Elsevier

The Lancet

Volume 382, Issue 9896, 14–20 September 2013, Pages 941-950
The Lancet

Articles
Efficacy 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

https://doi.org/10.1016/S0140-6736(13)60683-2Get rights and content

Summary

Background

Sodium–glucose cotransporter 2 (SGLT2) inhibitors improve glycaemia in patients with type 2 diabetes by enhancing urinary glucose excretion. We compared the efficacy and safety of canagliflozin, an SGLT2 inhibitor, with glimepiride in patients with type 2 diabetes inadequately controlled with metformin.

Methods

We undertook this 52 week, randomised, double-blind, active-controlled, phase 3 non-inferiority trial at 157 centres in 19 countries between Aug 28, 2009, and Dec 21, 2011. Patients aged 18–80 years with type 2 diabetes and glycated haemoglobin A1c (HbA1c) of 7·0–9·5% on stable metformin were randomly assigned (1:1:1) by computer-generated random sequence via an interactive voice or web response system to receive canagliflozin 100 mg or 300 mg, or glimepiride (up-titrated to 6 mg or 8 mg per day) orally once daily. Patients, study investigators, and local sponsor personnel were masked to treatment. The primary endpoint was change in HbA1c from baseline to week 52, with a non-inferiority margin of 0·3% for the comparison of each canagliflozin dose with glimepiride. If non-inferiority was shown, we assessed superiority on the basis of an upper bound of the 95% CI for the difference of each canagliflozin dose versus glimepiride of less than 0·0%. Analysis was done in a modified intention-to-treat population, including all randomised patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT00968812.

Findings

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). For lowering of HbA1c at 52 weeks, canagliflozin 100 mg was non-inferior to glimepiride (least-squares mean difference −0·01% [95% CI −0·11 to 0·09]), and canagliflozin 300 mg was superior to glimepiride (–0·12% [–0·22 to −0·02]). 39 (8%) patients had serious adverse events in the glimepiride group versus 24 (5%) in the canagliflozin 100 mg group and 26 (5%) in the 300 mg group. In the canagliflozin 100 mg and 300 mg groups versus the glimepiride group, we recorded a greater number of genital mycotic infections (women: 26 [11%] and 34 [14%] vs five [2%]; men: 17 [7%] and 20 [8%] vs three [1%]), urinary tract infections (31 [6%] for both canagliflozin doses vs 22 [5%]), and osmotic diuresis-related events (pollakiuria: 12 [3%] for both doses vs one [<1%]; polyuria: four [<1%] for both doses vs two [<1%]).

Interpretation

Canagliflozin provides greater HbA1c reduction than does glimepiride, and is well tolerated in patients with type 2 diabetes receiving metformin. These findings support the use of canagliflozin as a viable treatment option for patients who do not achieve sufficient glycaemic control with metformin therapy.

Funding

Janssen Research & Development, LLC.

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.

Section snippets

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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