Effects of Canagliflozin on Iron Metabolism in Patients With CKD

Previous studies of people with heart failure have shown that sodium-glucose cotransporter 2 inhibitors (SGLT2i) increase iron use and exacerbate erythropoiesis. In a post-hoc analysis of data from the CREDENCE trial, Akihiko Koshino, MD, PhD, and colleagues studied the effects of canagliflozin on iron metabolism in participants with chronic kidney disease (CKD) and sought to determine whether iron deficiency modified the effects of canagliflozin on hemoglobin and cardiorenal outcomes.  

The researchers measured the serum iron, total iron binding capacity (TIBC), transferrin saturation (TSAT), and ferritin of 4,401 randomized participants at baseline and 12 months. They used analysis of covariance to evaluate the effects of canagliflozin on iron markers, compared with placebo. Mixed-effect models and Cox regression models were used to study interactions between baseline iron deficiency (TSAT <20%) and the effects of canagliflozin on hemoglobin and cardiorenal outcomes, respectively.  

At baseline, 2,416 (54.9%) participants had iron markers measured; 924 (38.2%) were found to have iron deficiency. Canagliflozin increased TIBC by 2.1% (95% CI, 0.4-3.8; P=.014) and decreased ferritin by 11.5% (95% CI, 7.1-15.7; P<.001) compared with placebo but had no clear effect on serum iron or TSAT. In addition, canagliflozin increased hemoglobin over the trial period by 7.3 g/L (95% CI, 6.2-8.5; P<.001) in participants with iron deficiency and by 6.7 g/L (95% CI, 5.2-8.2; P<.001) in participants without iron deficiency (P-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 (HR, 0.70; 95% CI, 0.56-0.87) remained consistent regardless of iron deficiency (P-interaction=.83). Canagliflozin’s effects on other cardiovascular and mortality outcomes were also consistent regardless of iron deficiency (all P-interactions ≥.10).  

In sum, iron deficiency is prevalent among individuals with type 2 diabetes and CKD, and canagliflozin increased TIBC and decreased ferritin in such patients, implying increased iron utilization. In addition, the drug improved hemoglobin levels and clinical outcomes regardless of iron deficiency. 

Source: Nephrology Dialysis Transplantation