Glycemic Control and Effects of Canagliflozin in Reducing Albuminuria and eGFR: A Post Hoc Analysis of the CREDENCE Trial.

Background In the CREDENCE trial, the sodium-glucose co-transporter-2 (SGLT2) inhibitor canagliflozin improved kidney and cardiovascular outcomes and reduced the rate of estimated glomerular filtration decline (eGFR slope) in patients with type 2 diabetes and chronic kidney disease (CKD). In other clinical trials of patients with CKD or heart failure, the protective effects of SGLT2 inhibitors on eGFR slope were greater in participants with versus participants without type 2 diabetes. This post-hoc analysis of the CREDENCE trial assessed whether the effects of canagliflozin on eGFR slope varied according patient subgroups by baseline glycated hemoglobin A1c (HbA1c). Methods CREDENCE (clinicaltrials.gov (NCT02065791)) was a randomized controlled trial in adults with type 2 diabetes with HbA1c of 6.5-12.0%, an eGFR of 30-90 mL/min/1.73m2 and a urinary albumin-to-creatinine ratio (UACR) of 300-5000 mg/g. Participants were randomly assigned to canagliflozin 100 mg once daily or placebo. We studied the effect of canagliflozin on eGFR slope using linear mixed-effects models. Results The annual difference in total eGFR slope was 1.52 mL/min/1.73m2 (95% CI 1.11, 1.93) slower in participants randomized to canagliflozin compared to placebo. The rate of eGFR decline was faster in those with poorer baseline glycemic control. The mean difference in total eGFR slope between canagliflozin and placebo was greater in participants with poorer baseline glycemic control (difference in eGFR slope of 0.39, 1.36, 2.60, 1.63 mL/min/1.73m2 for Hba1c subgroups 6.5-7.0%, 7.0-8.0%, 8.0-10.0%, 10.0-12.0%, respectively; pinteraction=0.010). The mean difference in change from baseline in UACR between participants randomized to canagliflozin and placebo was smaller in patients with baseline HbA1c 6.5-7.0 (-17% (95% CI -28, -5)) compared to those with an HbA1c 7.0-12% (-32% (95% CI -40, -28); pinteraction=0.03). Conclusions The effect of canagliflozin on eGFR slope in patients with type 2 diabetes and CKD was more pronounced in patients with higher baseline HbA1c, due partly to the more rapid decline in kidney function in these individuals.