Clinical trial NCT02324842: Effect of Combined Incretin-Based Therapy Plus Canagliflozin on Glycemic Control and the Compensatory Rise in Hepatic Glucose Production in Type 2 Diabetic Patients
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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Type 2 Diabetes Mellitus
Lead sponsor: The University of Texas Health Science Center at San Antonio
Sponsor class: OTHER
Collaborators: name: Janssen Scientific Affairs, LLC
First posted: 2014-12-24
Enrollment: 45
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Eligibility 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

Primary outcomes:
measure: HbA1c at 4 Months
timeFrame: Approximately 4 months
measure: Fasting Plasma Glucose (FPG) at 4 Months
timeFrame: Baseline to Approximately 4 months
Secondary outcomes:
measure: Body Mass Index (BMI) at 4 Months
timeFrame: Approximately 4 months
Other outcomes:
measure: Change in Matsuda Index of Insulin Sensitivity, Insulin Secretion, and Beta Cell Function During Oral Glucose Tolerance Test (OGTT)
timeFrame: Change from Baseline to Approximately 4 months
measure: Change in Free Plasma Insulin at the End of the Study From Baseline Value
timeFrame: At Approximately 4 months
measure: Change in Plasma Glucagon Concentration at the End of the Study Compared to Baseline
timeFrame: Approximately 4 months
measure: Change in Total Body Weight at Study End Compared to Baseline
timeFrame: Approximately 4 months
measure: Change in 24-hour Blood Pressure at Study End Compared to Baseline.
timeFrame: Approximately 4 months
Locations:
city: San Antonio
country: United States
facility: University of Texas Health Science Center at San Antonio
state: Texas
Study officials:
affiliation: The University of Texas Health Science Center at San Antonio
name: Eugenio Cersosimo, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Ali AM, Mari A, Martinez R, Al-Jobori H, Adams J, Triplitt C, DeFronzo R, Cersosimo E, Abdul-Ghani M. Improved Beta Cell Glucose Sensitivity Plays Predominant Role in the Decrease in HbA1c with Cana and Lira in T2DM. J Clin Endocrinol Metab. 2020 Oct 1;105(10):dgaa494. doi: 10.1210/clinem/dgaa494.
citation: Ali AM, Martinez R, Al-Jobori H, Adams J, Triplitt C, DeFronzo R, Cersosimo E, Abdul-Ghani M. Combination Therapy With Canagliflozin Plus Liraglutide Exerts Additive Effect on Weight Loss, but Not on HbA1c, in Patients With Type 2 Diabetes. Diabetes Care. 2020 Jun;43(6):1234-1241. doi: 10.2337/dc18-2460. Epub 2020 Mar 27.