HIF-PHIs alter lipid profiles in CKD patients but show no cardiovascular mortality difference

This is a systematic review and meta-analysis of randomized controlled trials evaluating hypoxia-inducible factor prolyl hydroxilase inhibitors (HIF-PHIs) in chronic kidney disease. The analysis included dialysis-dependent and nondialysis-dependent CKD patients, with a total sample size of 12,155 participants. The intervention consisted of HIF-PHIs, specifically roxadustat, desidustat, and molidustat, compared against erythropoiesis-stimulating agents (ESAs) or placebo. The primary outcome was the change in lipid profiles, including low-density lipoprotein cholesterol (LDL-C), total cholesterol, triglycerides, and high-density lipoprotein cholesterol (HDL-C).

For roxadustat, the meta-analysis found a significant reduction in LDL-C among 10,510 patients, with a mean difference (MD) of -16.07 mg/dL (95% CI, -17.92 to -14.21). Total cholesterol was also significantly reduced in 5,538 patients (MD, -25.25 mg/dL; 95% CI, -29.70 to -20.81), and triglycerides were significantly reduced in 4,616 patients (MD, -19.70 mg/dL; 95% CI, -30.78 to -8.61). HDL-C decreased significantly in 5,132 patients (MD, -4.91 mg/dL; 95% CI, -6.80 to -3.02). For desidustat, LDL-C and total cholesterol were significantly reduced, but no significant effects were reported for triglycerides or HDL-C. Molidustat showed no significant effects on lipid profiles.

Key secondary outcomes included cardiovascular death, myocardial infarction, stroke, and all-cause mortality. Cardiovascular death was not associated with significant differences between HIF-PHIs and comparators (RR, 1.00; 95% CI, 0.84 to 1.18) in 9,371 patients. Myocardial infarction showed no significant difference (RR, 1.12; 95% CI, 0.90 to 1.38) in 11,265 patients. Stroke also showed no significant difference (RR, 1.18; 95% CI, 0.86 to 1.61) in 11,136 patients. All-cause mortality was not significantly different (RR, 1.06; 95% CI, 0.96 to 1.17) in 11,903 patients.

Safety and tolerability data were not reported in the input, including adverse events, serious adverse events, discontinuations, or tolerability assessments. The meta-analysis did not report any limitations, funding sources, or conflicts of interest. This synthesis compares to prior landmark studies in CKD, where ESAs have been the standard of care for anemia management, but lipid effects and cardiovascular outcomes with HIF-PHIs are a newer area of investigation.

Methodological limitations are not specified in the input, but potential biases in meta-analyses include heterogeneity among included trials, variation in dosing protocols, and differences in patient populations. The lack of reported safety data is a significant gap, as HIF-PHIs may have unknown risks. The certainty of evidence is not noted, but the findings are based on aggregated trial data.

Clinical implications suggest that HIF-PHIs may alter lipid profiles in CKD patients, but this has not translated to improved cardiovascular outcomes in the analyzed studies. Practice decisions should consider the lipid changes while noting the absence of benefit on mortality or major cardiovascular events. The results do not support a change in standard care based on current evidence.

Unanswered questions include the long-term cardiovascular safety of HIF-PHIs, the clinical significance of lipid profile changes, and the effects in specific subgroups such as dialysis-dependent versus nondialysis-dependent patients. Future research is needed to address these gaps.