Background: Empagliflozin and dapagliflozin are both approved for the treatment of chronic heart failure (CHF), but their comparative efficacy remains uncertain. Therefore, we aimed to prospectively compare the effects of 10 mg empagliflozin and 10 mg dapagliflozin on NT-proBNP levels and clinical outcomes in patients with stable CHF.

Methods and Results: In this single-center, open-label, prospective crossover study, 25 patients with stable CHF (age 74.3±11.9 years; 68% male) were enrolled. Patients were initially treated with either empagliflozin (n=6) or dapagliflozin (n=19) for ≥3 months before switching to the alternative agent. Follow-up assessments were conducted 1 month after the switch. Patients then selected their preferred agent and were followed for ≥1year. NT-proBNP levels were significantly higher in patients initially treated with empagliflozin compared to those treated with dapagliflozin (3,334±2,107 vs. 1,101±923 pg/mL, P=0.001). However, NT-proBNP levels did not change significantly in either group following the crossover. During follow-up, 6 patients (24%) were hospitalized for worsening HF, with no significant difference between treatment groups. Notably, NT-proBNP ≥1,453 pg/mL was significantly associated with poorer outcomes (P=0.008).

Conclusions: In this crossover study, empagliflozin and dapagliflozin showed comparable effects on NT-proBNP levels and clinical outcomes, supporting their interchangeable use in stable CHF.

Originally developed as antidiabetic agents, sodium-glucose cotransporter-2 inhibitors (SGLT2i) now have a substantially expanded role in cardiovascular medicine with demonstrated benefits that extend beyond glycemic control.¹ These agents not only improve glucose regulation in patients with diabetes but also markedly reduce heart failure (HF)-related hospitalizations and improve survival outcomes. Large-scale clinical trials have confirmed that SGLT2i confer consistent benefits in patients with chronic HF (CHF), irrespective of diabetic status or left ventricular ejection fraction (LVEF).^2–5 Consequently, they are now regarded as cornerstone therapies for the management of both diabetes and HF.^6–10

In Japan, both empagliflozin and dapagliflozin at a dose of 10 mg are approved for the treatment of CHF. However, their relative therapeutic potency in this setting remains unclear. In diabetes management, empagliflozin is typically prescribed at 10 mg with a maximum dose of 25 mg, whereas dapagliflozin is initiated at 5 mg and titrated up to a maximum of 10 mg. Accordingly, 10 mg of empagliflozin is considered a standard dose, whereas the same dose of dapagliflozin is regarded as relatively higher, raising the hypothesis that dapagliflozin may exert a more potent therapeutic effect in HF.

To address this clinical uncertainty, we conducted a prospective crossover study directly comparing the effects of 10 mg empagliflozin and 10 mg dapagliflozin in patients with stable CHF.

This single-center, open-label, prospective crossover study was conducted with the approval of the Ethics Committee of Saiseikai Fukuoka General Hospital (approval no. 2023-9-1). All procedures strictly adhered to the principles outlined in the Declaration of Helsinki, ensuring the highest ethical standards in research. The study was conducted within the framework of health insurance coverage.

The primary objective of this study was to evaluate the effect of switching between 10 mg of empagliflozin and 10 mg of dapagliflozin on N-terminal prohormone of B-type natriuretic peptide (NT-proBNP) levels in patients with CHF. The study population consisted of outpatients receiving CHF treatment. Eligible patients had to have been on a stable regimen of either 10 mg of empagliflozin or 10 mg of dapagliflozin for ≥3 months and in a stable clinical condition. There were no restrictions regarding age, sex, type of underlying heart disease or LVEF.

Patients were excluded if they had been hospitalized for any reason, including non-cardiac conditions, within the past 3 months or had undergone changes in diuretic or cardiovascular medications during the same period. Additionally, patients with an estimated glomerular filtration rate (eGFR) <25 mL/min/1.73 m² were excluded.

After obtaining informed consent, patients on 10 mg of empagliflozin were switched to 10 mg of dapagliflozin, and vice versa. Baseline data, including ECGs, chest X-rays, and blood tests collected within 1 month prior to the medication switch, were used. If these tests had not been performed within this timeframe, they were conducted with the patient’s consent before initiating the switch. Additionally, echocardiographic data obtained within the 3 months before the switch were included as baseline measurements.

Follow-up evaluations were conducted 1 month (28–35 days) after the medication switch, using the same tests and measurements obtained at baseline. These results were compared with baseline data to assess the effects of the crossover. After completing the crossover period, patients had the option to continue either their original medication or the newly introduced drug based on their preference. Patients were subsequently followed for ≥1 year.

All statistical analyses were performed using EZR version 1.54 (Saitama Medical Center, Jichi Medical University, Saitama, Japan), a graphical user interface for R (The R Foundation for Statistical Computing, Vienna, Austria).¹¹ Continuous variables are presented as mean±standard deviation. Comparisons between 2 independent groups were conducted using the unpaired Student’s t-test, while paired comparisons were performed using the paired Student’s t-test.

Categorical variables are expressed as frequencies and percentages and were compared using the chi-squared test or Fisher’s exact test, as appropriate. Survival curves were constructed using Kaplan-Meier analysis and compared using the log-rank test. Receiver operating characteristic curve analysis was used to determine optimal cutoff values for converting continuous variables into categorical variables.

All statistical tests were two-tailed, and P<0.05 was considered statistically significant.

Between September 2023 and February 2024, 25 patients with CHF receiving either empagliflozin or dapagliflozin were enrolled in this study. Their mean age was 74.3±11.9 years, 17 patients (68%) were male, 6 patients were treated with empagliflozin and 19 were treated with dapagliflozin.

The types of underlying heart disease were coronary artery disease (6 patients, 24%), including old myocardial infarction; valvular heart disease (3 patients, 12%), including aortic stenosis and mitral regurgitation; and cardiomyopathy (15 patients, 60%), including dilated, hypertrophic, and transthyretin amyloid cardiomyopathy. One patient (4%) had a history of decompensated HF due to tachycardia with atrial fibrillation (AF).

LVEF was <40% in 9 patients (36%). Among the 16 patients with LVEF >40%, 5 (31%) had a history of HF with reduced EF. At baseline, cardiac rhythm was sinus in 19 patients (76%) and AF in 6 patients (24%).

Diabetes mellitus was diagnosed in 13 patients (52%) with a hemoglobin (Hb) A1c of 6.67±0.61%. Most patients (92%) had chronic kidney disease with eGFR <60 mL/min/1.73 m². Baseline NT-proBNP levels were 1,636±1,584 pg/mL.

As summarized in Table 1, the key clinical characteristics of patients initially treated with empagliflozin were not significantly different from those treated with dapagliflozin, including age, sex, underlying heart disease, body weight, blood pressure, heart rate, cardiac rhythm, LVEF, eGFR, and HbA1c. However, NT-proBNP levels were significantly higher in patients initially treated with empagliflozin (3,334±2,107 pg/mL) than in those treated with dapagliflozin (1,101±923 pg/mL, P=0.001).

At 1 month after switching between empagliflozin and dapagliflozin, all baseline tests and measurements, except for echocardiography, were re-evaluated. As summarized in Table 2, no significant changes were observed in key clinical parameters, including body weight, blood pressure, heart rate, eGFR, and HbA1c.

Although NT-proBNP levels were significantly higher at baseline in patients initially treated with empagliflozin compared to those treated with dapagliflozin, no significant changes were observed after the medication switch in either direction (empagliflozin to dapagliflozin: 3,334±2,107 to 3,236±1,947 pg/mL; dapagliflozin to empagliflozin: 1,101±923 to 1,224±1,104 pg/mL, P=0.146), as illustrated in Figure 1. These results suggested that empagliflozin and dapagliflozin offer comparable therapeutic efficacy when exchanged under stable clinical conditions.

Figure 1.

Changes in clinical parameters with empagliflozin and dapagliflozin treatment: (A) hemoglobin (Hb) A1c, (B) systolic blood pressure (SBP), and (C) N-terminal prohormone of B-type natriuretic peptide (NT-proBNP).

Furthermore, as shown in Table 3, clinical characteristics did not significantly differ between patients with lower NT-proBNP levels while on empagliflozin and those with lower levels while on dapagliflozin, indicating no clear clinical predictors of a more favorable response to either drug.

Following the crossover, 13 patients selected empagliflozin and 12 chose dapagliflozin. Most patients based their decision on a better NT-proBNP response. However, 2 patients preferred empagliflozin due to reduced dizziness, 1 preferred dapagliflozin due to less dyspnea, and 1 chose empagliflozin because of lower cost.

During the 1-year follow-up period, 6 patients were hospitalized for worsening HF: 3 had been taking empagliflozin (3/13), and 3 had been on dapagliflozin (3/12). As shown in Figure 2A, there was no significant difference in freedom from decompensated HF between the 2 groups (P=0.898).

Figure 2.

Survival curves for freedom from decompensated heart failure or all-cause death: (A) patients treated with empagliflozin vs. dapagliflozin, and (B) patients with N-terminal prohormone of B-type natriuretic peptide (NT-proBNP) levels above vs. below 1,453 pg/mL.

When comparing patients who developed decompensated HF (n=6) with those who did not (n=19), there were no significant differences in clinical characteristics such as age, sex, underlying heart disease, body weight, blood pressure, heart rate, cardiac rhythm, LVEF, eGFR, or HbA1c. However, NT-proBNP levels were significantly higher in the patients who experienced decompensation (2,848±1,119 vs. 1,346±1,542 pg/mL, P=0.039).

Receiver operating characteristic analysis identified a cutoff NT-proBNP value of 1,453 pg/mL. As illustrated in Figure 2B, patients with values above this threshold had significantly poorer outcomes than those with lower levels (P=0.00819), supporting NT-proBNP as a surrogate marker of HF severity.

No adverse drug reactions or treatment discontinuations occurred during the study period, suggesting that both empagliflozin and dapagliflozin were well tolerated in this patient population.

This prospective crossover study is the first to directly compare the effects of empagliflozin and dapagliflozin in the same patients with stable CHF. The results demonstrated no significant differences in NT-proBNP levels or clinical outcomes between drugs. These findings suggested that both empagliflozin and dapagliflozin offer comparable therapeutic efficacy and may be used interchangeably in the management of stable HF.

Both NT-proBNP and BNP levels are well-established biomarkers that reflect the severity of HF.^10,12–14 In the EMPEROR-Reduced trial, higher baseline NT-proBNP levels were associated with increased risk of adverse HF and renal outcomes, while post-treatment NT-proBNP levels with empagliflozin were more predictive of subsequent prognosis than baseline values.¹⁵ Based on those findings, NT-proBNP was selected as the primary endpoint in the present study to assess the pharmacological effects of SGLT2i in patients with HF.

At the outset, we hypothesized that 10 mg of dapagliflozin might exert greater therapeutic effects than 10 mg of empagliflozin. This assumption was based on pharmacological considerations: 10 mg of empagliflozin is considered a standard dose, while 10 mg of dapagliflozin is regarded as the maximum dose. Indeed, baseline NT-proBNP levels were significantly lower in patients initially treated with dapagliflozin compared to those treated with empagliflozin (Table 1). However, NT-proBNP levels did not change significantly in either group following the crossover (Figure 1), and no differences were observed in other clinical parameters (Table 2). At the individual level, NT-proBNP responses varied, with no identifiable clinical characteristics predicting a more favorable response to either agent (Table 3).

Several studies have evaluated the pharmacological potency of SGLT2i using inhibition rates of renal glucose reabsorption and changes in urinary glucose excretion. For empagliflozin, renal glucose reabsorption inhibition has been reported as 36%, 42%, and 45% for 10 mg, 25 mg, and 100 mg doses, respectively.¹⁶ For 10 mg and 25 mg of empagliflozin, changes in urinary glucose excretion were reported as 80.9 and 93.0 g/day, respectively,¹⁷ indicating that 25 mg of empagliflozin was more potent than 10 mg. However, clinical outcomes in the EMPA-REG OUTCOME trial were comparable between the 10 mg and 25 mg doses,¹ suggesting that the clinical benefits of empagliflozin may plateau beyond 10 mg.

Similarly, Kasichayanula et al. reported that 2.5 mg, 10 mg, and 20 mg of dapagliflozin inhibited 26%, 42%, and 42% of renal glucose reabsorption, respectively, with corresponding changes in urinary glucose excretion of 42, 71, and 73 g/day.¹⁸ The comparable effectiveness of 10 mg and 20 mg of dapagliflozin suggests that the maximal clinical inhibition of SGLT2i may be achieved with 10 mg of dapagliflozin. When comparing 10 mg of empagliflozin and 10 mg of dapagliflozin, the rates of inhibition of renal glucose reabsorption were 36% and 42%, respectively, with corresponding changes in urinary glucose excretion of 80.9 g/day and 71 g/day. Therefore, both drugs appear to have comparable SGLT2 inhibitory potency, which might explain the lack of significant differences in NT-proBNP levels or clinical outcomes between empagliflozin and dapagliflozin in this study.

Two retrospective studies have reported differing findings regarding the comparative effectiveness of empagliflozin and dapagliflozin in clinical practice. A large Danish cohort study involving patients with type 2 diabetes (n=36,670 for empagliflozin; n=20,606 for dapagliflozin) found no significant difference in the 6-year risk of major adverse cardiovascular events, irrespective of dosage.¹⁹ In contrast, a North American retrospective study demonstrated a lower incidence of all-cause death and hospitalization among patients who initiated empagliflozin (n=15,976) compared to those who received dapagliflozin (n=12,099), although mortality rates alone did not differ between the groups.²⁰ In the present study, no significant differences were observed in HF hospitalizations or deaths within 1 year of follow-up between patients treated with empagliflozin and those treated with dapagliflozin (Figure 2). Notably, no evidence to date has demonstrated that 10 mg of dapagliflozin is superior to 10 mg of empagliflozin in direct comparison.

Our study provides novel insights by being the first to prospectively compare empagliflozin and dapagliflozin within the same individuals under stable clinical conditions. The study design minimized interpatient variability and allowed for a more reliable assessment of comparative effectiveness. However, several limitations should be acknowledged. First, the sample size was relatively small (n=25), potentially limiting the statistical power to detect modest differences and reducing generalizability. Second, the primary endpoint was NT-proBNP, a surrogate marker that may not fully reflect long-term clinical outcomes such as death or functional capacity. Third, the follow-up duration after the crossover was only 1 month, which may be insufficient to capture the sustained effects of therapy switching. Lastly, the open-label design may have introduced bias, particularly regarding subjective assessments and patient preferences. Future large-scale, randomized, and blinded studies are warranted to validate these findings and further refine individualized treatment strategies.

In this prospective crossover study of patients with stable CHF, empagliflozin and dapagliflozin demonstrated comparable effects on NT-proBNP levels and clinical outcomes. No clinical characteristics were identified to predict a differential response to either agent. These findings suggested that these SGLT2i may be used interchangeably, allowing clinicians to individualize treatment based on cost, tolerability, and patient preference.

During the preparation of this manuscript, the authors used ChatGPT, an AI language model developed by OpenAI, in order to assist with formatting and language refinement.

T.K. has received honoraria for lectures from Pfizer Japan Inc. The remaining authors declare no conflicts of interest.

This study did not receive any specific funding.

Ethics Committee of Saiseikai Fukuoka General Hospital (2023-9-1)

The deidentified participant data will not be shared.

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