Effects of Zibotentan Alone and in Combination with Dapagliflozin on Fluid Retention in Patients with CKD.

BACKGROUND: Endothelin receptor antagonists (ERAs) reduce albuminuria but are limited by fluid retention risk, particularly in patients with chronic kidney disease (CKD). Combining ERAs with sodium-glucose cotransporter 2 (SGLT2) inhibitors, which have diuretic effects, offers a promising strategy to mitigate fluid retention. In this post-hoc analysis of the ZENITH-CKD trial, we assessed fluid dynamics in patients with CKD treated with the ERA zibotentan alone, and in combination with the SGLT2 inhibitor dapagliflozin. METHODS: In ZENITH-CKD, 508 patients with CKD (estimated glomerular filtration rate ≥ 20 mL/min/1.73m2 and a urinary albumin-to-creatinine ratio of 150-5000 mg/g) were randomized to treatment with placebo, dapagliflozin 10 mg plus placebo, zibotentan (0.25, 1.5 or 5 mg) plus dapagliflozin 10 mg and zibotentan 5 mg plus placebo. We evaluated correlations between changes in fluid retention markers and bioimpedance-measured extracellular fluid (ECF) in response to zibotentan treatment. We used Cox proportional hazards regression to assess the association between zibotentan/dapagliflozin treatment, baseline characteristics, and fluid retention, and the relationship between zibotentan plasma exposure and fluid retention. RESULTS: After 3 weeks of treatment with zibotentan 0.25, 1.5 or 5 mg plus dapagliflozin 10 mg, changes in body weight (ß=0.36 [95%CI 0.26,0.45]) per kg, B-type natriuretic peptide (ß=0.38 [95%CI 0.22, 0.54]) per doubling, and hemoglobin (ß=-0.29 [95%CI -0.48, -0.10]) per g/dL were independently associated with changes in ECF. Higher doses of zibotentan were associated with significantly higher risk of fluid retention compared to dapagliflozin alone (zibotentan 5 mg HR 8.50 (95%CI 3.40, 21.30). The hazard ratio attenuated when zibotentan was combined with dapagliflozin (HR zibotentan/dapagliflozin 5/10 mg 3.09 [95%CI 1.08, 8.80], zibotentan/dapagliflozin 1.5/10 mg 2.70 [95%CI 1.44, 5.07] and zibotentan/dapagliflozin 0.25/10 mg HR 1.21 [95%CI 0.50, 2.91]). The risk of fluid retention was higher with higher zibotentan exposure and lower eGFR. CONCLUSIONS: High doses of zibotentan were associated with a higher risk of fluid retention, which was attenuated with lower doses and the addition of dapagliflozin.

Congestion as a crucial factor determining albuminuria in patients with cardiorenal disease.

Background: Albuminuria could potentially emerge as a novel marker of congestion in acute heart failure. However, the current evidence linking albuminuria and congestion in patients with congestive heart failure (CHF) remains somewhat scarce. This study aimed to evaluate the prevalence of albuminuria in a cohort of patients with CHF, identify the independent factors associated with albuminuria and analyse the correlation with different congestion parameters. Methods: This is a subanalysis of the Spanish Cardiorenal Registry, in which we enrolled 864 outpatients with heart failure and a value of urinary albumin:creatinine ratio (UACR) at the first visit. Results: The median age was 74 years, 549 (63.5%) were male and 438 (50.7%) had a reduced left ventricular ejection fraction. A total of 350 patients (40.5%) had albuminuria. Among these patients, 386 (33.1%) had a UACR of 30-300 mg/g and 64 (7.4%) had a UACR >300 mg/g. In order of importance, the independent variables associated with higher UACR were estimated glomerular filtration rate determined by the Chronic Kidney Disease Epidemiology Collaboration equation (R2 = 57.6%), systolic blood pressure (R2 = 21.1%), previous furosemide equivalent dose (FED; R2 = 7.5%), antigen carbohydrate 125 (CA125; R2 = 6.1%), diabetes mellitus (R2 = 5.6%) and oedema (R2 = 1.9%). The combined influence of oedema, elevated CA125 levels and the FED accounted for 15.5% of the model's variability. Conclusions: In patients with chronic stable heart failure, the prevalence of albuminuria is high. The risk factors of albuminuria in this population are chronic kidney disease and hypertension. Congestion parameters are also associated with increased albuminuria.

Effects of semaglutide with and without concomitant SGLT2 inhibitor use in participants with type 2 diabetes and chronic kidney disease in the FLOW trial.

People with type 2 diabetes and chronic kidney disease have a high risk for kidney failure and cardiovascular (CV) complications. Glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter-2 inhibitors (SGLT2i) independently reduce CV and kidney events. The effect of combining both is unclear. FLOW trial participants with type 2 diabetes and chronic kidney disease were stratified by baseline SGLT2i use (N = 550) or no use (N = 2,983) and randomized to semaglutide/placebo. The primary outcome was a composite of kidney failure, ≥50% estimated glomerular filtration rate reduction, kidney death or CV death. The risk of the primary outcome was 24% lower in all participants treated with semaglutide versus placebo (95% confidence interval: 34%, 12%). The primary outcome occurred in 41/277 (semaglutide) versus 38/273 (placebo) participants on SGLT2i at baseline (hazard ratio 1.07; 95% confidence interval: 0.69, 1.67; P = 0.755) and in 290/1,490 versus 372/1,493 participants not taking SGLT2i at baseline (hazard ratio 0.73; 0.63, 0.85; P < 0.001; P interaction 0.109). Three confirmatory secondary outcomes were predefined. Treatment differences favoring semaglutide for total estimated glomerular filtration rate slope (ml min-1/1.73 m2/year) were 0.75 (-0.01, 1.5) in the SGLT2i subgroup and 1.25 (0.91, 1.58) in the non-SGLT2i subgroup, P interaction 0.237. Semaglutide benefits on major CV events and all-cause death were similar regardless of SGLT2i use (P interaction 0.741 and 0.901, respectively). The benefits of semaglutide in reducing kidney outcomes were consistent in participants with/without baseline SGLT2i use; power was limited to detect smaller but clinically relevant effects. ClinicalTrials.gov identifier: NCT03819153 .

Performance of the Roche Elecsys® IGRA SARS-CoV-2 test for the detection and quantification of virus-reactive T cells in COVID-19-vaccinated immunosuppressed patients and healthy subjects.

PURPOSE: Comparing the performance of commercially available SARS-CoV-2 T-cell immunoassay responses may provide useful information for future observational or intervention studies as well as to their potential customers. METHOD: Whole blood was collected from a total of 183 subjects fully vaccinated against COVID-19: 55 healthy controls (Group 1), 50 hematological patients (Group 2), 50 chronic kidney disease patients (Group 3), and 28 elderly nursing home residents (Group 4). Samples were tested with the Roche Elecsys® IGRA (Interferon-gamma release assay) SARS-CoV-2 test (Roche Diagnostics, Rotkreuz, Switzerland), the Euroimmun SARS-CoV-2 test (Euroimmun, Lubeck, Germany), the SARS-CoV-2 T Cell Analysis Kit (Miltenyi Biotec, Bergisch Gladbach, Germany), and a flow-cytometry for intracellular cytokine (IFN-γ) staining-based immunoassay (FC-ICS). RESULTS: Overall, the Roche Elecsys® assay returned the highest number of positive results (151/179; 84.3%), followed by the Euroimmun test (127/183; 69%), and the FC-ICS (135/179; 75%). The Kappa coefficient of agreement was best between IGRAs (0.64). Most discordant results across assays involved patients from Group 2. Overall, IFN-γ concentrations measured by both IGRAs correlated strongly (rho = 0.78; 95% CI 0.71-0.84; P < 0.001) irrespective of the study group. The frequencies of SARS-CoV-2-reactive IFN-γ T cells and IFN-γ concentrations measured by the IGRAs correlated moderately for CD4+ T cells, however, weakly for CD8+ T cells. SARS-CoV-2-experienced participants displayed stronger responses than SARS-CoV-2-naïve when IGRAs, rather than FC-ICS, were used. CONCLUSION: The SARS-CoV-2 immunoassays evaluated in the present study did not return interchangeable qualitative or quantitative results either in seemingly healthy individuals or in immunosuppressed patients.

Non-valvular atrial fibrillation in patients on peritoneal dialysis, prevalence, treatment and professionals involved.

Atrial fibrillation is the most frequent chronic arrhythmia in patients with chronic kidney disease. Oral anticoagulation with vitamin K antagonists and now direct oral anticoagulants have been and are the fundamental pillars for the prevention of thromboembolic events. However, there are no randomized clinical trials on the risk-benefit profile of oral anticoagulation in patients with chronic kidney disease stage 5 on peritoneal dialysis and there is little evidence in the literature in this population. The objective of our study was to know the prevalence, treatment and professionals involved in the management of atrial fibrillation in peritoneal dialysis patients. For this purpose, we performed a descriptive analysis through a survey sent to different peritoneal dialysis units in Spain. A total of 1,403 patients on peritoneal dialysis were included in the study, of whom 186 (13.2%) had non-valvular atrial fibrillation. In addition, the assessment of the scores of thromboembolic and bleeding risks for the indication of oral anticoagulation was mainly carried out by the cardiologist (60% of the units), as well as its prescription (cardiologist 47% or in consensus with the nephrologist 43%). In summary, patients on peritoneal dialysis have a remarkable prevalence of non-valvular atrial fibrillation. Patients frequently receive oral anticoagulation with vitamin K antagonists, as well as direct oral anticoagulants. The data obtained regarding the scores used for the assessment of thromboembolic and bleeding risk, treatment and involvement by Nephrology indicates that there is a need for training and involvement of the nephrologist in this pathology.

Esteatosis hepática metabólica y nefropatía diabética: una llamada a la acción / Targeting metabolic-associated fatty liver disease in diabetic kidney disease: A call to action

La incidencia y la prevalencia de hígado graso no alcohólico o enfermedad hepática metabólica (EHmet) está en aumento y es mayor en pacientes con diabetes mellitus tipo 2 (DM2). El riesgo cardiovascular y renal está claramente incrementado en estos pacientes, especialmente cuando se desarrolla nefropatía diabética. El eje cardio-reno-hepato-metabólico, conformado por la enfermedad cardiovascular (ECV), la enfermedad renal crónica (ERC), la EHmet y la DM2, tiene una base fisiopatogénica común. La relación clínica entre todos los componentes es inevitable y multidireccional, pudiendo la EHmet preceder al desarrollo de complicaciones cardiovasculares y renales, y también empeorar el pronóstico de las mismas una vez desarrolladas. En esta revisión enfatizamos la importancia de buscar y tratar la EHmet en pacientes con ERC y DM2 con el objetivo de identificar pacientes de mayor riesgo y de mejorar su pronóstico.(AU)

Non-alcoholic fatty liver disease or metabolic-associated fatty liver disease (MAFLD) is a common condition with increasing prevalence and incidence, specially in patients with type 2 diabetes mellitus (DM2). Both cardiovascular and renal disease are clearly increased in these patients, particularly in those with diabetic nephropathy. In the liver–heart–kidney–metabolic axis, the common pathophysiological basis of MAFLD, cardiovascular disease (CVD), chronic kidney disease (CKD), and DM2 is the same. The clinical relationship between all of them is clear and is multidirectional: MAFLD may precede the development of cardiovascular and renal disease, and may also worsen the prognosis of these complications once developed. In this review we emphasize the importance of targeting MAFLD in diabetic kidney disease, with the goal of detecting high-risk patients in order to improve their prognosis.(AU)

Efecto de los inhibidores del cotransportador sodio-glucosa tipo 2 sobre la anemia: posibles implicaciones clínicas / Effect of SGLT2 inhibitors on anemia and their possible clinical implications

Los inhibidores del cotransportador sodio-glucosa tipo 2 (iSGLT2) han demostrado su beneficio cardiovascular y renal en pacientes con diabetes mellitus tipo 2, insuficiencia cardiaca (IC) o enfermedad renal crónica (ERC). Desde los primeros estudios, con estos fármacos se objetivó un incremento inicial de los niveles de hemoglobina/hematocrito que se atribuyó a un aumento de la hemoconcentración asociados a su efecto diurético, aunque pronto se constató que aumentaban los niveles de eritropoyetina (EPO) y eritropoyesis, mejorando el metabolismo férrico. Los estudios de mediación objetivaron que el incremento de hemoglobina se asociaba estrechamente con los beneficios cardiorrenales de estas sustancias. En la presente revisión se discuten los mecanismos de mejora de la eritropoyesis y la implicación del aumento de hemoglobina sobre el beneficio pronóstico cardiorrenal de estos medicamentos.(AU)

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have demonstrated cardiovascular and renal benefits in patients with type 2 diabetes mellitus, heart failure, or chronic kidney disease. Since the first studies with these drugs, an initial increase in hemoglobin/hematocrit levels was observed, which was attributed to an increase in hemoconcentration associated with its diuretic effect, although it was soon seen that these drugs increased erythropoietin levels and erythropoiesis, and improved iron metabolism. Mediation studies found that the increase in hemoglobin was strongly associated with the cardiorenal benefits of these drugs. In this review, we discuss the mechanisms for improving erythropoiesis and the implication of the increase in hemoglobin on the cardiorenal prognostic benefit of these drugs.(AU)

Targeting metabolic-associated fatty liver disease in diabetic kidney disease: A call to action.

Nonalcoholic fatty liver disease or metabolic-associated fatty liver disease (MAFLD) is a common condicion with increasing prevalence and incidence, specially in patients with type 2 diabetes mellitus (T2DM). Both cardiovascular and renal disease are clearly increased in these patients, particularly in those with diabetic nephropathy. In the liver-heart-kidney-metabolic axis, the common pathophysiological basis of MAFLD, cardiovascular disease (CVD), chronic kidney disease (CKD), and T2DM is the same. The clinical relationship between all of them is clear and is multidirectional: MAFLD may precede the development of cardiovascular and renal disease, and may also worsen the prognosis of these complications once developed. In this review we emphasize the importance of targeting MAFLD in Diabetic kidney disease, with the goal of detecting high-risk patients in order to improve their prognosis.

Urinary Cell Cycle Arrest Biomarkers and Diuretic Efficiency in Acute Heart Failure.

INTRODUCTION: This study aimed to evaluate the association between the NephroCheck® test AKIRisk® score, diuretic efficiency (DE), and the odds of worsening kidney function (WKF) within the first 72 h of admission in patients hospitalized for acute heart failure (AHF). METHODS: The study prospectively enrolled 125 patients admitted with AHF. NephroCheck® test was obtained within the first 24 h of admission. DE was defined as net fluid urine output per 40 mg of furosemide equivalents. RESULTS: The median AKIRisk® score was 0.11 (IQR 0.06-0.34), and 38 (30.4%) patients had an AKIRisk® score >0.3. The median cumulative DE at 72 h was 1,963 mL (IQR 1317-3,239 mL). At 72 h, a total of 10 (8%) patients developed an absolute increase in sCr ≥0.5 mg/dL (WKF). In a multivariable setting, there was an inverse association between the AKIRisk® score and DE within the first 72 h. In fact, the highest the AKIRisk® score (centered at 0.3), the higher the likelihood of poor DE (below the median) and WKF at 72 h (odds ratio [OR] 2.04; 95%; CI: 1.02-4.07; p = 0.043, and OR 3.31, 95% CI: 1.30-8.43; p = 0.012, respectively). CONCLUSION: In patients with AHF, a higher NephroCheck® AKIRisk® score is associated with poorer DE and a higher risk of WKF at 72 h. Further research is needed to confirm the role of urinary cell cycle arrest biomarkers in the AHF scenario.

Osteoporosis management in patients with chronic kidney disease (ERCOS Study): A challenge in nephrological care.

Fracture risk assessment in patients with chronic kidney disease (CKD) has been included in the CKD-MBD ("Chronic Kidney Disease-Mineral and Bone Disorders") complex in international and national nephrology guidelines, suggesting for the first time the assessment of bone mineral density (BMD) if the results can influence therapeutic decision-making. However, there is very little information on actual clinical practice in this population. The main objective of the ERCOS (ERC-Osteoporosis) study is to describe the profile of patients with CKD G3-5D with osteoporosis (OP) and/or fragility fractures treated in specialized nephrology, rheumatology and internal medicine clinics in Spain. Fifteen centers participated and 162 patients (mostly women [71.2%] postmenopausal [98.3%]) with a median age of 77 years were included. Mean estimated glomerular filtration rate (eGFR) was 36 mL/min/1.73 m2 and 38% of the included patients were on dialysis. We highlight the high frequency of prevalent fragility fractures [37.7%), mainly vertebral (52.5%) and hip (24.6%)], the disproportionate history of patients with glomerular disease compared to purely nephrological series (corticosteroids) and undertreatment for fracture prevention, especially in nephrology consultations. This study is an immediate call to action with the dissemination of the new, more proactive, clinical guidelines, and underlines the need to standardize a coordinated and multidisciplinary care/therapeutic approach to these patients in an efficient way to avoid current discrepancies and therapeutic nihilism.

Intrarenal Venous Flow Pattern Changes Do Relate With Renal Function Alterations in Acute Heart Failure.

BACKGROUND: There is scarce evidence supporting the clinical utility of congestive intrarenal venous flow (IRVF) patterns in patients with acute heart failure. OBJECTIVES: This study aims to: 1) investigate the association between IRVF patterns and the odds of worsening renal function (WRF); 2) track the longitudinal changes of serum creatinine (sCr) across IRVF at predetermined points and its association with decongestion; and 3) explore the relationship between IRVF/WRF categories and patient outcomes. METHODS: IRVF was assessed at baseline (pre-decongestive therapy), 72 hours, and 30 and 90 days postdischarge. Changes in sCr trajectories across dynamic IRVF variations and parameters of decongestion were assessed using linear mixed effect models. The association between IRVF/WRF categories and outcomes was evaluated using univariable/multivariable models. RESULTS: In this prospective, multicenter study with 188 participants, discontinuous IRVF patterns indicated higher odds of WRF (OR: 3.90 [95% CI: 1.24-12.20]; P = 0.020 at 72 hours; and OR: 5.76 [95% CI: 1.67-19.86]; P = 0.006 at 30 days) and an increase in sCr (Δ-72 hours 0.14 mg/dL [95% CI: 0.06-0.22]; P = 0.001; Δ-discharge 0.13 mg/dL [95% CI: 0.03-0.23]; P = 0.007). However, the diuretic response and decongestion significantly influenced the magnitude of these changes. Patients exhibiting both WRF and discontinuous IRVF at 30 days experienced an increased hazard of adverse events (HR: 5.96 [95% CI: 2.63-13.52]; P < 0.001). CONCLUSIONS: Discontinuous IRVF identifies patients with higher odds of WRF during admission and postdischarge periods. Nonetheless, adequate diuretic response and decongestion could modify this association. Patients showing both WRF and discontinuous IRVF at 30 days had increased rates of adverse events.

Prevalence and clinical profile of kidney disease in patients with chronic heart failure. Insights from the Spanish cardiorenal registry.

INTRODUCTION AND OBJECTIVES: Patients with combined heart failure (HF) and chronic kidney disease (CKD) have been underrepresented in clinical trials. The prevalence of CKD in these patients and their clinical profile require constant evaluation. This study aimed to analyze the prevalence of CKD, its clinical profile, and patterns of use of evidence-based medical therapies in HF across CKD stages in a contemporary cohort of ambulatory patients with HF. METHODS: From October 2021 to February 2022, the CARDIOREN registry included 1107 ambulatory HF patients from 13 HF clinics in Spain. RESULTS: The median age was 75 years, 63% were male, and 48% had heart failure with reduced left ventricular ejection fraction (HFrEF). A total of 654 (59.1%) had an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2, and 122 (11%) patients with eGFR ≥ 60 mL/min/1.73 m2 had a urine albumin-creatinin ratio ≥ 30 mg/g. The most important variables associated with lower eGFR were age (R2=61%) and furosemide dose (R2=21%). The proportion of patients receiving an angiotensin-converting enzyme inhibitor (ACEI)/ angiotensin II receptor blockers (ARB), an angiotensin receptor-neprilysin inhibitor (ARNi), a sodium-glucose cotransporter 2 inhibitor (SGLT2i), or a mineralocorticoid receptor antagonist (MRA) progressively decreased with lower eGFR categories. Notably, 32% of the patients with HFrEF and an eGFR <30 mL/min/1.73 m2 received the combination of ACEI/ARB/ARNi+beta-blockers+MRA+SGLT2i. CONCLUSIONS: In this contemporary HF registry, 70% of patients had kidney disease. Although this population is less likely to receive evidence-based therapies, structured and specialized follow-up approaches within HF clinics may facilitate the adoption of these life-saving drugs.

Kidney function changes in acute heart failure: a practical approach to interpretation and management.

Worsening kidney function (WKF) is common in patients with acute heart failure (AHF) syndromes. Although WKF has traditionally been associated with worse outcomes on a population level, serum creatinine concentrations vary greatly during episodes of worsening heart failure, with substantial individual heterogeneity in terms of their clinical meaning. Consequently, interpreting such changes within the appropriate clinical context is essential to unravel the pathophysiology of kidney function changes and appropriately interpret their clinical meaning. This article aims to provide a critical overview of WKF in AHF, aiming to provide physicians with some tips and tricks to appropriately interpret kidney function changes in the context of AHF.

Finerenone: towards a holistic therapeutic approach to patients with diabetic kidney disease.

Despite current treatments, which include renin angiotensin system blockers and SGLT2 inhibitors, the risk of progression of kidney disease among patients with diabetes and chronic kidney disease (CKD) remains unacceptably high. The pathogenesis of CKD in patients with diabetes is complex and includes hemodynamic and metabolic factors, as well as inflammation and fibrosis. Finerenone is a highly selective nonsteroidal mineralocorticoid antagonist that, in contrast to current therapies, may directly reduce inflammation and fibrosis, thus adding value in the management of these patients. In fact, finerenone decreases albuminuria and slows CKD progression in persons with diabetes. We now review the mechanisms of action of finerenone, the results of recent clinical trials, and the integration of the kidney and cardiovascular protection afforded by finerenone in the routine care of patients with diabetes and CKD.

La reducción temprana del filtrado glomerular se asocia con aumento de la hemoglobina tras el inicio de dapagliflozina en la insuficiencia cardiaca con fracción de eyección reducida / Early glomerular filtration rate decline is associated with hemoglobin rise following dapagliflozin initiation in heart failure with reduced ejection fraction

Introducción y objetivos: Los inhibidores del cotransportador 2 de sodio-glucosa (iSGLT2) inducen cambios a corto plazo en la función renal y la hemoglobina y su fisiopatología se comprende de manera incompleta. Nuestro objetivo es evaluar la relación entre los cambios de la tasa de filtrago glomerular estimado (TFGre) y la hemoglobina tras el inicio de dapagliflozina en pacientes estables con insuficiencia cardiaca y fracción de eyección reducida (IC-FEr). Métodos: Este análisis post hoc de un ensayo clínico aleatorizado evaluó el efecto de la dapagliflozina sobre el consumo máximo de oxígeno a 1 y 3 meses en pacientes ambulatorios con IC-FEr estable (ensayo DAPA-VO2, NCT04197635). Se utilizó un análisis de regresión lineal mixta para evaluar la relación entre los cambios en la TFGe y la hemoglobina a 1 y 3 meses. Resultados: Se evaluó a 87 pacientes. La media de edad era 67,0±10,5 años, y 21 pacientes (24,1%) eran mujeres. Las medias basales de TFGe y hemoglobina fueron de 66,9±20,7ml/min/1,73 m2 y 14,3±1,7g/dl respectivamente. En comparación con el placebo, la TFGe no cambió significativamente en el grupo de dapagliflozina, pero la hemoglobina aumentó significativamente a 1 y 3 meses. A 1 mes, el aumento de la hemoglobina se relacionó con la disminución de la TFGe solo en el grupo de dapagliflozina (p <0,001). A los 3 meses no había asociación significativa (p=0,123). Los cambios de la TFGe a 1 y 3 meses no se asociaron con cambios en el consumo pico de oxígeno, la calidad de vida o los péptidos natriuréticos. Conclusiones: En pacientes con IC-FEr estable, los cambios en la TFGe a 1 mes inducidos por la dapagliflozina están en relación inversa con cambios en la hemoglobina. Esta asociación no se observa a los 3 meses. (AU)

Introduction and objectives: Sodium-glucose cotransporter-2 inhibitors (SGLT2i) induce short-term changes in renal function and hemoglobin. Their pathophysiology is incompletely understood. We aimed to evaluate the relationship between 1- and 3-month estimated glomerular filtration rate (eGFR) and hemoglobin changes following initiation of dapagliflozin in patients with stable heart failure with reduced ejection fraction (HFrEF). Methods: This is a post hoc analysis of a randomized clinical trial that evaluated the effect of dapagliflozin on 1- and 3-month peak oxygen consumption in outpatients with stable HFrEF (DAPA-VO2 trial, NCT04197635). We used linear mixed regression analysis to assess the relationship between eGFR and hemoglobin changes across treatment arms. Results: A total of 87 patients were evaluated in this substudy. The mean age was 67.0± 10.5 years, and 21 (24.1%) were women. The mean baseline eGFR and hemoglobin were 66.9±20.7mL/min/1.73m2 and 14.3±1.7g/dL, respectively. Compared with placebo, eGFR did not significantly change at either time points in the dapagliflozin group, but hemoglobin significantly increased at 1 and 3 months. At 1 month, the hemoglobin increase was related to decreases in eGFR only in the dapagliflozin arm (P <.001). At 3 months, there was no significant association in either treatment arms (P=.123). Changes in eGFR were not associated with changes in peak oxygen consumption, quality of life, or natriuretic peptides. Conclusions: In patients with stable HFrEF, 1-month changes in eGFR induced by dapagliflozin are inversely related to changes in hemoglobin. This association was no longer significant at 3 months. (AU)

Short-Term Changes in Peak VO2 After Initiation of Dapagliflozin in Heart Failure Across Iron Status.

BACKGROUND: Some studies have indicated that sodium-glucose cotransporter-2 (SGLT2) inhibitors promote an increase in cell iron use. OBJECTIVES: The aim of this study was to examine, in patients with stable heart failure with reduced left ventricular ejection fraction (HFrEF), the effect of dapagliflozin on ferrokinetic parameters and whether short-term changes in peak oxygen consumption (Vo2) after dapagliflozin treatment are influenced by baseline and serial ferrokinetic status. METHODS: This was an exploratory analysis of a randomized, double-blind clinical trial that evaluated the effect of dapagliflozin vs placebo on peak Vo2 in patients with HFrEF (NCT04197635) and included 76 of the 90 patients initially enrolled in the trial. Changes in peak Vo2 at 1 and 3 months were explored according to baseline and longitudinal ferrokinetic parameters (natural logarithm [ln] ferritin, transferrin saturation index [TSAT], soluble transferrin receptor, and hepcidin). Linear mixed-effect regression was used for the analyses. RESULTS: Compared with placebo, dapagliflozin led to a significant decrease in 3-month ln ferritin (P = 0.040) and an increase in 1-month ln soluble transferrin receptor (P = 0.023). Between-treatment comparisons revealed a stepwise increase in peak Vo2 in the dapagliflozin group at 1 and 3 months, which was especially apparent at lower baseline values of TSAT and ferritin (P < 0.05). Lower time-varying values of TSAT (1 and 3 months) also identified patients with greater improvements in peak Vo2. CONCLUSIONS: In patients with stable HFrEF, treatment with dapagliflozin resulted in short-term increases in peak Vo2, which were most marked in patients with surrogates of greater iron deficiency at baseline and during treatment. (Short-Term Effects of Dapagliflozin on Peak Vo2 in HFrEF [DAPA-VO2]; NCT04197635).