Canagliflozin and Iron Metabolism in the CREDENCE Trial

Background. Studies in patients with heart failure have indicated that sodium-glucose cotransporter 2 (SGLT2) inhibitors increase iron use and enhance erythropoiesis. In this post hoc analysis of the Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial, we evaluated the effects of canagliflozin on iron metabolism in patients with chronic kidney disease (CKD) and whether the effects of canagliflozin on hemoglobin and cardiorenal outcomes were modified by iron deficiency. Methods. We measured serum iron, total iron binding capacity (TIBC), transferrin saturation (TSAT) and ferritin at baseline and 12 months. The effects of canagliflozin, relative to placebo, on iron markers were assessed with analysis of covariance. Interactions between baseline iron deficiency, defined as TSAT <20%, and the effects of canagliflozin on hemoglobin and cardiorenal outcomes were evaluated with mixed effect models and Cox regression models, respectively. Results. Of 4401 participants randomized in CREDENCE, 2416 (54.9%) had iron markers measured at baseline, of whom 924 (38.2%) were iron deficient. Canagliflozin, compared with placebo, increased TIBC by 2.1% [95% confidence interval (CI) 0.4, 3.8; P = .014] and decreased ferritin by 11.5% (95% CI 7.1, 15.7; P < .001) with no clear effect on serum iron or TSAT. Canagliflozin increased hemoglobin over the trial duration by 7.3 g/L (95% CI 6.2, 8.5; P < .001) and 6.7 g/L (95% CI 5.2, 8.2; P < .001) in patients with and without iron deficiency, respectively (P for interaction = .38). The relative effect of canagliflozin on the primary outcome of doubling of serum creatinine, kidney failure or death due to cardiovascular disease or kidney failure (hazard ratio 0.70, 95% CI 0.56, 0.87) was consistent regardless of iron deficiency (P for interaction = .83), as were effects on other cardiovascular and mortality outcomes (all P for interactions >= 0.10). Conclusion. Iron deficiency is highly prevalent in patients with type 2 diabetes and CKD. Canagliflozin increased TIBC and decreased ferritin in patients with type 2 diabetes and CKD, suggesting increased iron utilization, and improved hemoglobin levels and clinical outcomes regardless of iron deficiency.