December 2013, Volume 56, Issue 12, pp 2582-2592,
Open Access This content is freely available online to anyone, anywhere at any time.
Date: 13 Sep 2013
Efficacy and safety of canagliflozin compared with placebo and sitagliptin in patients with type 2 diabetes on background metformin monotherapy: a randomised trial
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.
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.
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.
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
This study was supported by Janssen Research & Development, LLC.
American Diabetes Association (2012) Standards of medical care in diabetes—2012. Diabetes Care 35:S11–S63CrossRef
Inzucchi SE, Bergenstal RM, Buse JB et al (2012) Management of hyperglycaemia in type 2 diabetes: a patient-centered approach. Position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetologia 55:1577–1596, Erratum in 56:680PubMedCrossRef
National Institute for Health and Clinical Excellence (2009) Type 2 diabetes: newer agents for blood glucose control in type 2 diabetes. NICE short clinical guideline 87. NICE, London
Schernthaner G, Gross JL, Rosenstock J et al (2013) Canagliflozin compared with sitagliptin for patients with type 2 diabetes who do not have adequate glycemic control with metformin plus sulfonylurea: a 52-week, randomized trial. Diabetes Care 36:2508–2515
Cefalu WT, Leiter LA, Yoon K-H et al (2013) Canagliflozin promotes body weight loss compared with glimepiride while providing glycaemic efficacy in subjects with type 2 diabetes on background metformin: 52-week findings from a randomised, double-blind trial. Lancet. doi:10.1016/S0140-6736(13)60683-2
Bode B, Stenlof K, Sullivan D, Fung A, Usiskin K (2013) Efficacy and safety of canagliflozin in older subjects with type 2 diabetes: a randomized trial. Hosp Pract 41:72–84CrossRef
Ferrannini E, Seman L, Seewaldt-Becker E, Hantel S, Pinnetti S, Woerle HJ (2013) A phase IIb, randomized, placebo-controlled study of the SGLT2 inhibitor empagliflozin in patients with type 2 diabetes. Diabetes Obes Metab 15:721–728
Food and Drug Administration (2008) Guidance for industry. Diabetes mellitus: developing drugs and therapeutic biologics for treatment and prevention. FDA, Rockville, MD
European Medicines Agency, Committee for Medicinal Products for Human Use (CHMP) (2012) Guideline on clinical investigation of medicinal products in the treatment or prevention of diabetes mellitus. CPMP/EWP/1080/00 Rev. 1. EMA, London
Weidmann P, de Courten M, Ferrari P (1992) Effect of diuretics on the plasma lipid profile. Eur Heart J 13(Suppl G):61–67
Nicolle LE, Capuano G, Fung A, Usiskin K (2013) Urinary tract infection (UTI) with canagliflozin (CANA) in subjects with type 2 diabetes mellitus (T2DM). Diabetes 62:A296 (Abstract)
Nauck MA, Meininger G, Sheng D, Terranella L, Stein PP (2007) Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, compared with the sulfonylurea, glipizide, in patients with type 2 diabetes inadequately controlled on metformin alone: a randomized, double-blind, non-inferiority trial. Diabetes Obes Metab 9:194–205PubMedCrossRef
- Efficacy and safety of canagliflozin compared with placebo and sitagliptin in patients with type 2 diabetes on background metformin monotherapy: a randomised trial
- Open Access
- Available under Open Access This content is freely available online to anyone, anywhere at any time.
Volume 56, Issue 12 , pp 2582-2592
- Cover Date
- Print ISSN
- Online ISSN
- Springer Berlin Heidelberg
- Additional Links
- Sodium glucose co-transporter 2 (SGLT2) inhibitor
- Type 2 diabetes mellitus
- Industry Sectors
- Author Affiliations
- 1. Endocrinology and Internal Medicine Department, Universidad Autonóma de Nuevo León, Avenida Madero y Gonzalitos, S/N Col. Mitras Centro, 64460, Monterrey, Nuevo León, Mexico
- 2. Department of Hypertension, Institute of Cardiology, Warsaw, Poland
- 3. Department of Medicine, University of Texas Southwestern Medical School, Dallas, TX, USA
- 4. Janssen Research & Development, LLC, Raritan, NJ, USA