DISCUSSION
This network meta-analysis aims to assess the safety and efficacy of different agents containing HIF-PHIs for treating anemia in DD CKD patients. Safety and efficacy data for HIF-PHIs are drawn from 20 trials comparing the HIF-PHI agent with ESAs controls in anemic DD patients. By summarizing their pairwise comparison and overall safety and efficacy, results showed that all 6 HIF-PHIs did not increase the risk of any adverse events and serious adverse events compared to ESAs. No notable differences were found in this network meta-analysis in the risk of cardiovascular events, hyperkalemia, cancer, pneumonia, upper respiratory tract infection, nasopharyngitis, urinary tract infection, hypotension, and muscle spasms between HIF-PHIs and ESAs. It is worth mentioning that Roxadustat and Enarodustat were associated with a statistical increase in the risk of gastrointestinal disorder. In the risk of vascular-access complication, Roxadustat performed worse with more risks than ESAs. However, compared to ESAs, there was a lower risk of vascular-access complications in Daprodustat and hypertension in Vadadustat. In terms of efficacy, compared with ESAs in Hb response, our meta-analysis showed significant increases in Roxadustat and Desidustat, whereas noticeable reductions in Vadadustat and Molidustat. There were no significant differences indicated between Daprodustat ESAs.
ESAs are widely taken in the remedy of anemic patients. Studies have shown that they can promote the proliferation of erythroid progenitors after erythropoietin receptor (EpoRs) binding[44], imitating the action of endogenous erythropoietin to promote Hb synthesis effectively[4, 11]. Based on the results presented, recent studies found that HIF-PHIs had therapeutic effects similar to ESAs without increasing significant adverse effects[34, 36, 45, 46]. HIF, an iron sensor and regulator, is a pharmacological approach that can enhance intestinal iron uptake and transport by imitating coordination of erythropoiesis and iron metabolism in response to hypoxia, providing a balanced physiological method of the treatment of renal anemia [11, 47, 48]. PHD enzymes, as dioxygenases, can prevent the formation of HIF transcription factors[49]. HIF-PHIs, potent reversible inhibitors of all PHD isoforms[50], correct and maintain hemoglobin levels in CKD patients by activating the HIF oxygen-sensing pathway. HIF-PHIs promote erythropoiesis by increasing the production of endogenous erythropoietin, reducing hepcidin levels, and regulating iron metabolism[48]. Therefore, HIF-PHIs have broad therapeutic potential for the remedy for renal anemia, and a reduction in intravenous iron supplementation replacement may result from this.
Our study compared the efficacy of 6 types of HIF-PHIs with ESAs in treating DD CKD patients with anemia, focusing on their safety on AEs, SAEs, and 12 common adverse events. Our results show that the overall risk of HIF-PHIs is not higher than ESAs in patients on dialysis, and the safety ranking of each agent in AEs is inconsistent with that in SAEs. When specific to a particular adverse reaction like cardiovascular events and gastrointestinal disorder, HIF-PHIs performed varied but generally as well as ESAs. For efficacy, we focused on Hb response, ΔHb, and iron metabolism. About increasing the Hb response and ΔHb, each agent of HIF-PHIs showed different performance and no significant difference compared to ESAs. Moreover, the influence of mean age, sex ratio, and duration of treatment was investigated, and the SUCRA score rankings were directly consistent across the subgroups. These evidences support that HIF-PHIs have promising therapeutic effects and can be extended to clinical application. And to increase the strength of the relevant study, more extensive, high-quality research, including but not limited to Enarodustat and Desidustat, is demanded further to confirm the efficacy and safety of these medicines.
HIF-PHIs have been compared and analyzed in the published literature with ESAs, including Roxadustat, Daprodusta, Molidustat, Vadadustat, Enarodustat, and Desidustat. Some meta-analyses concluded that Roxadustast increases the ΔHb and reduces hepcidin in either DD or NDD patients[42, 51]. Daprodustat may better influence DD-CKD patients’ optimizing iron metabolism [18], and is not inferior to ESAs regarding ΔHb and cardiovascular diseases[31]. Nevertheless, some literature proposed that safety data of HIF-PHIs like Roxadustat is still emerging, and attention must be poured into the risk of TEAE, especially SAEs during therapy[42, 52]. The above research is basically limited to studying a specific drug in HIF-PHI, and the safety is still controversial. In addition, some overall analyses of HIF-PHIs show that HIF-PHIs improve renal anemia and correct iron metabolism in a short time without increasing the occurrence rate of AEs and SAEs[46], or HIF-PHIs are effective and relatively well tolerated in renal anemia patients without dialysis[4]. However, these studies mainly focus on the overall analysis of the HIF-PHIs of AEs and SAEs instead of the risk comparison of specific adverse events, not to mention the direct comparison of different agents of HIF-PHIs.
HIF-PHIs hold great promise for the treatment and management of renal anemia patients. Although their safety is not inferior to current clinical agents like ESAs, attention should still be paid to possible problems surrounding their use. On the one hand, it is well known that many unrelated genes are regulated by HIF during erythropoiesis and regulation, leading to some potential adverse effects, which are currently unknown. For instance, HIF-PHIs may increase the risk of gastrointestinal bleeding because HIF can regulate abnormal angiogenesis in the gastrointestinal tract by directly targeting the VEGF pathway[53]. Also, via the treatment of HIF-PHIs, the consequences of maintaining physiologic levels of endogenous EPO and the cardiovascular effects of normalizing Hb levels have not been established in the clinical trials of HIF-PHI that we have learned to date. These require further research to elucidate.
This study has some advantages over previous related studies but also has its limitations. First, it is a network meta-analysis comparing different agents of HIF-PHIs treating DD anemic CKD patients, which mainly focuses on and analyzes the safety, providing evidence for the clinical use of HIF-PHIs. Based on direct and circumstantial evidence, we offered a comprehensive net-ranking and pairwise comparison of the safety of these agents of AEs and SAEs in two groups and conducted a comparative study of each agent for specific TEAEs, including cardiovascular diseases, at al. At the same time, we made an overall ranking analysis and pairwise comparison of Hb response and ΔHb, and conducted subgroup analyses of the influence of mean age, sex, and duration of treatment. By sensitivity analysis, the similar SUCRA scores of frequentist and Bayesian models increased our findings’ confidence. All these provide a research basis and reference value for guiding the use of clinical drugs and promoting the clinical application of new medicines. Also, this study had some limitations. First, the results were expected to be clarified by further research because of the small sample size of included studies and the large 95% CI width. Second, comparing HIF-PHIs with ESAs regarding their respective efficacy in correcting anemia mainly depended on the HIF-PHI dose chosen in the initial comparator trials. Therefore, our results remain to be verified by many extensive ongoing international studies (ClinicalTrials.gov numbers, NCT03409107, etc.).