Type 2 Diabetes
Conditions
Keywords
Diabetes Mellitus, Type 2, Diabetes Mellitus, Endocrine System Diseases, Glucose Metabolism Disorders, Metabolic Diseases, Angiotensin Receptor Antagonists, Angiotensin-Converting Enzyme Inhibitors, Hypoglycemic Agents, Pharmacologic Actions, Physiological Effects of Drugs
Brief summary
The purpose of this study is to learn whether dapagliflozin, after 12 weeks, can improve (decrease) blood pressure in patients with type 2 diabetes with uncontrolled hypertension who are on an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker. The safety of this treatment will also be studied.
Interventions
DRUGDapagliflozin
Oral tablets administered as 2.5, 5, or 10 mg, once daily for up to 12 weeks
DRUGPlacebo-matching dapagliflozin
Oral tablets administered as 0 mg once daily for up to 12 weeks
Sponsors
Bristol-Myers Squibb
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 89 Years
Healthy volunteers
No
Inclusion criteria
Key inclusion criteria * Participants willing and able to give signed and written informed consent * Males and females, aged 18 to 89 years, who have type 2 diabetes with inadequate glycemic control (hemoglobin A1c between 7% and 10.5%) and uncontrolled hypertension (seated systolic blood pressure of 140 to 165 mm Hg and seated diastolic blood pressure 85 to 105 mm Hg) * Mean 24-hour BP\>=130/80 mmHg determined by ABPM * Stable dose of oral antidiabetic agent (OAD) for at least 6 weeks (12 weeks for thiazolidinedione) or a stable daily dose of insulin as monotherapy or in combination with another OAD, for 8 weeks, and a stable dose of an angiotensin-converting enzyme inhibitor or angiotensin-receptor blocker for at least 4 weeks * C-peptide level ≥0.8 ng/mL * Body mass index ≤ 45.0 kg/m\^2 Key
Exclusion criteria
* Aspartate aminotransferase or alanine aminotransferase level \>3\*upper limit of normal (ULN) * Serum total bilirubin level \>1.5\*ULN * Serum creatinine ≥2.0 mg/dL unless subject was on metformin, where exclusionary limits were serum creatinine ≥1.50 mg/dL for men and ≥1.40 mg/dL for women * Estimated creatinine clearance of \<60 mL/min * Hemoglobin ≤10.0 g/dL for men and ≤9.0 g/dL for women * Creatine kinase \>3\*ULN * Positive for hepatitis B surface antigen * Positive for antihepatitis C virus antibody * Abnormal free T4 value * History of diabetes insipidus * Symptoms of poorly controlled diabetes that would preclude participation in this trial, including but not limited to, marked polyuria and polydipsia with greater than 10% weight loss during the 3 months prior to enrollment. * History of diabetic ketoacidosis or hyperosmolar nonketotic coma * History of malignant and accelerated hypertension * Known or suspected secondary hypertension * Any of the following within 6 months of enrollment visit: * Myocardial infarction * Cardiac surgery or revascularization (coronary artery bypass surgery /percutaneous transluminal coronary angioplasty) * Unstable angina * Unstable congestive heart disease or New York Heart Association Class III or IV * Transient ischemic attack or significant cerebrovascular disease * Unstable or previously undiagnosed arrhythmia
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Adjusted Mean Change From Baseline in Seated Systolic Blood Pressure (BP) at Week 12 | From Baseline to Week 12 | Seated BP was to be measured at every visit. Data after rescue medication was excluded. The patient first rested for at least 10 minutes in the seated position. Seated blood BP was determined from the mean of 3 replicated measurements obtained at least 1 minute apart. However, if the 3 consecutive seated BP readings were not within 8 mm Hg of each other, an additional 2 BP readings were to be obtained (total=5) and incorporated into the calculated mean for systolic BP and diastolic BP. For the initial BP recording, BP was measured in both arms. If the BP was higher in 1 arm, that arm was used for BP measurement. If there was no difference in BP measurements between arms, the dominant arm was used for all future BP measurements. All randomized participants who received at least 1 dose of study drug and who had nonmissing baseline and at least 1 postbaseline value during the double-blind treatment period were used for analysis. SD=standard deviation. |
| Adjusted Mean Change From Baseline in Hemoglobin (HbA1c) at Week 12 | From Baseline to Week 12 | HbA1c was measured as percent of hemoglobin by a central laboratory. All randomized participants who received at least 1 dose of study drug and who had nonmissing baseline and at least 1 postbaseline value during the double-blind treatment period were used for analysis. SD=standard deviation. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Adjusted Mean Change From Baseline in 24-Hour Ambulatory Systolic Blood Pressure at Week 12 (Last Observation Carried Forward) | From Baseline to Week 12 | Ambulatory blood pressure monitoring was performed twice during the study, at baseline and at the end of study, for a duration of 24-hrs each time. If the patient met the criteria for rescue due to hypertension, a second monitoring was performed prior to the first dose of rescue medication. Initiation of the 24-hr ambulatory blood pressure monitoring began between 6 and 11 am to ensure trough blood pressure measurements were obtained. Patients were instructed to withhold all medication on the morning of the study visit and to bring their medications to the visit with them. |
| Adjusted Mean Change From Baseline in Seated Diastolic Blood Pressure at Week 12 | From Baseline to Week 12 | All randomized participants who received at least 1 dose of study drug and who had nonmissing baseline and at least 1 postbaseline value during the double-blind treatment period were used for analysis. |
| Adjusted Mean Change in 24-Hour Ambulatory Diastolic Blood Pressure at Week 12 (Last Observation Carried Forward [LOCF]) | From Baseline to Week 12 | Ambulatory blood pressure monitoring was performed twice during the study, at baseline and at the end of study, for a duration of 24 hours each time. If the patient met the criteria for rescue due to hypertension, a second monitoring was performed prior to the first dose of rescue medication. Initiation of the 24-hour ambulatory blood pressure monitoring began between 6 and 11 am to ensure trough blood pressure measurements were obtained. Patients were instructed to withhold all medication on the morning of the study visit and to bring their medications to the visit with them. |
| Adjusted Mean Change From Baseline in Serum Uric Acid Levels at Week 12 | From Baseline to Week 12 | Central laboratory serum uric acid levels will be determined at the Enrollment, Day -28, Day 1, and at Week 4, 8, 12, and 13 visits. All randomized participants who received at least 1 dose of study drug and who had nonmissing baseline and at least 1 postbaseline value during the double-blind treatment period were used for analysis. |
Countries
Canada, Colombia, Czechia, Denmark, Finland, Germany, Hungary, India, Mexico, Peru, Poland, Puerto Rico, Romania, Russia, Spain, United States
Participant flow
Recruitment details
This study was originally designed with 2 additional double-blind treatment arms, dapagliflozin 2.5 and 5 mg, but randomization of new patients into these arms stopped with implementation of Protocol Amendment 8 on 1-11-11. Patients randomized to dapagliflozin 2.5 or 5 mg remained on their blinded medication until study completion.
Pre-assignment details
Of 2996 participants enrolled, 944 were randomized and received double-blind treatment.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants with type 2 diabetes and inadequate glycemic and hypertension control while taking an oral antidiabetic drug (OAD) with or without insulin and an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB), received dapagliflozin-matching placebo daily with a morning meal. | 311 |
| Dapagliflozin, 2.5 mg (Randomized Before Protocol Amendment 8) Participants with type 2 diabetes and inadequate glycemic control while taking an OAD with or without insulin and an ACE inhibitor or ARB, received dapagliflozin, 2.5 mg, daily with a morning meal. | 166 |
| Dapagliflozin, 5 mg (Randomized Before Protocol Amendment 8) Participants with type 2 diabetes and inadequate glycemic control while taking an OAD with or without insulin and an ACE inhibitor or ARB, received dapagliflozin, 5 mg, daily with a morning meal. | 165 |
| Dapagliflozin 10 mg Participants with type 2 diabetes and inadequate glycemic and hypertension control while taking an OAD with or without insulin and an ACE inhibitor or ARB, received dapagliflozin, 10 mg, daily with a morning meal. | 302 |
| Total | 944 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Administrative reason by sponsor | 0 | 1 | 0 | 0 |
| Overall Study | Adverse Event | 3 | 5 | 1 | 3 |
| Overall Study | Lack of Efficacy | 0 | 0 | 0 | 2 |
| Overall Study | Lost to Follow-up | 5 | 1 | 0 | 2 |
| Overall Study | No longer met study criteria | 6 | 1 | 0 | 5 |
| Overall Study | Other | 3 | 1 | 0 | 0 |
| Overall Study | Pregnancy | 0 | 1 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 7 | 2 | 6 | 9 |
Baseline characteristics
| Characteristic | Placebo | Total | Dapagliflozin 10 mg | Dapagliflozin, 5 mg (Randomized Before Protocol Amendment 8) | Dapagliflozin, 2.5 mg (Randomized Before Protocol Amendment 8) |
|---|---|---|---|---|---|
| Age, Customized 65 years and older to younger than 75 years | 46 Participants | 134 Participants | 42 Participants | 21 Participants | 25 Participants |
| Age, Customized 75 years and older | 6 Participants | 8 Participants | 0 Participants | 2 Participants | 0 Participants |
| Age, Customized Younger than 65 years | 259 Participants | 802 Participants | 260 Participants | 142 Participants | 141 Participants |
| Body Mass Index 25 kg/m^2 to 30 kg/m^2 | 131 Participants | 356 Participants | 95 Participants | 63 Participants | 67 Participants |
| Body Mass Index 30 kg/m^2 and greater | 152 Participants | 488 Participants | 173 Participants | 84 Participants | 79 Participants |
| Body Mass Index Less than 25 kg/m^2 | 28 Participants | 100 Participants | 34 Participants | 18 Participants | 20 Participants |
| Gender Female | 140 Participants | 415 Participants | 123 Participants | 76 Participants | 76 Participants |
| Gender Male | 171 Participants | 529 Participants | 179 Participants | 89 Participants | 90 Participants |
| Race/Ethnicity, Customized Asian | 54 Participants | 201 Participants | 49 Participants | 49 Participants | 49 Participants |
| Race/Ethnicity, Customized Black or African American | 14 Participants | 45 Participants | 12 Participants | 8 Participants | 11 Participants |
| Race/Ethnicity, Customized Other | 2 Participants | 5 Participants | 2 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 241 Participants | 693 Participants | 239 Participants | 108 Participants | 105 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 0 / 311 | 0 / 166 | 0 / 165 | 0 / 302 |
| serious Total, serious adverse events | 4 / 311 | 3 / 166 | 2 / 165 | 2 / 302 |
Outcome results
Primary
Adjusted Mean Change From Baseline in Hemoglobin (HbA1c) at Week 12
HbA1c was measured as percent of hemoglobin by a central laboratory. All randomized participants who received at least 1 dose of study drug and who had nonmissing baseline and at least 1 postbaseline value during the double-blind treatment period were used for analysis. SD=standard deviation.
Time frame: From Baseline to Week 12
Population: This study originally had 2 additional arms-dapagliflozin 2.5 and 5 mg-but randomization to these arms stopped when Protocol Amendment 8 (1-11-11) was implemented. Because endpoints focused only on 10-mg and placebo data, only patients in these arms who received study drug and who had nonmissing baseline and Week 12 values were included.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dapagliflozin 10 mg | Adjusted Mean Change From Baseline in Hemoglobin (HbA1c) at Week 12 | -0.10 Percent | Standard Error 0.0631 |
| Placebo | Adjusted Mean Change From Baseline in Hemoglobin (HbA1c) at Week 12 | -0.56 Percent | Standard Error 0.0633 |
Comparison: Change from baseline to week 12 was calculated using a longitudinal repeated measures analysis using direct likelihood with fixed categorical effects of treatment, week, treatment-by-week interaction, and randomization strata and continuous fixed covariates of baseline value and baseline value by week interaction. With 253 subjects per group, there is \>98% power to detect a difference of 0.4% at a=0.05, assuming a common SD of 1.1%.p-value: <0.000195% CI: [-0.59, -0.33]Longitudinal repeated measures analysis
Primary
Adjusted Mean Change From Baseline in Seated Systolic Blood Pressure (BP) at Week 12
Seated BP was to be measured at every visit. Data after rescue medication was excluded. The patient first rested for at least 10 minutes in the seated position. Seated blood BP was determined from the mean of 3 replicated measurements obtained at least 1 minute apart. However, if the 3 consecutive seated BP readings were not within 8 mm Hg of each other, an additional 2 BP readings were to be obtained (total=5) and incorporated into the calculated mean for systolic BP and diastolic BP. For the initial BP recording, BP was measured in both arms. If the BP was higher in 1 arm, that arm was used for BP measurement. If there was no difference in BP measurements between arms, the dominant arm was used for all future BP measurements. All randomized participants who received at least 1 dose of study drug and who had nonmissing baseline and at least 1 postbaseline value during the double-blind treatment period were used for analysis. SD=standard deviation.
Time frame: From Baseline to Week 12
Population: This study originally had 2 additional arms-dapagliflozin 2.5 and 5 mg-but randomization to these arms stopped when Protocol Amendment 8 (1-11-11) was implemented. Because endpoints focused only on 10-mg and placebo data, only patients in these arms who received study drug and who had nonmissing baseline and Week 12 values were included.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dapagliflozin 10 mg | Adjusted Mean Change From Baseline in Seated Systolic Blood Pressure (BP) at Week 12 | -10.40 mm Hg | Standard Error 0.8822 |
| Placebo | Adjusted Mean Change From Baseline in Seated Systolic Blood Pressure (BP) at Week 12 | -7.34 mm Hg | Standard Error 0.8812 |
Comparison: Change from baseline to week 12 calculated using a longitudinal repeated measures analysis using direct likelihood with fixed categorical effects of treatment, week, treatment-by-week interaction, and randomization strata and continuous fixed covariates of baseline value and baseline value by week interaction. Data after rescue were not included in the analysis. With 253 patients per group, there is \>80% power to detect a difference of 3.5 mm Hg at alpha=0.05, assuming a common SD of 14 mm Hg.p-value: 0.00195% CI: [-4.87, -1.24]Longitudinal repeated measures analysis
Secondary
Adjusted Mean Change From Baseline in 24-Hour Ambulatory Systolic Blood Pressure at Week 12 (Last Observation Carried Forward)
Ambulatory blood pressure monitoring was performed twice during the study, at baseline and at the end of study, for a duration of 24-hrs each time. If the patient met the criteria for rescue due to hypertension, a second monitoring was performed prior to the first dose of rescue medication. Initiation of the 24-hr ambulatory blood pressure monitoring began between 6 and 11 am to ensure trough blood pressure measurements were obtained. Patients were instructed to withhold all medication on the morning of the study visit and to bring their medications to the visit with them.
Time frame: From Baseline to Week 12
Population: This study originally had 2 additional arms-dapagliflozin 2.5 and 5 mg-but randomization to these arms stopped when Protocol Amendment 8 (1-11-11) was implemented. Because endpoints focused only on 10-mg and placebo data, only patients in these arms who received study drug and who had nonmissing baseline and Week 12 values were included.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dapagliflozin 10 mg | Adjusted Mean Change From Baseline in 24-Hour Ambulatory Systolic Blood Pressure at Week 12 (Last Observation Carried Forward) | -6.73 mm Hg | Standard Error 1.2427 |
| Placebo | Adjusted Mean Change From Baseline in 24-Hour Ambulatory Systolic Blood Pressure at Week 12 (Last Observation Carried Forward) | -9.62 mm Hg | Standard Error 1.2277 |
Comparison: Change from baseline to week 12 LOCF was calculated using an ANCOVA model with treatment group as an effect and baseline value and randomization strata as covariate. Data after rescue are excluded from blood pressure analyses.p-value: 0.004395% CI: [-4.88, -0.91]ANCOVA
Secondary
Adjusted Mean Change From Baseline in Seated Diastolic Blood Pressure at Week 12
All randomized participants who received at least 1 dose of study drug and who had nonmissing baseline and at least 1 postbaseline value during the double-blind treatment period were used for analysis.
Time frame: From Baseline to Week 12
Population: This study originally had 2 additional arms-dapagliflozin 2.5 and 5 mg-but randomization to these arms stopped when Protocol Amendment 8 (1-11-11) was implemented. Because endpoints focused only on 10-mg and placebo data, only patients in these arms who received study drug and who had nonmissing baseline and Week 12 values were included.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dapagliflozin 10 mg | Adjusted Mean Change From Baseline in Seated Diastolic Blood Pressure at Week 12 | -4.79 mm Hg | Standard Error 0.5418 |
| Placebo | Adjusted Mean Change From Baseline in Seated Diastolic Blood Pressure at Week 12 | -5.79 mm Hg | Standard Error 0.5425 |
Comparison: Change from baseline to week 12 was calculated using a longitudinal repeated measures analysis using direct likelihood with fixed categorical effects of treatment, week, treatment-by-week interaction, and randomization strata and continuous fixed covariates of baseline value and baseline value by week interaction. Data after rescue were not included in the analysis.p-value: 0.084395% CI: [-2.15, 0.14]Longitudinal repeated measures analysis
Secondary
Adjusted Mean Change From Baseline in Serum Uric Acid Levels at Week 12
Central laboratory serum uric acid levels will be determined at the Enrollment, Day -28, Day 1, and at Week 4, 8, 12, and 13 visits. All randomized participants who received at least 1 dose of study drug and who had nonmissing baseline and at least 1 postbaseline value during the double-blind treatment period were used for analysis.
Time frame: From Baseline to Week 12
Population: This study originally had 2 additional arms-dapagliflozin 2.5 and 5 mg-but randomization to these arms stopped when Protocol Amendment 8 (1-11-11) was implemented. Because endpoints focused only on 10-mg and placebo data, only patients in these arms who received study drug and who had nonmissing baseline and Week 12 values were included.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dapagliflozin 10 mg | Adjusted Mean Change From Baseline in Serum Uric Acid Levels at Week 12 | 0.05 mg/dL | Standard Error 0.0747 |
| Placebo | Adjusted Mean Change From Baseline in Serum Uric Acid Levels at Week 12 | -0.27 mg/dL | Standard Error 0.0754 |
Comparison: Change from baseline to week 12 was calculated using a longitudinal repeated measures analysis using direct likelihood with fixed categorical effects of treatment, week, treatment-by-week interaction, and randomization strata and continuous fixed covariates of baseline value and baseline value by week interaction.95% CI: [-0.46, -0.18]Longitudinal repeated measures analysis
Secondary
Adjusted Mean Change in 24-Hour Ambulatory Diastolic Blood Pressure at Week 12 (Last Observation Carried Forward [LOCF])
Ambulatory blood pressure monitoring was performed twice during the study, at baseline and at the end of study, for a duration of 24 hours each time. If the patient met the criteria for rescue due to hypertension, a second monitoring was performed prior to the first dose of rescue medication. Initiation of the 24-hour ambulatory blood pressure monitoring began between 6 and 11 am to ensure trough blood pressure measurements were obtained. Patients were instructed to withhold all medication on the morning of the study visit and to bring their medications to the visit with them.
Time frame: From Baseline to Week 12
Population: This study originally had 2 additional arms-dapagliflozin 2.5 and 5 mg-but randomization to these arms stopped when Protocol Amendment 8 (1-11-11) was implemented. Because endpoints focused only on 10-mg and placebo data, only patients in these arms who received study drug and who had nonmissing baseline and Week 12 values were included.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dapagliflozin 10 mg | Adjusted Mean Change in 24-Hour Ambulatory Diastolic Blood Pressure at Week 12 (Last Observation Carried Forward [LOCF]) | -5.53 mm Hg | Standard Error 0.8458 |
| Placebo | Adjusted Mean Change in 24-Hour Ambulatory Diastolic Blood Pressure at Week 12 (Last Observation Carried Forward [LOCF]) | -6.15 mm Hg | Standard Error 0.8353 |
Comparison: Change from baseline to week 12 LOCF was calculated using an ANCOVA model with treatment group as an effect and baseline value and randomization strata as covariate. Data after rescue are excluded from blood pressure analyses.95% CI: [-1.96, 0.73]ANCOVA