Introduction: Antigen carbohydrate 125 (CA125) has emerged as a proxy of fluid overload and inflammation in acute heart failure (AHF). We aimed to evaluate the influence of dapagliflozin on CA125 levels within the first weeks after discharge and whether CA125 changes were related to 6-month adverse clinical outcomes. Methods: In this retrospective observational study, data from 956 AHF patients discharged from a tertiary hospital were analyzed. CA125 levels were assessed during the index admission (visit 1) and at a median of 26 (15–39) days after discharge (visit 2). The primary endpoint was changes in CA125 and its correlation with the risk of 6-month death and recurrent readmissions (any or AHF-related). Multivariable mixed regression and a two-equation count model regression were used for the analyses. Results: The mean age of the cohort was 73.1 ± 11.1 years, 54.8% were males, 43.5% showed left ventricular ejection fraction ≥50%, and 18.7% of patients received dapagliflozin at discharge. Dapagliflozin treatment was associated with a greater reduction in CA125 levels at follow-up (−24 U/mL) compared to non-dapagliflozin patients (−14 U/mL, p = 0.034). The magnitude of CA125 reduction (per decrease in 10 U/mL) was significantly associated with a lower risk of 6-month death (incidence rate ratio [IRR] = 0.98, 95% CI = 0.96–0.99; p = 0.049), all-cause readmissions (IRR = 0.99, 95% CI = 0.98–0.99; p = 0.003), and HF readmissions (IRR = 0.98, 95% CI = 0.97–0.99; p < 0.001). Conclusion: Dapagliflozin treatment at discharge following an episode of AHF was associated with a greater reduction in CA125 during the first weeks after discharge. The greater CA125 reduction identified patients with a lower risk of 6-month adverse clinical outcomes.

Acute heart failure (AHF) is a clinical condition associated with high morbidity and mortality rates, [1]. Decompensations often lead to repeated hospital admissions, significantly burdening healthcare resources. Recent developments, such as the introduction of sodium-glucose cotransporter 2 inhibitors (SGLT2i), have shown promising results in improving clinical outcomes in AHF setting [1‒4].

Fluid overload is a central component in AHF patients, directly influencing patient symptoms and morbimortality risk [5, 6]. While natriuretic peptides have traditionally been used to assess congestion, their effectiveness can be limited in some frequent scenarios such as elderly, kidney dysfunction, obesity, and patients with predominant systemic interstitial fluid overload [7, 8]. Circulating levels of antigen carbohydrate 125 (CA125) have emerged as a surrogate marker of fluid overload and inflammation in AHF [9‒11]. Elevated CA125 levels are associated with greater fluid overload, especially extravascular, and poorer outcomes after AHF [9‒11]. Likewise, changes over time are closely related to clinical status and risk of adverse outcomes [9]. Additionally, two randomized clinical trials showed their utility for guiding diuretic therapy [12, 13].

Conversely to natriuretic peptides, the utility of CA125 seems not significantly influenced by age, renal impairment, and left ventricular ejection fraction (LVEF) status [7, 9]. Prior studies suggested a significant CA125 decrease following SGLT2i initiation in stable ambulatory heart failure (HF) patients [14, 15]. However, the impact of SGLT2i treatment on CA125 levels following hospitalization for AHF and whether these changes are related to the risk of adverse clinical outcomes remains unknown. This study aimed to investigate the impact of dapagliflozin, an SGLT2i, on short-term CA125 changes following AHF and to determine whether changes in CA125 levels are associated with adverse clinical outcomes.

Study Design and Participants

This retrospective observational study utilized a cohort of 1,088 consecutive patients discharged alive following hospitalization for AHF in a third-level center in Spain (Cardiology Department of Hospital Clínico Universitario de Valencia-Spain). Only patients with a primary diagnosis of AHF were considered. AHF was defined as a rapid or gradual onset of symptoms and/or signs of HF, severe enough for the patient to seek urgent medical attention, leading to an unplanned hospital admission or emergency department visit. All patients included in the study were diagnosed by cardiologists including measurement of natriuretic peptides and echocardiography assessment revealing cardiac structural or functional abnormalities. Patients with AHF not requiring hospital admission, those with cardiogenic shock or requiring mechanical circulatory support (n = 10), and those with known contraindications to the use of dapagliflozin or other SGLT2 inhibitors, such as advanced renal insufficiency (glomerular filtration rate <20 mL/min/1.73 m2) (n = 32) or history of diabetic ketoacidosis (n = 6) were excluded. Additionally, patients receiving other SGLT2 inhibitors besides dapagliflozin (n = 45), as well as those discharged to receive ambulatory follow-up outside our health center (n = 87), were excluded from the study.

Dapagliflozin was generally prescribed during admission after clinical stabilization by the attending cardiologist, based on the patient’s stability and eligibility for outpatient HF management. After discharge, patients were responsible for obtaining dapagliflozin from a pharmacy using a medical prescription. An echocardiographic assessment was performed in all patients during the index hospitalization. The study period spanned from October 14, 2019, to December 31, 2022. Following discharge, structured follow-up was conducted in a specialized HF unit. This study was conducted in compliance with the principles of the Declaration of Helsinki and was approved by an Institutional Review Committee.

Data Collection

Patient demographics, vital signs, physical examination, medical history, laboratory test, 12-lead electrocardiogram, echocardiogram results, and medications were collected during the index admission. Treatment with diuretics, SGLT2i, angiotensin-converting enzyme inhibitors (ACEI), angiotensin receptor blockers (ARB), angiotensin receptor-neprilysin inhibitors, β-blockers, aldosterone antagonists (MRA), diuretics, anticoagulants, and other therapeutic strategies were individualized according to established guidelines and clinical judgment [1, 2]. During the transitional phase (first weeks after discharge-visit 2), laboratory and clinical assessments were registered.

CA125 was measured at visit 1 (72 ± 24 h after admission) and visit 2 (26 days after discharge [p25% to p75%: 15–39]) using a commercially available immunoassay kit (Elecsys CA125 II assay-Roche Diagnostics). The normal range of CA125 established for the assays was 35 U/mL. Serum creatinine, blood urea nitrogen, hemoglobin, electrolytes (serum sodium and potassium), and amino-terminal pro-brain natriuretic peptide (NT-proBNP) were simultaneously measured using commercially available immunoassays at the same visits.

Post-Discharge Follow-Up

Patients’ follow-up continued until one of the following events occurred during the 6 months following visit 2. The outcomes were assessed by verifying the patients’ survival status or occurrence of hospital admissions by reviewing electronic medical records of the public healthcare system in the Valencian Community. This assessment utilized data from the SIA-GAIA and Orion Clinics electronic databases, which comprehensively record all medical interactions occurring in the public healthcare system of the Valencian Community.

Endpoints

The main endpoint was between-treatment (dapagliflozin vs. non-dapagliflozin at discharge), CA125 changes (between visits 1 and 2). As secondary objectives, we analyzed whether CA125 changes were related to 6-month adverse clinical outcomes, including all-cause readmissions, HF-related readmissions, and all-cause mortality. HF readmission was defined as an unscheduled hospital stay lasting more than 24 h during which the patient required parenteral diuretics or vasoactive drugs. Researchers in charge of endpoint ascertainment were blinded to the medical treatment at discharge and CA125 status.

Statistical Methods

Continuous variables were summarized as mean ± standard deviation for normally distributed data or median (interquartile range) for skewed data. Categorical variables were expressed as percentages. Group comparisons – between patients receiving or not receiving dapagliflozin and between patients with normal vs. elevated CA125 levels – were conducted using independent t tests or Wilcoxon rank-sum tests for continuous variables and chi-square tests for categorical variables.

Differences in CA125 were calculated by subtracting the value measured from visit 1 to visit 2. A quantile regression model [16] was applied to account for the skewed distribution of CA125 differences, with the CA125 values at visits 1 and 2 serving as the dependent variables. The model included an interaction term for dapagliflozin treatment (binary coded as 0/1) and the time (in days) between visits 1 and 2. It was adjusted for baseline characteristics, including the following covariates: age, sex, first hospitalization status, comorbid conditions, New York Heart Association (NYHA) class, systolic blood pressure, heart rate, hemoglobin, eGFR, NT-proBNP, LVEF, and medications at discharge (furosemide-equivalent dose, β-blockers, ACEI/ARB/sacubitril-valsartan, and MRA). Due to the longitudinal data, we clustered repeated CA125 measures by patient ID to account for within-patient correlation. The model outputs the median differences in CA125 between the dapagliflozin and non-dapagliflozin arms.

The study also utilized a two-equation count model (“bivcnto”), appropriate for analyzing correlated count outcomes and adjusting for informative censoring due to death [17]. This model evaluated the rates of all-cause mortality and recurrent all-cause and HF hospitalizations and incorporated dapagliflozin and CA125 differences as primary exposures and adjusted for the previously mentioned covariates, including the CA125 level at index admission. The following baseline covariates adjusted the final model: CA125 value at visit 1, age sex, NYHA class, first hospitalization status, ischemic heart disease, diabetes, atrial fibrillation, systolic blood pressure, heart rate, peripheral edema, pleural effusion, hemoglobin, eGFR, NT-proBNP, LVEF, furosemide equivalent dose at discharge, and treatment at discharge with β-blockers, ACEI/ARB/sacubitril-valsartan, and MRA. Results were reported as incidence rate ratios (IRRs) with 95% confidence intervals (CIs). All analyses were conducted at a significant level of p < 0.05. Data management and analysis were performed using STATA 17.0, with the “bivcnto” package for count regression analysis [18].

Overall Baseline Characteristics

The mean age of the sample was 73.1 ± 11.1 years; 524 (54.8%) patients were men, and 179 (18.7%) received dapagliflozin at discharge. The index admission for AHF corresponded to the first admission in 74.6% of the patients, and the proportion of patients with LVEF ≤40%, 41–49%, and ≥50% were 42.4%, 14.1%, and 43.5%, respectively. The median (p25% to p75%) values of NT-proBNP and CA125 during admission were 4,629 pg/mL (2,614–9,054), and 75 U/mL (34–156), respectively. The median length of stay was 7 days (p25% to p75%: 5–11) versus 6 days (5–9), p = 0.001, for the non-SGLT2i and the dapagliflozin group. The median values of CA125 were 76.9 U/mL (35–157) versus 70.0 U/mL (32–152), p = 0.336, for the non-SGLT2i and the dapagliflozin group. The proportion of patients with CA125 >35 U/mL at baseline was similar across treatment arms (dapagliflozin: 72.6% vs. non-SGLT2i: 74.9%, p = 0.523).

Baseline Characteristics Stratified by Baseline CA125

Baseline characteristics across CA125 (≤35 U/mL vs. >35 U/mL) are presented in Table 1. Patients with CA125 >35 U/mL at baseline were, on average, younger and more likely to be men and showed a greater comorbidity burden. These patients also showed greater facts of congestion and both left and right systolic dysfunction. At discharge, they received higher diuretic doses.

Table 1.

Baseline characteristics across CA125 value at baseline

VariableCA125 ≤35 U/mL (n = 243)CA125 >35 U/mL (n = 713)p value
Demographics and medical history 
 Age, years 76±10 72±11 <0.001 
 Sex (male), n (%) 115 (47.3) 409 (57.4) 0.007 
 Hypertension, n (%) 211 (86.8) 533 (74.8) <0.001 
 Dislipidemia, n (%) 140 (57.6) 402 (56.4) 0.738 
 Diabetes, n (%) 113 (46.5) 328 (46.0) 0.893 
 Smoking history, n (%) 56 (23.0) 203 (28.5) 0.100 
 First admission for AHF, n (%) 171 (70.4) 542 (76.0) 0.081 
 CHD etiology, n (%) 78 (32.1) 227 (31.8) 0.940 
 Charlson index, pointsa 5.0 (4.0–6.0) 5.0 (3.0–6.0) 0.017 
 Last NYHA class under stable conditions prior to admission, n (%)   0.968 
  I 86 (35.4) 246 (34.5)  
  II 126 (51.9) 374 (52.5)  
  III 31 (12.8) 93 (13.0)  
 Pleural effusion, n (%) 81 (33.3) 432 (60.6) <0.001 
 Lower limbs edema, n (%) 129 (53.1) 519 (72.8) <0.001 
ECG 
 BBB, n (%) 92 (37.9) 236 (33.1) 0.177 
 Atrial fibrillation, n (%) 108 (44.4) 338 (47.4) 0.424 
Vital signs on admission 
 Heart rate, bpm 99±28 100±28 0.751 
 SBP, mm Hg 150±34 143±29 0.001 
 DBP, mm Hg 84±22 82±19 0.250 
Echocardiography 
 LVEF, % 50±15 45±16 <0.001 
 LAD, mm 43±6 44±7 0.001 
 TAPSE, mma 19.3 (17.1–21.1) 18.0 (16.0–20.0) <0.001 
Laboratory data 
 Hemoglobin, g/dL 12.7±2.1 12.5±2.1 0.120 
 eGFR (CKD-EPI), mL/min/1.73 m2 59.1±23.7 60.4±26.3 0.486 
 Serum sodium, mEq/L 139±4 139±4 0.582 
 Serum potassium, mEq/L 4.1±0.4 4.1±0.5 0.717 
 NT-proBNP, pg/mLa 4,060 (2,386–8,125) 4,800 (2,713–9,595) 0.007 
 CA125, U/mLa 19 (14–28) 105 (65–186) <0.001 
Treatment at discharge 
 FED, mg/day 71±38 84±46 <0.001 
 Beta-blockers, n (%) 173 (71.2) 541 (75.9) 0.147 
 ACEI/ARB/ARNI, n (%) 194 (79.8) 540 (75.7) 0.327 
 MRA, n (%) 76 (31.3) 283 (39.7) 0.150 
 Dapagliflozin, n (%) 49 (20.2) 130 (18.2) 0.505 
VariableCA125 ≤35 U/mL (n = 243)CA125 >35 U/mL (n = 713)p value
Demographics and medical history 
 Age, years 76±10 72±11 <0.001 
 Sex (male), n (%) 115 (47.3) 409 (57.4) 0.007 
 Hypertension, n (%) 211 (86.8) 533 (74.8) <0.001 
 Dislipidemia, n (%) 140 (57.6) 402 (56.4) 0.738 
 Diabetes, n (%) 113 (46.5) 328 (46.0) 0.893 
 Smoking history, n (%) 56 (23.0) 203 (28.5) 0.100 
 First admission for AHF, n (%) 171 (70.4) 542 (76.0) 0.081 
 CHD etiology, n (%) 78 (32.1) 227 (31.8) 0.940 
 Charlson index, pointsa 5.0 (4.0–6.0) 5.0 (3.0–6.0) 0.017 
 Last NYHA class under stable conditions prior to admission, n (%)   0.968 
  I 86 (35.4) 246 (34.5)  
  II 126 (51.9) 374 (52.5)  
  III 31 (12.8) 93 (13.0)  
 Pleural effusion, n (%) 81 (33.3) 432 (60.6) <0.001 
 Lower limbs edema, n (%) 129 (53.1) 519 (72.8) <0.001 
ECG 
 BBB, n (%) 92 (37.9) 236 (33.1) 0.177 
 Atrial fibrillation, n (%) 108 (44.4) 338 (47.4) 0.424 
Vital signs on admission 
 Heart rate, bpm 99±28 100±28 0.751 
 SBP, mm Hg 150±34 143±29 0.001 
 DBP, mm Hg 84±22 82±19 0.250 
Echocardiography 
 LVEF, % 50±15 45±16 <0.001 
 LAD, mm 43±6 44±7 0.001 
 TAPSE, mma 19.3 (17.1–21.1) 18.0 (16.0–20.0) <0.001 
Laboratory data 
 Hemoglobin, g/dL 12.7±2.1 12.5±2.1 0.120 
 eGFR (CKD-EPI), mL/min/1.73 m2 59.1±23.7 60.4±26.3 0.486 
 Serum sodium, mEq/L 139±4 139±4 0.582 
 Serum potassium, mEq/L 4.1±0.4 4.1±0.5 0.717 
 NT-proBNP, pg/mLa 4,060 (2,386–8,125) 4,800 (2,713–9,595) 0.007 
 CA125, U/mLa 19 (14–28) 105 (65–186) <0.001 
Treatment at discharge 
 FED, mg/day 71±38 84±46 <0.001 
 Beta-blockers, n (%) 173 (71.2) 541 (75.9) 0.147 
 ACEI/ARB/ARNI, n (%) 194 (79.8) 540 (75.7) 0.327 
 MRA, n (%) 76 (31.3) 283 (39.7) 0.150 
 Dapagliflozin, n (%) 49 (20.2) 130 (18.2) 0.505 

Values for continuous variables are expressed as mean ± standard deviation.

ACEI, angiotensin-converting enzyme inhibitors; AHF, acute heart failure; AMI, acute myocardial infarction; ARB, angiotensin receptor blockers; BBB, bundle branch block; BUN, blood urea nitrogen; CA125, carbohydrate antigen 125; CHD, coronary heart disease; eGFR, estimated glomerular filtration rate; FED, furosemide-equivalent dose; LAD, left atrial diameter; MDRD, Modification of Diet in Renal Disease; MRA, mineralcorticoid receptor antagonist; NT-proBNP, amino-terminal pro-brain natriuretic peptide; NYHA, New York Heart Association; PASP, pulmonary artery systolic pressure; TAPSE, tricuspid annular plane systolic excursion; VHD, valve heart disease.

aValues expressed as mean (interquartile range).

Baseline Characteristics Stratified by Dapagliflozin Treatment

Patients receiving dapagliflozin were more likely to be men and showed higher rates of dyslipidemia, diabetes mellitus, and higher comorbidities but lower rates of ischemic etiology. They exhibited greater parameters of congestion and lower left and right systolic function. Patients treated with dapagliflozin were more likely to be discharged on neurohormonal inhibition agents. No differences in the diuretic regimen were found. Significant variations in eGFR and NT-proBNP were also found (Table 2).

Table 2.

Baseline characteristics across treatment with dapagliflozin at discharge

VariableNo dapagliflozin (n = 777)Dapagliflozin (n = 179)p value
Demographics and medical history 
 Age, years 73±11 73±11 0.403 
 Sex (male), n (%) 409 (52.6) 115 (64.2) 0.005 
 Hypertension, n (%) 604 (77.7) 140 (78.2) 0.890 
 Dislipidemia, n (%) 422 (54.3) 120 (67.0) 0.002 
 Diabetes, n (%) 338 (43.5) 103 (57.5) 0.001 
 Smoking history, n (%) 208 (26.8) 51 (28.5) 0.640 
 First admission for AHF, n (%) 570 (73.4) 143 (79.9) 0.070 
 CHD etiology, n (%) 270 (34.7) 35 (19.6) <0.001 
 Charlson indexa 5.0 (3.0–6.0) 5.0 (4.0–7.0) 0.024 
 Last NYHA class under stable conditions prior to admission, n (%)   0.001 
  I 266 (34.2) 66 (36.9)  
  II 395 (50.8) 105 (58.7)  
  III 116 (14.9) 8 (4.5)  
 Pleural effusion, n (%) 400 (51.5) 113 (63.1) 0.005 
 Lower limbs edema, n (%) 514 (66.2) 134 (74.9) 0.025 
ECG 
 BBB, n (%) 270 (34.7) 58 (32.4) 0.551 
 Atrial fibrillation, n (%) 365 (47.0) 81 (45.3) 0.677 
Vital signs on admission 
 Heart rate, bpm 99±28 102±28 0.231 
 SBP, mm Hg 145±32 141±26 0.113 
 DBP, mm Hg 82±19 85±21 0.070 
Echocardiography 
 LVEF, % 47±16 42±15 <0.001 
 LAD, mm 44±7 44±5 0.898 
 TAPSE, mma 18 (16–20) 17 (15–20) 0.007 
Laboratory data 
 Hemoglobin, g/dL 12.5±2.0 12.8±2.3 0.056 
 Creatinine at admission, mg/dL 1.35±0.64 1.24±0.55 0.031 
 eGFR (CKD-EPI), mL/min/1.73 m2 58.8±25.3 65.6±26.6 0.001 
 Serum sodium, mEq/L 139±4 139±4 0.844 
 Serum potassium, mEq/L 4.1±0.4 4.1±0.5 0.091 
 NT-proBNP, pg/mLa 4,774 (2,788–9,315) 3,719 (1,826–7,019) 0.001 
 CA125, U/mLa 77 (35–157) 70 (32–152) 0.322 
 CA125 >35 U/mL at baseline, n (%) 583 (75.0) 130 (72.6) 0.505 
Treatment at discharge 
 Diuretics, n (%) 764 (98.3) 174 (97.2) 0.320 
 FED, mg/day 81±44 81±47 0.966 
 Beta-blockers, n (%) 560 (72.1) 154 (86.0) <0.001 
 ACEI/ARB/ARNI, N (%) 521 135 0.252 
 MRA, n (%) 255 (32.8) 104 (58.1) 0.010 
VariableNo dapagliflozin (n = 777)Dapagliflozin (n = 179)p value
Demographics and medical history 
 Age, years 73±11 73±11 0.403 
 Sex (male), n (%) 409 (52.6) 115 (64.2) 0.005 
 Hypertension, n (%) 604 (77.7) 140 (78.2) 0.890 
 Dislipidemia, n (%) 422 (54.3) 120 (67.0) 0.002 
 Diabetes, n (%) 338 (43.5) 103 (57.5) 0.001 
 Smoking history, n (%) 208 (26.8) 51 (28.5) 0.640 
 First admission for AHF, n (%) 570 (73.4) 143 (79.9) 0.070 
 CHD etiology, n (%) 270 (34.7) 35 (19.6) <0.001 
 Charlson indexa 5.0 (3.0–6.0) 5.0 (4.0–7.0) 0.024 
 Last NYHA class under stable conditions prior to admission, n (%)   0.001 
  I 266 (34.2) 66 (36.9)  
  II 395 (50.8) 105 (58.7)  
  III 116 (14.9) 8 (4.5)  
 Pleural effusion, n (%) 400 (51.5) 113 (63.1) 0.005 
 Lower limbs edema, n (%) 514 (66.2) 134 (74.9) 0.025 
ECG 
 BBB, n (%) 270 (34.7) 58 (32.4) 0.551 
 Atrial fibrillation, n (%) 365 (47.0) 81 (45.3) 0.677 
Vital signs on admission 
 Heart rate, bpm 99±28 102±28 0.231 
 SBP, mm Hg 145±32 141±26 0.113 
 DBP, mm Hg 82±19 85±21 0.070 
Echocardiography 
 LVEF, % 47±16 42±15 <0.001 
 LAD, mm 44±7 44±5 0.898 
 TAPSE, mma 18 (16–20) 17 (15–20) 0.007 
Laboratory data 
 Hemoglobin, g/dL 12.5±2.0 12.8±2.3 0.056 
 Creatinine at admission, mg/dL 1.35±0.64 1.24±0.55 0.031 
 eGFR (CKD-EPI), mL/min/1.73 m2 58.8±25.3 65.6±26.6 0.001 
 Serum sodium, mEq/L 139±4 139±4 0.844 
 Serum potassium, mEq/L 4.1±0.4 4.1±0.5 0.091 
 NT-proBNP, pg/mLa 4,774 (2,788–9,315) 3,719 (1,826–7,019) 0.001 
 CA125, U/mLa 77 (35–157) 70 (32–152) 0.322 
 CA125 >35 U/mL at baseline, n (%) 583 (75.0) 130 (72.6) 0.505 
Treatment at discharge 
 Diuretics, n (%) 764 (98.3) 174 (97.2) 0.320 
 FED, mg/day 81±44 81±47 0.966 
 Beta-blockers, n (%) 560 (72.1) 154 (86.0) <0.001 
 ACEI/ARB/ARNI, N (%) 521 135 0.252 
 MRA, n (%) 255 (32.8) 104 (58.1) 0.010 

Values for continuous variables are expressed as mean ± standard deviation.

ACEI, angiotensin-converting enzyme inhibitors; AHF, acute heart failure; AMI, acute myocardial infarction; ARB, angiotensin receptor blockers; BBB, bundle branch block; BUN, blood urea nitrogen; CA125, carbohydrate antigen 125; CHD, coronary heart disease; eGFR, estimated glomerular filtration rate; FED, furosemide-equivalent dose; LAD, left atrial diameter; MDRD, modification of diet in Renal Disease; MRA, mineralcorticoid receptor antagonist; NT-proBNP, amino-terminal pro-brain natriuretic peptide; NYHA, New York Heart Association; PASP, pulmonary artery systolic pressure; TAPSE, tricuspid annular plane systolic excursion; VHD, valve heart disease; ARNI, angiotensin receptor-neprilysin inhibitors.

aValues expressed as mean (interquartile range).

CA125 Changes at the First Ambulatory Visit

The first ambulatory visit after discharge occurred at a median of 26 days after discharge (p25% to p75%: 15–39) with no differences across treatment (non-dapagliflozin: 27 days [16–36] vs. dapagliflozin: 23 days [21–26], p = 0.120). In the overall cohort, the median CA125 at visit 2 was 41.3 U/mL (19.0–96.0), with an estimated difference between visits 1 and 2 of −15.3 U/mL (−60 to −1.0) (p = 0.035). At visits 1 and 2, the frequency of patients with CA125 >35 U/mL was 713 (74.5%) and 524 (54.8%), respectively.

CA125 Changes across Dapagliflozin Treatment

Patients receiving dapagliflozin experienced a higher reduction in CA125 values at visit 2. The medians of CA125 difference between the treatment groups were −14 U/mL (−60 to 3) and −24 U/mL (−61 to −2) for those not receiving and receiving dapagliflozin, respectively (p = 0.034). Similar significant reductions were found regarding relative reductions from baseline (−26.5% vs. −41.2%, p = 0.007) and CA125 logarithm (−0.31 vs. −0.52, p = 0.008) for those not receiving and receiving dapagliflozin, respectively. Likewise, the proportion of patients with CA125 ≤35 U/mL at visit 2 was higher in those on dapagliflozin versus non-dapagliflozin (103 [57.5%] vs. 330 [42.4%], p = 0.001) (shown in Fig. 1).

Fig. 1.

Proportion of patients with CA125 values >35 U/mL at visits 1 and 2 in those receiving and not receiving SGLT2i. CA125, carbohydrate antigen 125; SGLT2i, sodium-glucose cotransporter 2 inhibitors.

Fig. 1.

Proportion of patients with CA125 values >35 U/mL at visits 1 and 2 in those receiving and not receiving SGLT2i. CA125, carbohydrate antigen 125; SGLT2i, sodium-glucose cotransporter 2 inhibitors.

Close modal

Multivariable quantile regression analyses showed that dapagliflozin treatment was associated with a greater reduction in CA125 (shown in Fig. 2). Indeed, the predicted difference at visit 2 in the median of CA125 for the control and dapagliflozin groups were 52.9 U/mL and 24.6 U/mL, respectively (p = 0.004).

Fig. 2.

Predicted difference in the median of CA125 from visit 1 to visit 2 in those receiving and not receiving dapagliflozin. CA125, carbohydrate antigen 125.

Fig. 2.

Predicted difference in the median of CA125 from visit 1 to visit 2 in those receiving and not receiving dapagliflozin. CA125, carbohydrate antigen 125.

Close modal

CA125 Changes and Adverse Clinical Endpoints

At 6-month follow-up after visit 2, a total of 90 patients (9.4%) died, resulting in a crude mortality incidence rate of 0.246 person-years (P-Y). We also registered 292 and 152 all-cause and HF-related readmission events, respectively. The estimated crude incidence rates of all-cause and HF readmissions were 1.09 P-Y (95% CI: 0.98–1.20) and 0.51 P-Y (95% CI: 0.44–0.59), respectively. The distribution of HF readmissions among patients was 128 (13.4%) had 1 admission, 18 (1.9%) had 2 admissions, 5 (0.5%) had 3 admissions, and 1 (0.1%) had 4 readmissions.

CA125 Reduction and 6-Month Adverse Clinical Outcomes across Treatment Allocation

Rates of 6-month mortality were 83 (10.7%) and 7 (3.9%) (p = 0.005) for those not receiving and receiving dapagliflozin, respectively. Likewise, we found a significant reduction in the rates of 6-month all-cause and HF readmissions in patients discharged with dapagliflozin (all-cause readmission: no dapagliflozin 1.20 P-Y [95% CI: 1.08–1.34] and dapagliflozin 0.60 P-Y [95% CI: 0.44–0.82], p < 0.001, and 2) HF readmissions: no dapagliflozin 0.59 P-Y [95% CI: 0.51–0.69] and dapagliflozin 0.18 P-Y [95% CI: 0.10–0.31], p < 0.001).

In the whole sample, CA125 reduction at visit 2 identified those with a better risk profile (reduction across endpoints) as depicted in Figure 3a (mortality), Figure 3b (any readmissions), and Figure 3c (HF readmissions). The effect of 6-month driven CA125 difference (per decrease in 10 U/mL) on clinical endpoints was borderline associated with reduction in all-cause mortality: IRR = 0.98 P-Y, 95% CI = 0.96–1.00; p = 0.050, and a statistically significant reduction in all-cause readmission (IRR = 0.99, 95% CI = 0.98–0.99; p = 0.003) and HF readmission (IRR = 0.98, 95% CI = 0.97–0.99; p < 0.001). We did not find statistical evidence of heterogeneity across treatment arms for any of the endpoints (death [p value for interaction = 0.920], any readmissions [p value for interaction = 0.366], and HF readmissions [p value for interaction = 0.325]).

Fig. 3.

Association of CA125 changes with 6-month clinical events. a All-cause mortality. b All-cause rehospitalization. c HF-rehospitalization. CA125, carbohydrate antigen 125; HF, heart failure.

Fig. 3.

Association of CA125 changes with 6-month clinical events. a All-cause mortality. b All-cause rehospitalization. c HF-rehospitalization. CA125, carbohydrate antigen 125; HF, heart failure.

Close modal

In this all-corner cohort of patients with AHF, treatment with dapagliflozin was associated with a significant decrease in CA125 values the first weeks after discharge, suggesting this agent provides an additional decongestive and anti-inflammatory effect. Likewise, the greater magnitude of CA125 reduction during the first weeks after discharge identified patients at lower risk of 6-month death and all-cause and HF readmissions. These findings confirm prior observations reported in ambulatory stable HF patients.

Mechanisms behind the Benefits of SGLT2i in HF

The evolving landscape of HF treatment has been significantly reshaped by the introduction of SGLT2i, including dapagliflozin [1]. These agents, initially developed for type 2 diabetes management, have demonstrated remarkable efficacy in improving clinical outcomes in patients with chronic HF, regardless of diabetes status and LVEF [2‒4]. The DAPA-HF and DELIVER trials showed that dapagliflozin significantly reduced the risk of cardiovascular death and HF hospitalizations [2, 4]. In AHF, the evidence is less consistent but also indicates that SGLT2i led to a greater decongestion, less requirement of loop diuretics, and improved surrogates of decongestion [19‒21].

The mechanisms behind the beneficial effect of SGLT2i in HF seem multifactorial but not fully understood. In AHF, the diuretic effect of SGLT2 inhibitors is primarily osmotic diuresis, resulting from the inhibition of sodium-glucose co-transporters in the renal tubules, leading to increased excretion of glucose and sodium [22], has been proposed as a crucial mechanism explaining the benefits of these drugs in decompensated HF [23, 24]. Conversely to traditional diuretics, some investigations suggest these drugs lead to hemoconcentration [25, 26] and increased osmolarity, favoring plasma refill, fluid redistribution and tissue decongestion rather than a reduction in total body water [23, 24, 26].

SGLT2i has also shown anti-inflammatory properties that may mediate the beneficial effects in situations with a greater inflammatory milieu, such as AHF [27]. Indeed, a systematic review and meta-analysis of randomized controlled trials have provided substantial evidence that SGLT2i, including dapagliflozin, significantly reduces markers of inflammation such as C-reactive protein [28].

Inflammatory stimuli, driven by inflammatory cytokines, are well-known drives for CA125 synthesis by mesothelial cells [29]. Thus, CA125 levels may also reflect persistent inflammatory burden [9, 10] and reduction in this biomarker may obey to decreased inflammatory milieu.

Interpreting the Impact of Dapagliflozin on CA125 Levels and Clinical Outcomes

In the AHF setting, current evidence endorsed the role of CA125 as a surrogate marker of the severity of fluid overload (especially extravascular data of congestion) and immunoinflammatory activity in AHF [9, 10]. This relationship is bidirectional, as increased inflammatory activity enhances vascular permeability, thus facilitating interstitial fluid overload [5, 30]. Our study builds upon this understanding by showing that dapagliflozin significantly reduces CA125 levels, suggesting its potential role in ameliorating inflammation and fluid overload in the first weeks following an episode of AHF patients. Consistent with these observations, we hypothesize that changes in CA125 over weeks could serve as a valuable indicator for assessing the decongestive and anti-inflammatory effects of SGLT2i. It is important to note that CA125 has a relatively long half-life (7–12 days), and then its changes are sustained but require more time than other surrogates of decongestion, such as natriuretic peptides.

Interestingly, after SGLT2i initiation, NT-proBNP changes are not meaningful and do not seem to be an accurate parameter for evaluating clinical response [31]. In contrast, some studies suggest that the short-term increase in hemoglobin and hematocrit predicts clinical response to SGLT2i [26, 32]. Thus, we envision changes in hemoglobin/hematocrit and CA125 as complementary tools for predicting the short- and mid-term clinical response to SGLT2i. A decrease of CA125 following SGLT2i has also been reported in ambulatory HF patients, suggesting also the extrapolation of these postulates to chronic HF [14, 15].

Limitations and Future Directions

To our knowledge, this is the first study correlating treatment with dapagliflozin with a significant plasmatic CA125 reduction following hospitalization for AHF. These findings support the role of CA125 in monitoring dapagliflozin treatment response. However, important limitations need to be noted. First, our findings stem from a retrospective observational study, which inherently carries limitations regarding causality. Second, several unmeasured confounders may be playing a role. In this regard, compliance with dapagliflozin or diuretic doses during hospitalization or changes occurred after discharge were not assessed. Third, we evaluated patients discharged after admission for AHF; thus, we cannot extrapolate these findings to other forms of HF or clinical scenarios, such as patients with AHF not requiring admission, or patients with cardiogenic shock or requiring mechanical circulatory support. Additionally, these findings cannot be extrapolated to other SGLT2i other than dapagliflozin. Lastly, we did not routinely measure inflammatory markers, such as C-reactive protein, which would have allowed us to evaluate the concordance between CA125 changes and other proxies of inflammation. Prospective studies are needed to confirm these observations and elucidate the underlying pathophysiological mechanisms behind these findings.

The administration of dapagliflozin upon discharge after an AHF episode was linked to a significant decrease in the levels of CA125 during the initial weeks following discharge. This reduction in CA125 was a marker for identifying patients at a reduced risk of experiencing adverse clinical outcomes within the next 6 months. The implications of this finding suggest that monitoring CA125 levels could be a valuable strategy in assessing the effectiveness of dapagliflozin treatment in this scenario.

This study protocol was reviewed and approved by the Ethics Committee of INCLIVA (Instituto de Investigación Sanitaria del Hospital Clínico Universitario de Valencia), Valencia, Spain, Approval No. 2022/281. As this is a retrospective observational study, it has been granted an exemption from requiring written informed consent (Ethical Committee of INCLIVA, Instituto de Investigación Sanitaria, Valencia, Spain).

Gema Miñana reports personal fees from Abbott Vascular and Prosmédica. Rafael de la Espriella reports personal fees from AstraZeneca, Novartis, Boehringer-Ingelheim, and NovoNordisk (outside the submitted work). Patricia Palau reports personal fees from Servier. Antoni Bayés-Genís has lectured and/or participated in Abbott, AstraZeneca, Bayer, Boehringer-Ingelheim, Novartis, Roche Diagnostics, and Vifor advisory boards (outside the submitted work). Juan Sanchis reports personal fees from Abbott Vascular and Prosmédica. Julio Nuñez reports personal fees or advisory boards from Alleviant, AstraZeneca, Boehringer Ingelheim, Bayer, Novartis, NovoNordisk, Rovi, and Vifor Pharma (outside the submitted work). The rest of the authors have no disclosures. There are no disclosures related to the content of this article.

This work has been funded by a non-conditional grant from AstraZeneca (ESR-22-22099) and CIBER Cardiovascular (Grant No. 16/11/00403 and 16/11/00420). The founders had no role in the investigation nor in the elaboration of the manuscript.

Gema Miñana and Rafael de la Espriella: conceptualization, data curation, investigation, methodology, project administration, validation, visualization, writing – original draft, and writing – review and editing. Miguel Lorenzo-Hernández, Enrique Rodriguez-Borja, Anna Mollar, Patricia Palau, Agustin Fernández-Cisnal, Ernesto Valero, Arturo Carratalá, Enrique Santas, Vicent Bodi, Juan Sanchis, Eduardo Nuñez, and Antoni Bayés-Genís: formal analysis, investigation, methodology, project administration, resources, software, supervision, validation, and writing – review and editing. Julio Nuñez: conceptualization, formal analysis, funding acquisition, investigation, methodology, project administration, resources, software, supervision, validation, visualization, writing – original draft, and writing – review and editing.

Additional Information

Gema Miñana and Rafael de la Espriella contributed equally to this work.

All data generated or analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author.

1.
McDonagh
TA
,
Metra
M
,
Adamo
M
,
Gardner
RS
,
Baumbach
A
,
Böhm
M
, et al
.
2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure
.
Eur Heart J
.
2021
;
42
(
36
):
3599
726
.
2.
McMurray
JJV
,
Solomon
SD
,
Inzucchi
SE
,
Køber
L
,
Kosiborod
MN
,
Martinez
FA
, et al
.
Dapagliflozin in patients with heart failure and reduced ejection fraction
.
N Engl J Med
.
2019
;
381
(
21
):
1995
2008
.
3.
Anker
SD
,
Butler
J
,
Filippatos
G
,
Ferreira
JP
,
Bocchi
E
,
Böhm
M
, et al
.
Empagliflozin in heart failure with a preserved ejection fraction
.
N Engl J Med
.
2021
;
385
(
16
):
1451
61
.
4.
Solomon
SD
,
McMurray
JJV
,
Claggett
B
,
de Boer
RA
,
DeMets
D
,
Hernandez
AF
, et al
.
Dapagliflozin in heart failure with mildly reduced or preserved ejection fraction
.
N Engl J Med
.
2022
;
387
(
12
):
1089
98
.
5.
Colombo
PC
,
Doran
AC
,
Onat
D
,
Wong
KY
,
Ahmad
M
,
Sabbah
HN
, et al
.
Venous congestion, endothelial and neurohormonal activation in acute decompensated heart failure: cause or effect
.
Curr Heart Fail Rep
.
2015
;
12
(
3
):
215
22
.
6.
de la Espriella
R
,
Cobo
M
,
Santas
E
,
Verbrugge
FH
,
Fudim
M
,
Girerd
N
, et al
.
Assessment of filling pressures and fluid overload in heart failure: an updated perspective
.
Rev Esp Cardiol
.
2023
;
76
(
1
):
47
57
.
7.
Miñana
G
,
de la Espriella
R
,
Mollar
A
,
Santas
E
,
Núñez
E
,
Valero
E
, et al
.
Factors associated with plasma antigen carbohydrate 125 and amino-terminal pro-B-type natriuretic peptide concentrations in acute heart failure
.
Eur Heart J Acute Cardiovasc Care
.
2020
;
9
(
5
):
437
47
.
8.
Núñez
J
,
de la Espriella
R
,
Rossignol
P
,
Voors
AA
,
Mullens
W
,
Metra
M
, et al
.
Congestion in heart failure: a circulating biomarker-based perspective. A review from the Biomarkers Working Group of the Heart Failure Association, European Society of Cardiology
.
Eur J Heart Fail
.
2022
;
24
(
10
):
1751
66
.
9.
Núñez
J
,
Bayés-Genís
A
,
Revuelta-López
E
,
Ter Maaten
JM
,
Miñana
G
,
Barallat
J
, et al
.
Clinical role of CA125 in worsening heart failure: a BIOSTAT-CHF study subanalysis
.
JACC Heart Fail
.
2020
;
8
(
5
):
386
97
.
10.
Núñez
J
,
de la Espriella
R
,
Miñana
G
,
Santas
E
,
Llácer
P
,
Núñez
E
, et al
.
Antigen carbohydrate 125 as a biomarker in heart failure: a narrative review
.
Eur J Heart Fail
.
2021
;
23
(
9
):
1445
57
.
11.
Núñez
J
,
Bayés-Genís
A
,
Revuelta-López
E
,
Miñana
G
,
Santas
E
,
Ter Maaten
JM
, et al
.
Optimal carbohydrate antigen 125 cutpoint for identifying low-risk patients after admission for acute heart failure
.
Rev Esp Cardiol
.
2022
;
75
(
4
):
316
24
.
12.
Núñez
J
,
Llàcer
P
,
Bertomeu-González
V
,
Bosch
MJ
,
Merlos
P
,
García-Blas
S
, et al
.
Carbohydrate antigen-125-guided therapy in acute heart failure: Chance-HF – a randomized study
.
JACC Heart Fail
.
2016
;
4
(
11
):
833
43
.
13.
Núñez
J
,
Llàcer
P
,
García-Blas
S
,
Bonanad
C
,
Ventura
S
,
Núñez
JM
, et al
.
CA125-guided diuretic treatment versus usual care in patients with acute heart failure and renal dysfunction
.
Am J Med
.
2020
;
133
(
3
):
370
80.e4
.
14.
de la Espriella
R
,
Miñana
G
,
Santas
E
,
Núñez
G
,
Lorenzo
M
,
Núñez
E
, et al
.
Effects of empagliflozin on CA125 trajectory in patients with chronic congestive heart failure
.
Int J Cardiol
.
2021
;
339
:
102
5
.
15.
Amiguet
M
,
Palau
P
,
Domínguez
E
,
Seller
J
,
Pinilla
JMG
,
de la Espriella
R
, et al
.
Dapagliflozin and short-term changes on circulating antigen carbohydrate 125 in heart failure with reduced ejection fraction
.
Sci Rep
.
2023
;
13
(
1
):
10591
.
16.
Parente
P
,
Santos Silva
J
.
Quantile regression with clustered data
.
J Econom Methods
.
2016
;
5
:
1
15
.
17.
Xu
X
,
Hardin
JW
.
Regression models for bivariate count outcomes
.
Stata J
.
2016
;
16
(
2
):
301
15
.
18.
Crowther
MJ
.
Merlin: a unified modeling framework for data analysis and methods development in Stata
.
Stata J
.
2020
;
20
(
4
):
763
84
.
19.
Voors
AA
,
Angermann
CE
,
Teerlink
JR
,
Collins
SP
,
Kosiborod
M
,
Biegus
J
, et al
.
The SGLT2 inhibitor empagliflozin in patients hospitalized for acute heart failure: a multinational randomized trial
.
Nat Med
.
2022
;
28
(
3
):
568
74
.
20.
Damman
K
,
Beusekamp
JC
,
Boorsma
EM
,
Swart
HP
,
Smilde
TDJ
,
Elvan
A
, et al
.
Randomized, double-blind, placebo-controlled, multicentre pilot study on the effects of empagliflozin on clinical outcomes in patients with acute decompensated heart failure (EMPA-RESPONSE-AHF)
.
Eur J Heart Fail
.
2020
;
22
(
4
):
713
22
.
21.
Cox
ZL
,
Collins
SP
,
Hernandez
GA
,
McRae
AT
3rd
,
Davidson
BT
,
Adams
K
, et al
.
Efficacy and safety of dapagliflozin in patients with acute heart failure
.
J Am Coll Cardiol
.
2024
;
83
(
14
):
1295
306
.
22.
Heerspink
HJ
,
Perkins
BA
,
Fitchett
DH
,
Husain
M
,
Cherney
DZ
.
Sodium glucose cotransporter 2 inhibitors in the treatment of diabetes mellitus: cardiovascular and kidney effects, potential mechanisms, and clinical applications
.
Circulation
.
2016
;
134
(
10
):
752
72
.
23.
Bjornstad
P
,
Greasley
PJ
,
Wheeler
DC
,
Chertow
GM
,
Langkilde
AM
,
Heerspink
HJL
, et al
.
The potential roles of osmotic and nonosmotic sodium handling in mediating the effects of sodium-glucose cotransporter 2 inhibitors on heart failure
.
J Card Fail
.
2021
;
27
(
12
):
1447
55
.
24.
Boorsma
EM
,
Beusekamp
JC
,
Ter Maaten
JM
,
Figarska
SM
,
Danser
AHJ
,
van Veldhuisen
DJ
, et al
.
Effects of empagliflozin on renal sodium and glucose handling in patients with acute heart failure
.
Eur J Heart Fail
.
2021
;
23
(
1
):
68
78
.
25.
Lorenzo
M
,
Miñana
G
,
Palau
P
,
Amiguet
M
,
Seller
J
,
Garcia Pinilla
JM
, et al
.
Short-term changes in hemoglobin and changes in functional status, quality of life and natriuretic peptides after initiation of dapagliflozin in heart failure with reduced ejection fraction
.
J Card Fail
.
2023
;
29
(
5
):
849
54
.
26.
Miñana
G
,
de la Espriella
R
,
Palau
P
,
Amiguet
M
,
Seller
J
,
García Pinilla
JM
, et al
.
Early glomerular filtration rate decline is associated with hemoglobin rise following dapagliflozin initiation in heart failure with reduced ejection fraction
.
Rev Esp Cardiol
.
2023
;
76
(
10
):
783
92
.
27.
Garofalo
M
,
Corso
R
,
Tomasoni
D
,
Adamo
M
,
Lombardi
CM
,
Inciardi
RM
, et al
.
Inflammation in acute heart failure
.
Front Cardiovasc Med
.
2023
;
10
:
1235178
.
28.
Wang
D
,
Liu
J
,
Zhong
L
,
Li
S
,
Zhou
L
,
Zhang
Q
, et al
.
The effect of sodium-glucose cotransporter 2 inhibitors on biomarkers of inflammation: a systematic review and meta-analysis of randomized controlled trials
.
Front Pharmacol
.
2022
;
13
:
1045235
.
29.
Zeillemaker
AM
,
Verbrugh
HA
,
Hoynck van Papendrecht
AA
,
Leguit
P
.
CA 125 secretion by peritoneal mesothelial cells
.
J Clin Pathol
.
1994
;
47
(
3
):
263
5
.
30.
Colombo
PC
,
Castagna
F
,
Onat
D
,
Wong
KY
,
Harxhi
A
,
Hayashi
Y
, et al
.
Experimentally induced peripheral venous congestion exacerbates inflammation, oxidative stress, and neurohormonal and endothelial cell activation in patients with systolic heart failure
.
J Card Fail
.
2024
;
30
(
4
):
580
91
.
31.
Januzzi
JL
Jr
,
Zannad
F
,
Anker
SD
,
Butler
J
,
Filippatos
G
,
Pocock
SJ
, et al
.
Prognostic importance of NT-proBNP and effect of empagliflozin in the EMPEROR-reduced trial
.
J Am Coll Cardiol
.
2021
;
78
(
13
):
1321
32
.
32.
Tian
Q
,
Guo
K
,
Deng
J
,
Zhong
Y
,
Yang
L
.
Effects of SGLT2 inhibitors on haematocrit and haemoglobin levels and the associated cardiorenal benefits in T2DM patients: a meta-analysis
.
J Cell Mol Med
.
2022
;
26
(
2
):
540
7
.