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.).