Effects of Canagliflozin in Patients with Baseline eGFR <30 ml/min per 1.73 m2: Subgroup Analysis of the Randomized CREDENCE Trial

Abstract

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 m². 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 m² at screening. This post hoc analysis evaluated participants with eGFR <30 ml/min per 1.73 m² 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 m² (mean [SD] eGFR, 26 [3] ml/min per 1.73 m²).

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 m² per year; difference, -2.54 ml/min per 1.73 m² 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 m² (all P interaction >0.20). The estimate for kidney failure in participants with eGFR <30 ml/min per 1.73 m² (hazard ratio, 0.67; 95% CI, 0.35 to 1.27) was similar to those with eGFR ≥30 ml/min per 1.73 m² (hazard ratio, 0.70; 95% CI, 0.54 to 0.91; P 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 m² (all P interaction >0.12).

Conclusions: This post hoc analysis suggests canagliflozin slowed progression of kidney disease, without increasing AKI, even in participants with eGFR <30 ml/min per 1.73 m².

Keywords: canagliflozin; chronic kidney disease; diabetes; diabetic nephropathy.

Graphical abstract

Figure 1.

There was no difference in discontinuation of treatment at eGFR <30 ml/min per 1.73 m² compared to eGFR >30 ml/min per 1.73 m². *Other reasons include poor adherence, safety or tolerability, disallowed therapy, protocol violation, site closure, and other. 95% CI, 95% confidence interval; HR, hazard ratio.

Figure 2.

There was sustained reduction in albuminuria with a increased effect in acute GFR change with canagliflozin in participants with randomization eGFR <30 ml/min per 1.73 m². Baseline levels of UACR (median) and eGFR (mean) are shown below the legend. Data are geometric mean ratio (95% CI) in (A). Data are mean (±SEM) in (B). UACR, urinary albumin-creatinine ratio.

Figure 3.

There was no difference in cardiovascular or kidney outcomes between those with eGFR <30 ml/min per 1.73 m² compared to those with eGFR >30 ml/min per 1.73 m².

Figure 4.

There was no difference in adverse events between those with eGFR <30 ml/min per 1.73 m² and >30 ml/min per 1.73 m². AE, adverse event.