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

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ClinicalTrials.gov Identifier: NCT03331289
Recruitment Status : Recruiting
First Posted : November 6, 2017
Last Update Posted : March 21, 2018
Sponsor:
Collaborator:
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Information provided by (Responsible Party):
Ralph DeFronzo, 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


Condition or disease Intervention/treatment Phase
Diabetes Mellitus, Type 2 Drug: Placebo Drug: Exenatide Drug: Dapagliflozin Drug: Exenatide and Dapagliflozin Phase 4

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 80 participants
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
Masking: None (Open Label)
Primary Purpose: Basic Science
Official Title: 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
Actual Study Start Date : February 28, 2018
Estimated Primary Completion Date : March 30, 2019
Estimated Study Completion Date : October 30, 2019

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Placebo Comparator: Placebo
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.
Drug: Placebo
Placebo will be administered to 20 subjects after a 3 hour tracer equilibration period

Active Comparator: Exenatide
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.
Drug: Exenatide
Exenatide will be administered to 20 subjects after a 3 hour tracer equilibration period
Other Name: Byetta, Bydureon

Active Comparator: Dapagliflozin
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.
Drug: Dapagliflozin
Dapagliflozin will be administered to 20 subjects after a 3 hour tracer equilibration period
Other Name: Farxiga

Active Comparator: Exenatide and Dapagliflozin
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.
Drug: Exenatide and Dapagliflozin
Exenatide and Dapagliflozin will be administered to 20 subjects after a 3 hour tracer equilibration period




Primary Outcome Measures :
  1. Change in EGP [ Time Frame: 240-300 minutes ]
    The difference in rate of EGP during the last hour of the study (from 240-300 minutes) between drug-treatment and placebo treatment studies represents the effect of drug treatment on EGP, which will be compared among the 3 drug treatments (exenatide; dapagliflozin; exenatide plus dapagliflozin) with ANOVA.

  2. change in EGP above baseline following dapagliflozin alone versus dapagliflozin/exenatide [ Time Frame: -35 - 0 minutes ]
    The following primary comparison will be performed: (i) change in EGP above baseline following dapagliflozin alone versus dapagliflozin/exenatide.



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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
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 <10.0%
  • 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)

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): NCT03331289


Contacts
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Contact: Ralph DeFronzo, MD 210-567-6691 defronzo@uthscsa.edu
Contact: Eugenio Cersosimo, MD PhD 210-358-7200 cersosimo@uthsca.edu

Locations
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United States, Texas
University Health System Texas Diabetic Institute Recruiting
San Antonio, Texas, United States, 78207
Contact: Ralph DeFronzo, MD    210-567-6691    defronzo@uthscsa.edu   
Sponsors and Collaborators
Ralph DeFronzo
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

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Responsible Party: Ralph DeFronzo, Chair in Diabetes, The University of Texas Health Science Center at San Antonio
ClinicalTrials.gov Identifier: NCT03331289     History of Changes
Other Study ID Numbers: HSC20170582H
R01DK107680 ( U.S. NIH Grant/Contract )
First Posted: November 6, 2017    Key Record Dates
Last Update Posted: March 21, 2018
Last Verified: March 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes

Additional relevant MeSH terms:
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Diabetes Mellitus
Diabetes Mellitus, Type 2
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Exenatide
2-(3-(4-ethoxybenzyl)-4-chlorophenyl)-6-hydroxymethyltetrahydro-2H-pyran-3,4,5-triol
Hypoglycemic Agents
Physiological Effects of Drugs
Anti-Obesity Agents
Incretins
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Sodium-Glucose Transporter 2 Inhibitors
Molecular Mechanisms of Pharmacological Action