Dose-Ranging Study in Treatment Naive Type 2 Diabetes Mellitus(T2DM)

Inclusion criteria

• Subjects with a documented diagnosis of T2DM and have an HbA1c level at Visit 1 of ≥7.0% and ≤9.5% as measured by a central laboratory. Subjects with HbA1c 45 years, in the absence of hormone replacement therapy. In addition to the above criteria, if the post-menopausal status is still questionable, a blood sample should be drawn for simultaneous measurement of follicle stimulating hormone and estradiol; values considered to confirm the post-menopausal state are respectively: FSH >40 MIU/mL and estradiol 5.5 mIU/L at Screening]. Hypothyroidism treated with the same dose and regimen of thyroid hormone replacement for at least 3 months prior to Screening is allowed.
• BMI of 43 kg/m2.
• Significant weight gain or loss (as defined as >5% of total body weight) in the 3 months prior to Screening.
• Diabetic Medication
• Has taken insulin or any oral or injectable anti-diabetic medication ≥4 weeks at any time prior to screening.
• Has taken insulin or any oral or injectable anti-diabetic medication within 3 months of screening.
• Cardiovascular Disease
• Recent history or presence of clinically significant acute cardiovascular disease including:
• Documented myocardial infarction in the 6 months prior to Screening.
• Coronary revascularization including percutaneous transluminal coronary angioplasty (PTCA) or coronary artery bypass graft (CABG) surgery either planned and/or occurred in the 6 months prior to Screening.
• Unstable angina in the 6 months prior to Screening.
• Clinically significant supraventricular arrhythmias requiring medical therapy, or history of nonsustained or sustained ventricular tachycardia. Symptomatic valvular heart disease or valvular heart disease requiring therapy other than endocarditis prophylaxis.
• Congestive heart failure (CHF, New York Heart Association (NYHA) Class II to IV) requiring pharmacologic treatment. NYHA Class I may be included in accordance with the local prescribing information for pioglitazone.
• Blood pressure (BP) >150/100mmHg. If a subject is receiving permitted antihypertensive therapy, then they must be on stable dose(s) of therapy for at least 4 weeks prior to Screening.
• Has a QTc interval (Bazett's) ≥450msec at Screening on a single ECG or an average value from 3 ECGs taken 5 minutes apart (on local reading of ECG).
• Other clinically significant ECG abnormalities which, in the opinion of the investigator, may affect the interpretation of efficacy and safety data, or which otherwise contraindicates participation in a clinical trial with a new chemical entity.
• Fasting triglycerides ≥400mg/dL (4.56mmol/L) at Screening. If a subject is receiving permitted lipid-lowering therapy, then they must be on a stable dose(s) of therapy for at least 6 weeks prior to Screening. Niacin and bile acid sequestrants are prohibited.
• Hepatic Disease

Has a diagnosis of active hepatitis (hepatitis B surface antigen or hepatitis C antibody), or clinically significant hepatic enzyme elevation including:

Any one of the following enzymes greater than 2 times the upper limit of the reference range (ULRR) value at Screening.

• alanine transaminase (ALT).
• aspartate transaminase (AST).
• alkaline phosphatase (AP). Has a total bilirubin level that is >1.5 times the ULRR at Screening with the exception of suspected or confirmed Gilbert's disease.
• Pancreatic Disease
• Secondary causes of diabetes:
• history of chronic or acute pancreatitis
• Renal Disease
• Significant renal disease at Screening as manifested by:

Glomerular filtration rate (GFR) <60mL/min (as estimated from serum creatinine at Visit 1 and demographic data using the MDRD equation).For the MDRD equation, please refer to the study procedures manual.

Proteinuria of ≥1+ by urinary dipstick

• Recurrent genitourinary tract infections defined as ≥2 episodes of complicated or uncomplicated cystitis or pyelonephritis in the 6 months prior to Screening
• A positive qualitative urinary dipstick for leukocy