# Real-World Data on Early Initiation of Sodium-Glucose Co-Transporter-2 Inhibitors in Newly Diagnosed HFrEF

Masatake Kobayashi, Luca Monzo, Guillaume Baudry, Gema Hernandez, Olivier Denquin, Kevin Duarte, Nicolas Girerd

► To cite this version:

Masatake Kobayashi, Luca Monzo, Guillaume Baudry, Gema Hernandez, Olivier Denquin, et al. Real-World Data on Early Initiation of Sodium-Glucose Co-Transporter-2 Inhibitors in Newly Diagnosed HFrEF. ESC Heart Failure, 2026, 10.1093/eschf/xvag008. hal-05527468

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Distributed under a Creative Commons CC BY 4.0 - Attribution - International License
1 **Real-World Data on Early Initiation of Sodium-Glucose Co-Transporter-2 Inhibitors in Newly Diagnosed HFrEF**
2
3 **Running title:** SGLT2i among patients with HFrEF in real world data
4
5 Masatake Kobayashi¹,², Luca Monzo¹, Guillaume Baudry¹, Gema Hernandez³, Olivier Denquin³, Kevin Duarte¹, Nicolas Girerd¹

6
7 1. Université de Lorraine, INSERM, Centre d'Investigations Cliniques Plurithématique 1433, Inserm U1116, CHRU de Nancy and F-CRIN INI-CRCT, Nancy, France.
8
9 2. Department of Cardiology, Tokyo Medical University Hospital, Tokyo, Japan.
10 3. TriNetX Europe NV, St.Martens-Latem, Belgium.

11
12
13 **Corresponding Author:** Nicolas Girerd
14
15 Centre d'Investigation Clinique 1433 module Plurithématique, CHRU Nancy - Hopitaux de Brabois, Institut Lorrain du Cœur et des Vaisseaux Louis Mathieu, Nancy, 54500, France
16 Email: n.girerd@chru-nancy.fr

17
18
19
**Total number of tables and figures:** 1 table and 3 figures

20
21
22 **Keywords:**
23 Heart failure, heart failure and reduced ejection fraction, prognosis, sodium glucose co-transporter 2 inhibitor.
# 1 Financial Disclosure

Dr. Kobayashi has received speaker fees from Boehringer Ingelheim, Bayer, AstraZeneca,

Novartis, Daiichi-Sankyo, and Ono and Mochida pharmaceutical company. Dr. Monzo

reported receiving personal fees from AstraZeneca and Vifor. Dr. Baudry reported receiving

personal fees from Abbott, AstraZeneca, and Boehringer Ingelheim. Pr. Girerd reported

receiving personal fees from Novartis, Bayer, AstraZeneca, Lilly, Boehringer, and Vifor,

outside the submitted work. Dr. Girerd is supported by the French National Research

Agency Fighting Heart Failure (ANR-15-RHU-0004), the French PIA project Lorraine

Université d'Excellence GEENAGE (ANR-15-IDEX-04-LUE) programmes, and the

Contrat de Plan Etat Région Lorraine and FEDER IT2MP; and has received honoraria from

AstraZeneca, Bayer, Boehringer, Lilly, Novartis, and Vifor. Other authors reported no

conflicts of interest regarding this manuscript.

# 13 Funding information

None for this work, including the use of data.

# 15 Author Contributions

NG designed the study; L.M, DK and NG analyzed the data; MK wrote the paper; LM, GB,

GH, OD and NG critically revised the manuscript. All the authors are familiar with the

primary data, revised and approved the submission of this manuscript.

# 19 Data Availability Statement

All data used in the generation of this paper was collected from the global TriNetX

network. The data that support the findings of this study are available from TriNetX,

LLC, https://trinetx.com/, but third-party restrictions apply to the availability of these data.

The data were used under license for this study with restrictions that do not allow the data

to be redistributed or made publicly available. However, for accredited researchers, the

TriNetX data are available for licensing at TriNetX, LLC. Data access may require a data

sharing agreement and may incur data access fees.
# 1 Ethic statement

2 This retrospective study is exempt from informed consent. The data reviewed is a
3 secondary analysis of existing data, does not involve intervention or interaction with human
4 subjects, and is de-identified per the de-identification standard defined in Section
5 §164.514(a) of the HIPAA Privacy Rule. The process by which the data is de-identified is
6 attested to through a formal determination by a qualified expert as defined in Section
7 §164.514(b)(1) of the HIPAA Privacy Rule. This formal determination by a qualified
8 expert refreshed on December 2020.
9

# 10 Abstract

# 11 Aims

12 Sodium-glucose cotransporter-2 inhibitors (SGLT2is) improve outcomes in patients with
13 heart failure (HF), and are recommended to be initiated in the 6 weeks following an HF
14 hospitalization. We aimed to explore prescription rates and clinical benefits of SGLT2is
15 among patients with newly diagnosed HF and reduced ejection fraction (HFrEF) in real-
16 world practice.

# 17 Methods

18 We conducted a retrospective analysis using the TriNetX Global Collaborative research
19 network. Patients with HFrEF who experienced their first HF hospitalization between
20 September 2021 and December 2023 were identified and were categorized into 2 groups
21 based on the initiation of SGLT2is within 6 weeks following HF hospitalization. After
22 using propensity score matching to baseline characteristics, Cox hazard ratios (HRs) were
23 calculated to compare outcomes over a 1-year period.

# 24 Results

25 Among the identified 70,042 patients with HFrEF, 21.3% were initiated on SGLT2is within
26 6 weeks following their first HF hospitalization. SGLT2i users were younger, more likely to
1

2

3

4

5

be male and had a higher prevalence of diabetes, compared with SGLT2i non-users. After matching, 14,670 matched pairs were created (mean age 64 ± 17 years; 41.6% female; 20% Black). SGLT2i users vs. non-users had a lower risk of 1-year all-cause mortality (HR, 95%CI=0.75, 0.69 to 0.83), all-cause hospitalizations (HR, 95%CI=0.86, 0.83 to 0.91), and emergency department visits (HR, 95%CI=0.91, 0.86 to 0.96).

6

## Conclusion

7

8

9

10

In this large multinational real-world data of patients with HFrEF, the prescription rate for SGLT2i within 6 weeks after the first HF hospitalization remained low. However, SGLT2i initiation was associated with improved outcomes, underscoring the importance of guideline-recommended early use.

11

12

## Introduction

13

14

15

16

17

18

19

20

The latest guidelines strongly recommend use of sodium glucose co-transporter 2 inhibitors (SGLT2is) for the treatment of heart failure (HF), regardless of left ventricular ejection fraction (LVEF), and presence or absence of diabetes (1,2). In the EMPEROR-Reduced (Cardiovascular and Empagliflozin Outcome Trial in Patients with Chronic Heart Failure and a Reduced Ejection Fraction) and the DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) trials, SGLT2i empagliflozin and dapagliflozin reduced the composite risk of cardiovascular death or hospitalization for HF in patients with HFrEF (3,4).

21

22

23

The updated European Society of Cardiology (ESC) guidelines recommended optimizing treatment before discharge and close follow-up visits in the first 6 weeks following a HF hospitalization (5). This Class I recommendation was supported by findings
1 of the Safety, Tolerability and Efficacy of Rapid Optimization, Helped by NT-proBNP

2 Testing, of Heart Failure Therapies (STRONG-HF) trial, which showed that intensified HF

3 treatment up-titration vs. usual care reduced the risk of all-cause mortality or HF

4 hospitalization over 6 months (6). Additionally, a recent meta-analysis showed that

5 SGLT2is reduced the early risk of all-cause mortality in patients hospitalized for HF (7).

6 However, initiation of SGLT2is was frequently delayed, especially in patients with newly

7 diagnosed HF, and overall prescription rates remained suboptimal in real-world practice (8-

8 10).

9 To address these potential uncertainties about the effectiveness of the early initiation

10 of SGLT2is in real-world clinical practice, we investigated its effects on clinical outcomes

11 in patients with de novo hospitalized for HF.

12 **Methods**

13 **Study population**

14 This study included individuals aged ≥18 years from 16 countries diagnosed with

15 HFrEF, who experienced a first HF hospitalization requiring intravenous diuretic therapy

16 within the preceding 6 weeks. Data were collected between September 2021 and December

17 2023 from the TriNetX Global Collaborative research network, which is a federated

18 multicenter research network that provides real-time access to an anonymized data from

19 participating healthcare organizations' electronic health records (EHRs) as described in

20 prior studies (11,12). Given regional variations in data types, new data are integrated into

21 the TriNetX common data model for syntactic harmonization. Custom connectors, tools,
1 and Application Programming Interfaces to ingest data from various common models and

2 healthcare exchange standards. Semantic harmonization is accomplished by mapping data

3 to TriNetX terminology standards, which are selected to reflect typical domain-specific data

4 capture (e.g., ICD for diagnoses) and reduce mapping burden. Medication terminologies are

5 updated quarterly, while other standards are refreshed annually. Unmapped concepts are

6 tracked, regularly reviewed, and compared against the latest standards (13).

7 A diagnosis with HFrEF was based on International Classification of Diseases-9th

8 Revision (ICD-9) and International Classification of Diseases-10th Revision, Clinical

9 Modification (ICD-10-CM) code 150.2 (i.e., 428.20, 428.21, 428.22, 428.23). Patients were

10 further divided into 2 groups based on whether they were treated or not with SGLT2i

11 (dapagliflozin or empagliflozin) within 6 weeks following an HF hospitalization.

12 **Statistical analysis**

13 Categorical variables are presented as frequencies (percentages) and continuous

14 variables as means ± standard deviations (SDs). Comparisons of baseline characteristics

15 between 2 treatment groups were analyzed using the independent-samples Student's t-tests

16 and chi-square test. All covariates are presented in *Table 1* and were matched extensively

17 by 1:1 propensity score matching method using absolute standardized difference (ASD).

18 The ASD quantifies the difference between the means of 2 groups, SGLT2i users and non-

19 users, regarding SD units to assess the balance of baseline variables in the sample weighted

20 by the inverse probability of treatment. The ASD of any baseline characteristics lower than

21 0.10 was considered well-matched.
1 Primary and secondary outcomes were analyzed over a 1-year follow-up period.

2 The primary outcome was all-cause mortality. Other secondary outcomes included all-cause

3 hospitalizations and emergency department visits. Time-to-event comparisons were

4 analyzed using log rank test and Cox proportional hazards models. Survival probabilities

5 were estimated using the Kaplan-Meier method and plotted as survival curves between

6 treatment allocations.

7 Statistical analyses were performed based on the TriNetX online platform using R

8 for statistical computing. A two-sided p-value <0.05 was considered statistically significant.

9

10 **Results**

11 **Baseline characteristics**

12 Baseline patient characteristics are presented in *Table 1*. Among 70,042 patients

13 newly diagnosed with HFrEF, 14,923 patients were initiated with SGLT2i (empagliflozin

14 53%; dapagliflozin 47%) within 6 weeks from their first HF hospitalization, while 55,119

15 patients did not receive this treatment.

16 SGLT2i users within 6 weeks were younger, more likely to be male, and Black or

17 African American, compared with SGLT2i non-users (all-P<0.001). Furthermore, SGLT2i

18 users had a higher prevalence of diabetes mellitus and ischemic heart disease, but a lower

19 prevalence of chronic kidney disease (CKD), and were more often treated with sacubitril-
20 valsartan, compared with SGLT2i non-users (all-P<0.001) (Table 1).
Following the matching process, 14,670 patients in each SGLT2i user and non-user group were retained and were included in the present analysis. The baseline characteristics of the 2 groups were well-balanced (SMD<0.1 for all covariates). Mean age was 64±17 years, 64.3% of matched participants were females, 46.1% had diabetes, 57.8% had ischemic heart disease and 26.7% had CKD. For HF treatments, 77.2% of patients were on angiotensin converting enzyme inhibitor (ACEi), angiotensin receptor blocker (ARB) or angiotensin receptor-neprilysin Inhibitor (ARNI), 66.7% were on beta-blockers and 22.9% were on mineralocorticoid receptor antagonists (MRAs) (Table 1).

## 9 Clinical outcomes

All-cause mortality was observed in 19.4% of SGLT2i users compared to 24.7% of SGLT2i non-users (hazard ratio [HR], 95% confidence interval [CI], =0.75, 0.68 to 0.83; P<0.001). Early initiation of SGLT2i after a first HF hospitalization reduced the risk of all-cause hospitalization (HR, 95%CI= 0.86, 0.83 to 0.91) and all-cause emergency department visits (HR, 95%CI= 0.91, 0.86 to 0.96). *Figure 1*.

In a landmark analysis at 6 months, risk of all-cause mortality did not differ significantly between patients who initiated SGLT2i within 6 weeks and those who did between 6 weeks and 6 months after hospitalization (HR, 95%CI= 0.94, 0.82 to 1.07).

For subgroups analysis, the efficacy of SGLT2i on mortality was consistent regardless of sex, obesity, and racial disparity (p-for-interaction >0.10). However, among patients under 75 years of age, the benefit from SGLT2i was more pronounced, while in
1 those aged 75 or older, the impact on all-cause mortality was neutral (HR, 95%CI= 1.07,

2 0.91 to 1.26; interaction p-value <0.001). *Figure 2*.

3

4 Discussion

5 In this large multinational real-world data network, we found that the initiation of

6 SGLT2is within 6 weeks following HF hospitalization was infrequent among patients with

7 newly diagnosed HFrEF. However, early initiation of SGLT2is reduced the risk of all-cause

8 mortality by 25%, hospitalization for any causes by 10% and emergency department visit

9 by 14%. The STRONG-HF trial, which supported the rapid initiation of HF treatments

10 following a hospitalization in the latest guidelines (5), primarily focused on conventional

11 HF treatments (i.e., ACEi/ARB/ARNI, β-blocker, and MRA), while a limited number of

12 patients were treated with SGLT2is per the study protocol (<10%). Nonetheless, more rapid

13 efficacy of SGLT2is was evidenced in clinical trials for chronic HFrEF (14,15).

14 Collectively, our findings suggest that the early initiation (<6 weeks) of SGLT2is, as

15 recently supported by the focused update of the ESC guidelines (5), could significantly

16 benefit clinical outcomes in patients with newly diagnosed HFrEF.

17 Patients included in the present analysis had relatively low prescription rates of HF

18 treatments as well as a low risk of mortality. Our study specifically focused on patients with

19 newly diagnosed HF, potentially explaining these observed low rates of life-saving drug use

20 and mortality risk (16-18). Furthermore, different practice patterns, in-hospital and post-

21 discharge managements and health insurances across countries may influence the prognosis
1 of patients hospitalized for HF (19,20). However, this unique analysis through the TriNetX
2 network unlocks access to global data, covering over 16 countries, thereby capturing the
3 pattern of therapeutic management on a global scale.

4 Interestingly, our results showed a greater reduction in all-cause mortality by 25%
5 with SGLT2i treatment in patients with HFrEF, which was higher than those from prior
6 published data across clinical trials for SGLT2is in HF, CKD, and type 2 diabetes (<10%
7 reduction of all-cause mortality) (3,4,21-26). Our study included patients hospitalized for
8 HF, whose prognosis were generally more likely to be impacted by the congested status.
9 The mechanisms, therefore, of the prominent effects may be underpinned by natriuretic or
10 diuretic effects of SGLT2is in the relatively early phase after its initiation (27-29). In the
11 Study to Test the Effect of Empagliflozin in Patients Who Are in Hospital for Acute Heart
12 Failure (EMPULSE) trial including 530 patients with hospitalized HF, empagliflozin vs.
13 placebo reduced all-cause mortality, HF events and symptoms at 90 days (30). In the Effect
14 of Sotagliflozin on Cardiovascular Events in Patients with Type 2 Diabetes Post Worsening
15 Heart Failure (SOLOIST-WHF) trial including 1,222 patients with recently hospitalized HF
16 and type 2 diabetes, sotagliflozin vs. placebo reduced cardiovascular deaths,
17 hospitalizations and urgent visits for HF over 9.0-month median follow-up (31).
18 Furthermore, a meta-analysis of these two trials together with the Dapagliflozin Effect on
19 Cardiovascular Events in Acute Heart Failure-Thrombolysis in Myocardial Infarction 68
20 (DAPA ACT HF-TIMI 68) trial showed that SGLT2i reduced mortality risk by 43%,
21 supporting the efficacy of SGLT2i observed in our real-world data (7). Additionally, the
22 observed reductions in hospitalization or emergency department visit suggests a potential
1 benefit of SGLT2i in preventing subsequent life-threatening events in individuals with

2 HFrEF, which align with the EMPEROR-reduced and DAPA-HF trials (15,32).

3 Interestingly, our landmark analysis showed that long-term outcomes appeared similar once

4 SGLT2i therapy was eventually initiated. However, even if long-term outcomes converge,

5 delays in SGLT2i initiation can still expose patients to preventable adverse events during

6 the vulnerable post-hospitalization phase (i.e., within the first 6 months).

7 Our results from large-sized data may also address several key uncertainties

8 regarding the potential efficacy of SGLT2i in under-represented subgroups of patients with

9 HFrEF such as women and Black patients (33). Although these clinical presentations may

10 influence an HF risk and the effects of certain HF treatments (34-36), we observed no

11 significant heterogeneity in the clinical benefits of SGLT2i across different sex, body mass

12 index and racial categories. These findings are supported by prior published data from

13 SGLT2i trial for chronic HFrEF (37-40) and provide the robust evidence regarding the

14 initiation of SGLT2i within 6 weeks following a first HF hospitalization. Additionally, our

15 analysis showed that older patients experienced diminished mortality benefits from

16 SGLT2i, likely reflecting both biological factors (e.g., frailty, multimorbidity and impaired

17 drug metabolism) and practical barriers (e.g., suboptimal dosing, polypharmacy, reduced

18 adherence, and limited monitoring) (41).

19 Randomized clinical trials showed in-hospital initiation of SGLT2i to be safe and

20 provide significant early post-discharge benefits on patient symptoms and quality of life

21 (30,31). Taken together, the present study is the first global study addressing the real-world
1 effectiveness of SGLT2i in a very large number of patients with newly diagnosed HFrEF.

2 These findings highlight the merits of early SGLT2i initiation and further support current

3 recommendations advocating early initiation of guideline-directed therapies in patients

4 hospitalized or recently discharged following acute HF (42,43).

5 Limitations

6 The results presented should be interpreted within the context of several potential
7 limitations. This retrospective study was observational in nature, and despite robust
8 propensity score matching, the possibility of residual or unmeasured confounding cannot be
9 excluded. Differences in healthcare systems, patient socioeconomic status, and clinical
10 practice patterns across 16 participating countries, as well as unmeasured clinically relevant
11 variables (e.g., natriuretic peptide levels, LVEF and doses of ACEi/ARB, ARNI, or beta-
12 blocker) may have influenced our results. Although we focused on patients with newly
13 diagnosed HF, this study included those with relatively low prescription rates of HF
14 treatments as well as a low mortality risk (16-18). An EHR-based data network is
15 susceptible to errors in coding, particularly for HFrEF diagnosis. Additionally, outcomes
16 that occurred outside of the TriNetX network were not well captured. We lack specific
17 information on the causes of death, hospitalization, and emergency department visits;
18 however, patients with hospitalized HFrEF, generally, tend to experience HF-related events
19 rather than non-cardiac causes during the 1-year post-discharge period (44,45).
20 Nonetheless, the present analysis included a substantially large number of patients,
1 potentially sufficient to mitigate the effects of “random noise”; for example, stemming from

2 non-cardiovascular deaths (46).

3

4 **Conclusions**

5 In this large multinational real-world data of patients with HFrEF, the prescription rate for

6 SGLT2i within 6 weeks after the first HF hospitalization remained limited. However,

7 SGLT2i initiation during this period was associated with improved clinical outcomes.

8 These findings highlight the importance of early initiation, as endorsed by the latest

9 guidelines.

10

11 **(references)**

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18 ejection fraction: Finding the right patients to treat. Journal of internal medicine

19 2023;293:550-558.

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21 heart failure: an updated evidence-based practical guidance for clinicians. Eur Heart

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7 46. Solomon SD, Wang D, Finn P et al. Effect of candesartan on cause-specific mortality in heart failure patients: the Candesartan in Heart failure Assessment of Reduction in Mortality and morbidity (CHARM) program. Circulation 2004;110:2180-3.

<table><caption>**Table 1. Baseline Characteristics before and after propensity score matching**</caption><tr><td>13</td><td>Values are Mean ±SD, n (%) or median (25th to 75th percentile)</td></tr><tr><td>14</td><td>SGLT2i, sodium glucose co-transporter 2 inhibitor; COPD, chronic obstructive pulmonary disease; ACEi,</td></tr><tr><td>15</td><td>angiotensin converting enzyme inhibitor; ARB, angiotensin receptor blocker; ARNI, angiotensin receptor</td></tr><tr><td>16</td><td>neprilysin inhibitor; MRA, mineralocorticoid receptor antagonist.</td></tr><tr><td>17</td><td></td></tr><tr><td>18</td><td></td></tr></table>
<table><caption>1 Table 1. Baseline Characteristics before and after propensity score matching</caption><thead><tr><th rowspan="2"></th><th colspan="3">Before matching</th><th colspan="3">After matching</th></tr><tr><th>SGLT2i users (N=14,923)</th><th>SGLT2i non-users (N=55,119)</th><th>P-Value</th><th>Absolute standardized difference</th><th>SGLT2i users (N=14,670)</th><th>SGLT2i non-users (N=14,670)</th><th>P-Value</th><th>Absolute standardized difference</th></tr></thead><tbody><tr><td>Age, years</td><td>63.8±14.5</td><td>68.2±16.1</td><td>&lt;0.001</td><td>0.287</td><td>64.0±14.4</td><td>64.1±16.7</td><td>0.658</td><td>0.005</td></tr><tr><td>Male, N (%)</td><td>9556 (64.0 %)</td><td>32053 (58.2 %)</td><td>&lt;0.001</td><td>0.121</td><td>9364 (63.8 %)</td><td>9438 (64.3 %)</td><td>0.368</td><td>0.011</td></tr><tr><td>Race, N (%)</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>White</td><td>9060 (60.7 %)</td><td>36916 (67 %)</td><td>&lt;0.001</td><td>0.131</td><td>8957 (61.1 %)</td><td>9002 (61.4 %)</td><td>0.590</td><td>0.006</td></tr><tr><td>Black</td><td>3066 (20.5 %)</td><td>8974 (16.3 %)</td><td>&lt;0.001</td><td>0.110</td><td>2968 (20.2 %)</td><td>2927 (20.0 %)</td><td>0.550</td><td>0.007</td></tr><tr><td>Medical history, N (%)</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Hypertension</td><td>7764 (52.0 %)</td><td>29909 (54.3 %)</td><td>&lt;0.001</td><td>0.045</td><td>7636 (52.1 %)</td><td>7520 (51.3 %)</td><td>0.175</td><td>0.016</td></tr><tr><td>Diabetes mellitus</td><td>6893 (46.2 %)</td><td>21986 (39.9 %)</td><td>&lt;0.001</td><td>0.128</td><td>6728 (45.9 %)</td><td>6766 (46.1 %)</td><td>0.656</td><td>0.005</td></tr><tr><td>Ischemic heart disease</td><td>8688 (58.2 %)</td><td>29868 (54.2 %)</td><td>&lt;0.001</td><td>0.081</td><td>8527 (58.1 %)</td><td>8480 (57.8 %)</td><td>0.578</td><td>0.006</td></tr><tr><td>Myocardial infarction</td><td>4855 (32.5 %)</td><td>17351 (31.5 %)</td><td>0.014</td><td>0.023</td><td>4776 (32.6 %)</td><td>4770 (32.5 %)</td><td>0.940</td><td>0.001</td></tr><tr><td>Atrial fibrillation</td><td>5808 (38.9 %)</td><td>24515 (44.5 %)</td><td>&lt;0.001</td><td>0.113</td><td>5735 (39.1 %)</td><td>5738 (39.1 %)</td><td>0.971</td><td>&lt;0.001</td></tr><tr><td>Overweight/obesity</td><td>4483 (30.0 %)</td><td>14656 (26.6 %)</td><td>&lt;0.001</td><td>0.077</td><td>4380 (29.9 %)</td><td>4460 (30.4 %)</td><td>0.309</td><td>0.012</td></tr><tr><td>COPD</td><td>4038 (27.1 %)</td><td>16720 (30.3 %)</td><td>&lt;0.001</td><td>0.072</td><td>3983 (27.2 %)</td><td>3999 (27.3 %)</td><td>0.834</td><td>0.002</td></tr><tr><td>Chronic kidney disease</td><td>4092 (27.4 %)</td><td>20128 (36.5 %)</td><td>&lt;0.001</td><td>0.196</td><td>4057 (27.7 %)</td><td>3920 (26.7 %)</td><td>0.072</td><td>0.021</td></tr><tr><td>Cerebrovascular disease</td><td>1947 (13.0 %)</td><td>10143 (18.4 %)</td><td>&lt;0.001</td><td>0.148</td><td>1937 (13.2 %)</td><td>1871 (12.8 %)</td><td>0.252</td><td>0.013</td></tr><tr><td>Medication, N (%)</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Beta-blocker</td><td>10025 (67.2 %)</td><td>37952 (68.9 %)</td><td>&lt;0.001</td><td>0.036</td><td>9830 (67.0 %)</td><td>9792 (66.7 %)</td><td>0.637</td><td>0.006</td></tr><tr><td>ACEi</td><td>3382 (22.7 %)</td><td>12368 (22.4 %)</td><td>0.56</td><td>0.005</td><td>3333 (22.7 %)</td><td>3265 (22.3 %)</td><td>0.342</td><td>0.011</td></tr><tr><td>ARB</td><td>5866 (39.3 %)</td><td>14326 (26 %)</td><td>&lt;0.001</td><td>0.287</td><td>5620 (38.3 %)</td><td>5560 (37.9 %)</td><td>0.471</td><td>0.008</td></tr><tr><td>ARNI</td><td>2804 (18.8 %)</td><td>3737 (6.8 %)</td><td>&lt;0.001</td><td>0.366</td><td>2564 (17.5 %)</td><td>2488 (17.0 %)</td><td>0.24</td><td>0.014</td></tr><tr><td>MRA</td><td>3601 (24.1 %)</td><td>7190 (13.0 %)</td><td>&lt;0.001</td><td>0.288</td><td>3385 (23.1 %)</td><td>3365 (22.9 %)</td><td>0.781</td><td>0.003</td></tr><tr><td>Loop diuretic</td><td>14913 (99.9 %)</td><td>55119 (100 %)</td><td>&lt;0.001</td><td>0.037</td><td>14669 (100 %)</td><td>14670 (100 %)</td><td>0.317</td><td>0.012</td></tr><tr><td>Laboratory</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Creatinine, mg/dl</td><td>1.5±5.5</td><td>1.7±4.2</td><td>&lt;0.001</td><td>0.041</td><td>1.5±5.6</td><td>1.3±2.6</td><td>&lt;0.001</td><td>0.046</td></tr><tr><td>≤1.20 mg/dL</td><td>10300 (69.0 %)</td><td>35651 (64.7 %)</td><td>&lt;0.001</td><td>0.092</td><td>10130 (69.1 %)</td><td>10199 (69.5 %)</td><td>0.383</td><td>0.010</td></tr></tbody></table>
<table><tr><td>1.20 to 1.50 mg/dL</td><td>5161 (34.6 %)</td><td>19275 (35 %)</td><td>0.381</td><td>0.008</td><td>5074 (34.6 %)</td><td>4960 (33.8 %)</td><td>0.161</td><td>0.016</td></tr><tr><td>1.50 to 2.00 mg/dL</td><td>3328 (22.3 %)</td><td>14735 (26.7 %)</td><td>&lt;0.001</td><td>0.103</td><td>3299 (22.5 %)</td><td>3243 (22.1 %)</td><td>0.432</td><td>0.009</td></tr><tr><td>2.00 to 3.00 mg/dL</td><td>1598 (10.7 %)</td><td>9929 (18.0 %)</td><td>&lt;0.001</td><td>0.209</td><td>1594 (10.9 %)</td><td>1570 (10.7 %)</td><td>0.651</td><td>0.005</td></tr><tr><td>&gt;3.00 mg/dL</td><td>577 (3.9 %)</td><td>6842 (12.4 %)</td><td>&lt;0.001</td><td>0.316</td><td>577 (3.9 %)</td><td>554 (3.8 %)</td><td>0.486</td><td>0.008</td></tr></table>

1

2
1 **Graphical abstract**

2

3

4 **Figure 1. Survival curves for the primary endpoint of all-cause mortality, and**

5 **secondary endpoints of all-cause hospitalizations and emergency department visits**

6 SGLT2i, sodium glucose co-transporter 2 inhibitor; HR, hazard ratio; CI, confidence

7 interval.

8

9

10 **Figure 2. Subgroup analysis for all-cause mortality**

11 SGLT2i, sodium glucose co-transporter 2 inhibitor; HR, hazard ratio; CI, confidence

12 interval.

13
# 1 Graphical abstract

## Real World Data on Early Initiation of SGLT2i in de novo HFrEF

<figure><img src="image_2.png" /></figure>

70,042 pts
from 16 countries

<figure><img src="image_3.png" /></figure>

Hospitalised de
novo HFrEF

<figure><img src="image_4.png" /></figure>

September 2021 – December 2023

### Aim

To explore early SGLT2i use within 6 weeks after de novo HFrEF hospitalization and subsequent benefit

### Findings

- 21.3% initiated SGLT2i is within 6 weeks after first HF hospitalization.

- After propensity score matching on 19 variables (e.g., age, diabetes, renal function), 14,670 balanced pairs were obtained (ASD <0.10).

- Early SGLT2i use was associated with significantly lower clinical events rates.

<figure><img src="image_5.png" /></figure>

<figure><img src="image_6.png" /></figure>

<figure><img src="image_7.png" /></figure>

2

3
<figure><img src="image_8.png" /><figcaption>Figure 1. Survival curves for the primary endpoint of all-cause mortality, and secondary endpoints of all-cause hospitalizations and emergency department visits</figcaption></figure>
<figure><img src="image_9.png" /><figcaption>1 Figure 2. Subgroup analysis for all-cause mortality</figcaption></figure>