ArticlesEfficacy and safety of canagliflozin versus glimepiride in patients with type 2 diabetes inadequately controlled with metformin (CANTATA-SU): 52 week results from a randomised, double-blind, phase 3 non-inferiority trial
Introduction
Type 2 diabetes is well known as a progressive disease, and to adequately manage hyperglycaemia after an initial period of lifestyle management and monotherapy, patients often need combination treatments to maintain glycaemic control.1, 2, 3 Metformin is the standard and preferred first-line pharmacological drug for type 2 diabetes.2 After metformin failure, various drugs are available as add-on therapy, such as sulphonylureas, insulin, thiazolidinediones, and incretins. However, many of these drugs not only reduce glucose concentrations, but also cause weight gain and increase the risk of hypoglycaemia.2 Thus, drugs are needed that can provide glycaemic control while having beneficial effects on weight and hypoglycaemia. In this regard, pharmacological inhibition of the sodium–glucose cotransporter 2 (SGLT2) is an appealing alternative. Specifically, SGLT2 inhibitors lower the renal threshold for glucose, leading to increased urinary glucose excretion, decreased plasma glucose, a mild osmotic diuresis, and a net loss of calories.4 Therefore, these inhibitors have an insulin-independent mechanism for the correction of hyperglycaemia through decreased renal glucose reabsorption.
Canagliflozin is an SGLT2 inhibitor developed for the treatment of type 2 diabetes.5, 6, 7, 8, 9 In patients with type 2 diabetes inadequately controlled with metformin, canagliflozin has been associated with significant reductions in glycated haemoglobin A1c (HbA1c), fasting plasma glucose, and bodyweight at 12 weeks, with a low frequency of hypoglycaemia.8 In view of these potential beneficial effects, we assessed the efficacy and safety of canagliflozin compared with glimepiride as add-on therapy in patients with type 2 diabetes inadequately controlled with metformin.
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Study design and participants
We report findings from our CANagliflozin Treatment And Trial Analysis versus SUlphonylurea (CANTATA-SU) study. We undertook this randomised, double-blind, active-controlled, phase 3 non-inferiority trial at 157 centres in 19 countries. 54 centres were in North America, 39 in Europe, and nine in Central or South America; the other 55 were spread around the rest of the world. The study consisted of a 2 week, single-blind, placebo run-in period and a 52 week, double-blind, core treatment period,
Results
Figure 1 shows the trial profile. 1450 of 1452 randomised patients received at least one dose of glimepiride (n=482), canagliflozin 100 mg (n=483), or canagliflozin 300 mg (n=485), and thus comprised the modified intention-to-treat group. 1161 (80%) patients completed 52 weeks of treatment, with similar rates of discontinuation between groups (figure 1). Demographic and baseline characteristics were similar between groups (table 1). For patients assigned glimepiride, the mean maximum dose
Discussion
At 52 weeks, both canagliflozin doses were non-inferior to glimepiride for reduction of HbA1c on the background of metformin therapy. Furthermore, canagliflozin 300 mg was associated with a modest, but statistically superior reduction in HbA1c versus glimepiride. As with all sulphonylureas, gradual up-titration of glimepiride is recommended to minimise the risk of hypoglycaemia. We up-titrated glimepiride over the entire treatment period to achieve aggressive glucose targets, with the maximum
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