Diabetes Mellitus, Type 2
Conditions
Brief summary
An open-label, phase II study to assess the acute and chronic effects of empagliflozin (BI 10773)on fasting and postprandial glucose homeostasis in patients with IGT and type 2 diabetes mellitus and assess the acute effects of empagliflozin in healthy subjects.
Interventions
DRUGBI 10773
BI 10773 tablets once daily high dose
Sponsors
Boehringer Ingelheim
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
1. Male and female patients diagnosed with IGT according to the current ADA guidelines as a two-hour glucose levels of 140 to 199 mg/dl (7.8 mmol/l to 11.1 mmol/l) on the 75-g oral glucose tolerance test (OGTT), with an OGTT performed at the time of the screening visit (Visit 1), or ¿ Male and female patients diagnosed with type 2 diabetes mellitus (T2DM) prior to informed consent, on diet and exercise regimen who are drug-naïve, defined as absence of any oral antihyperglycemic therapy for 12 weeks prior starting with open-label active treatment, or 2. Male and female patients diagnosed with type 2 diabetes mellitus prior to informed consent, who are pre-treated with metformin background therapy, on a stable dose of metformin of at least 1500 mg per day, unchanged for at least 12 weeks prior starting with open-label active treatment 3. HbA1c at Visit 1 (screening) 1. for patients diagnosed of IGT and for healthy subjects: HbA1c \< 6.5% 2. for patients diagnosed of T2DM: HbA1c =6.5% and =10.5% 4. Age = 18 at Visit 1 5. BMI = 20 and = 40 Kg/m2 at Visit 1 6. For patients with antihypertensive treatment, this must be stable (with no change in dosage) within 4 weeks prior starting with open-label active treatment 7. Signed and dated written informed consent by date of Visit 1 in accordance with GCP and local legislation Inclusion criteria for healthy subjects: 8. Males or females matching the below mentioned criteria and otherwise healthy according to the investigator¿s assessment, as based on the following criteria: a complete medical history including a physical examination, vital signs (BP, PR) and clinical laboratory tests . 9. HbA1c at Visit 1 (screening): HbA1c \< 6.5% 10. Confirmed normal glucose tolerance (NGT) by OGTT 11. Age = 45 and = 55 at Visit 1. 12. BMI = 30 and = 40 Kg/m2 (Body Mass Index) at Visit 1. 13. Signed and dated written informed consent by date of Visit 1 in accordance with GCP and local legislation.
Exclusion criteria
1. Acute coronary syndrome (non-STEMI \[ST elevation myocardial infarction\], STEMI, unstable AP \[angina pectoris\]), stroke or Transient Ischemic Attack (TIA) within 6 months prior to informed consent. 2. Uncontrolled hyperglycaemia with a glucose level \> 240 mg/dl (\> 13.3 mmol/L) after an overnight fast during placebo run-in and confirmed by a second measurement (not on the same day). 3. Any other antidiabetic drug within 12 weeks prior to starting the open-label active treatment (Visit 4) except those defined as background via inclusion criterion 1c. 4. Indication of liver disease, defined by serum levels of either Alanine Aminotransferase (ALT \[SGPT\]), Aspartate Aminotransferase (AST \[SGOT\]), or alkaline phosphatase above 3 x upper limit of normal (ULN) as determined during screening and/or run-in phase. 5. Impaired renal function, defined as estimated Glomerular Filtration Rate (eGFR) \< 60 ml/min (moderate and severe renal impairment) as determined during screening and/or run-in phase. 6. Medical history of insufficient bladder emptying (i.e. neurogenic bladder disorders). 7. Patients with an Haemoglobin (Hb) \< 11.5 g/dl (for males) and Hb \< 10.5 g/dl (for females) at Visit 1. 8. Bariatric surgery within the past two years and other gastrointestinal surgeries that induce chronic malabsorption within the last 5 years. 9. Medical history of cancer (except for basal cell carcinoma) and/or treatment for cancer within the last 5 years. 10. For patients on metformin background therapy, the investigator must check for potential
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Fasting Plasma Glucose at Day 1 | Baseline and day 1 | Change from baseline of Fasting Plasma glucose (FPG) 3 hours and 35 minutes before meal at day 1 |
| Change From Baseline in Fasting Plasma Glucose at Day 28 | Baseline and day 28 | Change from baseline of Fasting Plasma glucose (FPG) 3 hours and 35 minutes before meal at day 28. Note, healthy subjects only received a single dose of empa so assessments at day 28 are not applicable |
| Change From Baseline in Glucose Metabolism (Pre-meal and Postprandial Glucose), PPG iAUC 5h, at Day 1 | 0 minutes (min), 15min, 30min, 45min, 1hour (h), 1h 30min, 2h, 2h 30min, 3h, 3h 30min, 4h, 4h 30min and 5h after meal at baseline and day 1 | Change from baseline in the incremental area under the curve of postprandial plasma glucose from 0 to 5 hours (PPG iAUC 5h), defined as the area under the curve of timepoints 0 to 5 hours after meal reduced by the pre-meal plasma glucose at 0 hours. |
| Change From Baseline in Glucose Metabolism (Pre-meal and Postprandial Glucose), PPG iAUC 5h, at Day 28 | 0 minutes (min), 15min, 30min, 45min, 1hour (h), 1h 30min, 2h, 2h 30min, 3h, 3h 30min, 4h, 4h 30min and 5h after meal at baseline and day 28 | Change from baseline in the incremental area under the curve of postprandial plasma glucose from 0 to 5 hours (PPG iAUC 5h), defined as the area under the curve of timepoints 0 to 5 hours after meal reduced by the pre-meal plasma glucose at 0 hours. Note, healthy subjects only received a single dose of empa so assessments at day 28 are not applicable. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Rate of Endogenous Glucose Production: iAUC 5h, at Day 1 | 0 minutes (min), 15min, 30min, 45min, 1hour (h), 1h 30min, 2h, 2h 30min, 3h, 3h 30min, 4h, 4h 30min and 5h after drug administration at baseline and day 1 | Change from baseline in the incremental area under the curve of endogenous glucose production from 0 to 5 hours (EGP iAUC 5h), defined as the area under the curve of timepoints 0 to 5 hours after meal reduced by the pre-meal endogenous glucose production at 0 hour. |
| Change From Baseline in Rate of Endogenous Glucose Production: Fast, at Day 1 | Baseline and day 1 | Change from baseline in rate of endogenous glucose production (EGP) fast after one dose |
| Change From Baseline in Rate of Endogenous Glucose Production: iAUC 5h, at Day 28 | 0 minutes (min), 15min, 30min, 45min, 1hour (h), 1h 30min, 2h, 2h 30min, 3h, 3h 30min, 4h, 4h 30min and 5h after drug administration at baseline and day 28 | Change from baseline in the incremental area under the curve of endogenous glucose production from 0 to 5 hours (EGP iAUC 5h), defined as the area under the curve of timepoints 0 to 5 hours after meal reduced by the pre-meal endogenous glucose production at 0 hour. Note, healthy subjects only received a single dose of empa so assessments at day 28 are not applicable. |
| Change From Baseline in Rate of Endogenous Glucose Production: Fast, at Day 28 | Baseline and day 28 | Change from baseline in rate of endogenous glucose production (EGP) fast after 28 days of treatment. Note, healthy subjects only received a single dose of empa so assessments at day 28 are not applicable. |
| Change From Baseline in Rate of Endogenous Glucose Production: AUC 5h, at Day 1 | 0 minutes (min), 15min, 30min, 45min, 1hour (h), 1h 30min, 2h, 2h 30min, 3h, 3h 30min, 4h, 4h 30min and 5h after meal at baseline and day 1 | Change from baseline in the area under the curve of endogenous glucose production (EGP) from 0 to 5 hours (EGP AUC 5h) after meal. |
| Change From Baseline in Rate of Endogenous Glucose Production: AUC 5h, at Day 28 | 0 minutes (min), 15min, 30min, 45min, 1hour (h), 1h 30min, 2h, 2h 30min, 3h, 3h 30min, 4h, 4h 30min and 5h after meal at baseline and day 28 | Change from baseline in the area under the curve of endogenous glucose production (EGP) from 0 to 5 hours (EGP AUC 5h) after meal. Note, healthy subjects only received a single dose of empa so assessments at day 28 are not applicable. |
Countries
Austria, Germany, Italy
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| T2DM Naive Patients diagnosed with type 2 diabetes mellitus (T2DM) who have not been treated with any antihyperglycemic therapy for the last 12 weeks prior to the study. Patients received empagliflozin (empa) 25mg tablet once daily for 28 days. | 32 |
| T2DM Metformin Patients diagnosed with type 2 diabetes mellitus (T2DM) who are on stable dose of metformin of at least 1500 mg per day, for the last 12 weeks prior to the study. Patients received empagliflozin (empa) 25mg tablet once daily for 28 days. | 34 |
| Impaired Glucose Tolerance Patients diagnosed with impaired glucose tolerance (IGT) according to American Diabetes Association (ADA) guidelines. Patients received empagliflozin (empa) 25mg tablet once daily for 28 days. | 13 |
| Healthy Subjects Healthy subjects received a single dose of empagliflozin (empa) 25mg, in tablet form. | 12 |
| Total | 91 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | T2DM Naive | Impaired Glucose Tolerance | T2DM Metformin | Healthy Subjects | Total |
|---|---|---|---|---|---|
| Age, Continuous | 60.1 years STANDARD_DEVIATION 7 | 50.8 years STANDARD_DEVIATION 9.8 | 63.3 years STANDARD_DEVIATION 6.5 | 47.7 years STANDARD_DEVIATION 2.3 | 58.3 years STANDARD_DEVIATION 8.9 |
| Sex: Female, Male Female | 11 Participants | 5 Participants | 10 Participants | 2 Participants | 28 Participants |
| Sex: Female, Male Male | 21 Participants | 8 Participants | 24 Participants | 10 Participants | 63 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 | 8 / 32 | 5 / 34 | 4 / 13 | 1 / 12 |
| serious Total, serious adverse events | 0 / 32 | 1 / 34 | 0 / 13 | 0 / 12 |
Outcome results
Primary
Change From Baseline in Fasting Plasma Glucose at Day 1
Change from baseline of Fasting Plasma glucose (FPG) 3 hours and 35 minutes before meal at day 1
Time frame: Baseline and day 1
Population: Treated set which included all patients/healthy subjects with at least one dose of empagliflozin (original result (OR))
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| T2DM Naive | Change From Baseline in Fasting Plasma Glucose at Day 1 | 0.20 mmol/L | Standard Error 0.12 |
| T2DM Metformin | Change From Baseline in Fasting Plasma Glucose at Day 1 | 0.39 mmol/L | Standard Error 0.13 |
| Impaired Glucose Tolerance | Change From Baseline in Fasting Plasma Glucose at Day 1 | -0.96 mmol/L | Standard Error 0.86 |
| Healthy Subjects | Change From Baseline in Fasting Plasma Glucose at Day 1 | -0.47 mmol/L | Standard Error 0.97 |
Comparison: No formal testing, exploratory analysis only.p-value: 0.27995% CI: [-0.16, 0.55]ANCOVA
Primary
Change From Baseline in Fasting Plasma Glucose at Day 28
Change from baseline of Fasting Plasma glucose (FPG) 3 hours and 35 minutes before meal at day 28. Note, healthy subjects only received a single dose of empa so assessments at day 28 are not applicable
Time frame: Baseline and day 28
Population: Treated set, which included all patients/healthy subjects with at least one dose of empagliflozin (original result (OR)), for patients who completed the day 28 visit
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| T2DM Naive | Change From Baseline in Fasting Plasma Glucose at Day 28 | -1.02 mmol/L | Standard Error 0.13 |
| T2DM Metformin | Change From Baseline in Fasting Plasma Glucose at Day 28 | -0.79 mmol/L | Standard Error 0.15 |
| Impaired Glucose Tolerance | Change From Baseline in Fasting Plasma Glucose at Day 28 | -0.81 mmol/L | Standard Error 1.12 |
Comparison: No formal testing, exploratory analysis only.p-value: 0.243895% CI: [-0.16, 0.62]ANCOVA
Primary
Change From Baseline in Glucose Metabolism (Pre-meal and Postprandial Glucose), PPG iAUC 5h, at Day 1
Change from baseline in the incremental area under the curve of postprandial plasma glucose from 0 to 5 hours (PPG iAUC 5h), defined as the area under the curve of timepoints 0 to 5 hours after meal reduced by the pre-meal plasma glucose at 0 hours.
Time frame: 0 minutes (min), 15min, 30min, 45min, 1hour (h), 1h 30min, 2h, 2h 30min, 3h, 3h 30min, 4h, 4h 30min and 5h after meal at baseline and day 1
Population: Treated set (OR)
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| T2DM Naive | Change From Baseline in Glucose Metabolism (Pre-meal and Postprandial Glucose), PPG iAUC 5h, at Day 1 | -1.94 g/dL/h | Standard Error 0.53 |
| T2DM Metformin | Change From Baseline in Glucose Metabolism (Pre-meal and Postprandial Glucose), PPG iAUC 5h, at Day 1 | -3.52 g/dL/h | Standard Error 0.61 |
| Impaired Glucose Tolerance | Change From Baseline in Glucose Metabolism (Pre-meal and Postprandial Glucose), PPG iAUC 5h, at Day 1 | -5.49 g/dL/h | Standard Error 1.95 |
| Healthy Subjects | Change From Baseline in Glucose Metabolism (Pre-meal and Postprandial Glucose), PPG iAUC 5h, at Day 1 | -9.20 g/dL/h | Standard Error 3.91 |
Comparison: No formal testing, exploratory analysis only.p-value: 0.055295% CI: [-3.2, 0.04]ANCOVA
Primary
Change From Baseline in Glucose Metabolism (Pre-meal and Postprandial Glucose), PPG iAUC 5h, at Day 28
Change from baseline in the incremental area under the curve of postprandial plasma glucose from 0 to 5 hours (PPG iAUC 5h), defined as the area under the curve of timepoints 0 to 5 hours after meal reduced by the pre-meal plasma glucose at 0 hours. Note, healthy subjects only received a single dose of empa so assessments at day 28 are not applicable.
Time frame: 0 minutes (min), 15min, 30min, 45min, 1hour (h), 1h 30min, 2h, 2h 30min, 3h, 3h 30min, 4h, 4h 30min and 5h after meal at baseline and day 28
Population: Treated set (OR) for patients who completed the day 28 visit
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| T2DM Naive | Change From Baseline in Glucose Metabolism (Pre-meal and Postprandial Glucose), PPG iAUC 5h, at Day 28 | -0.71 g/dL/h | Standard Error 0.67 |
| T2DM Metformin | Change From Baseline in Glucose Metabolism (Pre-meal and Postprandial Glucose), PPG iAUC 5h, at Day 28 | -0.40 g/dL/h | Standard Error 0.72 |
| Impaired Glucose Tolerance | Change From Baseline in Glucose Metabolism (Pre-meal and Postprandial Glucose), PPG iAUC 5h, at Day 28 | -7.31 g/dL/h | Standard Error 2.91 |
Comparison: No formal testing, exploratory analysis only.p-value: 0.756195% CI: [-1.66, 2.27]ANCOVA
Secondary
Change From Baseline in Rate of Endogenous Glucose Production: AUC 5h, at Day 1
Change from baseline in the area under the curve of endogenous glucose production (EGP) from 0 to 5 hours (EGP AUC 5h) after meal.
Time frame: 0 minutes (min), 15min, 30min, 45min, 1hour (h), 1h 30min, 2h, 2h 30min, 3h, 3h 30min, 4h, 4h 30min and 5h after meal at baseline and day 1
Population: Treated set (OR)
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| T2DM Naive | Change From Baseline in Rate of Endogenous Glucose Production: AUC 5h, at Day 1 | 3.28 g | Standard Error 1.8 |
| T2DM Metformin | Change From Baseline in Rate of Endogenous Glucose Production: AUC 5h, at Day 1 | 8.76 g | Standard Error 1.77 |
| Impaired Glucose Tolerance | Change From Baseline in Rate of Endogenous Glucose Production: AUC 5h, at Day 1 | 3.70 g | Standard Error 2.73 |
| Healthy Subjects | Change From Baseline in Rate of Endogenous Glucose Production: AUC 5h, at Day 1 | 9.22 g | Standard Error 3.94 |
Comparison: No formal testing, exploratory analysis only.p-value: 0.032695% CI: [0.47, 10.5]ANCOVA
Secondary
Change From Baseline in Rate of Endogenous Glucose Production: AUC 5h, at Day 28
Change from baseline in the area under the curve of endogenous glucose production (EGP) from 0 to 5 hours (EGP AUC 5h) after meal. Note, healthy subjects only received a single dose of empa so assessments at day 28 are not applicable.
Time frame: 0 minutes (min), 15min, 30min, 45min, 1hour (h), 1h 30min, 2h, 2h 30min, 3h, 3h 30min, 4h, 4h 30min and 5h after meal at baseline and day 28
Population: Treated set (OR) for patients who completed the day 28 visit
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| T2DM Naive | Change From Baseline in Rate of Endogenous Glucose Production: AUC 5h, at Day 28 | 1.89 g | Standard Error 1.35 |
| T2DM Metformin | Change From Baseline in Rate of Endogenous Glucose Production: AUC 5h, at Day 28 | 5.02 g | Standard Error 1.33 |
| Impaired Glucose Tolerance | Change From Baseline in Rate of Endogenous Glucose Production: AUC 5h, at Day 28 | 3.14 g | Standard Error 2.35 |
Comparison: No formal testing, exploratory analysis only.p-value: 0.102495% CI: [-0.64, 6.9]ANCOVA
Secondary
Change From Baseline in Rate of Endogenous Glucose Production: Fast, at Day 1
Change from baseline in rate of endogenous glucose production (EGP) fast after one dose
Time frame: Baseline and day 1
Population: Treated set (OR)
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| T2DM Naive | Change From Baseline in Rate of Endogenous Glucose Production: Fast, at Day 1 | 4.21 umol/kgFFM/min | Standard Error 0.45 |
| T2DM Metformin | Change From Baseline in Rate of Endogenous Glucose Production: Fast, at Day 1 | 4.51 umol/kgFFM/min | Standard Error 0.6 |
| Impaired Glucose Tolerance | Change From Baseline in Rate of Endogenous Glucose Production: Fast, at Day 1 | 3.28 umol/kgFFM/min | Standard Error 0.89 |
| Healthy Subjects | Change From Baseline in Rate of Endogenous Glucose Production: Fast, at Day 1 | 1.10 umol/kgFFM/min | Standard Error 0.97 |
Comparison: No formal testing, exploratory analysis only.p-value: 0.693195% CI: [-1.19, 1.79]ANCOVA
Secondary
Change From Baseline in Rate of Endogenous Glucose Production: Fast, at Day 28
Change from baseline in rate of endogenous glucose production (EGP) fast after 28 days of treatment. Note, healthy subjects only received a single dose of empa so assessments at day 28 are not applicable.
Time frame: Baseline and day 28
Population: Treated set (OR) for patients who completed the day 28 visit
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| T2DM Naive | Change From Baseline in Rate of Endogenous Glucose Production: Fast, at Day 28 | 2.79 umol/kgFFM/min | Standard Error 0.71 |
| T2DM Metformin | Change From Baseline in Rate of Endogenous Glucose Production: Fast, at Day 28 | 4.63 umol/kgFFM/min | Standard Error 0.86 |
| Impaired Glucose Tolerance | Change From Baseline in Rate of Endogenous Glucose Production: Fast, at Day 28 | 1.47 umol/kgFFM/min | Standard Error 1.44 |
Comparison: No formal testing, exploratory analysis only.p-value: 0.102895% CI: [-0.38, 4.07]ANCOVA
Secondary
Change From Baseline in Rate of Endogenous Glucose Production: iAUC 5h, at Day 1
Change from baseline in the incremental area under the curve of endogenous glucose production from 0 to 5 hours (EGP iAUC 5h), defined as the area under the curve of timepoints 0 to 5 hours after meal reduced by the pre-meal endogenous glucose production at 0 hour.
Time frame: 0 minutes (min), 15min, 30min, 45min, 1hour (h), 1h 30min, 2h, 2h 30min, 3h, 3h 30min, 4h, 4h 30min and 5h after drug administration at baseline and day 1
Population: Treated set (OR)
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| T2DM Naive | Change From Baseline in Rate of Endogenous Glucose Production: iAUC 5h, at Day 1 | -8.52 g | Standard Error 1.79 |
| T2DM Metformin | Change From Baseline in Rate of Endogenous Glucose Production: iAUC 5h, at Day 1 | -7.22 g | Standard Error 2.33 |
| Impaired Glucose Tolerance | Change From Baseline in Rate of Endogenous Glucose Production: iAUC 5h, at Day 1 | -3.75 g | Standard Error 3.82 |
| Healthy Subjects | Change From Baseline in Rate of Endogenous Glucose Production: iAUC 5h, at Day 1 | 1.28 g | Standard Error 4.8 |
Comparison: No formal testing, exploratory analysis only.p-value: 0.657695% CI: [-4.53, 7.14]ANCOVA
Secondary
Change From Baseline in Rate of Endogenous Glucose Production: iAUC 5h, at Day 28
Change from baseline in the incremental area under the curve of endogenous glucose production from 0 to 5 hours (EGP iAUC 5h), defined as the area under the curve of timepoints 0 to 5 hours after meal reduced by the pre-meal endogenous glucose production at 0 hour. Note, healthy subjects only received a single dose of empa so assessments at day 28 are not applicable.
Time frame: 0 minutes (min), 15min, 30min, 45min, 1hour (h), 1h 30min, 2h, 2h 30min, 3h, 3h 30min, 4h, 4h 30min and 5h after drug administration at baseline and day 28
Population: Treated set (OR) for patients who completed the day 28 visit
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| T2DM Naive | Change From Baseline in Rate of Endogenous Glucose Production: iAUC 5h, at Day 28 | -6.95 g | Standard Error 2.26 |
| T2DM Metformin | Change From Baseline in Rate of Endogenous Glucose Production: iAUC 5h, at Day 28 | -10.63 g | Standard Error 2.5 |
| Impaired Glucose Tolerance | Change From Baseline in Rate of Endogenous Glucose Production: iAUC 5h, at Day 28 | -0.49 g | Standard Error 5.22 |
Comparison: No formal testing, exploratory analysis only.p-value: 0.279595% CI: [-10.41, 3.05]ANCOVA