Can Exenatide Prevent the Increase in EGP in Response to Dapagliflozin-induced Increase in Glucosuria

SGLT2 INHIBITION AND STIMULATION OF ENDOGENOUS GLUCOSE PRODUCTION Significance : Protocol- 4 Can the GLP-1 Receptor Agonist, Exenatide, Prevent the Increase in EGP in Response to Dapagliflozin-induced Increase in Glucosuria

Sponsors

Lead Sponsor: The University of Texas Health Science Center at San Antonio

Collaborator: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Source The University of Texas Health Science Center at San Antonio
Brief Summary

Research Design/Plan: After screening, each subject will receive 1 measurements of EGP with prime-continuous Infusion of 3-3H-glucose. After completing the EGP measurement each subject will receive a Double Tracer OGTT.

Methods: Visit 1: Screening. Medical history will be obtained, physical exam performed, and pregnancy test performed.

Visit 2: Endogenous Glucose Production Measurement: The rate of EGP will be measured with 3-3H-glucose.

Visit 3: Double Tracer OGTT

Detailed Description

Eligible subjects will receive a measurement of endogenous glucose production (EGP) with a prime-continuous infusion of 3-3H-glucose. The EGP measurement will be performed in the morning after a 10-12 hour overnight fast and will last 8 hours (from 6 AM to 2 PM). After a 3-hour tracer equilibration period, subjects (20 per group) will receive one of the following medications: (i) placebo; (ii) exenatide 5 ug subcutaneously; (iii) dapagliflozin (10 mg); and (iv) dapagliflozin 10 mg plus exenatide 5 ug. Following the test medication at 9 AM, blood samples will be drawn every 15 minutes for an additional 5 hours and plasma glucose, insulin, C-peptide, glucagon, cortisol, growth hormone, and catecholamine concentrations and glucose specific activity will be measured.

Visit 1: Screening. Medical history & physical exam will be performed. Blood will be drawn for FPG, routine blood chemistries, CBC, lipid profile, HbA1c, and thyroid function. Urinalysis, EKG, albumin/creatinine ratio and pregnancy test will be performed.

Visit 2: EPG Measurement: The rate of endogenous glucose production will be measured with 3-3H-glucose infusion. [3-3H]-glucose infusion will be started at 6 AM and continued until 2:30 PM (5 hours after drug administration). At 6 AM a catheter will be placed into an anticubital vein and a prime (40 uCi x FPG/100)- continuous (0.4 uCi) infusion of [3-3H]- glucose will be started and continued until 2:30 PM. (5 hours after drug administration). Participant's hand will be placed in a box heated to 50-60°C (122-140°F). Baseline blood samples will be obtained at-210, -60, -50, -45, -40, -35, -30, -20, -10, and 0 . After 3.5 hours of tracer equilibration blood samples will be obtained every 10-20 minutes from 9 AM to 2 PM. Plasma glucose, insulin, C-peptide, glucagon, cortisol, growth hormone, and catecholamine concentrations, and [3-3H]-glucose specific activity will be measured. Urine will be collected from 6 to 9 AM and from 9 AM to 2 PM. Urinary volume and glucose concentration will be measured and urinary glucose excretion rate calculated. The study will end at 2:30 PM.

Visit 3: Double Tracer Oral Glucose Tolerance Test: Within the week after the measurement of EGP, all subjects will have a 5-hour OGTT with measurement of plasma glucose, insulin (I), C-peptide (CP), and glucagon concentrations at -180, -6-, -5-, -45, -40, -35, -30, -20, -10, 0 and every 15-30 minutes thereafter to obtain a measure of overall glucose tolerance, insulin secretion (CP0-120/G0-120), insulin sensitivity ([MI]), beta cell function, (CP0-120/G0-120 x MI), and suppression of plasma glucagon concentration (64). At 7 AM a catheter will be placed into an anticubital vein and a prime (25 uCi x FPG/100)- continuous (0.25 uCi) infusion of [3-3H]- glucose will be started and continued until 3 PM. Urinary volume and glucose concentration will be measured and urinary glucose excretion rate calculated.

HbA1c will be measured 2x, 1 on the day of the OGTT & 1 on the day of the EGP measurement.

Overall Status Recruiting
Start Date February 28, 2018
Completion Date December 31, 2022
Primary Completion Date December 31, 2021
Phase Phase 4
Study Type Interventional
Primary Outcome
Measure Time Frame
Change in EGP 240-300 minutes
change in EGP above baseline following dapagliflozin alone versus dapagliflozin/exenatide -35 - 0 minutes
Enrollment 80
Condition
Intervention

Intervention Type: Drug

Intervention Name: Placebo

Description: Placebo will be administered to 20 subjects after a 3 hour tracer equilibration period

Arm Group Label: Placebo

Intervention Type: Drug

Intervention Name: Exenatide

Description: Exenatide will be administered to 20 subjects after a 3 hour tracer equilibration period

Arm Group Label: Exenatide

Other Name: Byetta, Bydureon

Intervention Type: Drug

Intervention Name: Dapagliflozin

Description: Dapagliflozin will be administered to 20 subjects after a 3 hour tracer equilibration period

Arm Group Label: Dapagliflozin

Other Name: Farxiga

Intervention Type: Drug

Intervention Name: Exenatide and Dapagliflozin

Description: Exenatide and Dapagliflozin will be administered to 20 subjects after a 3 hour tracer equilibration period

Arm Group Label: Exenatide and Dapagliflozin

Eligibility

Criteria:

Inclusion Criteria:

- Health Status: Type 2 Diabetes Mellitus according to ADA criteria (subjects must be in good general health as determined by physical exam, medical history, blood chemistry-CBC, TSH, T4, EKG and urinalysis)

- BMI: 21-45kg/m

- HbA1C>7.0% and <10.5%

- Medication: Drug naïve and/or on a stable dose of metformin and/or sulfonylurea (more than 3 months)

Exclusion Criteria:

- Health Status: Type 1 Diabetics

- Proliferative diabetic retinopathy

- Plasma Creatinine greater than 1.4mg/dL in females or greater than 1.5mg/dL in males, or 24 hour urine albumin excretion greater than 300mg/dL

- Medication: Subjects taking drugs known to affect glucose metabolism (other than metformin and sulfonylurea)

Gender: All

Minimum Age: 18 Years

Maximum Age: 70 Years

Healthy Volunteers: Accepts Healthy Volunteers

Overall Contact

Last Name: Ralph DeFronzo, MD

Phone: 210-567-6691

Email: [email protected]

Location
Facility: Status: Contact: University Health System Texas Diabetic Institute Ralph DeFronzo, MD 210-567-6691 [email protected]
Location Countries

United States

Verification Date

April 2020

Responsible Party

Type: Sponsor

Has Expanded Access No
Condition Browse
Number Of Arms 4
Arm Group

Label: Placebo

Type: Placebo Comparator

Description: we will examine whether the coadministration of exenatide plus dapagliflozin will prevent the increase in EGP and result in an additive or even synergistic decrease in plasma glucose conc compared to each agent alone.

Label: Exenatide

Type: Active Comparator

Description: we will examine whether the coadministration of exenatide plus dapagliflozin will prevent the increase in EGP and result in an additive or even synergistic decrease in plasma glucose conc compared to each agent alone.

Label: Dapagliflozin

Type: Active Comparator

Description: we will examine whether the coadministration of exenatide plus dapagliflozin will prevent the increase in EGP and result in an additive or even synergistic decrease in plasma glucose conc compared to each agent alone.

Label: Exenatide and Dapagliflozin

Type: Active Comparator

Description: we will examine whether the coadministration of exenatide plus dapagliflozin will prevent the increase in EGP and result in an additive or even synergistic decrease in plasma glucose conc compared to each agent alone.

Patient Data Yes
Study Design Info

Allocation: Randomized

Intervention Model: Single Group Assignment

Intervention Model Description: Participants will be randomized to one of four groups (20 per group): i) placebo; (ii) exenatide 5 ug subcutaneously; (iii) dapagliflozin (10 mg); and (iv) dapagliflozin 10 mg plus exenatide 5 ug

Primary Purpose: Basic Science

Masking: None (Open Label)

Source: ClinicalTrials.gov