Type 2 Diabetes Mellitus
Conditions
Brief summary
Specific Aim 1.To examine whether the combination of liraglutide plus canagliflozin can prevent the increase in Hepatic Glucose Production (HGP) following institution of canagliflozin therapy and produce an additive or even synergistic effect to lower the plasma glucose concentration and A1c. Specific Aim 2: To examine whether combination therapy with liraglutide plus canagliflozin can produce an additive, or even synergistic, effect to promote weight loss and reduction in hepatic and visceral fat content. Specific Aim 3. To examine whether combination therapy with liraglutide plus canagliflozin can produce an additive or even synergistic effect to reduce systolic/diastolic blood pressure and 24-hour integrated blood pressure.
Detailed description
Specific Aim 1.To examine whether the combination of liraglutide plus canagliflozin can prevent the increase in HGP following institution of canagliflozin therapy and produce an additive or even synergistic effect to lower the plasma glucose concentration and A1c. We will examine this hypothesis by comparing the effect of administration of liraglutide alone, canagliflozin alone, and the combination of liraglutide plus canagliflozin on:(i) the rate of HGP; (ii) decrease in fasting plasma glucose concentration; (iii) counter-regulatory hormone response and (iv) A1c. We anticipate that the addition of liraglutide to canagliflozin will prevent the increase in plasma glucagon concentration, augment insulin secretion, and blunt/block the increase in HGP in response to canagliflozin, resulting in a greater decrease in fasting plasma glucose concentration and A1c than observed with each therapy alone. Specific Aim 2: To examine whether combination therapy with liraglutide plus canagliflozin can produce an additive, or even synergistic, effect to promote weight loss and reduction in hepatic and visceral fat content. Specific Aim 3. To examine whether combination therapy with liraglutide plus canagliflozin can produce an additive or even synergistic effect to reduce systolic/diastolic blood pressure and 24-hour integrated blood pressure.
Interventions
DRUGCanagliflozin
Canagliflozin is a sodium-glucose co-transporter 2 (SGLT2) inhibitor indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus (1)
DRUGLiraglutide
Liraglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.
Sponsors
Janssen Scientific Affairs, LLC
The University of Texas Health Science Center at San Antonio
Study design
Allocation
RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* Male and female subjects between the ages of 18-70 * Subjects with Type 2 Diabetes Mellitus (T2DM) * Drug naïve or on stable dose (more than 3 months) of metformin with or without sulfonylurea * Have an HbA1c levels ≥7.0% and \<10.0% * Stable weight (± 3 lbs) over the preceding 3 months
Exclusion criteria
* Subjects taking drugs known to affect glucose metabolism (other than metformin) will be excluded. * Individuals with evidence of proliferative diabetic retinopathy or plasma creatinine \>1.4 females or \>1.5 males or estimated Glomerular Filtration Rate (eGFR)\< 60 ml/min.172m2 will be excluded * Unstable body weight (change of greater than ±3 lbs over the preceding 3 months) * Participates in excessively heavy exercise program
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| HbA1c at 4 Months | Approximately 4 months | Primary end point of the study is the HbA1c level in response to canagliflozin alone, liraglutide or canagliflozin with liraglutide. |
| Fasting Plasma Glucose (FPG) at 4 Months | Baseline to Approximately 4 months | Values will be presented as the mean + (Standard Deviation) SD. The difference in HGP and all secondary endpoints at study end versus baseline will be calculated and compared between each active treatment group with ANOVA. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Body Mass Index (BMI) at 4 Months | Approximately 4 months | A measure of BMI at 4 months to examine effects of combination therapy with liraglutide plus canagliflozin. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Change in Free Plasma Insulin at the End of the Study From Baseline Value | At Approximately 4 months | Values will be presented as the mean + SD. The difference in HGP and all secondary endpoints at study end versus baseline will be calculated and compared between each active treatment group with ANOVA. |
| Change in Plasma Glucagon Concentration at the End of the Study Compared to Baseline | Approximately 4 months | Values will be presented as the mean + SD. The difference in HGP and all secondary endpoints at study end versus baseline will be calculated and compared between each active treatment group with ANOVA. |
| Change in Total Body Weight at Study End Compared to Baseline | Approximately 4 months | Values will be presented as the mean + SD. The difference in HGP and all secondary endpoints at study end versus baseline will be calculated and compared between each active treatment group with ANOVA. The difference between baseline and study end will represent the change in body weight due to change in hepatic, visceral and abdominal subcutaneous fat. |
| Change in 24-hour Blood Pressure at Study End Compared to Baseline. | Approximately 4 months | Values will be presented as the mean + SD. The difference in HGP and all secondary endpoints at study end versus baseline will be calculated and compared between each active treatment group with ANOVA. |
| Change in Matsuda Index of Insulin Sensitivity, Insulin Secretion, and Beta Cell Function During Oral Glucose Tolerance Test (OGTT) | Change from Baseline to Approximately 4 months | Values will be presented as the mean + SD. The Matsuda Index is a novel assessment of insulin sensitivity that is simple to calculate and provides a reasonable approximation of whole-body insulin sensitivity from the OGTT. The index is calculated from plasma glucose (mg/dl) and insulin (mIU/l) concentrations in both fasting state and post-OGTT. The index value obtained is compared to normal physiologic values to assess insulin sensitivity or resistance. The higher the number, the more insulin sensitive and the lower the number the more insulin resistant the subjects are. Insulin secretion will be measured from plasma C-peptide concentration during the OGTT and the Mari Model will be used to measure beta cell glucose sensitivity |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Canagliflozin canagliflozin (film-coated tablet), 100 mg/day, increased to 300 mg/day after week two if tolerated without side effects
Canagliflozin: Canagliflozin is a sodium-glucose co-transporter 2 (SGLT2) inhibitor indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus (1) | 14 |
| Liraglutide liraglutide, 1.2 mg/day, increased to 1.8 mg/day after week two if tolerated without side effects
Liraglutide: Liraglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. | 14 |
| Canagliflozin Plus Liraglutide canagliflozin, 100 mg/day, plus liraglutide, 1.2 mg/day, increased to 300 mg/day and 1.8 mg/day, respectively at week two, if tolerated without side effects
Canagliflozin: Canagliflozin is a sodium-glucose co-transporter 2 (SGLT2) inhibitor indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus (1)
Liraglutide: Liraglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. | 13 |
| Total | 41 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Lost to Follow-up | 1 | 1 | 2 |
Baseline characteristics
| Characteristic | Total | Liraglutide | Canagliflozin Plus Liraglutide | Canagliflozin |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 41 Participants | 14 Participants | 13 Participants | 14 Participants |
| Race and Ethnicity Not Collected | 0 Participants | — | — | — |
| Region of Enrollment United States | 41 participants | 14 participants | 13 participants | 14 participants |
| Sex: Female, Male Female | 17 Participants | 6 Participants | 7 Participants | 4 Participants |
| Sex: Female, Male Male | 24 Participants | 8 Participants | 6 Participants | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 15 | 0 / 15 | 0 / 15 |
| other Total, other adverse events | 13 / 15 | 13 / 15 | 12 / 15 |
| serious Total, serious adverse events | 1 / 15 | 0 / 15 | 0 / 15 |
Outcome results
Primary
Fasting Plasma Glucose (FPG) at 4 Months
Values will be presented as the mean + (Standard Deviation) SD. The difference in HGP and all secondary endpoints at study end versus baseline will be calculated and compared between each active treatment group with ANOVA.
Time frame: Baseline to Approximately 4 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Canagliflozin | Fasting Plasma Glucose (FPG) at 4 Months | 174 mg/dl | Standard Deviation 12 |
| Liraglutide | Fasting Plasma Glucose (FPG) at 4 Months | 177 mg/dl | Standard Deviation 10 |
| Canagliflozin Plus Liraglutide | Fasting Plasma Glucose (FPG) at 4 Months | 180 mg/dl | Standard Deviation 15 |
Primary
HbA1c at 4 Months
Primary end point of the study is the HbA1c level in response to canagliflozin alone, liraglutide or canagliflozin with liraglutide.
Time frame: Approximately 4 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Canagliflozin | HbA1c at 4 Months | 8.2 percentage glycated hemoglobin | Standard Deviation 0.3 |
| Liraglutide | HbA1c at 4 Months | 8.4 percentage glycated hemoglobin | Standard Deviation 0.3 |
| Canagliflozin Plus Liraglutide | HbA1c at 4 Months | 8.1 percentage glycated hemoglobin | Standard Deviation 0.3 |
Secondary
Body Mass Index (BMI) at 4 Months
A measure of BMI at 4 months to examine effects of combination therapy with liraglutide plus canagliflozin.
Time frame: Approximately 4 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Canagliflozin | Body Mass Index (BMI) at 4 Months | 34.8 kg/m2 | Standard Deviation 1.7 |
| Liraglutide | Body Mass Index (BMI) at 4 Months | 35.1 kg/m2 | Standard Deviation 1.1 |
| Canagliflozin Plus Liraglutide | Body Mass Index (BMI) at 4 Months | 34.8 kg/m2 | Standard Deviation 1.1 |
Other Pre-specified
Change in 24-hour Blood Pressure at Study End Compared to Baseline.
Values will be presented as the mean + SD. The difference in HGP and all secondary endpoints at study end versus baseline will be calculated and compared between each active treatment group with ANOVA.
Time frame: Approximately 4 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Canagliflozin | Change in 24-hour Blood Pressure at Study End Compared to Baseline. | -5.2 mmHg | Standard Deviation 2.2 |
| Liraglutide | Change in 24-hour Blood Pressure at Study End Compared to Baseline. | 5.1 mmHg | Standard Deviation 3.8 |
| Canagliflozin Plus Liraglutide | Change in 24-hour Blood Pressure at Study End Compared to Baseline. | -14.1 mmHg | Standard Deviation 3 |
Other Pre-specified
Change in Free Plasma Insulin at the End of the Study From Baseline Value
Values will be presented as the mean + SD. The difference in HGP and all secondary endpoints at study end versus baseline will be calculated and compared between each active treatment group with ANOVA.
Time frame: At Approximately 4 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Canagliflozin | Change in Free Plasma Insulin at the End of the Study From Baseline Value | -2 mg/ml | Standard Deviation 2 |
| Liraglutide | Change in Free Plasma Insulin at the End of the Study From Baseline Value | 2 mg/ml | Standard Deviation 2 |
| Canagliflozin Plus Liraglutide | Change in Free Plasma Insulin at the End of the Study From Baseline Value | 0.7 mg/ml | Standard Deviation 1 |
Other Pre-specified
Change in Matsuda Index of Insulin Sensitivity, Insulin Secretion, and Beta Cell Function During Oral Glucose Tolerance Test (OGTT)
Values will be presented as the mean + SD. The Matsuda Index is a novel assessment of insulin sensitivity that is simple to calculate and provides a reasonable approximation of whole-body insulin sensitivity from the OGTT. The index is calculated from plasma glucose (mg/dl) and insulin (mIU/l) concentrations in both fasting state and post-OGTT. The index value obtained is compared to normal physiologic values to assess insulin sensitivity or resistance. The higher the number, the more insulin sensitive and the lower the number the more insulin resistant the subjects are. Insulin secretion will be measured from plasma C-peptide concentration during the OGTT and the Mari Model will be used to measure beta cell glucose sensitivity
Time frame: Change from Baseline to Approximately 4 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Canagliflozin | Change in Matsuda Index of Insulin Sensitivity, Insulin Secretion, and Beta Cell Function During Oral Glucose Tolerance Test (OGTT) | 0.8 index value | Standard Deviation 0.4 |
| Liraglutide | Change in Matsuda Index of Insulin Sensitivity, Insulin Secretion, and Beta Cell Function During Oral Glucose Tolerance Test (OGTT) | -0.5 index value | Standard Deviation 0.4 |
| Canagliflozin Plus Liraglutide | Change in Matsuda Index of Insulin Sensitivity, Insulin Secretion, and Beta Cell Function During Oral Glucose Tolerance Test (OGTT) | 0.1 index value | Standard Deviation 0.2 |
Other Pre-specified
Change in Plasma Glucagon Concentration at the End of the Study Compared to Baseline
Values will be presented as the mean + SD. The difference in HGP and all secondary endpoints at study end versus baseline will be calculated and compared between each active treatment group with ANOVA.
Time frame: Approximately 4 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Canagliflozin | Change in Plasma Glucagon Concentration at the End of the Study Compared to Baseline | 12 mg/ml | Standard Deviation 6 |
| Liraglutide | Change in Plasma Glucagon Concentration at the End of the Study Compared to Baseline | -7 mg/ml | Standard Deviation 5 |
| Canagliflozin Plus Liraglutide | Change in Plasma Glucagon Concentration at the End of the Study Compared to Baseline | -5 mg/ml | Standard Deviation 5 |
Other Pre-specified
Change in Total Body Weight at Study End Compared to Baseline
Values will be presented as the mean + SD. The difference in HGP and all secondary endpoints at study end versus baseline will be calculated and compared between each active treatment group with ANOVA. The difference between baseline and study end will represent the change in body weight due to change in hepatic, visceral and abdominal subcutaneous fat.
Time frame: Approximately 4 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Canagliflozin | Change in Total Body Weight at Study End Compared to Baseline | -3.5 kg | Standard Deviation 0.5 |
| Liraglutide | Change in Total Body Weight at Study End Compared to Baseline | -1.9 kg | Standard Deviation 0.8 |
| Canagliflozin Plus Liraglutide | Change in Total Body Weight at Study End Compared to Baseline | -6.0 kg | Standard Deviation 0.8 |