Long‐term efficacy and safety of hypoxia‐inducible factor prolyl hydroxylase inhibitors in anaemia of chronic kidney disease: A meta‐analysis including 13,146 patients

Abstract

What is known and objective Previous studies based on small‐sample clinical data proved that short‐term use of hypoxia‐inducible factor prolyl hydroxylase (HIF‐PHD) inhibitors increased haemoglobin levels in anaemic patients with chronic kidney disease (CKD). However, these studies reached conflicting conclusions on iron parameters and adverse event profiles. Our meta‐analysis aimed to evaluate the long‐term efficacy and safety of HIF‐PHD inhibitors in renal anaemia. Methods Randomized controlled trials comparing treatment with HIF‐PHD inhibitors versus placebo or erythropoiesis‐stimulating agents (ESAs) were thoroughly searched in the PubMed, Embase, Cochrane Library and international clinical trial registries. Meta‐analysis was performed on main outcomes with random effects models. Results and discussion A total of 30 studies comprising 13,146 patients were included. The HIF‐PHD inhibitors used included roxadustat, daprodustat, vadadustat, molidustat, desidustat and enarodustat. HIF‐PHD inhibitors significantly increased haemoglobin levels in comparison with placebo [weighted mean difference (WMD) 1.53, 95% confidence interval (CI) 1.39 to 1.67] or ESAs (WMD 0.13, 95% CI 0.03 to 0.22). Hepcidin, ferritin and serum iron levels were decreased, while total iron binding capacity and transferrin levels were increased in the HIF‐PHD inhibitor group versus those in placebo or ESAs group. Additionally, HIF‐PHD inhibitors medication was associated with cholesterol‐lowering effects. As for safety, the risk of serious adverse events in the HIF‐PHD inhibitor group was increased in comparison with placebo group [risk ratio (RR) 1.07, 95% CI 1.01 to 1.13], but comparable to the ESAs group (RR 1.02, 95% CI 0.94 to 1.10). Compared with placebo, the agents increased the risk of diarrhoea (1.21, 1.00 to 1.47), nausea (1.46, 1.09 to 1.97), oedema peripheral (1.32, 1.01 to 1.59), hyperkalemia (1.27, 1.05 to 1.54) and hypertension (1.34, 1.02 to 1.76). Compared with ESAs, the drugs increased the risk of vomiting (1.30, 1.02 to 1.65), headache (1.27, 1.05 to 1.53) and thrombosis events (1.31, 1.05 to 1.63). What is new and conclusion HIF‐PHD inhibitors treatment effectively increased haemoglobin levels and promoted iron utilization in anaemic patients with CKD, and they were well tolerated for long‐term use. In order to avoid unfavourable effects of excessive iron consumption, it was appropriate to administer HIF‐PHD inhibitors in combination with iron supplements for long‐term treatment.

Physiology and Inflammation Driven Pathophysiology of Iron Homeostasis—Mechanistic Insights into Anemia of Inflammation and Its Treatment

“…Another new promising therapy strategy is the inhibition of prolyl hydroxylase, which stabilizes hypoxia-inducible factor thus promoting erythropoietin production, increasing intestinal iron uptake and mobilization of iron stores [319]. Oral hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHI) including roxadustat, vadadustat, desidustat, daprodustat and molidustat were shown to significantly increase hemoglobin levels and total iron binding capacity concomitant to an decrease in hepcidin and ferritin levels in patients with anemia and chronic kidney disease [320]. Moreover, several preclinical studies have suggested a potential cardiovascular benefit due to direct actions of HIF activation in myocardial infarction, cardiac remodeling and atherosclerosis as well as amelioration of glucose and lipid metabolism [321].…”

“…In a recent meta-analysis by Chen and coworkers including 13,146 patients, HIF-PHI were well tolerated during long-term use with comparable risk of serious adverse events compared to patients treated only with ESAs. However, HIF-PHI treatment was associated with a slightly increased risk for thrombosis events when compared to patients treated only with ESAs [320]. Several phase 3 trials further evaluating the efficacy and safety of HIF-PHI in CKD patients including the long-term cardiovascular risk are currently ongoing.…”

Iron Deficiency in Heart Failure: Mechanisms and Pathophysiology

“…Several HIFs stabilisers are being developed, some of which have entered/finished phase 3 of clinical trials, including Vadadustat, Daprodustat and Roxadustat [ 273 ]. Meta-analyses of several randomised controlled trials showed that PHD inhibitors increase the levels of hemoglobin, serum transferrin and increase intestinal iron absorption while reducing levels of hepcidin in anaemic CKD patients [ 273 , 274 , 275 ]. These effects seem to be independent of inflammation [ 273 ].…”

The Effect of Roxadustat on Transfusion-Dependent Myelodysplastic Syndrome Complicated by Chronic Kidney Disease

“…HIF-PH inhibitors have rather peculiar complications; therefore, caution is warranted. In the clinical trials of HIF-PH inhibitor use for renal anaemia, it has been reported that the incidence of thromboembolism is higher than that of the control group [ 12 ]. Since the patient in our case report had ET, which is already associated with an increased risk of thrombosis [ 13 ], platelet count control and low-dose aspirin therapy were initiated; thus, thrombosis did not occur.…”