-Meier method. A stratified Cox proportional-hazards model was used to estimate the treatment effect using hazard ratios (HR) and 95% confidence intervals (CI). The proportional-hazards assumption was assessed and confirmed graphically and tested with the use of Schoenfeld residuals. We assessed the consistency of the treatment effect on the primary outcome in prespecified subgroups using the Cox model. The primary outcome was also analyzed using a Bayesian survival model (Supplemental Material).

Secondary time-to-event outcomes were evaluated using stratified Cox proportional-hazards models. The secondary hierarchical composite outcome was evaluated using an unmatched win ratio approach.17 Change in KCCQ-TSS from baseline to two months in surviving patients was compared using an analysis of covariance model, adjusting for baseline value. Safety analyses were performed in patients who had undergone randomization and received at least one dose of study drug. Chi-square or Fisher’s exact test was used to compare the incidence of each adverse event. Analyses were performed using SAS v9.4 and R v4.2.3.

Meta-analysis

Since DAPA ACT HF-TIMI 68 was the final planned randomized trial of in-hospital initiation of an SGLT2i, a prespecified meta-analysis was performed of randomized trials (or subgroup analyses from randomized trials) evaluating initiation of SGLT2i in patients hospitalized for HF to summarize the totality of the evidence base. Detailed methods are provided in the Supplemental Material. The main outcomes were: (1) cardiovascular death or first worsening HF event, and (2) all-cause death. Random effects models with inverse-variance weighting were used to generate estimates for the treatment effect of SGLT2i on each outcome. Between-trial heterogeneity of treatment effect was examined using Cochran’s Q test.

Results

Trial Population

From September 2020 through March 2025, a total of 2401 patients underwent randomization at 210 sites in 5 countries (Figure 1), of whom 1218 were assigned to receive dapagliflozin and 1183 to receive placebo. A total of 2389 patients received at least one dose of study drug and were included in the safety analyses. A total of 262 (11.0%) patients discontinued study drug prematurely, including 139 (11.5%) in the dapagliflozin group and 123 (10.4%) in the placebo group. In total, 25 (2.1%) patients in the dapagliflozin group and 25 (2.1%) in the placebo group received at least one dose of an open-label SGLT2i during trial follow-up; however, only 9 (0.7%) and 6 (0.5%) in the dapagliflozin and placebo groups, respectively, permanently stopped study drug to start an open-label SGLT2i. Rates of withdrawal of consent (13 patients, 0.5%) and loss to follow-up with unknown vital status (4 patients, 0.2%) were low (Figure 1).

Figure 1. CONSORT diagram.

Figure 1.

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Two patients were randomized in error and excluded from all analyses. Adverse event relatedness to study drug was based on blinded investigator assessment and includes events related, probably related, or possibly related to study drug.

The median time from hospital admission to randomization was 3.6 days (interquartile range [IQR], 2.1–5.4 days). At the time of randomization, reported signs and symptoms of congestion were prevalent, including 39.8% with elevated jugular venous pressure, 36.4% with rales on auscultation of the lungs, and 61.8% with peripheral edema. Baseline characteristics were well balanced between the treatment groups (Table 1). The median age was 69 years (IQR, 58–77 years); 815 (33.9%) were women, 448 (18.7%) were Black, 852 (35.5%) had type 2 diabetes, and 1717 (71.5%) had a LVEF ≤40%. The index hospitalization was the first presentation of HF in 1074 (44.7%) patients. Of the remaining 1327 (55.3%) patients with worsening chronic HF, 742 (55.9%) had at least one prior HF hospitalization. At screening, the median NT-proBNP concentration (n=1582) was 4803 pg/ml (IQR, 2812–8768 pg/ml) and the median BNP concentration (n=830) was 1106 pg/ml (IQR, 717–1859 pg/ml). At randomization, the median systolic blood pressure was 119 mmHg (IQR, 108–133 mmHg), and the median eGFR was 63 ml/min/1.73m2 (IQR, 48–82 ml/min/1.73m2). At randomization, 82.5% of patients were on a beta-blocker, 70.1% were on a renin-angiotensin system inhibitor, including 27.0% on an angiotensin receptor–neprilysin inhibitor (ARNI), and 48.6% were on a mineralocorticoid receptor antagonist (MRA). At discharge, 88.2% were on a beta-blocker, 75.5% were on a renin-angiotensin system inhibitor, including 30.6% on an ARNI, and 54.4% were on an MRA. The median time from randomization to hospital discharge was 2 days (IQR, 1–4 days).

Table 1.

Baseline characteristics of study participants.

Dapagliflozin
(N=1218)		 Placebo
(N=1183)
Age (years) 69 (58–77) 68 (58–76)
Female sex 403 (33.1%) 412 (34.8%)
Body-mass index (kg/m2) 29.0 (24.9–34.7) 29.5 (25.4–35.4)
Race
 Asian 26 (2.1%) 18 (1.5%)
 Black or African American 224 (18.4%) 224 (18.9%)
 White 957 (78.6%) 927 (78.4%)
 Other 11 (0.9%) 14 (1.2%)
Region
 North America 893 (73.3%) 869 (73.5%)
 Europe 325 (26.7%) 314 (26.5%)
Heart failure chronicity
 Newly diagnosed heart failure 556 (45.6%) 518 (43.8%)
 Worsening chronic heart failure 662 (54.4%) 665 (56.2%)
   Prior heart failure hospitalization 374/662 (56.5%) 368/665 (55.3%)
NYHA class 30 days prior to admission (worsening chronic heart failure patients only)
 I 33/655 (5.0%) 31/658 (4.7%)
 II 199/655 (30.4%) 221/658 (33.6%)
 III 369/655 (56.3%) 350/658 (53.2%)
 IV 54/655 (8.2%) 56/658 (8.5%)
Left ventricular ejection fraction (%) 30.0 (20.0–45.0) 30.0 (21.0–45.0)
 LVEF ≤40% 865 (71.0%) 852 (72.0%)
Principal cause of heart failure
 Ischemic 323 (26.5%) 296 (25.0%)
 Non-ischemic 727(59.7%) 716 (60.5%)
 Unknown 168 (13.8%) 171 (14.5%)
Type 2 diabetes mellitus 437 (35.9%) 415 (35.1%)
Prior myocardial infarction 243/1196 (20.3%) 222/1167 (19.0%)
History of atrial fibrillation 542/1207 (44.9%) 530/1174 (45.1%)
History of hypertension 943 (77.4%) 935 (79.0%)
KCCQ-12 total symptom score (at randomization) 33.3 (14.6–54.2);
N=1215		 33.3 (18.8–54.2);
N=1180
Natriuretic peptides (qualifying)
 NT-proBNP (pg/ml) 5016 (2867–8766);
N=803		 4696 (2760–8797);
N=779
 BNP (pg/ml) 1139 (743–1823);
N=421		 1092 (701–1889);
N=409
Systolic blood pressure (mmHg) 119 (108–132) 119 (108–133)
Heart rate (bpm) 79 (68–89) 77 (68–88)
Estimated GFR (ml/min/1.73m2) 63.5 (48.5–83.0) 62.5 (47.2–80.7)
 <60 ml/min/1.73m2 536 (44.0%) 551 (46.6%)
Serum potassium (mmol/L) 4.1 (3.8–4.4);
N=1218		 4.0 (3.7–4.4);
N=1181
Medication use (at randomization)
 Beta-blocker 992 (81.4%) 989 (83.6%)
 Renin-angiotensin system inhibitor 859 (70.5%) 823 (69.6%)
   ACE inhibitor or ARB 539 (44.3%) 533 (45.1%)
   ARNI 339 (27.8%) 309 (26.1%)
 Mineralocorticoid receptor antagonist 602 (49.4%) 565 (47.8%)
 Digoxin 68 (5.6%) 64 (5.4%)
 Loop diuretic 1041 (85.5%) 998 (84.4%)
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Continuous variables are reported as medians with interquartile ranges, and categorical variables as counts with percentages. Denominators less than the full number of patients in each arm are indicated. ACE = angiotensin converting enzyme; ARB = angiotensin receptor blocker; ARNI = angiotensin receptor-neprilysin inhibitor; BNP = B-type-natriuretic peptide; bpm = beats per minute; GFR = glomerular filtration rate; KCCQ = Kansas City Cardiomyopathy Questionnaire; kg/m2 = kilograms per meter-squared; LVEF = left ventricular ejection fraction; ml/min/1.73m2 = milliliters per minute per 1.73 * meter-squared; mmHg = millimeters of mercury; mmol/L = millimoles per liter; NT-proBNP = N-terminal pro-B-type-natriuretic peptide; NYHA = New York Heart Association; pg/ml = picograms per milliliter.

Efficacy

The primary outcome occurred in 133 patients (10.9%) in the dapagliflozin group and in 150 patients (12.7%) in the placebo group (HR, 0.86; 95% CI, 0.68–1.08; p=0.20) (Table 2 and Figure 2A). There was no heterogeneity in the treatment effect of dapagliflozin on the primary outcome across prespecified subgroups (Figure 3). The results of the Bayesian analysis are presented in the Supplemental Material.

Table 2.

Primary and secondary outcomes.

Dapagliflozin
(N=1218)		 Placebo
(N=1183)		 Hazard Ratio (95% CI)
Primary outcome
Primary composite outcome 133 (10.9%) 150 (12.7%) 0.86 (0.68, 1.08)*
 Cardiovascular death 30 (2.5%) 37 (3.1%) 0.78 (0.48, 1.27)
 Worsening heart failure 115 (9.4%) 122 (10.3%) 0.91 (0.71, 1.18)
   Worsening heart failure during index admission 9 (0.7%) 6 (0.5%) 1.49 (0.53, 4.19)
   Re-hospitalization for heart failure 90 (7.4%) 102 (8.6%) 0.85 (0.64, 1.13)
   Urgent heart failure visit 21 (1.7%) 23 (1.9%) 0.90 (0.50, 1.62)
Secondary outcomes
 Cardiovascular death, rehospitalization for heart failure, or urgent heart failure visit 127 (10.4%) 146 (12.3%) 0.84 (0.66, 1.07)
 Cardiovascular death or rehospitalization for heart failure 110 (9.0%) 133 (11.2%) 0.79 (0.62, 1.02)
 Rehospitalization for heart failure or urgent heart failure visit 107 (8.8%) 116 (9.8%) 0.89 (0.69, 1.16)
 All-cause death 36 (3.0%) 53 (4.5%) 0.66 (0.43, 1.00)
 Hierarchical composite (% wins) 172,221 (42.3%) 157,615 (38.7%) Win Ratio (95% CI)†
1.08 (0.98, 1.20)
   Time to cardiovascular death (% wins) 11,009 (2.7%) 8,440 (2.1%)
   Worsening heart failure events (% wins) 35,061 (8.6%) 31,247 (7.7%)
   Time to first worsening heart failure event (% wins) 1272 (0.3%) 1390 (0.3%)
   Change from baseline in KCCQ-12 TSS (% wins) 124,879 (30.7%) 116,538 (28.6%)
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*

p=0.20 for the comparison of dapagliflozin versus placebo (calculated using the log-rank test)

†

The hierarchical composite outcome was evaluated using the unmatched stratified win ratio. A win ratio greater than 1 favors dapagliflozin arm.

Figure 2. Cumulative incidence of cardiovascular outcomes.

Figure 2.

Figure 2.

Figure 2.

Figure 2.

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The primary outcome was a composite of cardiovascular death or worsening heart failure. The cumulative incidences of the primary outcome (Panel A), worsening heart failure event (Panel B), cardiovascular death (Panel C), and all-cause mortality (Panel D) were estimated using the Kaplan-Meier method. Hazard ratios and 95% confidence intervals were estimated using stratified Cox proportional-hazards models, with stratification based on type 2 diabetes status and established history of heart failure. The p-value for the primary outcome was calculated using the stratified log-rank test.

Figure 3. Primary composite outcome in prespecified subgroups.

Figure 3.

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The forest plot shows the primary composite outcome (cardiovascular death or worsening heart failure) in prespecified subgroups. Variation in treatment effect was assessed with interaction testing using the Cox proportional hazards model.

Most worsening HF events were rehospitalizations for HF, which occurred in 90 patients (7.4%) in the dapagliflozin group, as compared with 102 patients (8.6%) in the placebo group (HR, 0.85; 95% CI, 0.64–1.13) (Table 2 and Figure 2B). Cardiovascular death occurred in 30 patients (2.5%) and 37 patients (3.1%) in the dapagliflozin and placebo groups, respectively (HR, 0.78; 95% CI, 0.48–1.27) (Table 2 and Figure 2C). Death from any cause occurred in 36 patients (3.0%) and 53 patients (4.5%) in the dapagliflozin and placebo groups, respectively (HR, 0.66; 95% CI, 0.43–1.00) (Table 2 and Figure 2D).

The difference in the least-squares mean change in KCCQ-12 TSS from baseline to two months between groups was +1.3 (95% CI, −0.7 to +3.3). For the secondary hierarchical composite outcome, dapagliflozin was superior in 42.3% of paired comparisons, placebo was superior in 38.7%, and there were 19.0% ties, yielding a win ratio of 1.08 (95% CI, 0.98–1.20) (Table 2).

Safety

Symptomatic hypotension leading to hospitalization or study drug discontinuation occurred in 43 patients (3.6%) in the dapagliflozin group and 26 patients (2.2%) in the placebo group. A worsening kidney function event occurred in 71 patients (5.9%) in the dapagliflozin group and 55 patients (4.7%) in the placebo group (Table 3). Rates of major hypoglycemia were very low and did not differ between groups. There were no cases of diabetic ketoacidosis. The rate of permanent discontinuation of study drug owing to an adverse event also did not differ between treatment groups.

Table 3.

Safety outcomes.

Safety Endpoint Dapagliflozin
(N=1210)		 Placebo
(N=1179)
SAE related or probably related to study drug 2 (0.2%) 1 (0.1%)
SAE related, probably related, or possibly related to study drug 24 (2.0%) 21 (1.8%)
Adverse event leading to study drug discontinuation 58 (4.8%) 56 (4.7%)
Symptomatic hypotension* 43 (3.6%) 26 (2.2%)
Worsening kidney function† 71 (5.9%) 55 (4.7%)
Major hypoglycemia‡ 3 (0.2%) 3 (0.3%)
Diabetic ketoacidosis§ 0 (0.0%) 0 (0.0%)
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*

Symptomatic hypotension included events leading to hospitalization or study drug discontinuation

†

Worsening kidney function was defined as resulting in at least a doubling of serum creatinine, hospitalization, study drug discontinuation, dialysis, or renal death.

‡

Major hypoglycemia was defined as resulting in severe impairment in consciousness or behavior, or requiring emergency external assistance

§

Any clinically apparent diabetic ketoacidosis

Meta-analysis

Data from three trials were selected for inclusion in the meta-analysis. These studies tested dapagliflozin (DAPA ACT HF-TIMI 68),18 empagliflozin (EMPULSE),7 and sotagliflozin (subgroup analysis of patients initiated on study drug on or before the date of discharge in SOLOIST-WHF).8 Collectively, these 3 studies included 3,527 patients hospitalized for HF (Supplemental Material).7, 8 A total of 447 patients experienced cardiovascular death or a worsening HF event, and 153 patients died. In the meta-analysis, SGLT2i appeared to reduce the early risk of cardiovascular death or worsening HF by 29% (HR 0.71, 95% CI 0.54–0.93; p=0.012) and the risk of all-cause death by 43% (HR 0.57, 95% CI 0.41–0.80; p=0.001) (Figure 4). There was no between-trial heterogeneity of treatment effect for either outcome (Q=3.26 [p=0.20] and Q=1.40 [p=0.50], respectively).

Figure 4. Meta-analysis of randomized trials of in-hospital initiation of SGLT2i.

Figure 4.

Figure 4.

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Pooled estimates of the treatment effect of SGLT2i on the composite of cardiovascular death or worsening heart failure (Panel A) and on all-cause mortality (Panel B), relative to placebo, were generated using random effects models with inverse-variance weighting. There was no between-trial heterogeneity of treatment effect for either the composite outcome (Q=3.26; p=0.20) or all-cause mortality (Q=1.40; p=0.50). Pt-mos = patient-months.

Discussion

In this cardiovascular outcomes trial of patients hospitalized with a primary diagnosis of HF, in-hospital initiation of dapagliflozin did not significantly reduce the risk of cardiovascular death or worsening HF over two months. However, when the results of the DAPA ACT HF-TIMI 68 trial are considered in the context of other randomized trials evaluating in-hospital initiation of SGLT2i, the totality of evidence suggests a potential clinical benefit of this therapeutic class for reducing the early risks of cardiovascular death or worsening HF and of all-cause mortality when initiated in the inpatient setting.

In the SOLOIST-WHF trial, 596 patients were initiated on study drug on or before the date of discharge from their index HF hospitalization. In a post hoc analysis of this subgroup, sotagliflozin significantly reduced the composite of cardiovascular death or worsening HF (HR 0.54, 95% CI 0.35–0.82), and of all-cause mortality (HR 0.39, 95% CI 0.17–0.88) through 90 days.9 In the EMPULSE trial (n=530), all patients were initiated on study therapy (empagliflozin vs. placebo) while hospitalized for either newly diagnosed or worsening chronic HF, with a treatment duration of 90 days.7 Although EMPULSE was not powered to assess the impact of in-hospital initiation of SGLT2i therapy on clinical outcomes during and immediately following HF hospitalization, there were numerically lower rates of cardiovascular death or worsening HF (HR 0.69, 95% CI 0.45–1.08) and of all-cause mortality (HR 0.50, 95% CI 0.24–1.03) in patients randomly allocated to empagliflozin.

These studies had several important limitations, including modest sample sizes and lack of CEC adjudication of investigator-reported clinical events. Moreover, the short-term outcomes data for hospitalized HF patients from SOLOIST-WHF were based on a post hoc subgroup analysis, which carries a higher risk of bias compared to a full randomized trial population. In addition, there were important differences in the study populations, study designs, and follow-up durations between these two studies and the DAPA ACT HF-TIMI 68 trial. Nevertheless, these two trials contributed to a pre-trial likelihood of clinical benefit from the strategy of in-hospital initiation of SGLT2i. In a meta-analysis using all relevant trial data, there was a significant reduction in the early risk of cardiovascular death or worsening HF with SGLT2i treatment compared to placebo, with no evidence of between-trial heterogeneity in the treatment effect and with highly consistent event rates across studies. Still, given the limitations of the prior trials, which may have contributed to overly optimistic treatment effect estimates, as well as the neutral primary result of the largest and most rigorous trial contributing to the meta-analysis, we must be cautious about the magnitude of any clinical benefit from this strategy. Indeed, it may be that the true treatment effect of SGLT2i in this clinical setting is closer to the treatment effect estimate observed in DAPA ACT HF-TIMI 68.

Several factors may have contributed to the non-significant treatment difference on the primary outcome in our trial. In contrast to EMPULSE, we designed DAPA ACT HF-TIMI 68 to have a very short two-month follow-up duration given concerns about the equipoise of a placebo control beyond that time frame in the setting of data from chronic HF trials. It is possible that the risk of worsening HF events is less modifiable and related more to patient-specific factors or models of healthcare delivery in the first month following HF hospitalization. The same pattern was observed in EMPULSE with the largest treatment effect on worsening HF events emerging between 60- and 90-days post-randomization.7 In addition, to consider the impact of SGLT2i on in-hospital outcomes, we included worsening HF during the index hospitalization as a component of the primary composite outcome. Although there were very few such events in our trial, there was no suggestion that dapagliflozin reduced the risk of this outcome. Finally, there were fewer than expected primary outcome events, likely due to the high proportion of newly diagnosed HF patients, which reduced the overall power to detect a significant difference in the primary outcome.

Notably, the strongest potential efficacy signal in DAPA ACT HF-TIMI 68 as well as the other two trials of in-hospital initiation of SGLT2i was the early reduction in the risk of all-cause death. The effect on mortality appears to emerge very early, suggesting that in-hospital initiation has the potential to maximize this benefit.

We observed a modestly higher risk of symptomatic hypotension leading to hospitalization or study drug discontinuation with dapagliflozin. These data suggest that in more vulnerable populations, care should be taken to minimize other potential drivers of symptomatic hypotension, such as volume depletion or rapid escalation in the dosing of neurohormonal antagonists, when initiating SGLT2i. The rate of worsening kidney function events was low but numerically higher with dapagliflozin, consistent with the known initial decline in eGFR with SGLT2i before the long-term kidney protective effects become apparent.19, 20 Reassuringly, the rate of major hypoglycemia was low, and there were no cases of diabetic ketoacidosis. Overall, these data are highly consistent with the known safety profile of the drug class.

Conclusions

In-hospital initiation of dapagliflozin did not significantly reduce the risk of cardiovascular death or worsening HF over two months in patients admitted for HF in the DAPA ACT HF-TIMI 68 trial. However, the totality of randomized clinical trial data suggests that in-hospital initiation of SGLT2i may reduce the high risk of clinical events, including all-cause mortality, in the early post-discharge period.

Supplementary Material

Supplement
Statistical Analysis Plan

Online Supplemental Data

CONSORT checklist

Clinical Perspective.

What is new?

  • DAPA ACT HF-TIMI 68 was a randomized, double-blind, placebo-controlled trial evaluating the efficacy and safety of in-hospital initiation of dapagliflozin in patients hospitalized for heart failure (HF).

  • In this trial, in-hospital initiation of dapagliflozin did not significantly reduce the risk of cardiovascular death or worsening HF through 2 months (hazard ratio [HR] 0.86, 95% confidence interval [CI] 0.68–1.08).

  • In a prespecified meta-analysis of three trials evaluating in-hospital initiation of sodium-glucose cotransporter-2 inhibitors (SGLT2i) in patients hospitalized for HF, SGLT2i appeared to reduce the early risk of cardiovascular death or worsening HF (HR 0.71; 95% CI 0.54–0.93) and of all-cause death (HR 0.57; 95% CI 0.41–0.80).

What are the clinical implications?

  • The totality of randomized clinical trial data suggests that in-hospital initiation of SGLT2i during HF hospitalization may reduce the high risk of clinical events, including all-cause mortality, in the early post-discharge period.

Sources of Funding

AstraZeneca provided study drug and funding for the trial.

Disclosures

Dr. Berg, Dr. Patel, Dr. Haller, Ms. Cange, Mr. Palazzolo, Dr. Bellavia, Ms. Kuder, Dr. Ruff, Dr. O’Donoghue, Ms. Murphy, and Dr. Sabatine are members of the TIMI Study Group, which has received institutional research grant support through Brigham and Women’s Hospital from Abbott, Abiomed, Inc., Amgen, Anthos Therapeutics, ARCA Biopharma, Inc., AstraZeneca, Boehringer Ingelheim, Cleerly, Inc., Daiichi-Sankyo, Ionis Pharmaceuticals, Inc., Janssen Research and Development, LLC, MedImmune, Merck, Novartis, Pfizer, Regeneron Pharmaceuticals, Inc., Roche, Saghmos Therapeutics, Inc., Softcell Medical Limited, The Medicines Company, Verve Therapeutics, Inc., Zora Biosciences. Dr. Berg has received institutional research grant support through Brigham and Women’s Hospital from AstraZeneca, Merck, and Pfizer; has received consulting fees from AstraZeneca, Pfizer, Mobility Bio, and Youngene Therapeutics; has received honoraria from the Medical Education Speakers Network, Metabolic Endocrine Education Foundation, Pri-Med, and USV Private Limited; and has served on clinical endpoint committees for studies sponsored by Beckman Coulter, CeleCor Therapeutics, Kowa Pharmaceuticals, Novo Nordisk, and Tosoh Biosciences. Dr. Patel is supported by a K12TR004381 award through Harvard Catalyst, The Harvard Clinical and Translational Science Center (National Center for Advancing Translational Sciences, National Institutes of Health); and has received consultant/advisory fees from Janssen. Dr. Haller is funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation; 10086/1–1) and has received travel grants from the German Center of Cardiovascular Research (DZHK) and project grants by the German Heart Foundation. Dr. Bellavia has received consultancy fees from Arboretum LifeSciences and MarvelBiome, and honoraria from Columbia University and BioEpiEdu. Dr. Desai has received institutional research grants from Abbott, Alnylam Pharmaceuticals, AstraZeneca, Bayer, Novartis, and Pfizer; and personal consulting fees from Abbott, Alnylam Pharmaceuticals, AstraZeneca, Bayer, Biofourmis, Boston Scientific, Endotronix, GlaxoSmithKline, iRhythm Technologies, Medpace, Medtronic, Merck, Novartis, Parexel, Porter Health, Regeneron, River 2 Renal, Roche, Veristat, Verily, and Zydus. Dr. Inzucchi has received honoraria for consulting and/or clinical trial committee work from AstraZeneca, Boehringer Ingelheim, Corcept, Novo Nordisk, Pfizer, and Bayer; and has given lectures sponsored by AstraZeneca and Boehringer Ingelheim. Dr. McMurray has received payments to Glasgow University for clinical trials and other research projects from the National Institutes of Health–National Heart, Lung, and Blood Institute, AstraZeneca, Bayer, Cardurion, Cytokinetics, Novartis, and Roche; personal consultancy fees from AnaCardio, AstraZeneca, Bayer, Cardurion, Cytokinetics, Novartis, River BioMedics, Biohaven Pharmaceuticals, RyCarma Therapeutics, Inc, Regeneron, and DalCor Pharmaceuticals; and personal lecture fees from Alkem Metabolics, AstraZeneca, Canadian Medical and Surgical Knowledge Translation Research Group, Centrix Healthcare, Emcure Pharmaceuticals, Eris Lifesciences, Hikma Pharmaceuticals, Imagica Health, Intas Pharmaceuticals, J.B. Chemicals and Pharmaceuticals, Lupin Pharmaceuticals, ProAdWise Communications, Radcliffe Cardiology, Sun Pharmaceuticals, Translational Medicine Academy, and Hilton Pharmaceuticals; he serves on the Data Safety Monitoring Board of WCG Clinical Services; and he is a director at Global Clinical Trial Partners (which provides clinical trial services such as endpoint committees and educational programs). Dr. O’Meara holds the Montreal Heart Institute’s Carolyn and Richard J. Renaud Chair for Research in Heart Failure, with fees paid through her institution for this chair and for the following: Canadian Heart Function Alliance team grant, funded by the Canadian Institutes of Health Research (steering committee member), and involvement in the following trials as a steering committee member for DAPA ACT HF-TIMI 68 (TIMI Study Group and AstraZeneca), GARDEN-TIMI 74 (TIMI Study Group and Pfizer), HEART-FID (American Regent), CARDINAL-HF (Cardurion), HERMES (National Lead Investigator, Novo Nordisk), and BalancedD-HF (NLI, AstraZeneca); has received consulting fees from AstraZeneca, Boehringer Ingelheim, Bayer, Novartis, and Novo Nordisk; and has received speaker fees from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, Novo Nordisk, and Pfizer. Dr. Verma has received research grants and/or speaking honoraria from Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Canadian Medical and Surgical Knowledge Translation Research Group, Eli Lilly, HLS Therapeutics, Janssen, Novartis, Novo Nordisk, Pfizer, PhaseBio, S & L Solutions Event Management, and Sanofi. Dr. Bělohlávek has received lecture honoraria from Novartis, AstraZeneca, Boehringer Ingelheim, Getinge, Abiomed, and Resuscitec. Dr. Drożdż has received research grants from AstraZeneca; and lecture fees from Celon Pharma, Merck, Novo Nordisk and Servier Poland. Dr. Merkely has received payments for lectures or studies from Boehringer Ingelheim, Daiichi Sankyo, Duke Clinical Research Institute, and Novartis, and reports grants through his institution from Biotronik, Boehringer Ingelheim, Duke Clinical Research Institute, Eli Lilly, and Novartis. Dr. Ogunniyi has received institutional research grant support from AstraZeneca and Pfizer and serves on a clinical trial steering committee for Novartis. Dr. Izzo reports payments from AstraZeneca, Cardurion, Mineralys, and Brigham and Women’s Hospital. Dr. Ruff has received research grant support through his institution from: Anthos, AstraZeneca, Daiichi Sankyo, Janssen and Novartis, and honoraria for scientific advisory boards and consulting from: Anthos, Bayer, Bristol Myers Squibb, Daiichi Sankyo, Janssen, Pfizer. Dr. O’Donoghue reports grants to The TIMI Study Group through her institution from Amgen, AstraZeneca, Novartis, Merck, Janssen Medicines Company, consulting and/or DSMB fees from Amgen, Novartis, Janssen, AstraZeneca and CRICO, and honoraria received from Medscape Cardiology. Dr. Sabatine has received research grant support through Brigham and Women’s Hospital from: Abbott, Amgen, Anthos Therapeutics, Inc., AstraZeneca, Boehringer Ingelheim, Daiichi-Sankyo, Ionis, Marea, Merck, Novartis, Pfizer, Saghmos Therapeutics, and Verve Therapeutics, and consulting fees from: Amgen, AMPEL BioSolutions, Anthos Therapeutics, Inc., AstraZeneca, Beren Therapeutics, Boehringer Ingelheim, CCRN, Dr. Reddy’s Laboratories, General Medicines, Merck, NATF, Novo Nordisk, and Precision BioSciences. Dr. Wiviott has received research grants from Amgen, AstraZeneca, Janssen, Merck, and Pfizer; has received consulting fees from Icon, Novo Nordisk, and Verian; and has received speaking honoraria from Harvard Medical School. As of 16 June 2025, Dr. Wiviott is employed by AstraZeneca. Dr Wiviott’s wife, Dr Caroline Fox has been employed by Vertex Pharmaceuticals and Pfizer.

Non-standard Abbreviations and Acronyms

ARNI

angiotensin receptor–neprilysin inhibitor

BNP

B-type-natriuretic peptide

CEC

clinical events committee

DAPA ACT HF-TIMI 68

Dapagliflozin Effect on Cardiovascular Events in Acute Heart Failure – Thrombolysis in Myocardial Infarction 68

HF

heart failure

HFrEF

heart failure with reduced ejection fraction

KCCQ

Kansas City Cardiomyopathy Questionnaire

LVEF

left ventricular ejection fraction

MRA

mineralocorticoid receptor antagonist

NT-proBNP

N-terminal pro-B-type-natriuretic peptide

SGLT2i

sodium-glucose cotransporter-2 inhibitors

TIMI

Thrombolysis in Myocardial Infarction

TSS

total symptom score

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Supplementary Materials

Supplement
NIHMS2134685-supplement-Supplement.pdf (766.1KB, pdf)
Statistical Analysis Plan
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