Discussion
This study conducted a systematic review and meta-analysis of previous
clinical studies on Roxadustat to evaluate its impact on cardiovascular
and renal adverse events in CKD anemic patients either requiring or not
requiring dialysis. The meta-analysis of the 17 trials included in this
study revealed that there were no significant differences in terms of
cardiovascular events, renal-related adverse events, the risk of
progression to ESKD, or hyperkalemia between the Roxadustat group and
the placebo group or ESA group, regardless of whether dialysis was
received or not. However, a higher risk of hypertension was identified
in NDD patients who received oral Roxadustat, whereas no significant
risk of hypertension risk was detected in DD patients treated with oral
Roxadustat. A higher risk of hypertension in CKD patients with anemia
treated with oral Roxadustat compared to those receiving placebo, but no
significant hypertension risk was observed in the Roxadustat treatment
group compared to the ESA group. The results obtained in the
aforementioned study indicate that although treatment with oral
Roxadustat is associated with an increased risk of hypertension in
dialysis patients when compared to placebo, these risks do not seem to
translate into clinical outcomes related to cardiovascular or renal risk
events.
CVD is the primary cause of death in CKD patients [22], and anemia
is an independent risk factor for developing CVD in CKD patients
[23]. Although the management of anemia is crucial for CKD patients,
the current treatment regime comprising of the use of ESA and iron
supplements is far from satisfactory [24]. Hence, we evaluated a
novel drug called Roxadustat for the correction of renal anemia. As a
hypoxia-inducible factor-prolyl hydroxylase inhibitor (HIF-PHI),
Roxadustat promotes the production of endogenous EPO (erythropoietin),
increases sensitivity to EPO receptors, and improves iron homeostasis in
CKD patients [25]. In terms of cardiovascular outcomes, our analysis
suggests that there is no correlation between intake of oral Roxadustat
and adverse reactions related to cardiovascular events in CKD anemia
patients, regardless of whether the patients are undergoing dialysis
treatment or not. Previous studies have also demonstrated Roxadustat to
be relatively safe [26, 27]. Furthermore, compared to participants
receiving ESA treatment, patients treated with Roxadustat exhibit a
lower incidence of composite cardiovascular safety endpoints. First,
this may be attributed to the fact that Roxadustat, as described above,
can generate endogenous EPO levels close to the physiological range,
fully stimulating red blood cell production without exposing the
patients to excessively concentrated EPO levels that could potentially
exert a negative impact on vascular biology [28]. Second, the
potential improvement brought about by Roxadustat or its neutral effect
on certain traditional cardiovascular risk factors may be attributed to
its ability to lower serum cholesterol. Studies have confirmed the total
cholesterol and LDL cholesterol reducing effect exerted by Roxadustat
[29-31]. Its mechanism of action involves inhibition of cholesterol
synthesis and promoting its intestinal excretion [32]. Roxadustat is
not only involved in regulating lipid metabolism, but may plays a part
in adapting to acute and chronic ischemia, atherosclerosis, and vascular
calcification [33, 34].
However, the current results have
not been proven to be conclusive or consistent. Third, the protective
myocardial cell effect exerted by Roxadustat against ischemic injury to
cardiac cells can be attributed to its ability to enhance anaerobic
respiration and promote the production of oxygen-independent ATP,
thereby maintaining energy supply to the myocardial cells [35].
Finally, previous studies have indicated that Roxadustat stabilizes the
expression of HIF-1α and enhances GLUT1 and GLUT4, thereby promoting
glycolysis in cardiac myocytes and partially improving myocardial cell
death caused by elevated β-oHb levels[36]. However, current summary
data from three Phase 3 studies indicate that in NDD CKD patients with
concomitant anemia, Roxadustat’s cardiovascular safety is similar to
that of placebo, and there is no evidence suggesting that HIF-PHIs
confer significant cardiovascular protective advantages[37]. This is
consistent with our conclusion. While HIF-1α promotes glycolysis during
hypoxia, it also affects metabolism under normoxic conditions. Deletion
of HIF-1α in cardiac myocytes leads to reduced levels of ATP, as well as
impaired myocardial contractility [38]. Paradoxically,
overexpression of cardiac HIF-1α has also been observed to cause
contractile dysfunction [39]. In summary, HIF-PHIs may exert
cardioprotective effects under low-level inhibition/stabilization, and
further research is needed to investigate the dose and duration of
HIF-PHI use.
In terms of renal endpoints, our analysis indicates that oral Roxadustat
does not elevate the risk of progression to ESKD in patients with
chronic kidney disease-associated anemia, regardless of whether they are
on dialysis or not. Currently, some studies have partially supported
this conclusion by conducting in-depth investigations into the
mechanisms of Roxadustat. One study has demonstrated that Roxadustat can
protect against renal ischemia/reperfusion injury by regulating
inflammatory responses[40]. Additionally, the non-inferior efficacy
of Roxadustat in ESKD might be because of its ability to regulate
oxidative stress [41].
According to reports, activation of HIF can prevent the enhanced
occurrence of kidney oxidative stress induced by diabetes mellitus and
also prevent and ameliorate the progression of DN[42]. Roxadustat
does not increase the risk of hyperkalemia in patients with CKD in DD as
well as NDD patients. Currently, there is a lack of in-depth research on
the effects of Roxadustat on blood potassium levels. The impact of
Roxadustat on blood potassium levels may vary among individuals.
Roxadustat is primarily metabolized in the liver and is mainly excreted
through the bile, with a small portion being eliminated by the
kidneys[43]. In certain cases, Roxadustat may interfere with the
renal excretion of potassium, which could result in elevated potassium
levels in the blood. However, there is currently no reliable evidence
available.
Regarding the effect of Roxadustat on hypertension, our results
indicated that a higher risk of hypertension was observed in NDD
patients. Additionally, subgroup analysis based on the type of control
intervention further revealed a higher risk of hypertension associated
with oral Roxadustat treatment of anemia in CKD patients when compared
to the placebo group, but no statistically significant difference was
observed when compared with ESA group. However, considering the
relatively limited overall effect size and the instability of
sensitivity analysis results, further research is needed. Previous
animal studies have indicated that Roxadustat, in Angiotensin II (Ang
II)-induced hypertension models, prevented vascular thickening and
myocardial hypertrophy by downregulating AGTR1 expression. It also
enhanced AGTR2 and endothelial nitric oxide synthase (eNOS) protein
levels in the mouse aorta, thereby mitigating the hypertensive response
[41]. Current research on Roxadustat’s effects on blood pressure and
its potential mechanisms has not yet yielded consistent results. Further
studies with larger sample sizes are needed to conduct in-depth and
systematic research in the future.