Canagliflozin Linked to Improved Anemia in Patients with Diabetes and Renal Disease

The SGLT-2 inhibitor canagliflozin shows additional benefits besides lowering blood glucose, researchers say, including improving anemia.

SGLT-2 inhibitors such as canagliflozin are shown to be beneficial to patients who have both type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD) in regards to developing anemia. Canagliflozin targets sodium-glucose cotransporter 2 within renal cells, resulting in increased excretion of glucose through the urine and decreasing glucose reabsorption rates of filtered glucose.  

According to a recent post-hoc analysis of the CREDENCE trial (Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation), there was a statistically significant difference in the risk of developing anemia and other anemia events between the placebo and canagliflozin group. Anemia events were defined as the need for initiating iron preparations or erythropoiesis stimulating-agents. Before this study, little research was available that linked the effects of SGLT-2 inhibitors to anemia and erythropoiesis.  

The CREDENCE trial is a double-blinded, randomized trial that included 4401 patients across 690 clinical sites in 34 countries over three years (May 2014 – May 2017) with a median follow-up of 2.6 years. Eligible patients for the CREDENCE trial included patients with T2DM with HbA1c levels of 6.5-12.0% (48-108 mmol/mol) with concurrent CKD. CKD was defined as an eGFR between 90ml/min to 30ml/min per 1.73m2 and a urinary albumin-to-creatinine ratio higher than 33.9 up to 565.6mg/mmol (>300 to 5000mg/g).  

Roughly 36% of patients (n = 1599) had anemia at baseline, and 33 patients were on an erythropoiesis-stimulating agent. Additionally, 573 of the total 4401 patients developed anemia during the study period. Anemia was defined as patients with a hemoglobin of <130g/L in men or <120g/L in women. Of these 573 people, 358 reported anemia, 343 receiving iron supplementations, 141 initiating erythropoiesis-stimulating agents, and 114 receiving blood transfusions. The mean hemoglobin concentration at baseline was 132.0 g/L (SD 17.7).  

During the 2.6-year follow-up, mean hemoglobin concentration was 7.1 g/L (95% CI 6.4-7.8) higher, and hematocrit was 2.4% (2.2-2.6) higher in the canagliflozin group than the placebo group. Patients in the canagliflozin group also had lower risks of anemia events alone (0.58, 0.47-0.72; p<0.0001), initiation of iron preparations (0.64, 0.52-0.80; p<0.0001), and need for erythropoiesis-stimulating agents (0.65, 0.46-0.91; p=0.012) in comparison to the placebo group. There was also statistical significance when viewing anemia events, initiation of iron preparations, and need for erythropoiesis-stimulating agents as a composite outcome (hazard ratio 0.65, 95% CI 0.55-0.77; p<0.0001). 

The CREDENCE study’s primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15 ml per minute per 1.73m2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes.  

Results show that the relative risk for the renal-specific elements of the primary endpoint (excluding CV death) was 34% lower for those taking canagliflozin (HR, 0.66; 95% CI, 0.53-0.81; P <.001). The relative risk of end-stage renal disease was 32% lower for those taking canagliflozin (HR, 0.68; 95% CI, 0.54-0.86; P = .002). The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). 

The study organizers from the CREDENCE trial are currently looking into future studies to determine the impact that SGLT-2 inhibitors may have on patients without diabetes and the potential benefits they may have regarding reducing the risks of anemia and the need for erythropoietin stimulating agents. Comparing the effects of SGLT-2 inhibitors on the kidneys between patients with diabetes and those without diabetes could yield exciting results and expand the number of disease states that SGLT-2 inhibitors can treat.  

Trials involving other SGLT-2 inhibitors, such as the DAPA-CKD trial using dapagliflozin, have shown similar results, suggesting that this is a class-wide effect of all SGLT-2 inhibitors rather than a unique benefit of canagliflozin alone. The EMPA-Kidney trial also explores the renal benefits of the SGLT-2 inhibitor empagliflozin and is due to present results in June 2022. 

Practice Pearls: 

• Canagliflozin is superior to placebo in reducing the risk of developing anemia and additional anemia events. 
• During the 2.6-year follow-up of the CREDENCE trial, a post-hoc analysis showed that the mean hemoglobin concentration was 7.1 g/L (95% CI 6.4-7.8) higher, hematocrit was 2.4% (2.2-2.6) higher, in the canagliflozin group than the placebo group. 
• Participants in the canagliflozin group also had lower risks of anemia events alone (0.58, 0.47-0.72; p<0.0001), initiation of iron preparations (0.64, 0.52-0.80; p<0.0001), and need for erythropoiesis-stimulating agents (0.65, 0.46-0.91; p=0.012) in comparison to the placebo group. 

Bender, Kenneth.”Canagliflozin Improves Anemia in Diabetics with Renal Impairment” HCPLive, January 4, 2021  

Caffrey, Mary.”CREDENCE: First Renal Outcomes Trial Finds Canagliflozin Cuts Risk of Renal Failure, Death; Prompts ADA Updates” AJMC, June 29. 2019,  

Oshima, Megumi, et al. “Effects of Canagliflozin on Anaemia in Patients with Type 2 Diabetes and Chronic Kidney Disease: a Post-Hoc Analysis from the CREDENCE Trial.”  

Perkovic, Vlado, et al. “Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy.”  

Adrian Gavre, PharmD Candidate, Philadelphia College of Osteopathic Medicine