Men and women with type 2 diabetes, aged 18–77 years, were enrolled between September 2007 and July 2008 at 85 sites in the U.S., Canada, Mexico, and Russia. Eligible patients were treatment-naive subjects whose hyperglycemia was inadequately controlled with diet and exercise alone. Entry criteria included BMI ≤45 kg/m2 and fasting C-peptide ≥1.0 ng/ml. Patients were excluded if they had a history of type 1 diabetes, serum creatinine ≥133 μmol/l (men) or ≥124 μmol/l (women), urine albumin-to-creatinine ratio >200 mg/mmol, aspartate transaminase and/or alanine transaminase >3 times the upper limits of normal, creatine kinase ≥3 times the upper limit of normal, symptoms of severely uncontrolled diabetes (including marked polyuria and polydipsia with >10% weight loss during the last 3 months before enrollment); significant renal, hepatic, hematological, oncological, endocrine, psychiatric, or rheumatic diseases, a cardiovascular event (including New York Heart Association class III/IV congestive heart failure) within 6 months of enrollment, and severe uncontrolled blood pressure (systolic blood pressure ≥180 mmHg and/or diastolic blood pressure ≥110 mmHg).
This was a 24-week randomized, parallel-group, double-blind, placebo-controlled phase 3 trial with a 2-week diet/exercise placebo lead-in (1 week for patients with enrollment A1C 10.1–12.0%). The respective institutional review board or independent ethics committee approved the study protocol, and all patients gave informed consent. Patients with A1C 7.0–10% were randomly assigned equally to one of seven arms to receive once-daily placebo or 2.5, 5, or 10 mg dapagliflozin, administered once daily either in the morning (main cohort) or evening (exploratory cohort) for 24 weeks. Patients with A1C 10.1–12% (high-A1C exploratory cohort) were assigned randomly in a 1:1 ratio to receive blinded treatment with a morning dose of 5 or 10 mg/day dapagliflozin (a placebo group was not included because of the high A1C levels). Patients with fasting plasma glucose (FPG) >270 mg/dl at week 4, >240 mg/dl at week 8, or >200 mg/dl at weeks 12–24 were eligible for open-label rescue medication (500 mg metformin, titrated as needed up to 2,000 mg). Patients with A1C >8.0% for 12 weeks despite a maximum tolerated metformin dose were discontinued. Throughout the study, patients received diet/exercise counseling per American Diabetes Association recommendations.
This was a 24-week randomized, parallel-group, double-blind, placebo-controlled phase 3 trial with a 2-week diet/exercise placebo lead-in (1 week for patients with enrollment A1C 10.1–12.0%). The respective institutional review board or independent ethics committee approved the study protocol, and all patients gave informed consent. Patients with A1C 7.0–10% were randomly assigned equally to one of seven arms to receive once-daily placebo or 2.5, 5, or 10 mg dapagliflozin, administered once daily either in the morning (main cohort) or evening (exploratory cohort) for 24 weeks. Patients with A1C 10.1–12% (high-A1C exploratory cohort) were assigned randomly in a 1:1 ratio to receive blinded treatment with a morning dose of 5 or 10 mg/day dapagliflozin (a placebo group was not included because of the high A1C levels). Patients with fasting plasma glucose (FPG) >270 mg/dl at week 4, >240 mg/dl at week 8, or >200 mg/dl at weeks 12–24 were eligible for open-label rescue medication (500 mg metformin, titrated as needed up to 2,000 mg). Patients with A1C >8.0% for 12 weeks despite a maximum tolerated metformin dose were discontinued. Throughout the study, patients received diet/exercise counseling per American Diabetes Association recommendations.
