Effect of Roxadustat on Cardiometabolism in Healthy Individuals (ROXACardioMeta): Protocol for a Double-Blind,...

Hypoxia activates hypoxia-inducible factors (HIFs), which regulate genes involved in erythropoiesis, angiogenesis, and metabolism. HIF stability is controlled by oxygen-dependent HIF prolyl 4-hydroxylases (HIF-P4Hs). Pharmacological HIF-P4H inhibitors are approved for the treatment of anaemia in chronic kidney disease (CKD). Beyond erythropoiesis, these drugs have been linked to improved lipid profiles in CKD, and preclinical studies suggest benefits for glucose tolerance and cardiovascular protection. However, cardiometabolic effects of HIF-P4H inhibitors have not been systematically examined in healthy or non-anaemic individuals. This investigator-initiated, double-blind, placebo-controlled, randomised crossover trial evaluates the systemic effects of roxadustat, an orally administered pan-HIF-P4H inhibitor. The study consists of two 10-day study arms separated by a minimum 4-week washout. Participants receive 70 mg of roxadustat or a placebo thrice a week. The primary hypothesis is that roxadustat lowers plasma total cholesterol. Secondary outcomes include changes in LDL cholesterol, triglycerides, insulin sensitivity, glucose tolerance, body composition, 24 h blood pressure, exercise capacity, autonomic cardiovascular regulation, and skeletal muscle microcirculation. Healthy volunteers (n = 24) aged 18-40 years will be enrolled. This study will provide insights into the potential of HIF-P4H inhibitors for obesity, dyslipidaemia, insulin resistance, and hypertension, and may inform future therapeutic strategies for metabolic syndrome, type 2 diabetes, and cardiovascular disease.