ORIGINAL ARTICLE
original article
Diabetes, Obesity and Metabolism 17: 42–51, 2015. © 2014 John Wiley & Sons Ltd
Twice-daily dapagliflozin co-administered with metformin in type 2 diabetes: a 16-week randomized, placebo-controlled clinical trial P.-M. Schumm-Draeger1 , L. Burgess2 , L. Korányi3 , V. Hruba4 , J. E. Hamer-Maansson5 & T. W. A. de Bruin6 1 Clinic for Endocrinology, Diabetology, Angiology, Academic Teaching Hospital, Munich, Germany 2 TREAD Research, Cardiology Unit, Department of Internal Medicine, Tygerberg Hospital and Stellenbosch University, Parow, South Africa 3 Clinical Pharmacology Unit, Drug Research Center Gyógyszervizsgáló Központ, Balatonfüred, Hungary 4 Global Medicines Department, AstraZeneca, Prague, Czech Republic 5 Biostatistics Department, AstraZeneca R&D, Wilmington, DE, USA 6 Global Medicines Department, AstraZeneca, Gaithersburg, MD, USA
Aims: To evaluate the efficacy and safety of twice-daily dosing of dapagliflozin and metformin, exploring the feasibility of a fixed-dose combination. Methods: In this 16-week, phase III, randomized, double-blind placebo-controlled study, adults who were receiving metformin administered twice daily (≥1500 mg/day) and had inadequate glycaemic control were randomized 1 : 1 : 1 : 1 to receive dapagliflozin twice daily (2.5 or 5 mg), placebo or dapagliflozin 10 mg once daily (which was included as a benchmark). The primary endpoint was change from baseline glycated haemoglobin (HbA1c) level. Secondary endpoints included changes in fasting plasma glucose (FPG) level and body weight. Results: Four hundred adults were randomized to dapagliflozin (2.5 mg twice daily, 5 mg twice daily, 10 mg once daily) or placebo co-administered with metformin twice daily. At 16 weeks, the adjusted mean change in HbA1c from baseline was significantly reduced in the dapagliflozin 2.5 mg twice daily and 5 mg twice daily groups versus placebo (−0.52 vs. −0.30%, p = 0.0106 and −0.65% vs. −0.30%, p < 0.0001). There were also significantly greater improvements for dapagliflozin twice daily groups versus placebo in FPG body weight and achievement of HbA1c level of 15.0 mmol/l); renal disorders, including a calculated creatinine clearance (CrCl) 1800 mg/g; hepatic disorders, including hepatotoxicity with any medication; a recent cardiovascular event or New York Heart Association class III or IV congestive heart failure; blood pressure ≥160/≥100 mmHg at randomization; and clinically significant haematological or oncological conditions.
Treatments After initial screening and a 1-week enrolment period, there was a 4-week lead-in period. During this period, patients continued their metformin treatment and received placebo twice daily; metformin study medication was adjusted to 1500, 2000 or 2500 mg/day according to a prespecified adjustment table. Diet and lifestyle advice was provided to enhance glycaemic control; this was reinforced at each study visit. Patients were stratified by HbA1c levels at randomization: group 1 had HbA1c levels ≥6.5 and 15.0 mmol/l during first 4 weeks of treatment period, FPG >13.2 mmol/l from weeks 4 to 8, FPG >11.1 mmol/l from weeks 12 to 16) were discontinued from the study; an increase in metformin dosing was not allowed. Concomitant, non-antidiabetic medications (e.g. antihypertensive, diuretic and lipid-lowering drugs) were allowed, but changes in dosing were not allowed during the trial unless medically necessary. Upon completion of active study treatment, patients were monitored for 4 weeks to evaluate changes in physical signs, symptoms or laboratory variables that might be related to treatment with dapagliflozin. The last study visit followed this period.
Objectives and Assessments The primary efficacy objective was to compare the change from baseline in HbA1c achieved with dapagliflozin 2.5 mg twice daily and 5 mg twice daily co-administered with metformin versus placebo co-administered with metformin after 16 weeks of treatment. Key secondary endpoints included the percent change from baseline in body weight, change from baseline in FPG at weeks 1 and 16 and proportion of patients with HbA1c levels ≥7% at baseline achieving HbA1c levels
original article
Diabetes, Obesity and Metabolism 17: 42–51, 2015. © 2014 John Wiley & Sons Ltd
Twice-daily dapagliflozin co-administered with metformin in type 2 diabetes: a 16-week randomized, placebo-controlled clinical trial P.-M. Schumm-Draeger1 , L. Burgess2 , L. Korányi3 , V. Hruba4 , J. E. Hamer-Maansson5 & T. W. A. de Bruin6 1 Clinic for Endocrinology, Diabetology, Angiology, Academic Teaching Hospital, Munich, Germany 2 TREAD Research, Cardiology Unit, Department of Internal Medicine, Tygerberg Hospital and Stellenbosch University, Parow, South Africa 3 Clinical Pharmacology Unit, Drug Research Center Gyógyszervizsgáló Központ, Balatonfüred, Hungary 4 Global Medicines Department, AstraZeneca, Prague, Czech Republic 5 Biostatistics Department, AstraZeneca R&D, Wilmington, DE, USA 6 Global Medicines Department, AstraZeneca, Gaithersburg, MD, USA
Aims: To evaluate the efficacy and safety of twice-daily dosing of dapagliflozin and metformin, exploring the feasibility of a fixed-dose combination. Methods: In this 16-week, phase III, randomized, double-blind placebo-controlled study, adults who were receiving metformin administered twice daily (≥1500 mg/day) and had inadequate glycaemic control were randomized 1 : 1 : 1 : 1 to receive dapagliflozin twice daily (2.5 or 5 mg), placebo or dapagliflozin 10 mg once daily (which was included as a benchmark). The primary endpoint was change from baseline glycated haemoglobin (HbA1c) level. Secondary endpoints included changes in fasting plasma glucose (FPG) level and body weight. Results: Four hundred adults were randomized to dapagliflozin (2.5 mg twice daily, 5 mg twice daily, 10 mg once daily) or placebo co-administered with metformin twice daily. At 16 weeks, the adjusted mean change in HbA1c from baseline was significantly reduced in the dapagliflozin 2.5 mg twice daily and 5 mg twice daily groups versus placebo (−0.52 vs. −0.30%, p = 0.0106 and −0.65% vs. −0.30%, p < 0.0001). There were also significantly greater improvements for dapagliflozin twice daily groups versus placebo in FPG body weight and achievement of HbA1c level of 15.0 mmol/l); renal disorders, including a calculated creatinine clearance (CrCl) 1800 mg/g; hepatic disorders, including hepatotoxicity with any medication; a recent cardiovascular event or New York Heart Association class III or IV congestive heart failure; blood pressure ≥160/≥100 mmHg at randomization; and clinically significant haematological or oncological conditions.
Treatments After initial screening and a 1-week enrolment period, there was a 4-week lead-in period. During this period, patients continued their metformin treatment and received placebo twice daily; metformin study medication was adjusted to 1500, 2000 or 2500 mg/day according to a prespecified adjustment table. Diet and lifestyle advice was provided to enhance glycaemic control; this was reinforced at each study visit. Patients were stratified by HbA1c levels at randomization: group 1 had HbA1c levels ≥6.5 and 15.0 mmol/l during first 4 weeks of treatment period, FPG >13.2 mmol/l from weeks 4 to 8, FPG >11.1 mmol/l from weeks 12 to 16) were discontinued from the study; an increase in metformin dosing was not allowed. Concomitant, non-antidiabetic medications (e.g. antihypertensive, diuretic and lipid-lowering drugs) were allowed, but changes in dosing were not allowed during the trial unless medically necessary. Upon completion of active study treatment, patients were monitored for 4 weeks to evaluate changes in physical signs, symptoms or laboratory variables that might be related to treatment with dapagliflozin. The last study visit followed this period.
Objectives and Assessments The primary efficacy objective was to compare the change from baseline in HbA1c achieved with dapagliflozin 2.5 mg twice daily and 5 mg twice daily co-administered with metformin versus placebo co-administered with metformin after 16 weeks of treatment. Key secondary endpoints included the percent change from baseline in body weight, change from baseline in FPG at weeks 1 and 16 and proportion of patients with HbA1c levels ≥7% at baseline achieving HbA1c levels
