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.