Effects of SGLT2 inhibition on insulin use in CKD and type 2 diabetes: Insights from the CREDENCE trial

Insulin is a mainstay treatment for diabetes, but its use is associated with weight gain and hypoglycaemia. Data on the effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors on insulin use in people with chronic kidney disease (CKD) is limited. We conducted a post-hoc analysis of the CREDENCE (Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation) trial. Effects of canagliflozin versus placebo on insulin use (initiation, dose intensification, reduction and discontinuation) in people with CKD and type 2 diabetes were evaluated using Cox regression models. The primary outcome was insulin initiation or >25% insulin dose intensification (in those not receiving and receiving insulin at baseline, respectively). Effects on kidney, cardiovascular and safety outcomes by baseline insulin use were also assessed. Among 4401 participants, 2884 (65.5%) were receiving insulin at baseline; these participants were more likely to have lower estimated glomerular filtration rate, higher albuminuria and longer duration of diabetes (all P<0.001). Over a median on-treatment period of 2.0 years, canagliflozin reduced the need for insulin initiation or >25% dose intensification by 19% compared to placebo (HR 0.81, 95% CI 0.71-0.93), irrespective of baseline kidney function or albuminuria (both P-interaction>0.10). Sustained insulin dose reductions of >50% were achieved more frequently with canagliflozin than placebo (HR 1.49, 95% CI 1.15-1.91), although no difference in insulin discontinuation was observed between treatment arms. Effects of canagliflozin on kidney, cardiovascular and safety outcomes were consistent regardless of baseline insulin use (all P-interaction>0.05). In CKD and type 2 diabetes, canagliflozin reduces insulin use with consistent effects regardless of baseline kidney function. This supports the use of canagliflozin in people with CKD, not only for end organ protection, but also to improve glycaemic control and reduce exposure to insulin and its associated adverse effects.