Efficacy and safety of canagliflozin compared with placebo and sitagliptin in patients with type 2 diabetes on background metformin monotherapy: a randomised trial

Abstract

Aims/hypothesis: The aim of this work was to evaluate the efficacy and safety of canagliflozin vs placebo and sitagliptin in patients with type 2 diabetes who were being treated with background metformin.

Methods: This randomised, double-blind, four-arm, parallel-group, Phase 3 study was conducted at 169 centres in 22 countries between April 2010 and August 2012. Participants (N = 1,284) with type 2 diabetes aged ≥ 18 and ≤ 80 years who had inadequate glycaemic control (HbA1c ≥ 7.0% [53 mmol/mol] and ≤10.5% [91 mmol/mol]) on metformin therapy received canagliflozin 100 mg or 300 mg, sitagliptin 100 mg, or placebo (n = 368, 367, 366, 183, respectively) for a 26 week, placebo- and active-controlled period followed by a 26 week, active-controlled period (placebo group switched to sitagliptin [placebo/sitagliptin]) and were included in the modified intent-to-treat analysis set. Randomisation was performed using a computer-generated schedule; participants, study centres and the sponsor were blinded to group assignment. The primary endpoint was change from baseline in HbA1c at week 26; secondary endpoints included changes in HbA1c (week 52) and fasting plasma glucose (FPG), body weight, and systolic blood pressure (BP; weeks 26 and 52). Adverse events (AEs) were recorded throughout the study.

Results: At week 26, canagliflozin 100 mg and 300 mg reduced HbA1c vs placebo (-0.79%, -0.94%, -0.17%, respectively; p < 0.001). At week 52, canagliflozin 100 mg and 300 mg demonstrated non-inferiority, and canagliflozin 300 mg demonstrated statistical superiority, to sitagliptin in lowering HbA1c (-0.73%, -0.88%,-0.73%, respectively); differences (95% CI) vs sitagliptin were 0% (-0.12, 0.12) and -0.15% (-0.27, -0.03), respectively. Canagliflozin 100 mg and 300 mg reduced body weight vs placebo (week 26: -3.7%, -4.2%, -1.2%, respectively; p < 0.001) and sitagliptin (week 52: -3.8%, -4.2%, -1.3%, respectively; p < 0.001). Both canagliflozin doses reduced FPG and systolic BP vs placebo (week 26) and sitagliptin (week 52) (p < 0.001). Overall AE and AE-related discontinuation rates were generally similar across groups, but higher with canagliflozin 100 mg. Genital mycotic infection and osmotic diuresis-related AE rates were higher with canagliflozin; few led to discontinuations. Hypoglycaemia incidence was higher with canagliflozin.

Conclusions/interpretation: Canagliflozin improved glycaemia and reduced body weight vs placebo (week 26) and sitagliptin (week 52) and was generally well tolerated in patients with type 2 diabetes on metformin.

Clinical trial registry: ClinicalTrials.gov NCT01106677 FUNDING: This study was supported by Janssen Research & Development, LLC.

Figures

Fig. 1

Study flow diagram. aAmong 2,883 patients enrolled and screened, there were 1,599 screen failures (inclusion/exclusion criteria, n = 1,428; withdrawal of consent, n = 115; other, n = 50; adverse event, n = 6). bSome subjects withdrew from the study after completing period I and did not enter period II. CANA, canagliflozin; PBO, placebo; SITA, sitagliptin

Fig. 2

Changes in glycaemic variables (LOCF). (a) Change in HbA1c at week 26, (b) change in HbA1c at week 52, (c) mean HbA1c over time and (d) change in FPG at week 52. CANA, canagliflozin; PBO, placebo; SITA, sitagliptin. Light-grey triangles, PBO; white diamonds, SITA 100 mg; dark-grey squares, CANA 100 mg; black circles, CANA 300 mg. Error bars show SE. To convert values for HbA1c in % into mmol/mol, subtract 2.15 and multiply by 10.929 or use the conversion calculator at www.HbA1c.nu/eng/

Fig. 3

Per cent change in body weight (LOCF). CANA, canagliflozin; SITA, sitagliptin. White diamonds, SITA 100 mg; dark-grey squares, CANA 100 mg; black circles, CANA 300 mg. Error bars show SE