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

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ClinicalTrials.gov Identifier: NCT02324842
Recruitment Status : Completed
First Posted : December 24, 2014
Results First Posted : May 14, 2019
Last Update Posted : December 18, 2019
Sponsor:
Collaborator:
Janssen Scientific Affairs, LLC
Information provided by (Responsible Party):
The University of Texas Health Science Center at San Antonio

Study Description
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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 Not Applicable

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
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Study Type : Interventional  (Clinical Trial)
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 : November 2014
Actual Primary Completion Date : March 28, 2018
Actual Study Completion Date : March 31, 2019

Resource links provided by the National Library of Medicine


Arms and Interventions
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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 Name: 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 Name: 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 Name: 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 Name: Victoza


Outcome Measures
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Primary Outcome Measures :
  1. HbA1c at 4 Months [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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) [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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. [ Time Frame: 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
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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02324842


Locations
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United States, Texas
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
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Principal Investigator: Eugenio Cersosimo, MD The University of Texas Health Science Center at San Antonio
  Study Documents (Full-Text)

Documents provided by The University of Texas Health Science Center at San Antonio:
Study Protocol and Statistical Analysis Plan  [PDF] March 19, 2018

More Information
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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: The University of Texas Health Science Center at San Antonio
ClinicalTrials.gov Identifier: NCT02324842    
Other Study ID Numbers: 28431754DIA4009
HSC20140322H ( Other Identifier: University of Texas Health Science Center- San Antonio )
First Posted: December 24, 2014    Key Record Dates
Results First Posted: May 14, 2019
Last Update Posted: December 18, 2019
Last Verified: April 2019
Additional relevant MeSH terms:
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Canagliflozin
Diabetes Mellitus, Type 2
Diabetes Mellitus
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Liraglutide
 Hypoglycemic Agents
Physiological Effects of Drugs
Incretins
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Sodium-Glucose Transporter 2 Inhibitors
Molecular Mechanisms of Pharmacological Action