Type 2 Diabetes
Conditions
Keywords
Dapagliflozin, efficacy, safety, metformin, Type 2 diabetes
Brief summary
This study is being carried out to see if dapagliflozin as an addition to metformin is effective and safe in treating patients with type 2 diabetes when compared to glipizide (sulphonylurea) as an addition to metformin treatment.
Interventions
DRUGdapagliflozin
Tablet oral 2.5, 5, or 10 mg total daily dose once daily 208 weeks
DRUGglipizide
Capsule oral 5, 10, or 20 mg total daily dose once or split/twice daily 208 weeks
DRUGmetformin hydrochloride
Tablet oral 1500, 2000, or 2500 mg total daily dose split/twice daily 218 weeks
Sponsors
Bristol-Myers Squibb
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Type 2 Diabetes * Treated with oral anti-diabetic drug therapy therapy including Metformin for at least 8 weeks prior to enrolment * HbA1c \>6.5% and \</=10%
Exclusion criteria
* Type 1 Diabetes * Insulin therapy within one year of enrolment * Renal (kidney) failure or dysfunction
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Adjusted Mean Change in HbA1c Levels | Baseline to Week 52 | To assess the effect of dapagliflozin plus metformin compared to glipizide plus metformin on the absolute change from baseline in HbA1c level after 52 weeks double-blind treatment in patients with type 2 diabetes who have inadequate glycaemic control on 1500 mg/day or higher doses of metformin therapy alone. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Adjusted Mean Change in Body Weight | Baseline to Week 52 | To assess the effect of dapagliflozin plus metformin compared to glipizide plus metformin on body weight after 52 weeks double-blind treatment. |
| Proportion of Participants With at Least One Episode of Hypoglycemia | Baseline to Week 52 | To assess the effect of dapagliflozin plus metformin treatment compared to glipizide plus metformin on the occurrence of hypoglycemic events. Least Squares Mean represents the percent of participants adjusted for HbA1c baseline value. |
| Proportion of Participants With Body Weight Reduction of at Least 5% | Baseline to Week 52 | To evaluate the effect of dapagliflozin plus metformin compared to glipizide plus metformin on body weight assessed by a reduction after 52 weeks of at least 5% compared to baseline. Least Squares Mean represents the percent of participants adjusted for baseline value. |
Countries
Argentina, France, Germany, Italy, Mexico, Netherlands, South Africa, Spain, Sweden, United Kingdom
Participant flow
Recruitment details
The 1st patient was enrolled on 31 Mar 2008. The last patient last visit was on 15 Dec 2009. 1901 patients (pts) were screened and 1217 pts were enrolled with the aim to randomize 816. 2 randomized pts were excluded since they received no medication. Eventually, 814 pts received medication. This study was conducted at 95 centers world-wide.
Pre-assignment details
For participants with a metformin dose of less than 1500 mg/day, a change in metformin dose in the past 8 weeks or on an Oral Anti-Diabetic (OAD), an 8-week metformin-only dose stabilisation period occurred. A 2-week placebo lead in period occurred after the dose stabilisation period or after enrolment if dose stabilisation period was skipped.
Participants by arm
| Arm | Count |
|---|---|
| Dapagliflozin Plus Metformin Experimental dapagliflozin plus metformin | 400 |
| Glipizide Plus Metformin Active Comparator glipizide plus metformin | 401 |
| Total | 801 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 33 | 19 |
| Overall Study | Death | 1 | 3 |
| Overall Study | Incorrect Enrollment | 1 | 1 |
| Overall Study | Lost to Follow-up | 3 | 3 |
| Overall Study | Poor/Non-Compliance | 5 | 1 |
| Overall Study | Safety | 1 | 0 |
| Overall Study | Subject No Longer Meets Study Criteria | 6 | 27 |
| Overall Study | Various | 11 | 8 |
| Overall Study | Withdrawal by Subject | 23 | 32 |
Baseline characteristics
| Characteristic | Glipizide Plus Metformin | Total | Dapagliflozin Plus Metformin |
|---|---|---|---|
| Age, Continuous | 58.6 years STANDARD_DEVIATION 9.8 | 58.4 years STANDARD_DEVIATION 9.58 | 58.1 years STANDARD_DEVIATION 9.37 |
| BMI | 31.23 kg/m2 STANDARD_DEVIATION 5.053 | 31.47 kg/m2 STANDARD_DEVIATION 5.081 | 31.71 kg/m2 STANDARD_DEVIATION 5.104 |
| FPG | 163.91 ng/mL STANDARD_DEVIATION 41.559 | 163.07 ng/mL STANDARD_DEVIATION 39.708 | 162.24 ng/mL STANDARD_DEVIATION 37.796 |
| HbA1c | 7.74 percent STANDARD_DEVIATION 0.886 | 7.72 percent STANDARD_DEVIATION 0.87 | 7.69 percent STANDARD_DEVIATION 0.855 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 34 Participants | 61 Participants | 27 Participants |
| Race/Ethnicity, Customized Black or African American | 24 Participants | 50 Participants | 26 Participants |
| Race/Ethnicity, Customized More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Unknown or Not Reported | 20 Participants | 40 Participants | 20 Participants |
| Race/Ethnicity, Customized White | 323 Participants | 650 Participants | 327 Participants |
| Sex: Female, Male Female | 181 Participants | 360 Participants | 179 Participants |
| Sex: Female, Male Male | 220 Participants | 441 Participants | 221 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 163 / 406 | 260 / 408 |
| serious Total, serious adverse events | 35 / 406 | 46 / 408 |
Outcome results
Primary
Adjusted Mean Change in HbA1c Levels
To assess the effect of dapagliflozin plus metformin compared to glipizide plus metformin on the absolute change from baseline in HbA1c level after 52 weeks double-blind treatment in patients with type 2 diabetes who have inadequate glycaemic control on 1500 mg/day or higher doses of metformin therapy alone.
Time frame: Baseline to Week 52
Population: Full Analysis Set, participants with non-missing baseline and Week 52 (LOCF) values
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Dapagliflozin Plus Metformin | Adjusted Mean Change in HbA1c Levels | -0.52 percent |
| Glipizide Plus Metformin | Adjusted Mean Change in HbA1c Levels | -0.52 percent |
Comparison: The null hypothesis is given as H0: mean(treat) minus mean(reference) \>= delta versus the alternative HA: mean(treat) minus mean(reference) \< delta (with alpha = 0.025, one-sided)p-value: <0.000195% CI: [-0.11, 0.11]ANCOVA
Secondary
Adjusted Mean Change in Body Weight
To assess the effect of dapagliflozin plus metformin compared to glipizide plus metformin on body weight after 52 weeks double-blind treatment.
Time frame: Baseline to Week 52
Population: Full Analysis Set, participants with non-missing baseline and Week 52 (LOCF) values
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Dapagliflozin Plus Metformin | Adjusted Mean Change in Body Weight | -3.22 kg |
| Glipizide Plus Metformin | Adjusted Mean Change in Body Weight | 1.44 kg |
Comparison: H0: mean(treat) minus mean(reference) = 0 versus the alternative HA: mean(treat) minus mean(reference) =/= 0p-value: <0.000195% CI: [-5.14, -4.17]ANCOVA
Secondary
Proportion of Participants With at Least One Episode of Hypoglycemia
To assess the effect of dapagliflozin plus metformin treatment compared to glipizide plus metformin on the occurrence of hypoglycemic events. Least Squares Mean represents the percent of participants adjusted for HbA1c baseline value.
Time frame: Baseline to Week 52
Population: Full analysis set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Dapagliflozin Plus Metformin | Proportion of Participants With at Least One Episode of Hypoglycemia | 3.5 Percentage of participants |
| Glipizide Plus Metformin | Proportion of Participants With at Least One Episode of Hypoglycemia | 40.8 Percentage of participants |
Comparison: H0: proportion(treat) minus proportion(reference) = 0 versus the alternative HA: proportion(treat) minus proportion(reference) =/= 0p-value: <0.000195% CI: [-42.3, -32.2]Regression, Logistic
Secondary
Proportion of Participants With Body Weight Reduction of at Least 5%
To evaluate the effect of dapagliflozin plus metformin compared to glipizide plus metformin on body weight assessed by a reduction after 52 weeks of at least 5% compared to baseline. Least Squares Mean represents the percent of participants adjusted for baseline value.
Time frame: Baseline to Week 52
Population: Full Analysis Set, participants with non-missing baseline and Week 52 (LOCF) values
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Dapagliflozin Plus Metformin | Proportion of Participants With Body Weight Reduction of at Least 5% | 33.3 Percentage of participants |
| Glipizide Plus Metformin | Proportion of Participants With Body Weight Reduction of at Least 5% | 2.5 Percentage of participants |
Comparison: H0: proportion(treat) minus proportion(reference) = 0 versus the alternative HA: proportion(treat) minus proportion(reference) =/= 0p-value: <0.000195% CI: [26, 35.7]Regression, Logistic