Daprodustat for the Treatment of Anemia in Patients Undergoing Dialysis

Singh, Ajay K.; Carroll, Kevin; Perkovic, Vlado; Solomon, Scott D.; Jha, Vivekanand; Johansen, Kirsten L.; Lópes, Renato D.; Macdougall, Iain C.; Obrador, Gregorio T.; Waikar, Sushrut S.; Wanner, Christoph; Wheeler, David C.; Wiȩcek, Andrzej; Blackorby, Allison; Čižman, Borut; Cobitz, Alexander R.; Davies, Rosalyn; Dole, Jo; Kler, Lata; Meadowcroft, Amy; Zhu, Xinyi; McMurray, John J.V.

doi:10.1056/nejmoa2113379

Cited by 128 publications

(157 citation statements)

References 17 publications

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“…13 articles were excluded because they did not include a reference group or the comparisons were inappropriate. In total, 7 RCTs ( Holdstock et al, 2016 ; Holdstock et al, 2019 ; Meadowcroft et al, 2019 ; Akizawa et al, 2020 ; Singh et al, 2021a ; Singh et al, 2021b ; Nangaku et al, 2021 ) involving 7933 participants were included in this meta-analysis. Four studies ( Akizawa et al, 2020 ; Singh et al, 2021a ; Singh et al, 2021b ; Nangaku et al, 2021 ) were phase 3 clinical trials, and the other three ( Holdstock et al, 2016 ; Holdstock et al, 2019 ; Meadowcroft et al, 2019 ) were phase 2 clinical trials.…”

Section: Resultsmentioning

confidence: 99%

Efficacy and Safety of Daprodustat Vs rhEPO for Anemia in Patients With Chronic Kidney Disease: A Meta-Analysis and Trial Sequential Analysis

Geng

Chi

et al. 2022

Front. Pharmacol.

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Introduction: Daprodustat, a novel hypoxia-inducible factor prolyl-hydroxylase inhibitor (HIF-PHI), its efficacy and safety remain unclear. Thus, we conducted this meta-analysis aiming at investigating its efficacy and safety on the treatment of patients with chronic kidney disease (CKD)-related anemia.Methods: We systematically searched for relevant studies in PubMed, Embase, Cochrane Library and Clinical Trial Registries databases from inception until December 2021. We selected randomized controlled trials comparing daprodustat with recombinant human erythropoietin (rhEPO) in anemia patients with CKD with or without dialysis.Results: Seven studies including 7933 patients met the inclusion criteria. For both nondialysis-dependent (NDD-) CKD and dialysis-dependent (DD-) CKD patients, the pooled results showed that there was no significant difference in the changes in hemoglobin levels between the daprodustat and rhEPO groups (mean difference (MD) = −0.01, 95% confidence interval (CI) = −0.38, 0.35, p = 0.95; MD = 0.15, 95% CI = −0.29, 0.60, p = 0.50; respectively). In addition, a significant increase in transferrin saturation (TSAT), total iron binding capacity (TIBC) and total iron was observed in daprodustat groups compared with rhEPO groups in DD-CKD patients (p < 0.05). As for safety, the overall frequency of adverse events was similar between the daprodustat and rhEPO groups in DD-CKD patients (relative risk (RR) = 0.99, 95%CI = 0.92, 1.06, p = 0.76), and the trial sequential analysis (TSA) confirmed this result. But for NDD-CKD patients, the incidence of adverse events in the daprodustat groups was significantly higher than that of rhEPO groups (RR = 1.04, 95%CI = 1.01,1.07, p = 0.02), while the TSA corrected this result. No trend of increasing incidence of serious adverse events was found in all daprodustat treated patients, but the TSA could not confirm this result.Conclusion: Although daprodustat was noninferior to rhEPO in correcting anemia in both NDD-CKD and DD-CKD patients, it seemed to have a better effect on optimizing iron metabolism in DD-CKD patients. Daprodustat may be a promising alternative for the treatment of anemia in patients with CKD. However, due to the lack of included studies, future researches are needed to further evaluate the therapeutic effect of daprodustat.Systematic Review Registration:https://www.crd.york.ac.uk/prospero/, identifier CRD42021229636.

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Section: Resultsmentioning

confidence: 99%

Efficacy and Safety of Daprodustat Vs rhEPO for Anemia in Patients With Chronic Kidney Disease: A Meta-Analysis and Trial Sequential Analysis

Geng

Chi

et al. 2022

Front. Pharmacol.

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“…Unfortunately, retinal hemorrhage and hypersensitivity (rash, dermatitis, urticaria), higher acceptance of antihypertensive medications with increasing systolic blood pressure, fatal and nonfatal myocardial infarction and heart failure exacerbations were reported in the daprodustat group (Meadowcroft et al, 2019;Akizawa et al, 2020b;Tsubakihara et al, 2020;Nangaku et al, 2021a). In two newest published studies (Singh et al, 2021a;Singh et al, 2021b), daprodustat showed a tumor effect in NDD patients while not in DD patients, which has not been reported before. Thus, more trials are awaited with interest and the safety and tolerability of daprodustat remain a problem for its clinical usage.…”

Section: Daprodustat (Gsk-1278863)mentioning

confidence: 86%

Clinical Potential of Hypoxia Inducible Factors Prolyl Hydroxylase Inhibitors in Treating Nonanemic Diseases

Miao

et al. 2022

Front. Pharmacol.

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Hypoxia inducible factors (HIFs) and their regulatory hydroxylases the prolyl hydroxylase domain enzymes (PHDs) are the key mediators of the cellular response to hypoxia. HIFs are normally hydroxylated by PHDs and degraded, while under hypoxia, PHDs are suppressed, allowing HIF-α to accumulate and transactivate multiple target genes, including erythropoiesis, and genes participate in angiogenesis, iron metabolism, glycolysis, glucose transport, cell proliferation, survival, and so on. Aiming at stimulating HIFs, a group of small molecules antagonizing HIF-PHDs have been developed. Of these HIF-PHDs inhibitors (HIF-PHIs), roxadustat (FG-4592), daprodustat (GSK-1278863), vadadustat (AKB-6548), molidustat (BAY 85-3934) and enarodustat (JTZ-951) are approved for clinical usage or have progressed into clinical trials for chronic kidney disease (CKD) anemia treatment, based on their activation effect on erythropoiesis and iron metabolism. Since HIFs are involved in many physiological and pathological conditions, efforts have been made to extend the potential usage of HIF-PHIs beyond anemia. This paper reviewed the progress of preclinical and clinical research on clinically available HIF-PHIs in pathological conditions other than CKD anemia.

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“… 76 For human studies, a recent clinical trial reported that daprodustat was noninferior to EPO regarding cardiovascular outcomes in DD CKD patients. 77 while in NDD CKD patients, vadadustat did not meet the prespecified noninferiority criterion for cardiovascular safety. 78 In the CKD-associated myopathy model, our group demonstrated that MK-8617, a novel orally active HIF-PHI, could ameliorate muscle impairment due to the promoted angiogenesis in the skeletal muscle of CKD mice.…”

Section: Therapeutic Approaches That Target Chronic Hypoxia In Ckdmentioning

confidence: 96%

Hypoxia and chronic kidney disease

Wang¹,

Li²,

Zhang

et al. 2022

eBioMedicine

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Daprodustat for the Treatment of Anemia in Patients Undergoing Dialysis

Cited by 128 publications

References 17 publications

Efficacy and Safety of Daprodustat Vs rhEPO for Anemia in Patients With Chronic Kidney Disease: A Meta-Analysis and Trial Sequential Analysis

Efficacy and Safety of Daprodustat Vs rhEPO for Anemia in Patients With Chronic Kidney Disease: A Meta-Analysis and Trial Sequential Analysis

Clinical Potential of Hypoxia Inducible Factors Prolyl Hydroxylase Inhibitors in Treating Nonanemic Diseases

Hypoxia and chronic kidney disease

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