Type 2 Diabetes Mellitus
Conditions
Keywords
Dapagliflozin, Metformin, Type 2 diabetes, body weight
Brief summary
This study is being carried out to see if dapagliflozin in addition to metformin decreases body weight and if so, how it compares with metformin alone.
Interventions
DRUGDapagliflozin
Tablet oral 10 mg total daily dose once daily 102 weeks
DRUGMetformin
Tablet oral 1500 - 2500 mg total daily dose 1-3 times a day104 weeks
DRUGSitagliptin
Tablet oral 100 mg total daily dose once daily rescue medication
DRUGPlacebo
Matching placebo for dapagliflozin, tablet, oral, once daily, 102 weeks
Sponsors
Bristol-Myers Squibb
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
30 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Type 2 diabetes * Ongoing treatment with metformin on a stable dose of ≥1500 mg/day for at least 12 weeks prior to enrolment * Inadequate glycemic control, defined as HbA1c ≥6.5% and ≤8.5% * ≥30 years for males * ≥55 years for females
Exclusion criteria
* Type 1 Diabetes * Body weight change \>5% within 3 months prior to enrolment * Renal and liver impairment
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Adjusted Mean Change in Total Body Weight | Baseline to Week 24 | To evaluate the effect of dapagliflozin 10 mg daily in combination with metformin compared to placebo in combination with metformin on total body weight after 24 weeks of oral administration of double-blind treatment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Adjusted Mean Change in Waist Circumference | Baseline to Week 24 | To assess the effect of dapagliflozin 10 mg daily in combination with metformin compared to placebo in combination with metformin after 24 weeks of double-blind treatment on waist circumference. |
| Adjusted Mean Change in Body Fat Mass | Baseline to Week 24 | To assess the effect of dapagliflozin 10 mg daily in combination with metformin compared to placebo in combination with metformin after 24 weeks of double-blind treatment on total body fat mass measured by dual energy X-ray absorptiometry. |
| Proportion of Participants With Body Weight Decrease ≥5% | Baseline to Week 24 | To assess the effect of dapagliflozin 10 mg daily in combination with metformin compared to placebo in combination with metformin after 24 weeks of double-blind treatment on body weight decrease ≥5%. Least Squares Mean represents the percent of participants adjusted for body weight baseline value. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Adjusted Percent Change in Bone Mineral Density (BMD) at Femoral Neck | Baseline to Week 102 | To assess the effect of dapagliflozin 10 mg daily in combination with metformin compared to placebo in combination with metformin after 102 weeks of double-blind treatment on Bone Mineral Density at femoral neck as measured by Dual Energy X-ray Absorptiometry. |
| Adjusted Percent Change in Bone Mineral Density (BMD) at Total Hip | Baseline to Week 102 | To assess the effect of dapagliflozin 10 mg daily in combination with metformin compared to placebo in combination with metformin after 102 weeks of double-blind treatment on Bone Mineral Density at total hip as measured by Dual Energy X-ray Absorptiometry. |
| Adjusted Percent Change in Bone Mineral Density (BMD) at Lumbar Spine (L1-4) | Baseline to Week 102 | To assess the effect of dapagliflozin 10 mg daily in combination with metformin compared to placebo in combination with metformin after 102 weeks of double-blind treatment on Bone Mineral Density at lumbar spine (L1-4) as measured by Dual Energy X-ray Absorptiometry. |
Countries
Bulgaria, Czechia, Hungary, Poland, Sweden
Participant flow
Recruitment details
First participant enrolled: 13 Feb 2009. Last participant completed 24 week period: 03 Jun 2010. 314 participants were enrolled, 182 were randomized in 40 centers in 5 European countries. Men aged 30-75 years and women aged 55-75 years with inadequate glycemic control (HbA1c 6.5% to 8.5%), BMI of at least 25 kg/sqm and body weight \<= 120 kg.
Pre-assignment details
During a placebo lead-in period, participants were counselled on dietary and life-style modifications. The metformin dose was adjusted to open label 1500 mg/day, 2000 mg/day or 2500 mg/day. Neither gender should exceed 60% of the total number of randomized participants.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Plus Metformin Placebo oral once daily plus metformin over 24 weeks | 91 |
| Dapagliflozin Plus Metformin Dapagliflozin 10 mg oral once daily plus metformin over 24 weeks | 89 |
| Total | 180 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Administrative reasons by sponsor | 1 | 0 |
| Overall Study | Adverse Event | 0 | 2 |
| Overall Study | Death | 0 | 1 |
| Overall Study | Poor/non-compliance | 2 | 0 |
| Overall Study | Subject no longer meets study criteria | 1 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 4 |
Baseline characteristics
| Characteristic | Placebo Plus Metformin | Dapagliflozin Plus Metformin | Total |
|---|---|---|---|
| Age Continuous | 60.8 Years STANDARD_DEVIATION 6.82 | 60.6 Years STANDARD_DEVIATION 8.16 | 60.7 Years STANDARD_DEVIATION 7.49 |
| Body Mass Index | 31.68 kg/m2 STANDARD_DEVIATION 3.89 | 32.06 kg/m2 STANDARD_DEVIATION 3.887 | 31.87 kg/m2 STANDARD_DEVIATION 3.882 |
| Body Weight | 90.91 Kilogram STANDARD_DEVIATION 13.716 | 92.06 Kilogram STANDARD_DEVIATION 14.128 | 91.48 Kilogram STANDARD_DEVIATION 13.894 |
| Fasting Plasma Glucose | 149.60 Milligram per deciliter STANDARD_DEVIATION 25.086 | 148.01 Milligram per deciliter STANDARD_DEVIATION 24.65 | 148.82 Milligram per deciliter STANDARD_DEVIATION 24.815 |
| Glycosylated hemoglobin A1c (HbA1c) | 7.16 Percent STANDARD_DEVIATION 0.531 | 7.19 Percent STANDARD_DEVIATION 0.443 | 7.17 Percent STANDARD_DEVIATION 0.489 |
| Race/Ethnicity, Customized White | 91 Participants | 89 Participants | 180 Participants |
| Sex: Female, Male Female | 40 Participants | 40 Participants | 80 Participants |
| Sex: Female, Male Male | 51 Participants | 49 Participants | 100 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 9 / 91 | 7 / 91 |
| serious Total, serious adverse events | 1 / 91 | 6 / 91 |
Outcome results
Primary
Adjusted Mean Change in Total Body Weight
To evaluate the effect of dapagliflozin 10 mg daily in combination with metformin compared to placebo in combination with metformin on total body weight after 24 weeks of oral administration of double-blind treatment.
Time frame: Baseline to Week 24
Population: Full Analysis Set, participants with non-missing baseline and Week 24 (LOCF) values
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Plus Metformin | Adjusted Mean Change in Total Body Weight | -0.88 kg | 95% Confidence Interval 0.2746 |
| Dapagliflozin Plus Metformin | Adjusted Mean Change in Total Body Weight | -2.96 kg | 95% Confidence Interval 0.2766 |
Comparison: H0: mean(treat) minus mean(placebo) = 0 versus the alternative HA: mean(treat) minus mean(placebo) =/= 0p-value: <0.000195% CI: [-2.84, -1.31]ANCOVA
Secondary
Adjusted Mean Change in Body Fat Mass
To assess the effect of dapagliflozin 10 mg daily in combination with metformin compared to placebo in combination with metformin after 24 weeks of double-blind treatment on total body fat mass measured by dual energy X-ray absorptiometry.
Time frame: Baseline to Week 24
Population: Full Analysis Set, participants with non-missing baseline and Week 24 (LOCF) values
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Plus Metformin | Adjusted Mean Change in Body Fat Mass | -0.74 kg | 95% Confidence Interval 0.267 |
| Dapagliflozin Plus Metformin | Adjusted Mean Change in Body Fat Mass | -2.22 kg | 95% Confidence Interval 0.2626 |
Comparison: H0: mean(treat) minus mean(placebo) = 0 versus the alternative HA: mean(treat) minus mean(placebo) =/= 0p-value: 0.000195% CI: [-2.22, -0.74]ANCOVA
Secondary
Adjusted Mean Change in Waist Circumference
To assess the effect of dapagliflozin 10 mg daily in combination with metformin compared to placebo in combination with metformin after 24 weeks of double-blind treatment on waist circumference.
Time frame: Baseline to Week 24
Population: Full Analysis Set, participants with non-missing baseline and Week 24 (LOCF) values
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Plus Metformin | Adjusted Mean Change in Waist Circumference | -0.99 cm | 95% Confidence Interval 0.4349 |
| Dapagliflozin Plus Metformin | Adjusted Mean Change in Waist Circumference | -2.51 cm | 95% Confidence Interval 0.4388 |
Comparison: H0: mean(treat) minus mean(placebo) = 0 versus the alternative HA: mean(treat) minus mean(placebo) =/= 0p-value: 0.014395% CI: [-2.74, -0.31]ANCOVA
Secondary
Proportion of Participants With Body Weight Decrease ≥5%
To assess the effect of dapagliflozin 10 mg daily in combination with metformin compared to placebo in combination with metformin after 24 weeks of double-blind treatment on body weight decrease ≥5%. Least Squares Mean represents the percent of participants adjusted for body weight baseline value.
Time frame: Baseline to Week 24
Population: Full Analysis Set, participants with non-missing baseline and Week 24 (LOCF) values
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo Plus Metformin | Proportion of Participants With Body Weight Decrease ≥5% | 4.3 Percentage of participants |
| Dapagliflozin Plus Metformin | Proportion of Participants With Body Weight Decrease ≥5% | 30.6 Percentage of participants |
Comparison: H0: proportion(treat) minus proportion(placebo) = 0 versus the alternative HA: proportion(treat) minus proportion(placebo) =/= 0p-value: <0.000195% CI: [15.9, 36.7]Regression, Logistic
Other Pre-specified
Adjusted Percent Change in Bone Mineral Density (BMD) at Femoral Neck
To assess the effect of dapagliflozin 10 mg daily in combination with metformin compared to placebo in combination with metformin after 102 weeks of double-blind treatment on Bone Mineral Density at femoral neck as measured by Dual Energy X-ray Absorptiometry.
Time frame: Baseline to Week 102
Population: Safety Analysis Set (all participants who received at least one dose of double-blind study medication)
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo Plus Metformin | Adjusted Percent Change in Bone Mineral Density (BMD) at Femoral Neck | 0.09 Percent |
| Dapagliflozin Plus Metformin | Adjusted Percent Change in Bone Mineral Density (BMD) at Femoral Neck | -0.85 Percent |
Comparison: H0: mean(treat) minus mean(placebo) = 0 versus the alternative HA: mean(treat) minus mean(placebo) =/= 0p-value: 0.152195% CI: [-2.21, 0.35]Mixed Models Analysis
Other Pre-specified
Adjusted Percent Change in Bone Mineral Density (BMD) at Lumbar Spine (L1-4)
To assess the effect of dapagliflozin 10 mg daily in combination with metformin compared to placebo in combination with metformin after 102 weeks of double-blind treatment on Bone Mineral Density at lumbar spine (L1-4) as measured by Dual Energy X-ray Absorptiometry.
Time frame: Baseline to Week 102
Population: Safety Analysis Set (all participants who received at least one dose of double-blind study medication)
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo Plus Metformin | Adjusted Percent Change in Bone Mineral Density (BMD) at Lumbar Spine (L1-4) | 0.47 Percent |
| Dapagliflozin Plus Metformin | Adjusted Percent Change in Bone Mineral Density (BMD) at Lumbar Spine (L1-4) | 0.69 Percent |
Comparison: H0: mean(treat) minus mean(placebo) = 0 versus the alternative HA: mean(treat) minus mean(placebo) =/= 0p-value: 0.701395% CI: [-0.89, 1.34]Mixed Models Analysis
Other Pre-specified
Adjusted Percent Change in Bone Mineral Density (BMD) at Total Hip
To assess the effect of dapagliflozin 10 mg daily in combination with metformin compared to placebo in combination with metformin after 102 weeks of double-blind treatment on Bone Mineral Density at total hip as measured by Dual Energy X-ray Absorptiometry.
Time frame: Baseline to Week 102
Population: Safety Analysis Set (all participants who received at least one dose of double-blind study medication)
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo Plus Metformin | Adjusted Percent Change in Bone Mineral Density (BMD) at Total Hip | -0.37 Percent |
| Dapagliflozin Plus Metformin | Adjusted Percent Change in Bone Mineral Density (BMD) at Total Hip | -0.82 Percent |
Comparison: H0: mean(treat) minus mean(placebo) = 0 versus the alternative HA: mean(treat) minus mean(placebo) =/= 0p-value: 0.310595% CI: [-1.32, 0.43]Mixed Models Analysis