Intravenous ferric derisomaltose in patients with heart failure and iron deficiency in the UK (IRONMAN): an investigator-initiated, prospective, randomised, open-label, blinded-endpoint trial

The Lancet, Journal Year: 2022, Volume and Issue: 400(10369), P. 2199 - 2209

Published: Nov. 5, 2022

Language: Английский

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SGLT2 inhibitors: role in protective reprogramming of cardiac nutrient transport and metabolism

Nature Reviews Cardiology, Journal Year: 2023, Volume and Issue: 20(7), P. 443 - 462

Published: Jan. 6, 2023

Language: Английский

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Rationale and design of the FAIR‐HF2‐DZHK05 trial: Ferric carboxymaltose assessment of morbidity and mortality in patients with iron deficiency and chronic heart failure

European Journal of Heart Failure, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 28, 2025

Abstract Aims While it is widely accepted that intravenous (IV) iron improves functional capacity, symptoms, and cardiovascular outcomes in patients with heart failure (HF) reduced ejection fraction (HFrEF) diagnosed deficiency (ID), three recently published outcome trials (AFFIRM‐AHF, IRONMAN HEART‐FID) of IV supplementation HF failed to demonstrate a significant benefit on their respective primary endpoints. Dosing after the initial correction baseline ID – by design or as result trial circumstances was relatively low (i.e. <500 mg/year). The objective FAIR‐HF2 evaluate treatment effect ferric carboxymaltose (FCM) compared placebo ambulatory HFrEF using higher dose during follow‐up >1000 second study create prospective evidence for fulfilling new definition HF, i.e. those transferrin saturation <20%. Methods an investigator‐initiated, multicentre, randomized, double‐blind, placebo‐controlled has recruited 1105 chronic left ventricular ≤45% concomitant ID, defined serum ferritin <100 ng/ml 100–299 Patients were consented randomized receive either FCM (treatment) saline (placebo). During estimated median over 2 years, underwent repletion maintenance phase, up 2000 mg, followed 500 mg every 4 months unless stop criteria haemoglobin >16 mg/dl >800 are met repeat visits. will hypotheses: (i) time first event death hospitalization (ii) rate total (first recurrent) hospitalizations (both analysed full population), (iii) <20% at baseline. familywise type I error across endpoint hypotheses be controlled Hochberg procedure (alpha 0.05). Conclusion efficacy improving utilizing more aggressive approach towards ensuring prevention transitional targets have been met.

Language: Английский

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Effects of empagliflozin on erythropoiesis in heart failure: data from the Empire HF trial

European Journal of Heart Failure, Journal Year: 2022, Volume and Issue: 25(2), P. 226 - 234

Published: Nov. 15, 2022

It remains unknown whether the consistently observed increase in haematocrit with sodium-glucose cotransporter 2 inhibitors is caused by diuresis-associated haemoconcentration or increased erythropoiesis. We aimed to investigate early effect of empagliflozin on erythropoiesis and iron metabolism patients heart failure reduced ejection fraction (HFrEF).The Empire HF was a double-blind, randomized, placebo-controlled trial. Patients left ventricular (LVEF) ≤40%, New York Heart Association (NYHA) class I-III symptoms, stable guideline-directed HFrEF therapy were randomly assigned (1:1) matching placebo once daily for 12 weeks. Exploratory outcomes reflecting changes analysed. In total, 190 randomized. Baseline characteristics well-balanced between groups (age: mean 64 [± 11] years; male: 85%; LVEF: 29 8)%; NYHA II: 78%; type diabetes: 13%; anaemia: 28%; chronic kidney disease: 13%). this post hoc analysis, erythropoietin compared from baseline weeks (adjusted difference 2.6 IU/L, 95% confidence interval [CI] 0.8-4.4; p = 0.0046). Moreover, hepcidin ratio change 0.76, CI 0.59-0.97; 0.031), no erythroferrone 1.17, 0.86-1.60; 0.31) placebo. No significant treatment-by-subgroup interactions regarding diabetes, anaemia, disease (pinteraction >0.05).These findings suggest that increases augments utilization HFrEF. These mechanisms may contribute cardioprotective properties empagliflozin.

Language: Английский

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Potential Interactions When Prescribing SGLT2 Inhibitors and Intravenous Iron in Combination in Heart Failure

JACC Heart Failure, Journal Year: 2022, Volume and Issue: 11(1), P. 106 - 114

Published: Nov. 5, 2022

In patients with heart failure, sodium-glucose cotransporter 2 (SGLT2) inhibitors have been shown to decrease hepcidin and ferritin increase transferrin receptor protein, changes that are typically indicative of worsening absolute iron deficiency, as would be seen poor dietary intake or gastrointestinal bleeding, neither which is provoked by SGLT2 inhibitors. Therefore, alternative conceptual frameworks may explain the observed pattern in homeostasis proteins. According "cytosolic depletion hypothesis," effect related a decline cytosolic Fe2+ occurs after drug-induced erythropoietin-related use. Erythropoietin-mimetics (eg, darbepoietin) elicit this type iron-deficiency response, it accompanied erythropoietin resistance alleviated intravenous supplementation. contrast, according repletion represents direct action these drugs: 1) reverse inflammation-related increases ferritin, and, thus, alleviate functional blocks on utilization; 2) sirtuin-1 signaling, suppresses hepcidin, accelerates degradation up-regulates protein. Through either both mechanisms, suppression expected Fe2+, thus allowing an unattenuated erythrocytic response without need for The totality clinical evidence supports hypothesis" because full sustained erythrocytosis erythropoietin, even overtly iron-deficient absence therapy. emergence during inhibition does not reflect stores replenishment, but instead, potential alleviation state deficiency commonly chronic failure. Treatment unnecessary theoretically deleterious.

Language: Английский

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How can sodium–glucose cotransporter 2 inhibitors stimulate erythrocytosis in patients who are iron‐deficient? Implications for understanding iron homeostasis in heart failure

European Journal of Heart Failure, Journal Year: 2022, Volume and Issue: 24(12), P. 2287 - 2296

Published: Nov. 15, 2022

Many patients with heart failure have an iron‐deficient state, which can limit erythropoiesis in erythroid precursors and ATP production cardiomyocytes. Yet, treatment sodium–glucose cotransporter 2 (SGLT2) inhibitors produces consistent increases haemoglobin haematocrit, even who are before treatment, this effect remains unattenuated throughout though SGLT2 further aggravate biomarkers of iron deficiency. Heart is often accompanied by systemic inflammation, activates hepcidin, thus impairing the duodenal absorption release from macrophages hepatocytes, leading to a decline circulating iron. Inflammation oxidative stress also promote synthesis ferritin suppress ferritinophagy, intracellular stores depletion bioreactive cytosolic Fe 2+ . By alleviating inflammation stress, down‐regulate upregulate transferrin receptor protein 1 reduce ferritin; net result increase levels available mitochondria, enabling heme (in precursors) cardiomyocytes). The finding that induce erythrocytosis without supplementation suggests abnormalities diagnostic tests mild‐to‐moderate likely be functional, rather than absolute, is, they related inflammation‐mediated trapping hepcidin ferritin, reversed inhibitors. An augment mitochondrial cardiomyocytes, retarding progression failure. These effects on metabolism (i) proteomics analyses placebo‐controlled trials, shown homeostasis represent most inhibitors; (ii) statistical mediation analyses, reported striking parallelism events.

Language: Английский

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Mechanisms of benefits of sodium-glucose cotransporter 2 inhibitors in heart failure with preserved ejection fraction

European Heart Journal, Journal Year: 2023, Volume and Issue: 44(37), P. 3640 - 3651

Published: June 13, 2023

For decades, heart failure with preserved ejection fraction (HFpEF) proved an elusive entity to treat. Sodium-glucose cotransporter 2 (SGLT2) inhibitors have recently been shown reduce the composite of hospitalization or cardiovascular death in patients HFpEF landmark DELIVER and EMPEROR-Preserved trials. While improvements blood sugar, pressure, attenuation kidney disease progression all may play some role, preclinical translational research identified additional mechanisms these agents. The SGLT2 intriguingly induce a nutrient-deprivation hypoxic-like transcriptional paradigm, increased ketosis, erythropoietin, autophagic flux addition altering iron homeostasis, which contribute improved cardiac energetics function. These agents also epicardial adipose tissue alter adipokine signalling, role reductions inflammation oxidative stress observed inhibition. Emerging evidence indicates that drugs impact cardiomyocyte ionic homeostasis although whether this is through indirect via direct, off-target effects on other ion channels has yet be clearly characterized. Finally, myofilament stiffness as well extracellular matrix remodelling/fibrosis heart, improving diastolic established themselves robust, disease-modifying therapies recent trial results are incorporated into clinical guidelines, will likely become foundational therapy HFpEF.

Language: Английский

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Mechanisms of enhanced renal and hepatic erythropoietin synthesis by sodium–glucose cotransporter 2 inhibitors

European Heart Journal, Journal Year: 2023, Volume and Issue: 44(48), P. 5027 - 5035

Published: April 22, 2023

Abstract Sodium–glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of major heart failure events, an action that is statistically linked to enhanced erythropoiesis, suggesting stimulation erythropoietin and cardioprotection are related a shared mechanism. Four hypotheses have been proposed explain how these drugs increase production: (i) renal cortical reoxygenation with rejuvenation erythropoietin-producing cells; (ii) counterregulatory distal sodium reabsorption leading increased tubular workload oxygen consumption, thus, localized hypoxia; (iii) iron mobilization as stimulus hypoxia-inducible factor-2α (HIF-2α)-mediated synthesis; (iv) direct HIF-2α activation gene transcription due sirtuin-1 (SIRT1) signaling. The first two assume source interstitial fibroblast-like cells in deep cortex. However, SGLT2 do not alter regional tissue tension non-diabetic kidney, synthesis markedly impaired patients anemia chronic kidney disease, yet, produce unattenuated erythrocytic response patients. This observation raises possibility liver contributes production during inhibition. Hypoxia-inducible coexpressed only but also hepatocytes; site when maintained for prolonged periods. ability improve by derepressing hepcidin ferritin would be expected cytosolic ferrous iron, which might stimulate expression both through regulatory protein 1. Alternatively, established enhance SIRT1 mechanism drugs. In hepatic cell lines, can directly activate deacetylation, additionally, effect SIRT liver, peroxisome proliferator-activated receptor-γ coactivator-1α binds nuclear factor 4 promote erythropoietin. Since up-regulation exerts cytoprotective effects on stimulates erythropoietin, it well-positioned represent links erythropoiesis

Language: Английский

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Dapagliflozin and Anemia in Patients with Chronic Kidney Disease

NEJM Evidence, Journal Year: 2023, Volume and Issue: 2(6)

Published: May 19, 2023

BackgroundIn the DAPA-CKD (Dapagliflozin in Patients with Chronic Kidney Disease) trial, dapagliflozin improved kidney and cardiovascular outcomes patients chronic disease (CKD) or without type 2 diabetes (T2D). In this post hoc analysis of DAPA-CKD, we assessed effects on correction prevention anemia.MethodsThe trial randomized (1:1) an estimated glomerular filtration rate 25 to 75 ml/min/1.73 m2 a urinary albumin-to-creatinine ratio 200 5000 mg/g receive 10 mg placebo daily. Hematocrit was measured at baseline, weeks, 4 months, every months thereafter. Anemia defined as hematocrit less than 39% men 36% women. Correction incidence anemia were two consecutive measurements above below these thresholds relative respectively, during follow-up. We classified anemia-related adverse events using data from site investigator reports.ResultsMean age 4304 participants 61.8 years, 67.5% had T2D. Among 4292 (99.7%) baseline data, 1716 (40.0%) anemia. Over 2.4-year median follow-up, assigned increase 2.3 percentage points (95% confidence interval [CI], 2.1 2.5) greater those placebo. corrected 443 (53.3%) 247 (29.4%) (hazard ratio, 2.29; 95% CI, 1.96 2.68). 10.4% developed incident compared 23.7% group 0.39; 0.31 0.48). Anemia-related occurred 2.2% 3.8% Effects consistent The event profile similar that known for dapagliflozin.ConclusionsThis exploratory suggests is associated CKD (Funded by AstraZeneca; ClinicalTrials.gov number, NCT03036150.)

Language: Английский

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Iron Deficiency in Heart Failure: A Scientific Statement from the Heart Failure Society of America

Journal of Cardiac Failure, Journal Year: 2023, Volume and Issue: 29(7), P. 1059 - 1077

Published: May 1, 2023

Language: Английский

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