Canaglif lozin Provides Durable Glycemic Improvements and Body Weight Reduction Over 104 Weeks Versus Glimepiride in Patients With Type 2 Diabetes on Metformin: A Randomized, Double-Blind, Phase 3 Study Diabetes Care 2015;38:355–364 | DOI: 10.2337/dc13-2762 OBJECTIVE To assess the efficacy/safety of canagliflozin, a sodium–glucose cotransporter 2 inhibitor, compared with glimepiride over 104 weeks in patients with type 2 di- abetes inadequately controlled with metformin. RESEARCH DESIGN AND METHODS In this randomized, double-blind study, patients (N = 1,450) received canagliflozin 100 or 300 mg or glimepiride (titrated up to 6 or 8 mg/day) during a 52-week core period followed by a 52-week extension. RESULTS At week 104, reductions from baseline in A1C were 20.65%, 20.74%, and 20.55% (27.1, 28.1, and 26.0 mmol/mol) with canagliflozin 100 and 300 mg and glime- piride, respectively. Durability analyses showed sustained A1C lowering with both canagliflozin doses versus glimepiride. Reductions in body weight (24.1%, 24.2%, and 0.9%, respectively) and systolic blood pressure (22.0, 23.1, and 1.7 mmHg, respectively) were seen with canagliflozin 100 and 300 mg compared with glime- piride at week 104. The overall adverse event (AE) incidence was 73.3%, 77.9%, and 78.4% with canagliflozin 100 and 300 mg and glimepiride; the incidence of AE-related discontinuations was low across groups (6.2%, 9.5%, and 7.3%, respec- tively). Incidences of genital mycotic infections, urinary tract infections, and osmotic diuresis–related AEs were higher with canagliflozin than glimepiride; these were generally mild to moderate in intensity and led to few discontinua- tions. Fewer patients had hypoglycemia episodes with canagliflozin 100 and 300 mg than glimepiride (6.8%, 8.2%, and 40.9%). Mild decreases in estimated glo- merular filtration rate occurred initially with canagliflozin; these attenuated over 104 weeks. CONCLUSIONS Canagliflozin provided durable glycemic improvements compared with glimepiride and was generally well tolerated in patients with type 2 diabetes receiving background treatment with metformin over 104 weeks. 1 Keenan Research Centre, The Li Ka Shing Knowl- edge Institute, St. Michael’s Hospital; Division of Endocrinology and Metabolism, University of Toronto, Toronto, Ontario, Canada 2 Department of Endocrinology & Metabolism, Seoul St. Mary’s Hospital, The Catholic University of Korea, Seoul, South Korea 3 University of Rosario Medical School, Rosario, Argentina 4 Litoral University Medical School, Santa Fe, Argentina 5 Lipid Clinic, Oslo University Hospital, Oslo, Norway 6 Janssen Research & Development, LLC, Raritan, NJ 7 Janssen Research & Development, Beerse, Belgium Corresponding author: Lawrence A. Leiter, leiterl@smh.ca. Received 25 November 2013 and accepted 5 July 2014. Clinical trial reg. no. NCT00968812, clinicaltrials .gov. This article contains Supplementary Data online at http://care.diabetesjournals.org/lookup/ suppl/doi:10.2337/dc13-2762/-/DC1. © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See accompanying articles, pp. 352, 365, 373, 376, 384, 394, 403, 412, 420, 429, and 431. Lawrence A. Leiter, 1 Kun-Ho Yoon, 2 Pablo Arias, 3,4 Gisle Langslet, 5 John Xie, 6 Dainius A. Balis, 6 Dawn Millington, 6 Frank Vercruysse, 7 William Canovatchel, 6 and Gary Meininger 6 Diabetes Care Volume 38, March 2015 355 INHIBITION OF SODIUM–GLUCOSE COTRANSPORTERS