Renal benefit with SGLT2i in patients with eGFR <30 ml/min/1.73m²
Effects of Canagliflozin in Patients with Baseline eGFR <30 ml/min per 1.73 m²
Introduction and methods
The Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) study has shown that canagliflozin reduces the risk of kidney failure and CV events in patients with T2DM and CKD [1,2]. Canagliflozin was, based on data from the CREDENCE trial, approved by the US Food and Drug Administration to reduce the risk of kidney failure, doubling of serum creatinine, CV death, and hospitalization for HF in adults with type 2 diabetes and diabetic nephropathy with albuminuria . The indication was updated to allow patients who were already receiving canagliflozin, but whose eGFR had fallen below 30 ml/min/1.73m² and with an urinary albumin-creatinine ratio (UACR) >300 mg/g to continue with their canagliflozin treatment until initiation of dialysis or kidney transplantation . Yet, the potential renal and CV beneficial effects in patients with eGFR <30 ml/min/1.73m² have not been reported.
This post hoc subgroup analysis of CREDENCE trial evaluated the efficacy and safety of canagliflozin in patients with eGFR levels of <30 ml/min/1.73m².
The CREDENCE trial was a randomized, double-blind, event-driven, placebo-controlled, multicentered study of the effects of canagliflozin on renal and CV outcomes in patients with T2DM (n=4401). Eligible participants had an eGFR of ≥30 to <90 ml/min/1.73m² at screening, glycated hemoglobin (HbA1c) of 6.5%-12%, UACR of >300-5000 mg/g (>33.9-565.6 mg/mmol), and received maximum or maximum tolerated dose of ARB or ACE inhibitor for ≥4 weeks before randomization. Patients were randomized to 100 mg canagliflozin once daily or matching placebo. Intermediate outcomes were change from baseline in HbA1c, SBP, and urinary albumin-creatine ratio (UACR). Change in eGFR was defined as the acute change in eGFR from baseline to week 3, the annualized chronic change in eGFR from week 3 until the end of the treatment (week 182), and the total annualized change in eGFR from baseline to week 130. The primary composite outcome was kidney failure, doubling of serum creatinine, or renal or CV death. The median follow-up was 2.62 (IQR 2.11-3.09) years. While all participants had an eGFR ≥30 to <90 ml/min/1.73m² at the time of screening, the eGFR of 174 (4%) participants dropped below 30 ml/min/1.73m² at the time of randomization (an average of 29 days after screening). This subgroup analysis assessed outcomes in patients who had an eGFR <30 ml/min/1.73m² at randomization.
- Patients treated with canagliflozin had a 33% (95% CI: -49 to -10) lower geometric mean for UACR compared to patients receiving placebo. Canagliflozin treatment had no effect on Hb1Ac levels or SBP. The treatment effects on HbA1c, systolic BP, or UACR were similar between patients with <30 or ≥30 ml/min/1.73m² eGFR levels (P for heterogeneity=0.86, 0.66, and 1.0, respectively)
- The mean annual decline in eGFR from baseline to week 130 was slower in patients treated with canagliflozin compared to patients on placebo (0.03 vs. -1.88 ml/min/1.73m²). The placebo-subtracted difference between the canagliflozin and placebo group was 1.91 ml/min/1.73m² per year (95% CI: 0.18-3.64).
- The mean acute change in eGFR from baseline to week 3 in patients with canagliflozin was 3.26 ml/min/1.73m² and 4.14 ml/min/1.73m² in the ones receiving placebo. The placebo-subtracted difference between the two groups was -0.88 ml/min/1.73m² (95% CI:-3.16 to 1.39).
- There was a 66% difference in mean rate of eGFR decline with canagliflozin compared with placebo from week 3 to the end of the study (week 182) (-1.30 vs. -3.83 ml/min/1.73m² per year, respectively). The placebo-subtracted difference was 2.54 ml/min/1.73m² per year (95% CI: 0.90 to 4.17).
- Treatment with canagliflozin reduced the risk of kidney failure in patients with an eGFR of <30 ml/min/1.73m² with 33% (HR 0.67, 95% CI: 0.35 to 1.27), compared to placebo. This reduction in risk of kidney failure was similar to the risk reduction observed in patients with an eGFR of ≥30 ml/min/1.73m² (HR 0.70, 95% CI: 0.54 to 0.91, P interaction = 0.80).
- Despite a limited number of events in the subgroups, the point estimates for the effects of canagliflozin on most kidney and CV outcomes were comparable to those observed in patients with an eGFR of ≥30 ml/min/1.73m² (all P interactions ≥0.20).
- Rates of adverse events were similar among the canagliflozin and placebo groups in patients with an eGFR of <30 ml/min/1.73m². Moreover, there was no difference in adverse event rates between patients with an eGFR of <30 ml/min/1.73m² and those with an eGFR of ≥30 ml/min/1.73m².
This post hoc analysis of the CREDENCE trial suggests that canagliflozin reduced albuminuria and slowed the rate of eGFR decline in patients with eGFR <30 ml/min/1.73m², compared to placebo. Effects of canagliflozin on kidney, CV and mortality outcomes in patients with an eGFR of <30 ml/min/1.73m² were similar to those with an eGFR of ≥30 ml/min/1.73m². In addition, there was no imbalance in adverse event rates between patients with eGFR of <30 ml/min/1.73m² and those with an eGFR of ≥30 ml/min/1.73m². These data suggest that there is no reason to discontinue treatment with canagliflozin if the eGFR drops below 30 ml/min/1.73m² until initiation of dialysis or kidney transplantation. Of note, other studies that investigate the effect of SGLT2 inhibitors in people with lower initial eGFR levels are ongoing. The authors state that they would not recommend initiating treatment with an SGLT2 inhibitor in patients with <30 ml/min/1.73m² until results from these pending studies are available.