A Randomized, Double-Blind, Active-Controlled, Multicenter Study to Evaluate the Efficacy, Safety, and Tolerability of Canagliflozin Versus Sitagliptin in the Treatment of Subjects With Type 2 Diabetes Mellitus With Inadequate Glycemic Control on Metformin and Sulphonylurea Therapy

* Man or woman *18 years of age with T2DM and currently treated with metformin and an SU
* Meet the following HbA1c eligibility criteria:
HbA1c at least 7.0% and less than 10.5% and on Metformin at least 2,000 mg/day (or at least 1,500 mg/day if intolerant of higher dose); and SU on specific dose* FPG <300 mg/dL (16.7 mmol/L) at Week -2
Note: at the investigator*s discretion, based upon review of recent SMBG values, subjects not meeting the Week -2 FPG criterion may return to the investigational site within 7 days for a one-time repeat FPG and continue in the study if the subject*s repeat FPG meets the criterion
* Site fasting fingerstick glucose of at least 110 mg/dL (6.1 mmol/L) on Day 1
Note: at the investigator*s discretion, based upon review of recent SMBG values, subjects not meeting the Day 1 criterion may return to the investigational site within 7 days for a one-time repeat fingerstick glucose and continue in the study if the subject*s repeat fingerstick glucose meets the criterion
* Women must be:
* postmenopausal, defined as
* >45 years of age with amenorrhea for at least 18 months, or
* >45 years of age with amenorrhea for at least 6 months and *18 months and a serum follicle stimulating hormone (FSH) level >40 IU/mL, or
* surgically sterile (have had a hysterectomy, bilateral oophorectomy, or tubal ligation) or otherwise be incapable of pregnancy, or
* heterosexually active and practicing a highly effective method of birth control, including hormonal prescription oral contraceptives, contraceptive injections, contraceptive patch, intrauterine device, double-barrier method (eg, condoms, diaphragm, or cervical cap with spermicidal foam, cream, or gel), or male partner sterilization, and consistent with local regulations regarding use of birth control methods for subjects participating in clinical trials, for the duration of their participation in the study, or
* not heterosexually active
Note: subjects who are not heterosexually active at screening must agree to utilize a highly effective method of birth control if they become heterosexually active during their participation in the study.
* Women of childbearing potential must have a negative urine beta human chorionic gonadotropin (beta hCG) pregnancy test at screening and baseline (predose, Day 1)
* Willing and able to adhere to the prohibitions and restrictions specified in this protocol
* Subjects must have signed an informed consent document indicating that they understand the purpose of and procedures required for the study and are willing to participate in the study
* To participate in the optional pharmacogenomic component of this study, subjects must have signed the informed consent form for pharmacogenomic research indicating willingness to participate in the pharmacogenomic component of the study (where local regulations permit). Refusal to give consent for this component does not exclude a subject from participation in the clinical study
* Adequate compliance with the run in period study procedures, including performance of the SMBG measurements (completed at least 3 or more SMBG measurements per week) with appropriate diary entries, and at least 80% compliance (by pill count) with single-blind placebo capsules

* History of diabetic ketoacidosis, T1DM, pancreas or beta cell transplantation, or diabetes secondary to pancreatitis or pancreatectomy
* Repeated (ie, 2 or more over a 1 week period) FPG and/or fasting SMBG measurements higher than or equal to 300 mg/dL (16.7 mmol/L) during the pretreatment phase, despite reinforcement of diet and exercise counseling
* Have proliferative diabetic retinopathy for which treatment is planned during the course of the study
* History of 1 or more severe hypoglycemic episode within 6 months before screening.
Note: a severe hypoglycemic episode is defined as an event that requires the help of another person (refer to Attachment 4, Hypoglycemia: Definitions, Symptoms, and Treatment, for a definition of severe hypoglycemia)
* History of hereditary glucose-galactose malabsorption or primary renal glucosuria
* Ongoing, inadequately controlled thyroid disorder (eg, subject has a known thyroid stimulating hormone [TSH] value that is either <0.2 or >10 mIU/L)
Note: subjects on thyroid hormone replacement therapy must be on stable doses for at least 6 weeks prior to Day 1
* On either a PPAR* agonist (eg, a thiazolidinedione [pioglitazone or rosiglitazone]) or ongoing insulin therapy within 12 weeks before the screening visit
Note: subjects who have been treated with only a single dose of insulin may participate.
* Ongoing eating disorder or significant weight loss or weight gain within 12 weeks before the screening visit, defined as an increase or decrease of 5% in body weight based upon clinic-based measurement or, if not available, subject report
Renal/Cardiovascular
* Renal disease that required treatment with immunosuppressive therapy or a history of dialysis or renal transplant
Note: subjects with a history of treated childhood renal disease, without sequelae, may participate
* Myocardial infarction, unstable angina, revascularization procedure (eg, stent or bypass graft surgery), or cerebrovascular accident within 3 months before screening, or revascularization procedure is planned, or subject has a history of New York Heart Association (NYHA) Class III-IV cardiac disease (refer to Attachment 5, New York Heart Association Classification of Cardiac Disease, for a description of the classes)
* Findings on 12-lead ECG that would require urgent diagnostic evaluation or intervention (eg, new clinically important arrhythmia or conduction disturbance)
* Uncontrolled hypertension (ie, using an average of 3 seated blood pressure readings with a diastolic blood pressure *100 mmHg or systolic blood pressure *160 mmHg) at Week -2
Note: subjects may have their blood pressure lowering medication regimen adjusted and be re-evaluated to assess this criterion
Gastrointestinal
* History of hepatitis B surface antigen or hepatitis C antibody positive (unless associated with documented persistently stable/normal range aspartate aminotransferase [AST] and ALT levels), or other clinically active liver disease
* History of prior bariatric surgical procedure within 3 years before the screening visit
Note: subjects with bariatric surgery more than 3 years before screening must be at a stable weight to be eligible to participate
Laboratory
* Estimated glomerular filtration rate (eGFR) <55 mL/min/1.73 m2 or serum creatinine *1.4 mg/dL (124 micromol/L) for men and higer than or equal to 1.3 mg/dL (115 micro mol/L) for women
* Estimated glomerular filtration rate (eGFR) <55 mL/min/1.73 m2 (or <60 mL/min/1.73 m2 if based upon restriction of metformin use in the metformin local label) or serum creatinine > or = 1.4 mg/dL (124 micromol/L) for men and > or= 1.3 mg/dL (115 micromol/L) for women
* Fasting serum triglycerides higer than or equal to 600 mg/dL (6.74 mmol/L) at screening (or subsequent visit if not fasting at screening)
Note: a one-time repeat of the serum triglycerides is allowed, at the discretion of the investigator, if the screening value is not consistent with recent values
* Alanine aminotransferase level >2.0 times the ULN or total bilirubin >1.5 times the ULN at screening (for elevations in bilirubin: if, in the opinion of the investigator and agreed upon by the sponsor*s medical officer, the elevation in bilirubin is consistent with Gilbert*s disease, the subject may participate)
Other conditions
* History of malignancy within 5 years before screening (eg, any evidence of active disease within 5 years, or diagnosis of malignancy within this period)
Note: subjects with squamous or basal cell carcinomas of the skin, carcinomas in situ of the cervix, or a malignancy that in the opinion of the investigator, with concurrence with the sponsor*s medical monitor, is considered cured with minimal risk of recurrence, may participate.
* Clinically important hematologic disorder (eg, symptomatic anemia, proliferative bone marrow disorder, thrombocytopenia) or an abnormality of hemoglobin such that a HbA1c cannot be accurately measured (as reported by the central laboratory)
* History of positive human immunodeficiency virus (HIV) antibody
* Investigator*s assessment that the subject*s life expectancy is less than 1 year
* Any condition that in the opinion of the investigator would make participation not in the best interest of the subject, or could prevent, limit, or confound the protocol specified assessments
* Major surgery (ie, requiring general anesthesia) within 12 weeks before screening, or has not fully recovered from surgery, or planned surgery during the time the subject is expected to participate in the study
Note: subjects with planned surgical procedures to be conducted under local anesthesia may participate
Medications/Therapies
* Current use of a disallowed therapy:
* Any other SGLT2 inhibitor
* Antihyperglycemic agents (including agents such as colesevelam and bromocriptine that have indications in some regions for treatment of T2DM) except as indicated in the study inclusion criteria
* Subjects receiving antihypertensive or antihyperlipidemic therapy not on a stable regimen (same medication and dose[s]) for at least 4 weeks before Day 1
* Known allergies, hypersensitivity, or intolerance to canagliflozin or its excipients (refer to Section 14.1, Physical Description of Study Drugs)
* Contraindication to the use of metformin, an SU, or sitagliptin (per local prescribing information)
Note: investigators should be aware of restrictions/contraindications to the use of these agents in the local label. Subjects who do not meet, but have screening laboratory results only slightly above (eg, for eGFR) local label restrictions on use should be enrolled in the study only if the investigator believes that it is unlikely that the subject would have a change in status such that they developed a contraindication to the use of either agent during the subject*s participation in the study.
* Current use of a corticosteroid medication or immunosuppressive agent, or likely to require treatment with a corticosteroid medication (for longer than 2 weeks in duration) or an immunosuppressive agent
Note: subjects using inhaled, intranasal, intra-articular, or topical corticosteroids, or corticosteroids in therapeutic replacement doses may participate.
* Received an investigational drug (including vaccines), other than a placebo agent, or used an investigational medical device within 3 months before the planned start of treatment or received 1 or more doses of canagliflozin in a prior study
General
* History of drug or alcohol abuse within 3 years before screening
* Pregnant or breast-feeding or planning to become pregnant or breast-feed during the study
* Employees of the investigator or study site, with direct involvement in the proposed study or other studies under the direction of that investigator or study site, as well as family members of the employees or the investigator;Note: investigators should assure that all study enrollment criteria have been met and determine that the subject has not had any interval change in clinical status since screening. Before randomization, subjects whose status changes after screening (including based upon laboratory study results), such that they now meet an exclusion criterion, should be excluded from participation.