Effects of hypoxia-inducible factor prolyl hydroxylase inhibitors on lipid profiles in patients with chronic kidney disease: a systematic review and meta-analysis

Clinical Snapshot

Key Findings

• P Value: Not explicitly reported but confidence intervals suggest statistical significance for roxadustat lipid effects

• Effect Size: Moderate lipid-lowering effects for roxadustat, minimal for other HIF-PHIs

• Primary Outcome: Roxadustat significantly reduced LDL-C by 16.07 mg/dL (95% CI: -17.92 to -14.21)

• Nnt Or Sensitivity: No cardiovascular benefit: RR 1.00 for CV death (95% CI: 0.84-1.18), RR 1.06 for all-cause mortality (95% CI: 0.96-1.17)

• Confidence Interval: Narrow confidence intervals suggesting good precision for lipid outcomes

Clinical Application

HIF-PHIs are oral agents, potentially more convenient than injectable ESAs, but lipid benefits don't translate to cardiovascular outcomes Relevant to Australian nephrology practice; roxadustat approved by TGA for CKD anemia. Lipid effects may be considered alongside established cardiovascular risk management per RACGP guidelines CKD patients requiring anemia management, both dialysis-dependent and non-dialysis-dependent

Abstract

BACKGROUND: Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) are novel oral agents for treating anemia in chronic kidney disease (CKD), with potential effects on lipid modulation. We aimed to systematically evaluate the effects of HIF-PHIs on lipid profiles and cardiovascular outcomes in CKD patients. MATERIALS AND METHODS: PubMed, the Cochrane Central Register of Controlled Trials (CENTRAL), and Embase (Ovid) were searched for randomized controlled trials comparing HIF-PHIs with erythropoiesis-stimulating agents (ESAs) or placebo in dialysis-dependent (DD) or nondialysis-dependent (NDD) CKD patients. Primary outcomes included changes in low-density lipoprotein cholesterol (LDL-C), total cholesterol, triglycerides, and high-density lipoprotein cholesterol (HDL-C). Secondary outcomes included cardiovascular outcomes, including cardiovascular death, myocardial infarction, stroke, and all-cause mortality. RESULTS: A total of 20 trials involving 12,155 patients were analyzed in this review. Roxadustat significantly reduced LDL-C (mean difference [MD], -16.07 mg/dL; 95% CI, -17.92 to -14.21; 14 randomized controlled trials [RCTs], 10,510 patients), total cholesterol (MD, -25.25 mg/dL; 95% CI, -29.70 to -20.81; 10 RCTs, 5,538 patients), triglycerides (MD, -19.70 mg/dL; 95% CI, -30.78 to -8.61; 9 RCTs, 4,616 patients), but also decreased HDL-C (MD, -4.91 mg/dL; 95% CI, -6.80 to -3.02; 9 RCTs, 5,132 patients). Desidustat significantly reduced LDL-C and total cholesterol, but showed no significant effects on triglycerides or HDL-C, whereas molidustat showed no significant lipid-lowering effects. Overall, treatment with HIF-PHIs was not associated with significant differences in cardiovascular death (RR, 1.00; 95% CI, 0.84 to 1.18; 10 RCTs, 9,371 patients), myocardial infarction (RR, 1.12; 95% CI, 0.90 to 1.38; 15 RCTs, 11,265 patients), stroke (RR, 1.18; 95% CI, 0.86 to 1.61; 14 RCTs, 11,136 patients), or all-cause mortality (RR, 1.06; 95% CI, 0.96 to 1.17; 19 RCTs, 11,903 patients), compared with ESAs or placebo. CONCLUSION: Roxadustat showed the most substantial lipid-lowering effects, while desidustat showed significant reductions in LDL-C and total cholesterol but no significant effects on triglycerides or HDL-C, and molidustat showed no significant effects. Despite these changes in lipid profiles, no significant differences in cardiovascular outcomes were observed for these three HIF-PHIs, compared with ESAs or placebo.

References

1. 1.Huang, Y. H., Huang, Y. H., Peng, T. R., & Wu, T. W. (2026). Effects of hypoxia-inducible factor prolyl hydroxylase inhibitors on lipid profiles in patients with chronic kidney disease: a systematic review and meta-analysis. European Journal of Clinical Pharmacology. https://doi.org/10.1161/CIR.0000000000001423