Abstract Background Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are a foundational therapy for chronic kidney disease (CKD). Clinical practice guidelines recommend initiation of SGLT2 inhibitors when eGFR is≥20ml/min/1.73m2. While such guidelines recommend continuing SGLT2i when eGFR falls below 20ml/min/1.73m2, data on the efficacy and safety of SGLT2i in this setting are limited. Methods The CREDENCE trial was an international, multi-centre, randomised, double-blind, placebo-controlled trial assessing the efficacy and safety of the SGLT2i canagliflozin in patients with type 2 diabetes (T2D) and CKD. Patients with an eGFR 30 ml/min/1.73m2 at the time of screening were excluded; however, randomized treatment was continued until dialysis or transplantation. In this post-hoc analysis, we used time-updated Cox proportional hazards models to assess the association between deterioration in eGFR to less than 20 ml/min/1.73m2, efficacy and safety outcomes, and treatment with canagliflozin. The primary outcome was a composite of doubling of serum creatinine, kidney failure, cardiovascular or renal death. Results Among 4,401 randomized participants, 443 (10.1%) experienced eGFR deterioration to less than 20 ml/min/1.73m2 at least once during trial follow up. These participants experienced a higher risk of both the primary composite outcome (HR 9.50; 95%CI: 7.58-11.83; P0.001) as well as the composite of CV death or HF hospitalization (HR 3.40; 95%CI: 2.38-4.67; P0.001). The risk of the primary outcome was lower with canagliflozin compared with placebo among participants who did (HR 0.88; 95%CI: 0.63-1.24) and did not (HR 0.69; 95%CI: 0.57-0.83) experience deterioration of eGFR to 20 ml/min/1.73m2 (PInteraction=0.18) (Figure 1). Canagliflozin was also associated with lower risk of CV death or HF hospitalization among participants whose eGFR did (HR 0.70, 95% CI 0.40-1.24) and did not (HR 0.69, 95% CI 0.57-0.85) fall to 20 ml/min/1.73m2 (Pinteraction =0.94) (Figure 1). While the incidence of adverse outcomes including any serious adverse event, hyperkalemia and kidney related adverse events were higher among participants whose eGFR fell 20 ml/min/1.73m2, canagliflozin was not associated with an increased risk of these outcomes, relative to placebo (Figure 1). Conclusions In patients with T2D and albuminuric CKD experiencing progression of CKD to eGFR levels below guideline recommended thresholds for initiation, continuation of canagliflozin was associated with persistent benefit for kidney and cardiovascular outcomes with no additional safety concerns. These data support current guideline recommendations to continue SGLT2i until dialysis or transplantation and highlight the need for additional randomized evidence in this patient population.
Chatur et al. (2025) studied this question.