Effect of Combined Incretin-Based Therapy Plus Canagliflozin on Glycemic Control and the Compensatory Rise in Hepatic Glucose Production in Type 2 Diabetic Patients

• Sponsor: The University of Texas Health Science Center at San Antonio (Other)
• Overall Status: Completed
• CT.gov ID: NCT02324842
• Collaborator: Janssen Scientific Affairs, LLC (Industry)
• Enrollment: 45
• Location: 1
• Arms: 3
• Duration (Months): 52.9
• Patients Per Site Per Month: 0.9

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Type 2 Diabetes Mellitus	Drug: Canagliflozin; Drug: Liraglutide	N/A

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 45 participants
• Allocation: Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Effect of Combined Incretin-Based Therapy Plus Canagliflozin on Glycemic Control and the Compensatory Rise in Hepatic Glucose Production in Type 2 Diabetic Patients
• Study Start Date: Nov 1, 2014
• Actual Primary Completion Date: Mar 28, 2018
• Actual Study Completion Date: Mar 31, 2019

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Canagliflozin canagliflozin (film-coated tablet), 100 mg/day, increased to 300 mg/day after week two if tolerated without side effects	Drug: 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); Other Names: Invokana
Active Comparator: liraglutide liraglutide, 1.2 mg/day, increased to 1.8 mg/day after week two if tolerated without side effects	Drug: 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.; Other Names: Victoza
Active Comparator: 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	Drug: 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); Other Names: Invokana ; Drug: 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.; Other Names: Victoza

Outcome Measures

Primary Outcome Measures

1. 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.

2. 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 Outcome Measures

1. 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 Outcome Measures

1. 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

2. 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.

3. 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.

4. 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.

5. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 70 Years
• Sexes Eligible for Study: All
• Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Texas Health Science Center at San Antonio	San Antonio	Texas	United States	78229

Sponsors and Collaborators

• The University of Texas Health Science Center at San Antonio
• Janssen Scientific Affairs, LLC

Investigators

• Principal Investigator: Eugenio Cersosimo, MD, The University of Texas Health Science Center at San Antonio

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Mar 19, 2018

More Information

Publications

None provided.

• Responsible Party: The University of Texas Health Science Center at San Antonio
• ClinicalTrials.gov Identifier: NCT02324842
• Other Study ID Numbers: 28431754DIA4009; HSC20140322H
• First Posted: Dec 24, 2014
• Last Update Posted: Dec 18, 2019
• Last Verified: Apr 1, 2019

• Additional relevant MeSH terms: Diabetes Mellitus, Type 2; Liraglutide; Canagliflozin

Study Results

Participant Flow

Arm/Group Title	Canagliflozin	Liraglutide	Canagliflozin Plus Liraglutide
Arm/Group Description	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)	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.	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.
Period Title: Overall Study
STARTED	15	15	15
COMPLETED	14	14	13
NOT COMPLETED	1	1	2

Baseline Characteristics

Arm/Group Title	Canagliflozin	Liraglutide	Canagliflozin Plus Liraglutide	Total
Arm/Group Description	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)	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.	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.	Total of all reporting groups
Overall Participants	14	14	13	41
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	14 100%	14 100%	13 100%	41 100%
>=65 years	0 0%	0 0%	0 0%	0 0%
Sex: Female, Male (Count of Participants)
Female	4 28.6%	6 42.9%	7 53.8%	17 41.5%
Male	10 71.4%	8 57.1%	6 46.2%	24 58.5%
Race and Ethnicity Not Collected (Count of Participants)
Count of Participants [Participants]	0 0%
Region of Enrollment (participants) [Number]
United States	14 100%	14 100%	13 100%	41 100%

Outcome Measures

1. Primary Outcome

Title	HbA1c at 4 Months
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Canagliflozin	Liraglutide	Canagliflozin Plus Liraglutide
Arm/Group Description	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)	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.	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.
Measure Participants	15	15	15
Mean (Standard Deviation) [percentage glycated hemoglobin]	8.2 (0.3)	8.4 (0.3)	8.1 (0.3)

2. Primary Outcome

Title	Fasting Plasma Glucose (FPG) at 4 Months
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Canagliflozin	Liraglutide	Canagliflozin Plus Liraglutide
Arm/Group Description	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)	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.	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.
Measure Participants	15	15	15
Mean (Standard Deviation) [mg/dl]	174 (12)	177 (10)	180 (15)

3. Secondary Outcome

Title	Body Mass Index (BMI) at 4 Months
Description	A measure of BMI at 4 months to examine effects of combination therapy with liraglutide plus canagliflozin.
Time Frame	Approximately 4 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Canagliflozin	Liraglutide	Canagliflozin Plus Liraglutide
Arm/Group Description	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)	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.	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.
Measure Participants	15	15	15
Mean (Standard Deviation) [kg/m2]	34.8 (1.7)	35.1 (1.1)	34.8 (1.1)

4. Other Pre-specified Outcome

Title	Change in Matsuda Index of Insulin Sensitivity, Insulin Secretion, and Beta Cell Function During Oral Glucose Tolerance Test (OGTT)
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Canagliflozin	Liraglutide	Canagliflozin Plus Liraglutide
Arm/Group Description	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)	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.	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.
Measure Participants	15	15	15
Mean (Standard Deviation) [index value]	0.8 (0.4)	-0.5 (0.4)	0.1 (0.2)

5. Other Pre-specified Outcome

Title	Change in Free Plasma Insulin at the End of the Study From Baseline Value
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Canagliflozin	Liraglutide	Canagliflozin Plus Liraglutide
Arm/Group Description	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)	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.	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.
Measure Participants	15	15	15
Mean (Standard Deviation) [mg/ml]	-2 (2)	2 (2)	0.7 (1)

6. Other Pre-specified Outcome

Title	Change in Plasma Glucagon Concentration at the End of the Study Compared to Baseline
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Canagliflozin	Liraglutide	Canagliflozin Plus Liraglutide
Arm/Group Description	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)	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.	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.
Measure Participants	15	15	15
Mean (Standard Deviation) [mg/ml]	12 (6)	-7 (5)	-5 (5)

7. Other Pre-specified Outcome

Title	Change in Total Body Weight at Study End Compared to Baseline
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Canagliflozin	Liraglutide	Canagliflozin Plus Liraglutide
Arm/Group Description	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)	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.	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.
Measure Participants	15	15	15
Mean (Standard Deviation) [kg]	-3.5 (0.5)	-1.9 (.8)	-6.0 (0.8)

8. Other Pre-specified Outcome

Title	Change in 24-hour Blood Pressure at Study End Compared to Baseline.
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Canagliflozin	Liraglutide	Canagliflozin Plus Liraglutide
Arm/Group Description	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)	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.	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.
Measure Participants	15	15	15
Mean (Standard Deviation) [mmHg]	-5.2 (2.2)	5.1 (3.8)	-14.1 (3.0)

Adverse Events

Time Frame	Adverse Events were reported from Baseline to 4 months
Arm/Group Title	Canagliflozin		Liraglutide		Canagliflozin Plus Liraglutide
Arm/Group Description	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)		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.		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.
All Cause Mortality
	Canagliflozin		Liraglutide		Canagliflozin Plus Liraglutide
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/15 (0%)		0/15 (0%)		0/15 (0%)
Serious Adverse Events
	Canagliflozin		Liraglutide		Canagliflozin Plus Liraglutide
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/15 (6.7%)		0/15 (0%)		0/15 (0%)
General disorders
Dehydration/Hyperkalemia	1/15 (6.7%)	1	0/15 (0%)	0	0/15 (0%)	0
Other (Not Including Serious) Adverse Events
	Canagliflozin		Liraglutide		Canagliflozin Plus Liraglutide
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	13/15 (86.7%)		13/15 (86.7%)		12/15 (80%)
Gastrointestinal disorders
Nausea	1/15 (6.7%)	1	9/15 (60%)	11	8/15 (53.3%)	12
Dry Mouth	4/15 (26.7%)	5	0/15 (0%)	0	6/15 (40%)	7
Abdominal Discomfort	3/15 (20%)	3	7/15 (46.7%)	11	4/15 (26.7%)	4
Decreased Appetite	0/15 (0%)	0	3/15 (20%)	3	2/15 (13.3%)	2
Gastrointestinal Reflux/Indigestion	0/15 (0%)	0	1/15 (6.7%)	1	4/15 (26.7%)	7
Constipation	0/15 (0%)	0	5/15 (33.3%)	5	5/15 (33.3%)	6
General disorders
Fatigue	3/15 (20%)	3	2/15 (13.3%)	2	1/15 (6.7%)	1
Metabolism and nutrition disorders
Symptomatic Hypoglycemia	0/15 (0%)	0	3/15 (20%)	3	3/15 (20%)	3
Musculoskeletal and connective tissue disorders
Bilateral Leg Cramps	1/15 (6.7%)	1	1/15 (6.7%)	1	0/15 (0%)	0
Nervous system disorders
Light-headedness/Dizziness	4/15 (26.7%)	5	1/15 (6.7%)	1	2/15 (13.3%)	3
Headache	2/15 (13.3%)	2	0/15 (0%)	0	1/15 (6.7%)	1
Anxiety	0/15 (0%)	0	0/15 (0%)	0	1/15 (6.7%)	1
Renal and urinary disorders
Urinary Frequency increased	13/15 (86.7%)	15	0/15 (0%)	0	3/15 (20%)	3
Urinary Tract Infection	1/15 (6.7%)	1	0/15 (0%)	0	0/15 (0%)	0
Reproductive system and breast disorders
Vaginal Candidiasis	0/15 (0%)	0	0/15 (0%)	0	3/15 (20%)	3
Vaginal itching or foreskin pain	2/15 (13.3%)	3	0/15 (0%)	0	0/15 (0%)	0
Respiratory, thoracic and mediastinal disorders
Cough and nasal congestion	2/15 (13.3%)	2	0/15 (0%)	0	1/15 (6.7%)	1
Skin and subcutaneous tissue disorders
Redness at Injection Site	0/15 (0%)	0	1/15 (6.7%)	1	2/15 (13.3%)	2
Rash	1/15 (6.7%)	1	0/15 (0%)	0	0/15 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.