Effects of Canagliflozin in Patients with Baseline eGFR <30 ml/min per 1.73 m: Subgroup Analysis of the Randomized CREDENCE Trial.

Background And Objectives: The Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial demonstrated that the sodium glucose cotransporter 2 (SGLT2) inhibitor canagliflozin reduced the risk of kidney failure and cardiovascular events in participants with type 2 diabetes mellitus and CKD. Little is known about the use of SGLT2 inhibitors in patients with eGFR <30 ml/min per 1.73 m. The participants in the CREDENCE study had type 2 diabetes mellitus, a urinary albumin-creatinine ratio >300-5000 mg/g, and an eGFR of 30 to <90 ml/min per 1.73 m at screening. This analysis evaluated participants with eGFR <30 ml/min per 1.73 m at randomization.

Design, Setting, Participants, & Measurements: Effects of eGFR slope through week 130 were analyzed using a piecewise, linear, mixed-effects model. Efficacy was analyzed in the intention-to-treat population, on the basis of Cox proportional hazard models, and safety was analyzed in the on-treatment population. At randomization (an average of 29 days after screening), 174 of 4401 (4%) participants had an eGFR <30 ml/min per 1.73 m (mean [SD] eGFR, 26 [3] ml/min per 1.73 m).

Results: From weeks 3 to 130, there was a 66% difference in the mean rate of eGFR decline with canagliflozin versus placebo (mean slopes, -1.30 versus -3.83 ml/min per 1.73 m per year; difference, -2.54 ml/min per 1.73 m per year; 95% confidence interval [CI], 0.90 to 4.17). Effects of canagliflozin on kidney, cardiovascular, and mortality outcomes were consistent for those with eGFR <30 and ≥30 ml/min per 1.73 m (all interaction >0.20). The estimate for kidney failure in participants with eGFR <30 ml/min per 1.73 m (hazard ratio, 0.67; 95% CI, 0.35 to 1.27) was similar to those with eGFR ≥30 ml/min per 1.73 m (hazard ratio, 0.70; 95% CI, 0.54 to 0.91; interaction=0.80). There was no imbalance in the rate of kidney-related adverse events or AKI associated with canagliflozin between participants with eGFR <30 and ≥30 ml/min per 1.73 m (all interaction >0.12).

Conclusions: This analysis suggests canagliflozin slowed progression of kidney disease, without increasing AKI, even in participants with eGFR <30 ml/min per 1.73 m.