Canagliflozin Enhances Iron Utilization and Hemoglobin Levels in Diabetic CKD Patients, CREDENCE Trial Reveals

The study, published in Nephrology Dialysis Transplantation, revealed that treatment with canagliflozin led to an increase in total iron binding capacity (TIBC) while decreasing ferritin levels. These changes suggest a shift in iron metabolism, indicating that Canagliflozin may enhance iron utilization in the body.

"Canagliflozin was linked to enhanced iron utilization and elevated hemoglobin levels in adults with type 2 diabetes and chronic kidney disease," the researchers wrote.

Iron deficiency is a common complication in individuals with type 2 diabetes and CKD, often leading to anemia and exacerbating the overall health of patients. Research involving patients with heart failure has shown that sodium-glucose cotransporter 2 (SGLT2) inhibitors can boost iron utilization and promote erythropoiesis. In a post hoc analysis of the CREDENCE trial, Hiddo J L Heerspink, The George Institute for Global Health, UNSW Sydney, Sydney, Australia, and colleagues assessed the impact of canagliflozin on iron metabolism in CKD patients. They investigated how iron deficiency influenced the drug's effects on hemoglobin levels and cardiorenal outcomes.

For this purpose, the researchers measured serum iron, total iron binding capacity (TIBC), transferrin saturation (TSAT), and ferritin levels at baseline and after 12 months. They used analysis of covariance to assess the effects of canagliflozin compared to placebo on these iron markers. Additionally, mixed-effect and Cox regression models were employed to evaluate how baseline iron deficiency, defined as TSAT <20%, influenced the impact of canagliflozin on hemoglobin levels and cardiorenal outcomes.

The study revealed the following findings:

• Of the 4,401 participants randomized in the CREDENCE trial, 2,416 had their iron markers measured at baseline, with 924 identified as iron deficient.
• Compared to placebo, Canagliflozin resulted in a 2.1% increase in TIBC and an 11.5% reduction in ferritin levels, without significantly impacting serum iron or transferrin saturation (TSAT).
• Over the trial period, Canagliflozin increased hemoglobin by 7.3 g/L for patients with iron deficiency and 6.7 g/L for those without iron deficiency, with no significant interaction effect.
• The relative impact of Canagliflozin on the primary outcome—defined as a doubling of serum creatinine, kidney failure, or death from cardiovascular disease or kidney failure—was consistent across both groups, with a hazard ratio of 0.70 and no significant interaction effect.
• Similar consistency was observed for other cardiovascular and mortality outcomes.

According to the authors, iron deficiency is highly prevalent among patients with type 2 diabetes and chronic kidney disease.

"Their findings indicate that Canagliflozin increases total iron binding capacity and decreases ferritin levels in this population, suggesting enhanced iron utilization. Additionally, the treatment is associated with improved hemoglobin levels and favorable clinical outcomes, regardless of whether patients have iron deficiency," the authors concluded.

Reference:

Koshino, A., Heerspink, H. J., Jongs, N., Badve, S. V., Arnott, C., Neal, B., Jardine, M., Mahaffey, K. W., Pollock, C., Perkovic, V., Hansen, M. K., Bakker, S. J., Wada, T., & Neuen, B. L. Canagliflozin and iron metabolism in the CREDENCE trial. Nephrology Dialysis Transplantation. https://doi.org/10.1093/ndt/gfae198