Abstract
Background
Heart failure with preserved ejection fraction is the fastest-growing subtype of heart failure, especially among the elderly.
Aim
It is aimed to determine whether the addition of 10 mg of Dapagliflozin for HFpEF patient can lead to a decrease in epicardial adipose tissue volume.
Methods
this non-randomized clinical trial included 60 patients presented with left ventricular diastolic dysfunction (30 patients fulfilling HFpEF diagnostic criteria received dapagliflozin 10 mg once daily in addition to standard medical therapy and 30 patients with LV diastolic dysfunction who did not meet HFpEF criteria received standard medical care only).
Results
The mean EAT volume was significantly (p < 0.001) higher in the HFpEF + dapagliflozin group vs. standard care group at baseline while it was comparable in the two groups at follow-up (p = 0.081). For within group comparisons, insignificant (p = 0.124) change was recorded for the standard care group while there was significant reduction in the HFpEF + dapagliflozin arm (p < 0.001). Additionally, EAT reduction in the HFpEF + dapagliflozin group was confirmed by the interaction between time and treatment modality (p < 0.001).
Conclusions
SGLT2 inhibitor use was associated with a significant reduction in epicardial adipose tissue, a fat depot implicated in HFpEF pathophysiology. This finding suggested a possible structural association that warrants confirmation in randomized out-come driven trials.
Trial registration
NO. (NCT06510270) (first submitted date 15/7/2024, first posted date 19/7/2024)
Supplementary Information
The online version contains supplementary material available at 10.1186/s12872-026-05819-4.
Keywords: HFpEF, Dapagliflozin, EAT, CMR
Introduction
Due in part to the growing incidence of obesity, heart failure with preserved ejection fraction (HFpEF) is emerging as the most common cause of heart failure globally [1].
While visceral and generalized adiposity play a significant role in the pathophysiology of obesity-related HFpEF, epicardial adipose tissue (EAT) may also play a role. EAT is metabolically active tissue that is situated right underneath the visceral pericardium on the surface of the heart. Locally released adipokines immediately coat the surface of the heart and cause underlying myocardial remodeling because of its anatomical interaction with the heart and the absence of fascial separation between the underlying myocardium and epicardial fat [2].
Because of its location on the myocardium’s surface, EAT can directly increase the size of the heart overall by stretching the pericardium and causing relative pericardial restriction with constrictive physiology [3–5]. In order to quantify epicardial fat thickness, EAT is often evaluated by echocardiography in the parasternal long axis view perpendicular to the right ventricle (RV). This has been linked to worse hemodynamic abnormalities and worse outcomes in HFpEF [6, 7]. As an alternative, cardiac MRI or CT can offer a more thorough volumetric evaluation of epicardial fat volume and has been linked to unfavorable outcomes and functional measures in the majority of HFpEF studies, though not all of them [8–12].
The effects of medicinal manipulation of epicardial fat in HFpEF are poorly understood. The sodium–glucose cotransporter-2 inhibitors (SGLT2i) are the first medications that have been shown to improve heart failure hospitalization and quality of life in HFpEF [12]. These medications have shown a decrease in epicardial fat despite relatively slight weight loss, indicating a direct lipolytic action on epicardial fat, even though the mechanisms of benefit are unclear [13]. Further, SGLT2i’s diuretic action may help lower plasma volume, and mechanistic research indicates that it also encourages ventricular mass regression, which may reduce pericardial constraint over time [13].
The current study aimed to determine whether the addition of 10 mg of Dapagliflozin for cases with HFpEF can lead to a decrease in EAT volume, which is a new approach for management of HFpEF.
Patients and methods
Study design
A prospective, non-randomized, controlled, diagnosis-driven interventional clinical study with a reference standard care group.
Study site and population
Patient presented to emergency room, out-patient clinic or echo-lab in Aswan university hospitals by LV diastolic dysfunction in the period from August/2024 to October /2025. The first screening comprises 200 patients, but after applying inclusion and exclusion criteria, 64 patients are qualified to participate in our study, four of whom refuse to participate.
Sample size calculation
Sample size calculation was carried out using G*Power 3 software [14]. A calculated minimum sample of 54 patients presented with LV diastolic dysfunction assigned to one of two equal groups according to fulfilling criteria for HFpEF (Group I [HFpEF + dapagliflozin group]: received dapagliflozin 10 mg once daily in addition to standard medical therapy, including diuretics for symptomatic relief and treatment of associated comorbidities such as hypertension and diabetes mellitus and Group II LV diastolic dysfunction without HFpEF (standard care group): received treatments related to any concurrent disorders, such as HTN or D.M) was needed to detect an effect size of 1.1 [15] in the mean EAT difference between HFpEF + dapagliflozin group and control, with an error probability of 0.05 and 95% power on a two-tailed test. To compensate for dropouts and attrition, the sample will be raised by 10% to include 60 cases (30 in each arm).
Inclusion criteria
Patients > 18 years old with BMI > 27 kg/m2 and LVDD (Impaired relaxation or increased stiffness of the left ventricle as detected by echocardiography) [16] with or without established diagnosis with HFpEF (1. Signs and Symptoms of Heart Failure. 2. Preserved Ejection Fraction (EF): EF greater than or equal to 50% is generally considered preserved. 3.Echo-cardiography: Evidence of left ventricular hypertrophy (LVH) or Evidence of diastolic dysfunction, such as impaired relaxation or increased stiffness of the left ventricle. 4.Elevated Natriuretic Peptides: brain natriuretic peptide ≥35 pg/mL can support the diagnosis of HFpEF in the presence of symptoms and other findings) [16].
Exclusion criteria
patients with Type 1 diabetes, significant renal impairment, uncontrolled hypertension, severe hepatic impairment, pregnancy or breastfeeding. Also, those underwent bariatric surgery, with other serious medical conditions (e.g. cancer or severe infections) and recent cardiovascular events (e.g. myocardial infarction or stroke) within 3-months. Additionally, those on statin therapy or diabetic patients who are on glucan like peptide or Dipeptidyl peptidase-4 inhibitors to avoid possible confounders.
Procedure
All the patients were subjected to:
Detailed history and clinical examination including Body mass index calculation.
Complete echocardiographic assessment before enrollment in the study and after 6 months for follow up by using (Vivid E95, GE health care cardiovascular ultrasound): 2-D to assess dimensions and ejection fraction as well as epicardial adipose tissue thickness assessment in parasternal long axis view. Doppler to assess diastolic function.
Laboratory assessment: BNP for confirmation of diagnosis of HFpEF, complete blood count, serum urea, serum creatinine, Na+, glycosylated hemoglobin HGA1c.
Cardiac magnetic resonance (CMR) before enrollment in the study and after 6 months for follow up by using (1.5T Philips Ingenia scanner in Aswan military hospital): total epicardial adipose tissue (EAT) volume was determined by manually delineated the outer wall of myocardium and the visceral layer of pericardium on end diastolic short axis slices from the base towards the apex. Volume was calculated by summation of EAT volume of each slice using the modified Simpsons rule (Fig. 1). The EAT volume was measured twice by two independent operators who were blinded to each other's data to guarantee accuracy and consistency.
Follow Up after 6 months: Echocardiography and CMR to detect changes in epicardial adipose tissue.
Fig. 1.
EAT volume measurement by CMR
Statistical analysis
Data was verified, coded by the researcher, and analyzed via Statistical Package for Social Sciences (IBM-SPSS/PC/VER 27) [17]. Descriptive statistics: continuous variables were expressed as mean ± standard deviation, median, range, interquartile range (IQR) and qualitative data were expressed as frequencies and percentage. Test of significances: Chi square/Monte Carlo exact test was used to compare the difference in distribution of frequencies among different groups as appropriate while McNemar test was used for repeated measures. Shapiro-Wilk test was used to test for data normality. For continuous variables with more than two categories; Two-way ANOVA test was calculated to test the mean differences of the data that follow normal distribution and had repeated measures (between groups, within groups and overall difference), post-hoc test was calculated using Bonferroni corrections for pairwise comparisons between the two HFpEF + dapagliflozin groups. Significant was considered when p ≤ 0.05.
Ethical consideration
The Medical Ethic Committee of Aswan University's Faculty of Medicine granted IRB permission (IRB 865/11/23). Clinical trial.gov was used to prospectively register the study (NCT06510270) (first submitted date 15/7/2024, first posted date 19/7/2024). The study was conducted following the principles outlined in the Helsinki Declaration. [18] and in accordance with CONSORT checklist for research ethics [19]. Prior to the start of the study, the title and goal of the study were fully explained and informed consent from each patient was acquired. All information gathered was kept private and utilized exclusively for scientific study. Each research participant was free to leave the study at any moment without affecting the quality of the medical care they received.
Results
Baseline characteristics of the studied cohort
Table 1 showed the baseline characteristics of the studied cohort. Both groups were matched for age (p = 0.752), sex (p = 1.000), DM (p = 0.796), HTN (p = 0.190), Chronic obstructive pulmonary disease (COPD) (P = 1.0) and Atrial fibrillation (AF) (p = 0.792). For BMI, the mean was comparable in the two groups at the baseline (p = 0.718) while it was significantly (p = 0.036) lower in the HFpEF + dapagliflozin group (27.8) vs. standard care (28.7) group. For within group comparisons, insignificant (p = 0.809) change was recorded for the standard care group (28.63 vs. 28.66) while there was significant reduction (28.73 vs. 27.77) in the HFpEF + dapagliflozin arm (p < 0.001). Additionally, BMI decrease in the HFpEF + dapagliflozin group was confirmed by the interaction between time and treatment (p < 0.001). Regarding functional status, NYHA class improved significantly in the HFpEF + dapagliflozin group during follow-up. At baseline, 4 patients (13.3%) were NYHA class II, 14 (46.7%) were class III, and 12 (40.0%) were class IV, whereas at follow-up, 24 patients (80.0%) were class I and 6 patients (20.0%) were class II. Overall, 29 of 30 patients improved by at least one NYHA class, while 1 patient showed no change and none deteriorated, indicating a statistically significant within-group improvement (Wilcoxon signed-rank test, p < 0.001). In contrast, all patients in the standard care group were NYHA class I at baseline and remained class I at follow-up, with no detectable within-group change. Because the standard care group was already at the best functional class at study entry, between-group comparison of change in NYHA should be interpreted cautiously due to a ceiling effect. During follow-up, only one patient in the HFpEF + dapagliflozin group required rehospitalization for rapid atrial fibrillation. No heart failure rehospitalizations or mortality were recorded in either group.
Table 1.
Baseline characteristics of the studied groups
| Standard care group (n = 30) |
HFpEF + dapagliflozin group (n = 30) |
P-value | |
|---|---|---|---|
| Age/years | 57.03 ± 14.7 | 56.67 ± 4.3 | = 0.752* |
| Sex | |||
| • Male | 12 (40%) | 12 (40%) | = 1.000** |
| • Female | 18 (60%) | 18 (60%) | |
| Comorbidity | |||
| • DM | 15 (50%) | 16 (53.3%) | = 0.796** |
|
• HTN • COPD • AF |
15 (50%) 2 (6%) 11 (36%) |
20 (66.7%) 3 (10%) 13 (43%) |
= 0.190** = 1.000** = 0.792** |
| BMI | |||
| • Baseline | 28.63 ± 1.7 | 28.73 ± 1.5 | = 0.718$ |
| • Follow-up | 28.66 ± 1.8 | 27.77 ± 1.4 | = 0.036 $ |
| P-value$$ | = 0.809 | < 0.001 | P $ $ $ <0.001 |
*Independent Sample T-test was used to compare the difference in mean between groups
**Chi-square test was used to compare frequency between groups
***Fisher’s exact test was used to compare frequency between groups
Wilcoxon signed-rank test was used ****
Two-way Repeated Measure ANOVA was used $between groups, $$within group and $$$interaction between group and time
Differences in laboratory findings and medications of the studied cohort
Table 2 showed the differences in laboratory findings and medications between the studied groups. There were insignificant differences between groups regarding b. urea (p = 0.077), s. creatinine (p = 0.259), GFR (p = 0.642), Hgb level (p = 0.503), Na level (p = 0.429) and HbA1c (p = 0.712). However, HFpEF + dapagliflozin group had significantly (p < 0.001) higher mean BNP than standard care group (306.8 vs. 20.03). All participants with diabetes in our study were treated with insulin, metformin, sulfonylureas, or a combination of two or more of these medications. for DM medications, there were insignificant differences in insulin (p = 0.713), metformin (p = 0.598), and Sulfonylurea (p = 0.519). All participants with hypertension in our study were treated with angiotensin converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), diuretics, calcium channel blockers (CCBs), β-blockers or a combination of two or more of these medications. Also, for HTN medications, there were insignificant differences in ACEIs (p = 0.918), ARBs (p = 0.911), diuretics (p = 0.767), CCBs (p = 1.000) and β-blockers (p = 0.845).
Table 2.
Laboratory findings and medications of the studied groups
| Standard care group (n = 30) |
HFpEF + dapagliflozin group (n = 30) |
P-value | |
|---|---|---|---|
| Laboratory Findings | |||
| • Blood Urea (mg/dl) | 39.75 ± 3.9 | 44.31 ± 6.3 | = 0.077* |
| • Serum Creatinine (mg/dl) | 1.35 ± 0.3 | 1.44 ± 0.3 | = 0.259* |
| • GFR (mL/min/1.73 m2) | 57.53 ± 8.1 | 56.51 ± 8.8 | = 0.642* |
| • Hgb (g/dl) | 10.76 ± 1.4 | 10.52 ± 1.3 | = 0.503* |
| • Na (mEq/L) | 133.10 ± 4.6 | 132.02 ± 5.7 | = 0.429* |
| • HbA1c% | 8.66 ± 0.9 | 8.57 ± 1.1 | = 0.712* |
| • BNP (pg/ml) | 20.03 ± 6.3 | 306.83 ± 8.7 | < 0.001 * |
| DM Medications | n = 15 | n = 16 | |
| • Insulin | 8 (53.3%) | 9 (56.3%) | = 0.713** |
| • Metformin | 11 (73.3%) | 13 (81.3%) | = 0.598** |
| • Sulfonylurea | 4 (26.7%) | 6 (37.5%) | = 0.519** |
| HTN Medications | n = 15 | n = 20 | |
| • ACEI | 5 (33.3%) | 7 (35%) | = 0.918** |
| • ARBs | 4 (26.7%) | 5 (25%) | = 0.911** |
| • Diuretics | 6 (40%) | 9 (45%) | = 0.767** |
| • CCB | 6 (40%) | 8 (40%) | = 1.000** |
| • B-blockers | 7 (46.7%) | 10 (50%) | = 0.845** |
*Independent Sample T-test was used to compare the difference in mean between groups
**Chi-square test was used to compare the difference in Frequency between groups
Treatment effect on the echo parameters among the study cohort
As shown in Table 3, the mean LVEF% was comparable in the two groups at the baseline (p = 0.228) as well as at follow-up (p = 0.053). For within group comparisons, insignificant (p = 0.974) change was recorded for the standard care group (66.93% vs. 66.92%) while there was significant increase (68.7% vs. 69.8%) in the HFpEF + dapagliflozin arm (p < 0.001). Additionally, LVEF% improvement in the HFpEF + dapagliflozin group was confirmed by the interaction between time and treatment modality (p = 0.003). While the HFpEF + dapagliflozin group showed a statistically significant change in LVEF, the magnitude of this change is likely clinically negligible. For LVEDD, the mean was comparable in the two groups at the baseline (p = 0.641) as well as at follow-up (p = 0.253). For within group comparisons, insignificant (p = 0.283) change was recorded for the standard care group (4.8 mm vs. 4.7 mm) while there was significant reduction (4.8 mm vs. 4.5 mm) in the HFpEF + dapagliflozin arm (p < 0.001). Additionally, LVEDD improvement in the HFpEF + dapagliflozin group was confirmed by the interaction between time and treatment modality (p < 0.001). For LVESD, the mean was comparable in the two groups at the baseline (p = 0.641) while it was significantly (p = 0.019) lower in the HFpEF + dapagliflozin (2.66 mm) vs. standard care (2.99 mm) group at follow up. For within group comparisons, insignificant (p = 0.348) change was recorded for the standard care group (2.96 mm vs. 2.99 mm) while there was significant reduction (2.97 mm vs. 2.66 mm) in the HFpEF + dapagliflozin arm (p < 0.001). Additionally, LVESD improvement in the HFpEF + dapagliflozin group was confirmed by the interaction between time and treatment modality (p < 0.001). Also, the mean LAD was significantly (p < 0.001) higher in the HFpEF + dapagliflozin (4.01 mm) vs. standard care (3.53 mm) group while it was comparable in the two groups at follow-up (p = 0.081). For within group comparisons, insignificant (p = 0.339) change was recorded for the standard care group (3.53 mm vs. 3.51 mm) while there was significant reduction (4.01 mm vs. 3.71 mm) in the HFpEF + dapagliflozin arm (p < 0.001). Additionally, LAD improvement in the HFpEF + dapagliflozin group was confirmed by the interaction between time and treatment modality (p < 0.001). For EFT, the mean was significantly higher in HFpEF + dapagliflozin groups at the baseline (p = 0.025) while it was significantly (p < 0.001) lower in the HFpEF + dapagliflozin group (0.41 cm) vs. standard care (0.54 cm) group at follow up. For within group comparisons, insignificant change occurred in standard care group (p = 0.263) while significant reduction was recorded for HFpEF + dapagliflozin group (p = < 0.001) i.e., standard care group (0.55 cm vs. 0.54 cm) and HFpEF + dapagliflozin group (0.61 cm vs. 0.41 cm). Notably, LAD the reduction was more evident in the HFpEF + dapagliflozin group as confirmed by the interaction between time and treatment modality (p < 0.001).
Table 3.
Effect of treatment on echocardiographic parameter
| (Mean ± SD) | Standard care group (n = 30) |
HFpEF + dapagliflozin group (n = 30) |
P-value* |
|---|---|---|---|
| LVEF% | |||
| • Baseline | 66.93 ± 4.6 | 68.73 ± 6.6 | = 0.282 |
| • Follow-up | 66.92 ± 4.7 | 69.82 ± 6.4 | = 0.053 |
| P-value** | = 0.974 | < 0.001 | P ***=0.003 |
| LVEDD (mm) | |||
| • Baseline | 4.76 ± 0.5 | 4.81 ± 0.5 | = 0.641 |
| • Follow-up | 4.68 ± 0.7 | 4.50 ± 0.5 | = 0.235 |
| P-value** | = 0.283 | < 0.001 | P ***<0.001 |
| LVESD (mm) | |||
| • Baseline | 2.96 ± 0.4 | 2.97 ± 0.6 | = 0.896 |
| • Follow-up | 2.99 ± 0.4 | 2.66 ± 0.6 | = 0.019 |
| P-value** | = 0.348 | < 0.001 | P ***<0.001 |
| LAD (mm) | |||
| • Baseline | 3.53 ± 0.3 | 4.01 ± 0.5 | < 0.001 |
| • Follow-up | 3.51 ± 0.4 | 3.71 ± 0.3 | = 0.081 |
| P-value** | = 0.339 | < 0.001 | P ***<0.001 |
| EFT (cm) | |||
| • Baseline | 0.55 ± 0.1 | 0.61 ± 0.1 | = 0.025 |
| • Follow-up | 0.54 ± 0.1 | 0.41 ± 0.1 | < 0.001 |
| P-value** | = 0.263 | < 0.001 | P ***<0.001 |
| E/e | |||
| • Baseline | 11.02 ± 1.4 | 17.40 ± 4.4 | < 0.001 |
| • Follow-up | 10.68 ± 1.4 | 10.08 ± 1.8 | = 0.145 |
| P-value** | = 0.001 | < 0.001 | P ***<0.001 |
Two-way Repeated Measure ANOVA was used *between groups, **within group and ***interaction between group and time
To compare Frequency between groups $Monte Carlo exact and $$Chi-square test were used and to compare Frequency within each group $$$McNemar test was used
Respecting E/e, there was significantly (p < 0.001) higher mean in the HFpEF + dapagliflozin group (17.4) than standard care group (11.02) while it was comparable in the two groups at follow-up (p = 0.145). For within group comparisons, significant (p = 0.001 and < 0.001) reduction was recorded for both groups i.e., standard care group (11.02 at baseline vs. 10.7 at FU) and HFpEF + dapagliflozin group (17.4 at baseline vs. 10.1 at FU). Notably, the reduction was mor evident in the HFpEF + dapagliflozin group as confirmed by the interaction between time and treatment modality (p < 0.001).
Treatment effect on the CMR parameters among the study cohort
As illustrated in Table 4, for LVEDV, the mean was comparable in the two groups at the baseline (p = 0.732) while it was significantly (p < 0.001) lower in the HFpEF + dapagliflozin group (81.5 ml) vs. standard care (106.2 ml) group. For within group comparisons, insignificant (p = 0.605) change was recorded for the standard care group (106.8 vs. 106.2) while there was significant decrease (103.9 vs. 81.5) in the HFpEF + dapagliflozin arm (p < 0.001). Further, LVEDV improvement in the HFpEF + dapagliflozin group was confirmed by the interaction between time and treatment modality (p < 0.003). For LVESV, the mean was comparable in the two groups at the baseline (p = 0.755) as well as at follow-up (p = 0.059). For within group comparisons, insignificant (p = 0.645) change was recorded for the standard care group (34.7 ml vs. 34.9 ml) while there was significant decrease (33.3 ml vs. 27.2 ml) in the HFpEF + dapagliflozin group arm (p = 0.003). Further, LVESV improvement in the HFpEF + dapagliflozin group was confirmed by the interaction between time and treatment modality (p = 0.002). Regarding the EAT, the mean was significantly (p < 0.001) higher in the HFpEF + dapagliflozin group (159.1 ml/m2) vs. standard care (110.2 ml/m2) group at baseline while it was comparable in the two groups at follow-up (p = 0.081). For within group comparisons, insignificant (p = 0.124) change was recorded for the standard care group (110.2 vs. 108.8 ml/m2) while there was significant reduction (159.1 vs. 139.9 ml/m2) in the HFpEF + dapagliflozin arm (p < 0.001). Additionally, EAT reduction in the HFpEF + dapagliflozin group was confirmed by the interaction between time and treatment modality (p < 0.001). Likewise, the mean EAT% reduction was significantly (p < 0.001) higher in the HFpEF + dapagliflozin group (12.2%) in comparison with the standard care group (1.3%) (Fig. 2).
Table 4.
Effect of treatment on CMR parameter
| (Mean ± SD) | Standard care group (n = 30) |
HFpEF + dapagliflozin group (n = 30) |
P-value* |
|---|---|---|---|
| LVEDV (ml) | |||
| • Baseline | 106.76 ± 24.8 | 103.90 ± 38.3 | = 0.732 |
| • Follow-up | 106.21 ± 26.3 | 81.53 ± 14.4 | = 0.011 |
| P-value** | = 0.605 | < 0.001 | P ***<0.001 |
| LVESV (ml) | |||
| • Baseline | 34.70 ± 5.6 | 33.31 ± 3.8 | = 0.755 |
| • Follow-up | 34.94 ± 6.3 | 27.15 ± 4.1 | = 0.059 |
| P-value** | = 0.645 | = 0.003 | P ***=0.002 |
| EAT (ml/m2) | |||
| • Baseline | 110.21 ± 8.1 | 159.13 ± 8.9 | < 0.001 |
| • Follow-up | 108.79 ± 8.9 | 139.89 ± 6.4 | = 0.081 |
| P-value** | = 0.124 | < 0.001 | P ***<0.001 |
Two-way Repeated Measure ANOVA was used *between groups, **within group and ***interaction between group and time
Fig. 2.
Mean EAT% change difference between groups
Further, Table 5 showed the multivariate linear regression analysis of the independent effect of treatment on the EAT reduction. After adjusting for all baseline correlates, treatment was found to had significant independent effect on the EAT reduction i.e., the intercept (EAT reduction) was 3.1 (0.03–33.98, p = 0.041), HFpEF + dapagliflozin cases had significantly (p < 0.001) 23.4 points (12.5–34.3 points) increase in the EAT reduction compared with standard care group.
Table 5.
Multivariable linear regression analyses of EAT reduction predictors
| Estimate | SE** | t-stat*** | P-value | VIF | |
|---|---|---|---|---|---|
| Intercept | 3.09 (0.03–33.98) * | 1.66 | 1.78 | = 0.041 | |
| • HFpEF + dapagliflozin group vs. standard care | 23.37 (12.50–34.25) | 5.04 | 4.32 | < 0.001 | |
| • Age | -0.01 (-0.37: 0.36) | 0.18 | -0.03 | = 0.974 | 1.2 |
| • Sex (Male vs. Female) | -0.39 (-3.67: 2.88) | 1.60 | -0.24 | = 0.811 | 1.3 |
| • BNP (pg/ml) | -0.18 (-0.38: 0.03) | 0.10 | -1.71 | = 0.095 | 1.7 |
| • LVEDD (ml) | 14.22 (-39.08: 67.53) | 2.65 | 0.54 | = 0.594 | 3.2 |
| • LVESD (ml) | -16.59 (-45.07: 11.89) | 1.42 | -1.17 | = 0.274 | 0.95 |
| • LAD (mm) | -1.22 (-5.43: 2.99) | 2.09 | -0.58 | = 0.563 | 2.1 |
| • EFT (cm) | 3.95 (-12.91: 20.81) | 8.38 | 0.74 | = 0.640 | 2.2 |
| • E/e | 0.03 (-0.45: 0.53) | 0.24 | 0.14 | = 0.886 | 2.3 |
| • LVEDV (ml) | -0.26 (-1.29: 0.76) | 0.51 | -0.51 | = 0.610 | 3.3 |
| • LVESV (ml) | 0.45 (-0.46: 1.36) | 0.46 | 0.99 | = 0324 | 5.1 |
| • EAT Baseline (ml/m2) | -0.02 (-0.19: 0.15) | 0.09 | -0.23 | = 0.818 | 1.6 |
*CI Confidence Interval, **SE Standard Error, ***T-stat = T-test value $ VIF Variance Inflation Factor
Discussion
A strong predictor of HFpEF was found to be the increased EAT volume, indicating that it may be useful for early diagnosis. Additionally, it was linked to a higher incidence of MACE, suggesting that it is a predictor of poor outcomes in patients with HFpEF [20]. In this study, we explored whether the addition of 10 mg of Dapagliflozin was associated with a decrease in EAT volume in patients with HFpEF.
There is growing evidence that the metabolism of epicardial adipocytes is affected by SGLT2 inhibition [21]. Despite the conflicting results, SGLT2 inhibitors are said to be able to alter the volume and metabolism of fatty tissues around the heart [22]. Most earlier studies were conducted in diabetic populations over follow-up periods ranging from three to six months [21–23]. In our study, however, only 50% of the HFpEF + dapagliflozin group and 53.3% of the standard care group were diabetic.
Moreover, the current study found that at baseline, the mean BMI was similar for both groups (p = 0.718), but at follow-up, it was considerably (p = 0.036) lower in the HFpEF + dapagliflozin group (27.8) compared to the standard care group (28.7). Our results were in line with multiple type 2 diabetes trials that reported weight loss in patients using SGLT2 inhibitors either by itself or in conjunction with other glucose-lowering medications [24].
For LVEF, the standard care group showed an insignificant (p = 0.974) change (66.93% vs. 66.92%), but the HFpEF + dapagliflozin arm showed a substantial rise (68.7% vs. 69.8%) at follow-up (p < 0.001). This was in line with the findings of CD Yang et al. [25], who studied successive heart failure patients with reduced ejection fraction between 2017 and 2022 and discovered that treatment with SGLT2 inhibitors is linked to an increased risk of HF improved EF, particularly in those with an ischemic etiology [25].
Regarding LVEDD and LVESD, the standard care group showed minor changes (p = 0.283, p = 0.348, respectively) (4.8 mm vs. 4.7 mm, 2.96 mm vs. 2.99 mm), whereas the HFpEF + dapagliflozin arm showed significant reductions (4.8 mm vs. 4.5 mm, 2.97 mm vs. 2.66 mm, respectively) (p < 0.001 for both). In parallel, Carluccio E. et al. [26] conducted a meta-analysis of RCTs of SGLT2i administration in HF outpatients that were published up until June 2022 by searching four electronic databases. LVEDV [MD = -10.59 ml (-17.27; -3.91), P = 0.0019], LVESV [MD = -8.80 ml (-16.91; -0.694), P = 0.0334], and LVMI [MD = -5.34 gr/m2 (-9.76; -0.922), P = 0.0178], however LVEF considerably increased [MD = + 1.98% (0.67; 0.306), P = 0.0031] [26].
Further, LAD showed a substantial decrease (4.01 mm vs. 3.71 mm) in the HFpEF + dapagliflozin arm (p < 0.001) but a negligible change (p = 0.339) for the standard care group (3.53 mm vs. 3.51 mm). This was in line with the findings of El-Saied et al. [27], who included 70 patients with stable HFmrEF and type 2 diabetes (T2DM) (35 patients got either empagliflozin or dapagliflozin as an SGLT-2I). They discovered that improving LA volume and functions in patients with T2DM and HFmrEF is linked to adding SGLT-2I to current guideline-directed medical therapy [27].
At baseline, mean EAT was significantly greater in the HFpEF + dapagliflozin group than in the standard care group (159.1 vs. 110.2 ml/m2, p < 0.001), which is consistent with previous observations that patients with HFpEF tend to have higher EAT burden than controls [20]. Over follow-up, the standard care group showed no significant change in EAT (110.2 vs. 108.8 ml/m2, p = 0.124), whereas a significant reduction was observed in the HFpEF + dapagliflozin group (159.1 vs. 139.9 ml/m2, p < 0.001. This pattern agrees with previous reports by Iacobellis et al. [28] using echocardiography to measure epicardial thickness, Braha et al. [29] using CT to quantify EAT volume, and Fukuda et al. [30] using CMR to assess EAT volume; however, the present findings should be viewed with caution. Because of the non-randomized design and the clear baseline imbalance in EAT between groups, the observed reduction cannot be taken as definitive evidence of a direct mechanistic effect of dapagliflozin on epicardial adipose tissue. Rather, the findings indicate an association that may support a possible role of dapagliflozin in EAT reduction, but this remains hypothesis-generating and requires confirmation in larger randomized studies. On the other hand, our findings were inconsistent with Shiina et al. [31], who enrolled sixty-seven type 2 diabetic patients with metabolic syndrome then they were randomized to receive dapagliflozin 10 mg or only nutrition education (= control) for 12 weeks on top of their glucose lowering medications. They concluded despite improvements in metabolic disorders and reduction in visceral fat, therapy with dapagliflozin exerted no significant effect on epicardial fat measured by CT [31]. This may be due to the shorter follow-up period.
Currently, the available evidence is insufficient to fully explain the molecular mechanisms by which SGLT2 inhibitors modulate EAT. However, the current evidence that is available suggests that SGLT2 inhibitors have a significant impact on lipid metabolism and are recognized as potent fat-burning agents [32]. They have significant impacts on various aspects of lipid metabolism, such as lipogenesis and lipolysis [33], lipid peroxidation [34], free fatty acid beta-oxidation [35] and cholesterol synthesis [36]. It has been suggested that this effect of SGLT2is is independent of their glucose-lowering effects [37]. Additionally, SGLT2is can modulate adipocyte differentiation leading to lower levels of adipose droplets around the heart muscle [11]. It has also been suggested that SGLT2 inhibition ameliorates EAT via lowering the leptin adipokine and modulating body composition and BMI [30].
SGLT2 inhibition may reduce EAT via modulating systemic metabolism [21]. Sato and colleagues in 2018 provided clinical evidence suggesting that dapagliflozin decreases the epicardial adipose tissue volume by improving systemic metabolic parameters such as HbA1c, TNF-α, PAI-1 and body weight in T2DM patients [21]. Improvement in insulin resistance may be another link between SGLT2is and EA. Cardiometabolic factors and body weight are also likely important factors [30]. When combined, metabolic elements, inflammatory mediators, and body weight appear to be the most significant determinants, while further research is needed to determine the possible routes by which SGLT2 inhibitors reduce EAT.
Study limitations
The current study encountered some limitations, treatment assignment is determined by diagnosis, not randomization and this endures possible selection bias. Also, outcomes may be influenced by factors intrinsic to HFpEF (symptoms, volume status, neurohormonal activation). Baseline imbalance in EAT between groups also represents a limitation. Furthermore, the study was limited by its small sample size, single-center design as well as short follow up-duration.
Conclusions
These findings suggest a potential association between dapagliflozin use and reduction in EAT volume. Larger randomized studies are needed to confirm these observations and clarify clinical implications.
Supplementary Information
Acknowledgements
The authors expressed their thanks for the help and support of the staff members of the cardiology department, Aswan University Hospital. Also, we acknowledge the eminent role of the participants; their keen participation was the cornerstone for accomplishment of this work.
Authors' contributions
All authors contributed to the study conception and design. performed literature search, clinical studies, statistical analysis and manuscript preparation was performed by Aml M. Soliman, Ramadan Ghaleb , Amr H. Mahmoud and Ayman Ibrahim. The first draft of the manuscript was written by [Aml M. Soliman] and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
Funding
None.
Data availability
The datasets generated and/or analyzed during the current study are not publicly available due to participant privacy considerations but are available from the corresponding author on reasonable request.
Declarations
Consent to participate
The Medical Ethic Committee of Aswan University’s Faculty of Medicine granted IRB permission (IRB865/11/23). Clinical trial.gov was used to prospectively register the study (NCT06510270). The study was conducted following the principles outlined in the Helsinki Declaration and in accordance with CONSORT checklist for research ethics.
Informed consent was obtained from all individual participants included in the study.
Consent for publication
Not applicable.
Competing interests
The authors declare no competing interests.
Footnotes
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
The datasets generated and/or analyzed during the current study are not publicly available due to participant privacy considerations but are available from the corresponding author on reasonable request.