Hypoxia inducible factor-prolyl hydroxylase inhibitors in anemic patients with non-dialysis dependent chronic kidney disease: a meta-analysis of randomized clinical trials

Mohamed, Mohamed M G; Oyenuga, Mosunmoluwa; Shaikh, Safia; Oyenuga, Abayomi; Kheiri, Babikir; Nwankwo, Christian

doi:10.1007/s11255-022-03300-7

Cited by 8 publications

(8 citation statements)

References 11 publications

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“…These drugs block the enzymes that are responsible for the degradation of hypoxia-inducible factors (HIFs), which are the principal stimuli for endogenous erythropoietin production [8]. As with ESAs, HIF-PHD inhibitors are given together with iron supplements [9], and they have the advantages of being orally bioavailable and being able to achieve erythropoiesis in some patients in whom inflammation blunts the erythrocytic response to ESAs [10]. In large-scale randomized clinical trials, treatment with HIF-PHD inhibitors has been accompanied by increases in hemoglobin that are comparable to those achieved by ESAs [9].…”

Section: The Cardiovascular Risks Of Erythropoiesis-stimulating Agent...mentioning

confidence: 99%

“…As with ESAs, HIF-PHD inhibitors are given together with iron supplements [9], and they have the advantages of being orally bioavailable and being able to achieve erythropoiesis in some patients in whom inflammation blunts the erythrocytic response to ESAs [10]. In large-scale randomized clinical trials, treatment with HIF-PHD inhibitors has been accompanied by increases in hemoglobin that are comparable to those achieved by ESAs [9]. However, in these direct comparator trials, when given to patients with chronic kidney disease not on dialysis, high doses of HIF-PHD inhibitors has been accompanied by an increased risk of cardiovascular death, myocardial infarction, stroke, heart failure, and thrombotic events that has been greater than that seen with ESAs [11, 12].…”

Section: The Cardiovascular Risks Of Erythropoiesis-stimulating Agent...mentioning

confidence: 99%

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Mechanistic and Clinical Comparison of the Erythropoietic Effects of SGLT2 Inhibitors and Prolyl Hydroxylase Inhibitors in Patients with Chronic Kidney Disease and Renal Anemia

Packer¹

2023

Am J Nephrol

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Renal anemia is treated with erythropoiesis-stimulating agents (ESAs), even though epoetin alfa and darbepoetin increase the risk of cardiovascular death and thromboembolic events, including stroke. Hypoxia-inducible factor prolyl hydroxylase domain (HIF-PHD) inhibitors have been developed as an alternative to ESAs, producing comparable increases in hemoglobin. However, in advanced chronic kidney disease, HIF-PHD inhibitors can increase the risk of cardiovascular death, heart failure, and thrombotic events to a greater extent than that with ESAs, indicating that there is a compelling need for safer alternatives. Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of major cardiovascular events, and they increase hemoglobin, an effect that is related to an increase in erythropoietin and an expansion in red blood cell mass. SGLT2 inhibitors increase hemoglobin by ≈0.6–0.7 g/dL, resulting in the alleviation of anemia in many patients. The magnitude of this effect is comparable to that seen with low-to-medium doses of HIF-PHD inhibitors, and it is apparent even in advanced chronic kidney disease. Interestingly, HIF-PHD inhibitors act by interfering with the prolyl hydroxylases that degrade both HIF-1α and HIF-2α, thus enhancing both isoforms. However, HIF-2α is the physiological stimulus to the production of erythropoietin, and upregulation of HIF-1α may be an unnecessary ancillary property of HIF-PHD inhibitors, which may have adverse cardiac and vascular consequences. In contrast, SGLT2 inhibitors act to selectively increase HIF-2α, while downregulating HIF-1α, a distinctive profile that may contribute to their cardiorenal benefits. Intriguingly, for both HIF-PHD and SGLT2 inhibitors, the liver is likely to be an important site of increased erythropoietin production, recapitulating the fetal phenotype. These observations suggest that the use of SGLT2 inhibitors should be seriously evaluated as a therapeutic approach to treat renal anemia, yielding less cardiovascular risk than other therapeutic options.

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Section: The Cardiovascular Risks Of Erythropoiesis-stimulating Agent...mentioning

confidence: 99%

Section: The Cardiovascular Risks Of Erythropoiesis-stimulating Agent...mentioning

confidence: 99%

Mechanistic and Clinical Comparison of the Erythropoietic Effects of SGLT2 Inhibitors and Prolyl Hydroxylase Inhibitors in Patients with Chronic Kidney Disease and Renal Anemia

Packer¹

2023

Am J Nephrol

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“…A total of 89 records were returned from the literature search after the removal of duplicates. After the title and abstract screening, 39 publications were kept for full text review, among which 25 were further excluded, leaving 14 systematic reviews for the umbrella review ( Liu et al, 2020 ; Wang et al, 2020 ; Li et al, 2021 ; Liu et al, 2021 ; Qie et al, 2021 ; Xiong et al, 2021 ; Zhang et al, 2021 ; Zheng et al, 2021 ; Fatima et al, 2022 ; Lei et al, 2022 ; Wu et al, 2022 ; Mohamed et al, 2023 ; Takkavatakarn et al, 2023 ; Zheng et al, 2023 ) ( Figure 1 ) (justification for the excluded articles after removing duplicates is presented in Supplementary Table S2 ).…”

Section: Resultsmentioning

confidence: 99%

Efficacy and safety of hypoxia-inducible factor-prolyl hydroxylase inhibitor treatment for anemia in chronic kidney disease: an umbrella review of meta-analyses

Ren,

Yao,

et al. 2023

Front. Pharmacol.

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The objective was to provide a comprehensive summary of existing evidence on the efficacy and safety of hypoxia-inducible factor-prolyl hydroxylase inhibitors (HIF-PHIs) for the treatment of anemia in chronic kidney disease (CKD). A systematic search was conducted in the Medline, Embase, and Cochrane databases. Only meta-analyses that evaluated the efficacy and safety of HIF-PHI treatment for anemia in CKD were included. The efficacy outcomes included hemoglobin levels and iron metabolism indices, while the safety outcomes were assessed by examining adverse events. The qualities of methodologies and evidence were assessed using the AMSTAR 2 system and the NutriGrade tool, respectively. Fourteen meta-analyses, comprising 105 distinct comparisons, were included. The comparisons were backed by evidence of high, moderate, and low levels, distributed in approximately equal proportions. None of the studies were deemed to possess a high level of confidence. In both the overall and individual treatment groups of HIF-PHI, there was an increase in the levels of hemoglobin, transferrin, and transferrin saturation, while the levels of hepcidin and total iron binding capacity decreased. Serum ferritin exhibited a reduction to some extent, while serum iron did not show significant alterations following HIF-PHI treatments. There were no notable disparities in safety outcomes between the HIF-PHI and erythropoietin stimulating agents or placebo groups. This umbrella review suggests that HIF-PHI treatment can effectively increase hemoglobin levels in CKD patients and enhance iron metabolism by decreasing hepcidin levels and improving iron transport. The safety profiles of HIF-PHIs were generally comparable to those of ESA therapies or placebos.

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“…HIF-PHIs influence iron homeostasis through effects on transferrin, transferrin receptor expression, hepcidin, and other iron-related proteins [ 142 ]. They activate HIF1α without iron deprivation [ 143 ] in patients with heart failure and renal anemia. HIF-PHIs increase plasma hemoglobin levels by restoring physiological erythropoietin production in the kidney, while hepcidin levels tend to decrease [ 144 ].…”

Section: Protective Treatmentsmentioning

confidence: 99%

Why Is Iron Deficiency/Anemia Linked to Alzheimer’s Disease and Its Comorbidities, and How Is It Prevented?

Fehsel

2023

Biomedicines

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Impaired iron metabolism has been increasingly observed in many diseases, but a deeper, mechanistic understanding of the cellular impact of altered iron metabolism is still lacking. In addition, deficits in neuronal energy metabolism due to reduced glucose import were described for Alzheimer’s disease (AD) and its comorbidities like obesity, depression, cardiovascular disease, and type 2 diabetes mellitus. The aim of this review is to present the molecular link between both observations. Insufficient cellular glucose uptake triggers increased ferritin expression, leading to depletion of the cellular free iron pool and stabilization of the hypoxia-induced factor (HIF) 1α. This transcription factor induces the expression of the glucose transporters (Glut) 1 and 3 and shifts the cellular metabolism towards glycolysis. If this first line of defense is not adequate for sufficient glucose supply, further reduction of the intracellular iron pool affects the enzymes of the mitochondrial electron transport chain and activates the AMP-activated kinase (AMPK). This enzyme triggers the translocation of Glut4 to the plasma membrane as well as the autophagic recycling of cell components in order to mobilize energy resources. Moreover, AMPK activates the autophagic process of ferritinophagy, which provides free iron urgently needed as a cofactor for the synthesis of heme- and iron–sulfur proteins. Excessive activation of this pathway ends in ferroptosis, a special iron-dependent form of cell death, while hampered AMPK activation steadily reduces the iron pools, leading to hypoferremia with iron sequestration in the spleen and liver. Long-lasting iron depletion affects erythropoiesis and results in anemia of chronic disease, a common condition in patients with AD and its comorbidities. Instead of iron supplementation, drugs, diet, or phytochemicals that improve energy supply and cellular glucose uptake should be administered to counteract hypoferremia and anemia of chronic disease.

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Hypoxia inducible factor-prolyl hydroxylase inhibitors in anemic patients with non-dialysis dependent chronic kidney disease: a meta-analysis of randomized clinical trials

Cited by 8 publications

References 11 publications

Mechanistic and Clinical Comparison of the Erythropoietic Effects of SGLT2 Inhibitors and Prolyl Hydroxylase Inhibitors in Patients with Chronic Kidney Disease and Renal Anemia

Mechanistic and Clinical Comparison of the Erythropoietic Effects of SGLT2 Inhibitors and Prolyl Hydroxylase Inhibitors in Patients with Chronic Kidney Disease and Renal Anemia

Efficacy and safety of hypoxia-inducible factor-prolyl hydroxylase inhibitor treatment for anemia in chronic kidney disease: an umbrella review of meta-analyses

Why Is Iron Deficiency/Anemia Linked to Alzheimer’s Disease and Its Comorbidities, and How Is It Prevented?

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