Efficacy and safety of twice-daily treatment with canagliflozin, a sodium glucose co-transporter 2 inhibitor, added on to metformin monotherapy in patients with type 2 diabetes mellitus

Abstract

Aim: To evaluate the efficacy/safety of canagliflozin twice daily (BID) compared with placebo in patients with type 2 diabetes mellitus (T2DM) on metformin.

Methods: In this 18-week, randomized, double-blind, placebo-controlled study, patients (N = 279) at 60 centers in 7 countries received canagliflozin 50 or 150 mg or placebo BID. The pre-specified primary endpoint was change from baseline in HbA1c at Week 18. Pre-specified secondary endpoints included proportion of patients reaching HbA1c <7.0%, change in fasting plasma glucose (FPG), and percent change in body weight; changes in systolic blood pressure (BP) and fasting plasma lipids were also evaluated. Adverse events (AEs) were recorded throughout the study.

Results: From a mean baseline HbA1c of 7.6% (60 mmol/mol), canagliflozin 50 and 150 mg BID significantly reduced HbA1c compared with placebo at Week 18 (-0.45%, -0.61%, -0.01% [-5, -7, -0.1 mmol/mol], respectively; P < 0.001). More patients achieved HbA1c <7.0% with canagliflozin than placebo (P < 0.05). Relative to placebo, both canagliflozin doses significantly lowered FPG and body weight (P < 0.001), and reduced systolic BP. Overall AE incidence was 35.5%, 40.9%, and 36.6% with canagliflozin 50 and 150 mg BID and placebo, respectively. Canagliflozin was associated with increased incidences of urinary tract infections, female genital mycotic infections, and osmotic diuresis-related AEs; these led to few discontinuations. The incidence of documented hypoglycemia was low across groups.

Conclusions: Canagliflozin 50 and 150 mg BID provided significant glycemic efficacy and body weight reduction, and were generally well tolerated in patients with T2DM on background metformin.ClinicalTrials.gov Identifier: NCT01340664.

Keywords: Canagliflozin; Metformin; Sodium glucose co-transporter 2 (SGLT2) inhibitor; Twice daily (BID); Type 2 diabetes mellitus.

Figures

Figure 1

Study flow diagram. PBO, placebo; CANA, canagliflozin; BID, twice daily; AE, adverse event; eGFR, estimated glomerular filtration rate; mITT, modified intent-to-treat.

Figure 2

Changes in efficacy parameters (LOCF). (A) Change in HbA1c over time, (B) mean HbA1c over time, (C) change in HbA1c at Week 18 in patients with baseline HbA1c ≥7.0%, (D) change in FPG over time, and (E) percent change in body weight over time. LOCF, last observation carried forward; FPG, fasting plasma glucose; PBO, placebo; CANA, canagliflozin; BID, twice daily; LS, least squares; SE, standard error; CI, confidence interval. (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/)