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Effect of Empagliflozin as an Add-On Therapy on Decongestion and Renal Function in Patients With Diabetes Hospitalized for Acute Decompensated Heart Failure

A Prospective Randomized Controlled Study
Originally publishedhttps://doi.org/10.1161/CIRCHEARTFAILURE.120.007048Circulation: Heart Failure. 2021;14:e007048

Abstract

Background:

Empagliflozin reduces the risk of hospitalization for heart failure in patients with type 2 diabetes and cardiovascular disease. We sought to elucidate the effect of empagliflozin as an add-on therapy on decongestion and renal function in patients with type 2 diabetes admitted for acute decompensated heart failure.

Methods:

The study was terminated early due to COVID-19 pandemic. We enrolled 59 consecutive patients with type 2 diabetes admitted for acute decompensated heart failure. Patients were randomly assigned to receive either empagliflozin add-on (n=30) or conventional glucose-lowering therapy (n=29). We performed laboratory tests at baseline and 1, 2, 3, and 7 days after randomization. Percent change in plasma volume between admission and subsequent time points was calculated using the Strauss formula.

Results:

There were no significant baseline differences in left ventricular ejection fraction and serum NT-proBNP (N-terminal pro-B-type natriuretic peptide), hematocrit, or serum creatinine levels between the 2 groups. Seven days after randomization, NT-proBNP level was significantly lower in the empagliflozin group than in the conventional group (P=0.040), and hemoconcentration (≥3% absolute increase in hematocrit) was more frequently observed in the empagliflozin group than in the conventional group (P=0.020). The decrease in percent change in plasma volume between baseline and subsequent time points was significantly larger in the empagliflozin group than in the conventional group 7 days after randomization (P=0.017). The incidence of worsening renal function (an increase in serum creatinine ≥0.3 mg/dL) did not significantly differ between the 2 groups.

Conclusions:

In this exploratory analysis, empagliflozin achieved effective decongestion without an increased risk of worsening renal function as an add-on therapy in patients with type 2 diabetes with acute decompensated heart failure.

Registration:

URL: https://www.umin.ac.jp/ctr/index.htm; Unique identifier: UMIN000026315.

What Is New?

  • Empagliflozin as an add-on therapy reduced natriuretic peptide levels and caused hemoconcentration and plasma volume contraction in patients with type 2 diabetes admitted for acute decompensated heart failure (ADHF).

  • More efficient decongestion by empagliflozin was achieved without a higher risk of worsening renal function or increased sympathetic nerve activity.

  • Empagliflozin also reduced serum uric acid levels, as in other trials with empagliflozin, even in patients with ADHF.

What are the Clinical Implications?

  • Our findings provide mechanistic insight into the beneficial effect of SGLT2 (sodium-glucose cotransporter type 2) inhibitors in patients with ADHF, as shown in previous reports, and provide a theoretical basis for the use of SGLT2 inhibitors as adjunctive diuretic agents in patients with ADHF.

  • Future studies are needed to examine whether the addition of SGLT2 inhibitors as an add-on therapy may be a potent therapeutic option for patients with ADHF, regardless of their left ventricular ejection fraction and the presence or absence of type 2 diabetes.

Introduction

Acute decompensated heart failure (ADHF) is a major health problem worldwide and is associated with a poor prognosis and a high rehospitalization rate.1 The main reason for hospitalization for ADHF is signs and symptoms of congestion,2 and residual congestion is associated with poor clinical outcomes in patients with ADHF.3 Surrogates of decongestion, such as hemoconcentration and contraction of plasma volume (PV), have been shown to be associated with better prognosis in patients admitted for ADHF.4,5 Thus, relief of congestion is an important therapeutic goal in patients with ADHF. Loop diuretics remain the cornerstone of decongestive therapy, although their use is reportedly associated with worsening renal function (WRF),6 increased sympathetic nerve activity (SNA),7 and elevated serum uric acid levels,8 all of which are related to a worse prognosis in patients with heart failure (HF).9–11

It has been reported that the prevalence of diabetes in HF cohorts ranges from 10% to 47% and that it is higher in patients hospitalized for HF, with some reports indicating a prevalence of >40%.12 The prognosis is particularly dismal for patients with ADHF with diabetes.13 Patients with ADHF with diabetes have an increased risk for the development of WRF.14 In addition, the combination of diabetes and increased cardiac SNA is an independent predictor of the progression of HF.15 Elevated serum uric acid is associated with adverse outcomes in patients with HF irrespective of the presence or absence of diabetes.11 Therefore, decongestive strategies without increased risk of WRF or a significant effect on SNA or serum uric acid levels would be of great clinical value to improve the prognosis of patients with ADHF with diabetes.

Empagliflozin, a selective inhibitor of SGLT2 (sodium-glucose cotransporter type 2), has been shown to reduce the risk of hospitalization for HF in patients with type 2 diabetes (T2D) and cardiovascular disease.16 This may be explained by the natriuresis and osmotic diuresis caused by empagliflozin, leading to PV contraction and decongestion. A recent large-scale trial showed that another SGLT2 inhibitor, dapagliflozin, reduced major adverse outcomes in patients with established chronic HF with reduced ejection fraction with no impact on the risk of WRF.17 Furthermore, a recent pilot study reported the beneficial effect of empagliflozin in patients with ADHF.18 However, little is known about the therapeutic effects of empagliflozin on decongestion and its association with renal function, SNA, and serum uric acid levels in patients with T2D with ADHF. Accordingly, we aimed to prospectively evaluate the effect of empagliflozin as an add-on therapy on natriuretic peptide levels, hemoconcentration, PV contraction, and renal function in patients with T2D with ADHF.

This was a trial terminated early due to the COVID-19 pandemic, and hence the analyses are exploratory.

Methods

The authors declare that all supporting data are available within the article.

Study Design

This was a prospective, single-center, randomized, open-label study to evaluate the efficacy of empagliflozin add-on therapy compared with conventional glucose-lowering therapy in patients with T2D with ADHF. This study was carried out in accordance with the principles outlined in the Declaration of Helsinki, and the institutional ethics committee approved the study protocol. Written informed consent was obtained from all patients. This study was registered in the University Hospital Medical Information Network Clinical Trials Registry.

Study Patients

Consecutive patients with ADHF with T2D who were admitted to the hospital and met the eligibility criteria were enrolled. ADHF was defined as a gradual or rapid change in the signs and symptoms of HF sufficient to warrant hospitalization.19,20 HF was diagnosed according to the Framingham criteria,21 and T2D was diagnosed according to the Japan Diabetes Society criteria.22 The inclusion and exclusion criteria are provided in Table 1.

Table 1. Inclusion and Exclusion Criteria

Inclusion criteria
 Male and female patients ≥20 y old
 Diagnosis of ADHF made within 24 h of hospital admission
 Patients newly diagnosed with T2D (HbA1c ≥6.5% and ≤12.0%) or those who had already been diagnosed with T2D (HbA1c ≥6.0% and ≤12.0%) in whom diabetes medication can be modified
 eGFR ≥15 mL/(min·1.73 m2)
Exclusion criteria
 Severe primary valvular heart disease
 Acute coronary syndrome
 Heart transplantation
 No need for diuretic therapy because of dehydration
 Cardiogenic shock
 Intubation and mechanical ventilation
 Need for mechanical circulatory assist device
 Myocarditis
 Hypertrophic obstructive cardiomyopathy
 Type 1 diabetes
 Reduced endogenous insulin secretion (fasting C-peptide level <1.0 ng/mL)
 Already receiving therapy with an SGLT2 inhibitor
 Severe diabetic ketoacidosis or diabetic coma
 History of hypersensitivity reaction to empagliflozin
 Inability to have diet or receive enteral nutrition therapy within 96 h of admission
 Severe infection, pre or post surgery, or serious trauma
 Life expectancy is less than 6 mo due to extracardiac disease
 Severe renal dysfunction (eGFR <15 mL/[min·1.73 m2]) or dialysis
 History of acute coronary syndrome, stroke, or transient ischemic attack within one month
 Pregnant, possibly pregnant, or lactating women
 Judged inappropriate for the study by the primary physicians

ADHF indicates acute decompensated heart failure; eGFR, estimated glomerular filtration rate; HbA1c, glycated hemoglobin; SGLT2, sodium-glucose cotransporter type 2; and T2D, type 2 diabetes.

Treatment Protocol

Eligible patients were enrolled within 96 hours of admission. Enrolled patients were randomly assigned in a 1:1 ratio to receive either empagliflozin add-on therapy or conventional glucose-lowering therapy according to a computer-generated block randomization table (4 per block). Empagliflozin was started and maintained throughout the study period at a dose of 10 mg/day. The choice of therapy, except for empagliflozin, was left to the discretion of each primary physician.

Data Collection

Transthoracic echocardiography was performed at baseline according to standard techniques using a commercially available machine as previously reported.23 Body weight and vital signs, such as blood pressure and heart rate, were measured, and blood samples were collected at baseline (day 0) and 1 (day 1), 2 (day 2), 3 (day 3), and 7 days after randomization (day 7). Urine samples were collected during the first 24 hours of the study period to assess urine volume and urinary excretion of glucose and sodium. Serum NT-proBNP (N-terminal pro-B-type natriuretic peptide), plasma BNP (B-type natriuretic peptide), and norepinephrine levels were measured at baseline and 3 and 7 days after randomization. NT-proBNP and BNP levels were measured using an electrochemiluminescence immunoassay with the Cobas e801 system (Roche Diagnostics GmbH, Mannheim, Germany) and a chemiluminescence immunoassay with the Alinity i system (Abbott Laboratories, Abbott Park, IL), respectively. The normal ranges of NT-proBNP and BNP levels were ≤125 and ≤18.4 pg/mL, respectively. Plasma norepinephrine levels were measured using a high-performance liquid chromatography assay with the HLC-725CA system (Tosoh Corporation, Tokyo, Japan). The normal range of plasma norepinephrine levels was 150 to 570 pg/mL. Hemoconcentration was defined as a ≥3% absolute increase in the hematocrit level.4 Percent change in PV between baseline and subsequent time points (%ΔPV) was calculated using the Strauss formula as follows: %ΔPV=([(hemoglobin1/hemoglobin2)×([100−hematocrit2]/[100−hematocrit1])]−1)×100 (%), where 1=baseline values and 2=subsequent values.5 WRF was defined as an increase in serum creatinine by ≥0.3 mg/dL above baseline within 7 days of randomization.9 The estimated glomerular filtration rate (eGFR) was calculated using the modified isotope dilution mass spectrometry traceable modification of diet in renal disease study equation with a Japanese coefficient.24 The total furosemide-equivalent dose of loop diuretics was calculated according to previous reports.25,26

End Points

The primary end point of this study was the extent of decongestion as assessed based on NT-proBNP levels. Key secondary end points included BNP levels, incidence of hemoconcentration, PV contraction, incidence of WRF, and plasma norepinephrine and serum uric acid levels. Other secondary end points were the change in body weight from baseline, systolic blood pressure, heart rate, urine volume, urinary excretion of glucose, urinary excretion of sodium, and total furosemide-equivalent dose of loop diuretics.

Statistical Analysis

Baseline characteristics were summarized using medians and interquartile ranges (or means and standard deviations) for continuous variables depending on their distributions and percentages for categorical variables.

Linear mixed-effects models were fitted separately for all continuous outcomes to estimate the effect of empagliflozin add-on therapy. The fixed effect of the baseline value of the outcome, a group indicator, variable indicating days of measurements, and a product term of the days and the group indicator were included in each regression model. Random intercepts were used to model between-patient variability. Log-transformation was performed for outcomes where the distribution of the residuals was skewed. The changes in body weight from baseline were compared between the groups using Wilcoxon rank-sum test due to the violation of the normality assumption of the residuals. The urine volume, urinary excretion of glucose, urinary excretion of sodium, and the total furosemide-equivalent dose of loop diuretics were compared with Wilcoxon rank-sum tests as we could not use linear mixed-effect models due to the lack of baseline values for these outcomes.

For the incidence of hemoconcentration and incidence of WRF, multivariable logistic regression analyses were used which included the following covariates: baseline values of each outcome variable, a group indicator, days of measurements, a product term of the days, and the group indicator variable. To account for the correlations between repeated measurements within each patient, robust standard errors were calculated using the Huber-White sandwich estimator using the rms package of R software version 3.6.3 (www.r-project.org).

All statistical analyses were carried out with a 2-sided significance level of 5% and performed using the R software.

Sample Size Calculations

This study was originally planned to evaluate the noninferiority of the addition of empagliflozin to standard glucose-lowering therapy to conventional glucose-lowering therapy in patients with T2D with ADHF. As there was no information available on the effect of empagliflozin on NT-proBNP in patients with HF, we assumed an 18% difference in the change in NT-proBNP from randomization to 36 months between the 2 groups and a common SD for the log scale of the ratio of 0.80, according to a previous report.27 A sample size of 125 for each group was projected to achieve 80% power with a 1-sided t test with an α level of 0.025, a noninferiority margin of 1.1 in the upper limit of the 2-sided 95% CI for the group ratio of the percentage changes from randomization to 36 months in NT-proBNP levels, and a dropout rate of 10%, to demonstrate noninferiority of empagliflozin as an add-on therapy. However, owing to a pandemic problem worldwide, we had to halt the enrollment and follow-up prematurely to ensure patient safety and data integrity and perform the final analysis using the full analysis set obtained at the termination of this study. For this reason, the results of the first 7 days after randomization are presented in this report and are considered exploratory.

Results

Study Population

A total of 62 patients were enrolled between January 2017 and February 2020. The CONSORT flow diagram of this study is shown in Figure 1. After enrollment, 2 patients randomized to the conventional group and 1 patient randomized to the empagliflozin group were found to have acute coronary syndrome and were excluded from analysis. Thus, 59 patients were included in the final analysis. The comparison of baseline characteristics at randomization is shown in Table 2. There were no significant differences in the baseline characteristics between the 2 groups. Empagliflozin was not discontinued due to side effects in any of the study patients within 7 days of randomization. The total furosemide-equivalent dose of loop diuretics used within 7 days of randomization in the empagliflozin group was lower than that in the conventional group, although this was not statistically significant (median, 150 [interquartile range, 102–207] mg versus 180 [126–241] mg, P=0.071). During the study period, 3 patients (2 patients in the conventional group and 1 patient in the empagliflozin group) received a red blood cell transfusion, and they were excluded from the analysis of the incidence of hemoconcentration and %ΔPV. No patients were on sacubitril/valsartan because the drug had not yet been approved for clinical use in Japan.

Table 2. Baseline Characteristics of Study Patients

CharacteristicsEmpagliflozin group(n=30)Conventional group(n=29)
Age, y80 (77–83)82 (75–84)
Male sex60%62%
DM duration, y11 (6–19)17 (9–25)
NYHA class IV*80%90%
Body mass index, kg/m225±426±4
Comorbidities
 Atrial fibrillation60%38%
 Hypertension97%93%
 Dyslipidemia63%72%
 Hyperuricemia43%48%
 Coronary artery disease67%59%
Prior HF-related hospitalization20%28%
Category of HF
 HFrEF43%55%
 HFmrEF10%17%
 HFpEF47%28%
Heart rate, beats per min70 (65–80)72 (63–85)
Systolic blood pressure, mm Hg120±18115±16
Diastolic blood pressure, mm Hg67±1565±11
Echocardiographic data
 LVEDD, mm52±1053±8
 LVEF, %44 (32–61)39 (32–51)
 LAD, mm44±844±5
Laboratory data
 Hemoglobin, g/dL11±211±2
 Sodium, mEq/L140±2138±3
 Creatinine, mg/dL1.3 (1.0–1.5)1.4 (0.9–1.8)
 BUN, mg/dL24 (14–29)23 (17–34)
 eGFR, mL/(min·1.73 m2)40 (31–54)35 (23–54)
 HbA1c, %6.9 (6.4–7.6)7.4 (6.8–8.4)
 NT-proBNP, pg/mL2750 (1660–4710)3950 (2200–8870)
 BNP, pg/mL424 (260–561)436 (311–601)
 Uric acid, mg/dL7.9 (6.0–9.2)8.1 (6.0–8.8)
 Norepinephrine, pg/mL350 (270–530)360 (270–470)
Oral medications
 Loop diuretic53%48%
 ACE inhibitor/ARB50%55%
 β-blocker47%52%
 Aldosterone antagonist13%10%
 Glucose-lowering therapy
 Insulin20%31%
 DPP-4I53%55%
 GLP-1 RA10%3%
 SU37%17%
 α-GI3%7%
 Thiazolidinedione10%10%
 Metformin20%17%
Intravenous agents
 Inotropic agent0%3%
 Vasodilator53%55%

Normally distributed continuous variables are presented as mean±SD, non-normally distributed variables as median and 25th–75th percentile. Categorical variables are presented as percentage. α-GI indicates α-glucosidase inhibitors; ACE, angiotensin-converting enzyme; ARB, angiotensin II type 1 receptor blocker; BNP, B-type natriuretic peptide; BUN, blood urea nitrogen; DM, diabetes mellitus; DPP-4I, dipeptidyl peptidase-4 inhibitor; eGFR, estimated glomerular filtration rate; GLP-1 RA, glucagon-like peptide-1 receptors agonists; HbA1c, glycated hemoglobin; HF, heart failure; HFmrEF, heart failure with mid-range ejection fraction; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; LAD, left atrial dimension; LVEDD, left ventricular end-diastolic dimension; LVEF, left ventricular ejection fraction; NT-proBNP, N-terminal pro-B-type natriuretic peptide; NYHA, New York Heart Association; and SU, sulfonylureas.

* Data at admission.

Figure 1.

Figure 1. The CONSORT flow diagram. ACS indicates acute coronary syndrome; ADHF, acute decompensated heart failure; and SGLT2, sodium-glucose cotransporter type 2.

Body Weight and Hemodynamic Parameters

There was no significant difference in the change in body weight between the 2 groups at day 7 (Figure 2A). There was also no significant difference in systolic blood pressure and heart rate between the 2 groups at day 7 (Figure 2B and 2C).

Figure 2.

Figure 2. Change in body weight (BW) and vital signs.A, Change in BW. B, Systolic blood pressure (SBP). C, Heart rate (HR). Error bars represent 95% CIs.

Urinary Data

Urine volume during the first 24 hours of the study period was significantly greater in the empagliflozin group (Figure 3A). Urinary excretion of glucose and sodium during the first 24 hours of the study period was also significantly greater in the empagliflozin group (Figure 3B and 3C).

Figure 3.

Figure 3. Urinary data during the first 24 h of the study period.A, Urine volume. B, Urinary excretion of glucose. C, Urinary excretion of sodium.

Indices of Decongestion

NT-proBNP and BNP levels in the empagliflozin group were significantly lower than those in the conventional group at day 7 (Figure 4A and 4B). Hemoconcentration was more frequently observed in the empagliflozin group than in the conventional group at day 7 (odds ratio, 3.84 [95% CI, 1.24–11.92], Figure 4C). In addition, %ΔPV in the empagliflozin group was significantly lower than that in the conventional group at day 7 (Figure 4D).

Figure 4.

Figure 4. Indices of decongestion.A, Serum NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels. B, Plasma BNP (B-type natriuretic peptide) levels. C, Incidence of hemoconcentration. D, Percent change in plasma volume (PV) between baseline and subsequent time points (%ΔPV). Error bars represent 95% CIs.

Incidence of WRF and eGFR

The incidence of WRF did not significantly differ between the empagliflozin and conventional groups (odds ratio, 0.50 [95% CI, 0.10–2.54], Figure 5A). The individual eGFR and the slopes of change of eGFR are shown in Figure 5B and 5C. Of the 59 patients, 24 patients (13 patients in the conventional group and 11 patients in the empagliflozin group) had an increase in eGFR from baseline to day 7. There was no relationship between the change in eGFR from baseline to day 7 and the total furosemide-equivalent dose of loop diuretics used within 7 days of randomization in all patients (Spearman correlation, −0.21, P=0.115).

Figure 5.

Figure 5. Worsening renal function (WRF) and the individual change in estimated glomerular filtration rate (eGFR).A, Incidence of WRF. B, The individual eGFR and the slopes of change of eGFR in the conventional group. C, The individual eGFR and the slopes of change of eGFR in the empagliflozin group. Error bars represent 95% CIs.

Plasma Norepinephrine and Serum Uric Acid Levels

There was no significant difference in plasma norepinephrine levels between the 2 groups at day 7 (Figure 6A). The serum uric acid levels in the empagliflozin group were significantly lower than those in the conventional group at day 7 (Figure 6B).

Figure 6.

Figure 6. Plasma norepinephrine and serum uric acid levels.A, Plasma norepinephrine levels. B, Serum uric acid levels. Error bars represent 95% CIs.

Discussion

In this study, empagliflozin as an add-on therapy was shown to be more beneficial for the relief of congestion when compared with conventional glucose-lowering therapy in patients with T2D with ADHF, as reflected by the significantly lower NT-proBNP and BNP levels, higher rate of hemoconcentration, and lower %ΔPV after therapy in the empagliflozin group. Our findings suggest that the significantly greater urine volume and natriuretic response observed during the first 24 hours of intervention in the empagliflozin group may be attributable to these results. We observed no significant difference in the occurrence of WRF and plasma norepinephrine levels between the conventional group and the empagliflozin group during the study period. In addition, the serum uric acid level was significantly lower in the empagliflozin group after the therapy. Our prospective study suggests that empagliflozin as an add-on therapy might be a potent therapeutic option for congestion without the risk of WRF or neurohumoral activation in patients with T2D with ADHF. Recently, Damman et al18 reported that treatment with empagliflozin reduced the combined end point of worsening HF, rehospitalization for HF, or death in patients with ADHF in the EMPA-RESPONSE trial (Effects of Empagliflozin on Clinical Outcomes in Patients With Acute Decompensated Heart Failure). Our study has expanded on their findings by showing the mechanistic insights into the beneficial effect of empagliflozin in ADHF.

ADHF is the leading cause of hospital admissions worldwide, and there are currently no therapies available to improve the prognosis of these patients. The primary reason for hospitalization for ADHF is reported to be signs and symptoms of congestion.2 As residual congestion has a significant impact on the prognosis in patients with ADHF,3 the establishment of an effective decongestion strategy might be a breakthrough for the improvement of the prognosis of ADHF. Patients with diabetes account for a substantial proportion of patients admitted with ADHF.12 In 2015, one of the antihyperglycemic drugs used in the treatment of T2D, empagliflozin, was unexpectedly reported to significantly reduce HF-related hospitalizations in patients with T2D and cardiovascular disease.16 Another study has subsequently shown that canagliflozin also reduced HF-related hospitalization in patients with T2D with a high cardiovascular disease risk,28 suggesting that a reduction in HF-related hospitalization is an effect attributable to SGLT2 inhibitors. Because the majority of patients in these studies did not have a prior diagnosis of HF,16,28 it remains uncertain as to whether the beneficial effect on HF is generalizable to patients with HF with a long disease duration. However, a recent trial has shown that dapagliflozin reduces the risk of cardiovascular death and HF-related hospitalization in patients with established HF with reduced ejection fraction.17 Moreover, a small study reported that short-term ipragliflozin therapy promotes diuresis without affecting renal function and SNA in patients with T2D with decompensated HF, although there was no control group in this study.29 Therefore, we decided to investigate the therapeutic effect of empagliflozin as an add-on therapy in patients with T2D with ADHF.

The precise mechanisms responsible for the cardioprotective properties of SGLT2 inhibitors are not fully understood; however, promotion of natriuresis and osmotic diuresis caused by SGLT2 inhibition, leading to PV contraction and reduced preload, is generally thought to play a role.30 In line with this hypothesis, empagliflozin add-on therapy was associated with a significantly higher urinary excretion of glucose and sodium, which was accompanied by a significantly higher urine volume in this study. In patients with ADHF, it has been reported that a higher degree of sodium excretion at the early stage of decongestive therapy is strongly associated with better post-discharge outcomes.31 Moreover, in this study, empagliflozin add-on therapy resulted in significantly lower NT-proBNP and BNP levels, significantly higher incidence of hemoconcentration, and significant PV contraction, all of which have been reported to be associated with a better prognosis.4,5,32 Hence, our results suggest that empagliflozin as an add-on therapy might possibly improve the post-discharge prognosis in patients with T2D with ADHF.

It has been reported that rapid intravascular volume removal induced by decongestive therapy can cause WRF, possibly through the activation of the renin-angiotensin-aldosterone pathway and increased SNA, leading to a decrease in renal perfusion and glomerular filtration pressure.33 In addition, it has been reported that SGLT2 inhibitor therapy causes an initial acute reduction in eGFR followed by recovery to baseline in patients with T2D.30 However, we did not find any difference in the incidence of WRF or SNA represented by plasma norepinephrine levels between the conventional and empagliflozin groups. As reported previously, the presence of diabetes is a risk factor for WRF in hospitalized patients with HF,14 and diabetes and increased SNA synergistically worsen the prognosis of HF.15 Therefore, decongestive strategies that are not associated with a risk of WRF and harmful effects on SNA would be particularly beneficial for patients with T2D with HF. Although this might be due to a reduction in the total furosemide-equivalent dose of loop diuretics used during the study period in the empagliflozin group, the difference between the 2 groups did not reach statistical significance. The reduction in preload and relief of renal edema may have compensated for the adverse effects of immediate intravascular volume reduction on renal perfusion or SNA. In this study, empagliflozin add-on therapy also resulted in a significant decrease in serum uric acid levels. It is well known that SGLT2 inhibitors have a uric acid–lowering effect because increased glycosuria induced by SGLT2 inhibitors leads to secretion of uric acid in exchange for glucose reabsorption via the GLUT9 transporter.30 However, our study is the first to demonstrate the uric acid–lowering effect of empagliflozin in patients with T2D with ADHF. As previously reported, elevated uric acid is independently associated with poor clinical outcomes in patients with HF.11 Elevated uric acid levels have been noted to induce reduced nitric oxide production, chronic inflammation, and increased oxidative stress, and it has been suggested that a reduction in the circulating concentration of uric acid by SGLT2 inhibitors might ameliorate these detrimental effects, leading to a reduction in cardiovascular events in patients with T2D.34 Moreover, although evidence is limited regarding the cardiovascular benefits of reducing uric acid, reduction in uric acid levels has been shown to be a significant contributor to reduce the risk of cardiovascular death with empagliflozin in the analysis of data from the EMPA-REG OUTCOME trial (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients).35 Therefore, the uric acid–lowering effect of empagliflozin would be advantageous for patients with ADHF who require loop diuretics for decongestion therapy, which can cause elevation of serum uric acid levels.8

In a recent trial, dapagliflozin has been shown to be effective in reducing the risk of cardiovascular death and HF-related hospitalization in patients with established HF with reduced ejection fraction.17 In addition, more recently, empagliflozin has also been shown to improve prognosis in this population.36 However, approximately half of all patients with HF have preserved left ventricular ejection fraction, commonly referred to as HF with preserved ejection fraction. There is no established therapy to improve the prognosis of patients with HF with preserved ejection fraction. Conversely, SGLT2 inhibitors are expected to have favorable effects on many of the comorbidities associated with the pathophysiology of HF with preserved ejection fraction.30 For these reasons, SGLT2 inhibitors might be a potential therapeutic option for the treatment of HF with preserved ejection fraction. In addition, as shown in the DAPA-HF trial (Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure), the EMPEROR-Reduced trial (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction), and the EMPA-RESPONSE trial, SGLT2 inhibitors might also be beneficial for the reduction of HF risk and cardiovascular death in patients with ADHF without diabetes. Further studies are needed to address these issues.

Study Limitations

First, as this was a single-center, open-label study with a small sample size, we must emphasize the preliminary nature of this study. Second, this study included primarily elderly hypertensive patients, and a substantial number of patients had preserved or only mildly impaired left ventricular ejection fraction. Third, this study included only Japanese patients, and we did not include patients without diabetes. Fourth, a less sick population than in most ADHF studies was included in this study, as represented by the lower baseline prescription rate of loop diuretics and lower prior HF-related hospitalization rates. Fifth, there was no standardization of treatment for the study patients. Sixth, the urine samples were collected only for the first 24 hours after randomization. Seventh, because we did not obtain data on fluid input/output balance for the study period, we could not explain the absence of significant weight loss in the empagliflozin group despite more frequent hemoconcentration and significant decrease in PV. Eighth, we did not measure the components of the renin-angiotensin-aldosterone system. Therefore, it remains unknown whether empagliflozin add-on therapy has a neutral effect on the renin-angiotensin-aldosterone system in patients with T2D with ADHF. Ninth, although we should not have excluded 3 patients who were diagnosed with acute coronary syndrome after randomization from the analysis, we could not include these patients because of failure to obtain data. Lastly, we should emphasize that this study included an inadequate sample size to make definitive conclusions due to the early termination of the trial.

Conclusions

In this exploratory analysis, empagliflozin as an add-on therapy achieved effective decongestion without an increased risk of WRF or harmful effects on SNA and reduced serum uric acid levels in patients with T2D with ADHF. Large randomized, placebo-controlled, double-blind, multicenter studies are encouraged to further investigate the efficacy of SGLT2 inhibitors in patients with T2D with ADHF.

Nonstandard Abbreviations and Acronyms

%ΔPV

percent change in plasma volume between baseline and subsequent time points

ADHF

acute decompensated heart failure

BNP

B-type natriuretic peptide

DAPA-HF

Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure

eGFR

estimated glomerular filtration rate

EMPA-REG

Empagliflozin Cardiovascular Out-OUTCOME come Event Trial in Type 2 Diabetes Mellitus Patients

EMPA-

Effects of Empagliflozin on Clinical RESPONSE Outcomes in Patients With Acute Decompensated Heart Failure

EMPEROR-

Empagliflozin Outcome Trial in Reduced Patients With Chronic Heart Failure With Reduced Ejection Fraction

HF

heart failure

NT-proBNP

N-terminal pro-B-type natriuretic peptide

PV

plasma volume

SGLT2

sodium-glucose cotransporter type 2

SNA

sympathetic nerve activity

T2D

type 2 diabetes

WRF

worsening renal function

Disclosures None.

Footnotes

For Sources of Funding and Disclosures, see page 336.

Correspondence to: Shunsuke Tamaki, MD, PhD, Division of Cardiology, Osaka General Medical Center, 3-1-56, Mandai-Higashi, Sumiyoshi-ku, Osaka 558-8558, Japan. Email

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