Efficacy and safety of Canagliflozin in subjects with type 2 diabetes mellitus on background metformin
Question: Canagliflozin (CANA) is a sodium glucose co-transporter 2 inhibitor in development for the treatment of type 2 diabetes mellitus (T2DM). This study evaluated the efficacy and safety of CANA in subjects with T2DM inadequately controlled with metformin (MET).
Methodology: In this randomised, double-blind, Phase 3 study, subjects with T2DM on stable MET (N = 1,284) received CANA 100 or 300 mg, sitagliptin (SITA) 100 mg, or placebo (PBO) daily (2:2:2:1) for a 26-week, PBO- and active-controlled period (results reported here) followed by a 26-week, active-controlled period (PBO subjects switched to SITA; results to be reported elsewhere). Primary endpoint was change from baseline in HbA1c at Week 26 for CANA versus PBO. Secondary endpoints included proportion of subjects reaching HbA1c < 7.0%, change in fasting plasma glucose (FPG), 2-h postprandial glucose (PPG), and systolic BP, and percent change in body weight, HDL-C, and triglycerides. Statistical comparisons for SITA versus PBO or CANA at Week 26 were not performed (not pre-specified). Adverse events (AEs) were recorded throughout the study.
Results: Mean baseline characteristics were similar across groups (age, 55.4 y; HbA1c, 7.9%; FPG, 9.4 mmol/L; BMI, 31.8 kg/m2). At Week 26, CANA 100 and 300 mg reduced HbA1c relative to PBO (-0.62% and -0.77%; P< 0.001), with a decrease of -0.66% with SITA versus PBO. More subjects reached HbA1c < 7.0% with CANA 100 and 300 mg and SITA than PBO (45.5%, 57.8%, 54.5%, 29.8%; P= 0.0 for both CANA doses vs. PBO). CANA 100 and 300 mg and SITA decreased FPG (-1.7, -2.2, -1.3 mmol/L) and 2-h PPG (-2.1, -2.6, -2.2 mmol/L) versus PBO (P< 0.001 for both CANA doses vs. PBO). CANA 100 and 300 mg reduced body weight relative to PBO (-2.5% and -2.9%; P< 0.001); no change was seen with SITA. CANA 100 and 300 mg and SITA were associated with decreased systolic BP (-5.4, -6.6, -3.3 mmHg) and increased HDL-C (6.6%, 8.4%, 1.3%) relative to PBO (P< 0.001 for both CANA doses vs. PBO); LDL-C was increased versus PBO (7.9%, 12.2%, 5.5%). Overall AE rates were modestly higher with CANA 100 mg (61.1%) than CANA 300 mg, SITA, or PBO (55.6%, 55.2%, 58.5%); serious AE and AE-related discontinuation rates were low across groups. Rates of genital mycotic infections (female: 8.8%, 9.4%, 1.0%, 0%; male: 4.0%, 2.4%, 1.2%, 1.1%) and osmotic diuresis-related AEs (ie, pollakiuria [5.7%, 2.7%, 0.5%, 0.5%], polyuria [0.5%, 0.5%, 0%, 0%]) were higher with CANA 100 and 300 mg than SITA or PBO; these AEs led to few discontinuations. Urinary tract infection rates were higher with CANA 100 and 300 mg and SITA than PBO (5.4%, 3.5%, 3.6%, 2.2%); most events were mild to moderate in severity. Documented hypoglycaemia rates were higher with CANA 100 and 300 mg than SITA or PBO (4.3%, 4.6%, 1.4%, 1.6%).
Conclusions: CANA 100 and 300 mg significantly improved glycaemic control and reduced body weight compared with PBO at Week 26 and were generally well tolerated in subjects with T2DM on background MET.