Renal, Cardiovascular, and Safety Outcomes of Canagliflozin by Baseline Kidney Function: A Secondary Analysis of the CREDENCE Randomized Trial.

BACKGROUND: Canagliflozin reduced renal and cardiovascular events in people with type 2 diabetes in the CREDENCE trial. We assessed efficacy and safety of canagliflozin by initial estimated glomerular filtration rate (eGFR). METHODS: CREDENCE randomly assigned 4401 participants with an eGFR of 30 to <90 ml/min per 1.73 m2 and substantial albuminuria to canagliflozin 100 mg or placebo. We used Cox proportional hazards regression to analyze effects on renal and cardiovascular efficacy and safety outcomes within screening eGFR subgroups (30 to <45, 45 to <60, and 60 to <90 ml/min per 1.73 m2) and linear mixed effects models to analyze the effects on eGFR slope. RESULTS: At screening, 1313 (30%), 1279 (29%), and 1809 (41%) participants had an eGFR of 30 to <45, 45 to <60, and 60 to <90 ml/min per 1.73 m2, respectively. The relative benefits of canagliflozin for renal and cardiovascular outcomes appeared consistent among eGFR subgroups (all P interaction >0.11). Subgroups with lower eGFRs, who were at greater risk, exhibited larger absolute benefits for renal outcomes. Canagliflozin's lack of effect on serious adverse events, amputations, and fractures appeared consistent among eGFR subgroups. In all subgroups, canagliflozin use led to an acute eGFR drop followed by relative stabilization of eGFR loss. Among those with an eGFR of 30 to <45 ml/min per 1.73 m2, canagliflozin led to an initial drop of 2.03 ml/min per 1.73 m2. Thereafter, decline in eGFR was slower in the canagliflozin versus placebo group (-1.72 versus -4.33 ml/min per 1.73 m2; between-group difference 2.61 ml/min per 1.73 m2). CONCLUSIONS: Canagliflozin safely reduced the risk of renal and cardiovascular events, with consistent results across eGFR subgroups, including the subgroup initiating treatment with an eGFR of 30 to <45 ml/min per 1.73 m2. Absolute benefits for renal outcomes were greatest in subgroups with lower eGFR. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Evaluation of the Effects of Canagliflozin on Renal and Cardiovascular Outcomes in Participants With Diabetic Nephropathy (CREDENCE), NCT02065791.

Acute pancreatitis risk in type 2 diabetes patients treated with canagliflozin versus other antihyperglycemic agents: an observational claims database study.

Objective: Observational evidence suggests that patients with type 2 diabetes mellitus (T2DM) are at increased risk for acute pancreatitis (AP) versus those without T2DM. A small number of AP events were reported in clinical trials of the sodium glucose co-transporter 2 inhibitor canagliflozin, though no imbalances were observed between treatment groups. This observational study evaluated risk of AP among new users of canagliflozin compared with new users of six classes of other antihyperglycemic agents (AHAs).Methods: Three US claims databases were analyzed based on a prespecified protocol approved by the European Medicines Agency. Propensity score adjustment controlled for imbalances in baseline covariates. Cox regression models estimated the hazard ratio of AP with canagliflozin compared with other AHAs using on-treatment (primary) and intent-to-treat approaches. Sensitivity analyses assessed robustness of findings.Results: Across the three databases, there were between 12,023-80,986 new users of canagliflozin; the unadjusted incidence rates of AP (per 1000 person-years) were between 1.5-2.2 for canagliflozin and 1.1-6.6 for other AHAs. The risk of AP was generally similar for new users of canagliflozin compared with new users of glucagon-like peptide-1 receptor agonists, dipeptidyl peptidase-4 inhibitors, sulfonylureas, thiazolidinediones, insulin, and other AHAs, with no consistent between-treatment differences observed across databases. Intent-to-treat and sensitivity analysis findings were qualitatively consistent with on-treatment findings.Conclusions: In this large observational study, incidence rates of AP in patients with T2DM treated with canagliflozin or other AHAs were generally similar, with no evidence suggesting that canagliflozin is associated with increased risk of AP compared with other AHAs.