Comparative Outcomes of Empagliflozin to Dapagliflozin in Patients With Heart Failure

Key Points Question What are the comparative outcomes of empagliflozin and dapagliflozin in reducing all-cause mortality and hospitalizations in patients with heart failure? Findings In this cohort study of 28 075 patients with heart failure naive to sodium-glucose cotransporter-2 inhibitor therapy, patients who started using empagliflozin were less likely to experience the primary outcome of composite of all-cause mortality or hospitalization compared with those who started using dapagliflozin. Meaning These findings suggest that further studies are needed to clarify mechanisms that could explain outcomes of empagliflozin and dapagliflozin in patients with heart failure.


Introduction
The sodium-glucose cotransporter-2 (SGLT2) inhibitors empagliflozin and dapagliflozin reduce cardiovascular death and heart failure hospitalizations in patients with heart failure. 1 However, cardiac medications within the same class may not all have the same benefit.For example, carvedilol reduces mortality by 16% relative to metoprolol in patients with heart failure, 2 and chlorthalidone is more potent than hydrochlorothiazide in the treatment of essential hypertension. 3In patients with diabetes, empagliflozin may be associated with greater weight loss, reduction of blood pressure, and reduction of cholesterol compared with dapagliflozin. 4 In patients with heart failure, a single center retrospective study suggested that empagliflozin may be associated with improvements in left ventricular ejection fraction and functional status compared with dapagliflozin. 5 However, the outcomes of empagliflozin vs dapagliflozin on clinically important patient-centered outcomes for patients with heart failure is unclear.In this multicenter retrospective cohort study, we sought to compare the composite outcome of all-cause mortality and hospitalization between those initiated on empagliflozin vs dapagliflozin in patients with heart failure.

Methods
This study follows the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.Informed consent and review were not required because this study was designated to not be human participant research by the institutional review board of Boston University.

Data Source and Cohort
We used the TriNetX Research Collaborative Network, 6,7 a network of 81 health care organizations primarily in North America that contribute deidentified electronic medical record data to a central database.We included patients with heart failure (International Statistical Classification of Diseases and Related Health Problems, Tenth Revision [ICD-10] code: I50x), who had never received SGLT2 inhibitors previously, and were newly started on empagliflozin or dapagliflozin.Patients were included if they met criteria between August 18, 2021 (after publication of the Dapagliflozin Evaluation to Improve the Lives of Patients with Preserved Ejection Fraction Heart Failure, or DELIVER, Trial 8 and after both SGLT2 inhibitors were approved for heart failure by the US Food and Drug Administration), 9,10 and December 6, 2022 (to allow all patients to have 1-year of follow-up time).Study day 0 was defined as the day of SGLT2 inhibitor initiation.

Exposure
The intervention group was defined as initiation of empagliflozin, and the comparator group was defined as initiation of dapagliflozin.Consistent with an intention-to-treat clinical trial, all patients were analyzed according to the SGLT2 inhibitor initially received, regardless of changes in medication use after initiation.

Outcomes
The primary outcome was the time to the composite of all-cause mortality or hospitalization between study days 1 to 365.Due to limitations in the online TriNetX Query Builder and Analytics platforms, we were unable to determine cause-specific mortality or hospitalizations.Secondary outcomes were all-cause mortality, hospitalization, and last measured hemoglobin A 1c .Adverse effects were defined as occurrence of urinary tract infection (ICD-10 code: N39.0) or diabetic ketoacidosis (ICD-10 codes: E10.1x or E11.1x).

Statistical Analysis
Prior to matching, covariables were summarized using mean (SD) and No. (%) as appropriate.We generated propensity scores for empagliflozin vs dapagliflozin initiation using logistic regression and included all covariables in the model.Covariables, except for age, were included in the model as categorical variables.For other variables that were originally continuous (glomerular filtration rate, hemoglobin A 1c , natriuretic peptides, and left ventricular ejection fraction), values were assigned into clinically relevant categories.This categorization allows for the inclusion of all covariables and patients in the models, even in the setting of multiple measurements or missing data.For example, a patient with no hemoglobin A 1c measured in the year prior to study day 0 would be assigned a 0 for all hemoglobin A 1c categories, and a patient with multiple hemoglobin A 1c measurements in the year prior to study day 0 could potentially be assigned a 1 for multiple hemoglobin A 1c categories.After propensity score generation, we used 1:1 greedy nearest neighbor propensity score matching without replacement to create balanced cohorts.Balance was visualized using density curves of the propensity score and formally assessed using absolute standardized mean differences (SMDs) with a SMD of less than 0.1 defining similarity.We then used the Kaplan-Meier method 11 and log-rank test to compare outcomes between matched groups; hazard ratios (HRs), 95% CIs, and absolute risk differences (95% CI) were also reported.Patients were censored from the Kaplan-Meier analysis on the day after the last fact in their TriNetX record.4][15] We repeated analyses in patients with heart failure with reduced ejection fraction (HFrEF) (ICD-10 codes: I50.2x or I50.4x) and heart failure with preserved ejection fraction (HFpEF) (ICD-10 codes: I50.3x or I50.4x).For the secondary outcome of last measured hemoglobin A 1c , patients with no values were excluded from the analysis and the t statistic was used to compare mean values between patients who received empagliflozin and dapagliflozin.
Cohort identification and statistical analyses were conducted using the TriNetX Platform 16 Query Builder and Analytics Functions, respectively, on December 6, 2023.This point-and-click platform allows users to conduct observational studies using curated variable definitions and a limited set of analytic approaches.Kaplan-Meier curves were recreated using R version 4.2.1 (R Project for Statistical Computing).α was set at .05, and all hypothesis tests were 2-sided.We did not account for multiple testing.Thus, secondary outcomes and analyses should be considered hypothesis generating only.

Discussion
In this multicenter retrospective cohort study that used clinical data, patients who initiated empagliflozin were less likely to experience the composite of all-cause mortality or hospitalization compared with patients who initiated dapagliflozin.These results were determined by differences in rates of hospitalization.Our results suggest that there were possible differences in medication outcomes between specific medications within the SGLT2 inhibitor class.Future studies are needed to clarify potential mechanisms that could explain the observed differences.Our results should be considered in the context of prior work.A small, single center retrospective study found that empagliflozin (vs dapagliflozin) was associated with greater increases in left ventricular ejection fraction and New York Heart Association Class. 5The results of Hao et al 17   and our own may suggest that there are differences in the degree of cardiac remodeling between different SGLT2 inhibitors.Unlike our results, a recent meta-analysis 1 of clinical trials showed similar improvements in cardiovascular outcomes between empagliflozin and dapagliflozin compared with placebo.We speculate that the discrepant results between the association and observational outcomes data could be explained by differences in adherence (that were unable to be determined in our study) or differences in comorbidity burden (eg, diabetes) and treatments 4,19 that could lead to synergistic outcomes of empagliflozin relative to dapagliflozin 4 or differences in all-cause outcomes associated with heart failure-specific outcomes.Future studies should explore potential mechanisms by which the association and outcomes may differ and directly compare outcomes of empagliflozin to dapagliflozin in a pragmatic comparative effectiveness randomized controlled trial.

Limitations
This study has limitations.Observational studies are at risk for unmeasured confounding (eg, New York Heart Association functional class); however, the E-value of 1.36 suggests that our findings would only be altered in the presence of an unmeasured confounder with a 30% or greater association with treatment assignment and outcome.

Conclusions
In this cohort study using propensity score matching, empagliflozin was associated with lower rates of hospitalization at 1 year compared with dapagliflozin.Future studies are needed confirm these findings and to understand why outcomes may differ from those of efficacy trial meta-analyses.

Figure 1 .
Figure 1.Study Flow Diagram SI conversion factors: To convert B-type natriuretic peptide to ng/L, multiply by 1.0; hemoglobin A 1c to proportion of total hemoglobin, multiply by 0.01; N-terminal pro-brain natriuretic peptide, multiply by 1.0.a To protect patient confidentiality, values of 10 may represent fewer than 10 patients.SMDs less than 0.1 suggest balance of characteristics between exposure groups.b Other race is defined internally by TriNetX.c International Statistical Classification of Diseases and Related Health Problems, Tenth Revision code Z55-Z65.

Figure 2 .
Figure 2. Survival Curve and Associated 95% CIs for the Composite Outcome of All-Cause Mortality or Hospitalization 1.00 Empagliflozin vs Dapagliflozin in Patients With Heart FailureCovariablesFrom each patient, we extracted covariables from study days −365 to 0 for inclusion in propensity score models that we thought were likely to confound the association between SGLT2 inhibitor selection and the composite outcome.Covariables included demographics, cardiac and diabetes- JAMA Network Open.2024;7(5):e249305.doi:10.1001/jamanetworkopen.2024.9305(Reprinted) May 2, 2024 2/9 Empagliflozin vs Dapagliflozin in Patients With Heart Failure with those who received empagliflozin (Table).Postmatching characteristics (11 007 patients per group) were all similar between groups (Table).The largest difference in covariables after matching was for the use of angiotensin converting enzyme inhibitors (empagliflozin: 2917 [26.5%] vs dapagliflozin: 2982 [27.1%];SMD, 0.013).Propensity score density curves before and after matching are shown in eFigure 1 in Supplement 1.

Table .
Characteristics of Patients With Heart Failure in the 12 Months Prior to Empagliflozin or Dapagliflozin Initiation a (continued) Current guidelines18recommend treating patients with heart failure with quadruple therapy, including angiotensin receptor-neprilysin inhibitors, SGLT2 inhibitors, β blockers, and mineralocorticoid receptor antagonists.In our study, use of each component of quadruple therapy ranged from approximately 30% to 80% of patients.The reasons that patients did not receive all components of quadruple therapy is unclear.Our results should not be used as evidence to include empagliflozin over dapagliflozin in quadruple therapy regimens.We were unable to calculate cause-specific mortality or hospitalization due to limitations in the TriNetX platform.TriNetX platform limitations did not allow us to calculate cluster-robust standard errors to account for pair membership or patient practice clustering.Finally, due to the platform limitations, we were unable to determine the specific onset of heart failure in included patients, thus unable to quantify potential risks for immortal time bias.20However,both exposures in this study have the same indications, and inclusion was limited to time after both treatments were available and approved for use in patients with heart failure, all of which likely minimize risks of immortal time.