Clincosm LogoSign in Get a demo

Modulation of Human Myocardial Metabolism by GLP-1 Dose Response

Sponsor
Indiana University (Other)
Overall Status
Completed
CT.gov ID
NCT01607450
Collaborator
National Heart, Lung, and Blood Institute (NHLBI) (NIH)
33
Enrollment
1
Location
4
Arms
31
Duration (Months)
1.1
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The objective of this proposal is to provide quantitative dose-response data for effects of GLP-1 on myocardial glucose uptake in healthy control subjects and obese type 2 diabetic subjects, in support of the design of later studies evaluating therapeutic applications of GLP-1 to heart disease.

Aim 1: To measure the effects of GLP-1 infusion on myocardial fuel selection in lean healthy humans under fasting (fatty acid-dominant) conditions. Four groups of 10 lean healthy subjects will be studied during infusions of 0 (saline control), 0.5, 1.5, and 4.0 pmol/kg/min GLP-1 (one study per subject). Cardiac metabolism will be measured using PET, using a dual-tracer approach which allows measurement of myocardial glucose uptake (the primary endpoint) along with total oxidation rate and myocardial perfusion (secondary endpoints). In concert with measures of circulating metabolites and regulatory hormones, the investigators will produce the most comprehensive assessment of actions of GLP-1 on myocardial metabolism in humans to date. Effects of each dose will be compared to the saline control, plus the investigators will combine all data and use nonlinear curve-fitting to derive sensitivity (ED50) and maximal responses for GLP-1 effects on myocardial glucose uptake.

Aim 2: To measure the effects of GLP-1 infusion on myocardial fuel selection in obese type 2 diabetic humans under fasting (fatty acid-dominant) conditions Four groups of 10 obese type 2 diabetic subjects will be studied during infusions of 0, 0.5, 1.5, and 4.0 pmol/kg/min GLP-1 as under Aim 1. Analyses will be parallel to those described under Aim 1. Results from Aims 1 and 2 will be combined to allow direct comparison of the dose-response between nondiabetic control and type 2 diabetic subjects.

No literature has been published to inform dose selection in the design of clinical trials of GLP-1 for modulation of heart fuel selection. With our expertise and experience in PET measurement of heart metabolism in diabetes, the investigators are uniquely positioned to fill this gap in knowledge. These studies are a necessary preamble to further evaluation of the potential for GLP-1 based treatments in heart disease.

Condition or Disease Intervention/Treatment Phase
  • Drug: GLP-1 Low Dose
  • Drug: GLP-1 Mid-Range Dose
  • Drug: GLP-1 High Dose
  • Drug: Saline
 Phase 2/Phase 3

Study Design

Study Type:
Interventional
Actual Enrollment :
33 participants
Allocation:
Non-Randomized
Intervention Model:
Parallel Assignment
Masking:
Single (Participant)
Primary Purpose:
Treatment
Official Title:
Modulation of Human Myocardial Metabolism by GLP-1 Dose Response
Study Start Date :
May 1, 2010
Actual Primary Completion Date :
Dec 1, 2012
Actual Study Completion Date :
Dec 1, 2012

Arms and Interventions

Arm Intervention/Treatment
Other: Saline

12 hour saline (control) infusion prior to PET study

Drug: Saline
Normal saline placebo infusion for 12 hours prior to PET study
Other Names:
  • Normal Saline

    		•
    Experimental: GLP-1 Low dose

    GLP-1 Low Dose: 0.5 pmol/kg/min for 12 hours prior to PET study

    Drug: GLP-1 Low Dose
    0.5mmol/kg/hr GLP-1 for 12 hours prior to PET study
    Experimental: GLP-1 Mid-Range Dose

    GLP-1 Mid-Range Dose: 1.5 pmol/kg/min for 12 hours prior to PET study

    Drug: GLP-1 Mid-Range Dose
    1.5mmol/kg/min for 12 hours prior to PET study
    Experimental: GLP-1 High Dose

    GLP-1 High Dose: 4.0 pmol/kg/min for 12 hours prior to PET study

    Drug: GLP-1 High Dose
    4.0mmol/kg/min GLP-1 for 12 hours prior to PET study

    Outcome Measures

    Primary Outcome Measures

    1. Myocardial Glucose Uptake. [After 12 hours of glucagon-like peptide 1 (GLP-1) exposure]

      Myocardial glucose uptake measured using 18FDG PET, quantified using a 3-compartment model with a lumped constant of 1.0.

    Secondary Outcome Measures

    1. Myocardial Blood Flow [After 12 hours of GLP-1 exposure]

      Myocardial perfusion derived from acetate kinetics

    2. Myocardial Total Oxidation Rate [After 12 hours of GLP-1 exposure]

      MVO2 derived from acetate kinetics

    3. Cardiac Index [After 12 hours of GLP-1 exposure]

      Impedance cardiography-derived measurement of cardiac index, assessed following 12 hour exposure to treatment condition concurrent with the PET measurements.

    4. GLP-1 Concentrations [After 12 hours of GLP-1 exposure]

      Achieved GLP-1 concentrations at the end of the 12 hour treatment exposure

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years to 60 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    Yes
    Inclusion Criteria:

    • Age 18-60

    • Lean subjects will be defined as having a BMI <25 kg/m2, in good general health, taking no regular medications

    • Diabetic subjects will be obese (BMI >30 kg/m2 but <40 kg/m2), HbA1c 7.0-10.0%, treated with diet and exercise plus oral agents or injected insulin. All diabetic subjects will be treated with injected insulin for 2 weeks prior to study, to avoid potential confounding effects of other antidiabetic agents.

    Exclusion Criteria:

    • Chronic illnesses or infections (other than type 2 diabetes)

    • Known coronary artery disease or abnormal ECG on screening evaluation

    • Blood pressure > 160/100 mmHg on two occasions during screening evaluations. Current use of 3 or fewer blood pressure medications with blood pressure below this cutpoint will be acceptable.

    • Total cholesterol > 240 mg/dL. Current use of 2 or fewer lipid lowering agents with cholesterol below this cutpoint will be acceptable.

    • Diabetic subjects: Treatment with a GLP-1 agonist or DPP4 inhibitor within the past 6 months

    • Known intolerance to injected GLP-1 agonist

    • Treatment with PPAR gamma agonists currently or within the past 6 months

    • Recognized microvascular complications (retinopathy, nephropathy, neuropathy)

    • Unwillingness or inability to use injected insulin for the purposes of this study

    • Chronic pain or other physical conditions which limit ability to remain supine for the duration of the study protocol

    • History of claustrophobia, musculoskeletal or other factors which would result in an inability to comfortably remain within PET scanner gantry for the duration of the imaging protocol

    • Occupational, investigational or other known radiation exposure which, together with the planned radiologic studies, will result in greater than 500 mrem total exposure in a contiguous 12 month period

    • For female participants, current pregnancy

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Indiana Clinical Research Center Indianapolis Indiana United States 46202

    Sponsors and Collaborators

    • Indiana University
    • National Heart, Lung, and Blood Institute (NHLBI)

    Investigators

    • Principal Investigator: Kieren J Mather, MD, Indiana University

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Indiana University
    ClinicalTrials.gov Identifier:
    NCT01607450
    Other Study ID Numbers:
    • 1010002497
    • R21HL092799
    First Posted:
    May 30, 2012
    Last Update Posted:
    Feb 17, 2016
    Last Verified:
    Jan 1, 2016
    Keywords provided by Indiana University
    Type 2 diabetes mellitus
    lean healthy control
    Additional relevant MeSH terms:
    Diabetes Mellitus
    Diabetes Mellitus, Type 2
    Glucagon
    Glucagon-Like Peptide 1

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail
    Arm/Group Title Lean Placebo Lean GLP-1 Mid-Range Dose Type 2 DM GLP-1 Mid-Range Dose Lean GLP-1 Low Dose Type 2 DM GLP-1 Low Dose Lean GLP-1 High Dose Type 2 DM GLP-1 High Dose
    Arm/Group Description 12 hour placebo (saline) infusion prior to PET study Placebo: Saline placebo infusion for 12 hours prior to PET study GLP-1 Mid-Range Dose: 1.5 pmol/kg/min for 12 hours prior to PET study GLP-1 Mid-Range Dose: 1.5 pmol/kg/min for 12 hours prior to PET study GLP-1 Low Dose: 0.5 pmol/kg/min for 12 hours prior to PET study GLP-1 Low Dose: 0.5 pmol/kg/min for 12 hours prior to PET study GLP-1 High Dose: 4.0 pmol/kg/min for 12 hours prior to PET study GLP-1 High Dose: 1.5 pmol/kg/min for 12 hours prior to PET study
    Period Title: Overall Study
    STARTED 6 8 7 11 1 0 0
    COMPLETED 6 8 7 11 1 0 0
    NOT COMPLETED 0 0 0 0 0 0 0

    Baseline Characteristics

    Arm/Group Title Lean Saline Lean GLP-1 0.5 Pmol/kg/Min Type 2 DM GLP-1 0.5 Pmol/kg/Min Lean GLP-1 1.5 Pmol/kg/Min Type 2 DM GLP-1 1.5 Pmol/kg/Min Lean GLP-1 4.0 Pmol/kg/Min Type 2 DM GLP-1 4.0 Pmol/kg/Min Total
    Arm/Group Description 12 hour placebo (saline) infusion prior to PET study Placebo: Saline placebo infusion for 12 hours prior to PET study GLP-1 Low Dose: 0.5 pmol/kg/min for 12 hours prior to PET study GLP-1 Low Dose: 0.5 pmol/kg/min for 12 hours prior to PET study GLP-1 Mid-Range Dose: 1.5 pmol/kg/min for 12 hours prior to PET study GLP-1 Mid-Range Dose: 1.5 pmol/kg/min for 12 hours prior to PET study GLP-1 High Dose:4.0 pmol/kg/min for 12 hours prior to PET study GLP-1 High Dose:4.0 pmol/kg/min for 12 hours prior to PET study Total of all reporting groups
    Overall Participants 6 11 1 8 7 0 0 33
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    35.5
    (10.6)
    38.0
    (6.0)
    42
    (0)
    46.0
    (5.8)
    45.1
    (7.9)
    42.7
    (7.9)
    Gender (participants) [Number]
    Female
    5
    83.3%
    3
    27.3%
    0
    0%
    3
    37.5%
    1
    14.3%
    12
    Infinity
    Male
    1
    16.7%
    8
    72.7%
    1
    100%
    5
    62.5%
    6
    85.7%
    21
    Infinity
    Region of Enrollment (participants) [Number]
    United States
    6
    100%
    11
    100%
    1
    100%
    8
    100%
    7
    100%
    33
    Infinity
    Body Mass Index (kg/m2) (kg/m^2) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [kg/m^2]
    23.9
    (1.6)
    23.0
    (1.5)
    31.0
    (0)
    22.9
    (1.8)
    30.3
    (1.7)
    25.7
    (1.7)
    HbA1c (%) (%) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [%]
    5.47
    (0.40)
    5.47
    (0.40)
    7.0
    (0)
    5.56
    (0.34)
    8.40
    (3.02)
    6.48
    (1.24)

    Outcome Measures

    1. Primary Outcome
    Title Myocardial Glucose Uptake.
    Description Myocardial glucose uptake measured using 18FDG PET, quantified using a 3-compartment model with a lumped constant of 1.0.
    Time Frame After 12 hours of glucagon-like peptide 1 (GLP-1) exposure

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Lean Saline Lean GLP-1 Low Dose Type 2 DM GLP-1 Low Dose Lean GLP-1 1.5 Pmol/kg/Min Type 2DM GLP-1 1.5 Pmol/kg/Min Lean GLP-1 High Dose Type 2 DM GLP-1 High Dose
    Arm/Group Description 12 hour placebo (saline) infusion prior to PET study Placebo: Saline placebo infusion for 12 hours prior to PET study GLP-1 Low Dose: 0.5 pmol/kg/min for 12 hours prior to PET study GLP-1 Low Dose: 0.5 pmol/kg/min for 12 hours prior to PET study GLP-1 Mid-Range Dose: 1.5 pmol/kg/min for 12 hours prior to PET study GLP-1 Mid-Range Dose: 1.5 pmol/kg/min for 12 hours prior to PET study GLP-1 High Dose: 4.0 pmol/kg/min for 12 hours prior to PET study GLP-1 High Dose: 4.0 pmol/kg/min for 12 hours prior to PET study
    Measure Participants 6 11 1 8 7 0 0
    Mean (Standard Deviation) [umol/min/100g]
    7.46
    (8.49)
    7.22
    (9.26)
    0.05
    (0)
    20.89
    (12.47)
    5.57
    (19.39)
    2. Secondary Outcome
    Title Myocardial Blood Flow
    Description Myocardial perfusion derived from acetate kinetics
    Time Frame After 12 hours of GLP-1 exposure

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Lean Saline Lean GLP-1 Low Dose Type 2 DM GLP-1 Low Dose Lean GLP-1 1.5 Pmol/kg/Min Type 2DM GLP-1 1.5 Pmol/kg/Min Lean GLP-1 High Dose Type 2 DM GLP-1 High Dose
    Arm/Group Description 12 hour placebo (saline) infusion prior to PET study Placebo: Saline placebo infusion for 12 hours prior to PET study GLP-1 Low Dose: 0.5 pmol/kg/min for 12 hours prior to PET study GLP-1 Low Dose: 0.5 pmol/kg/min for 12 hours prior to PET study GLP-1 Mid-Range Dose: 1.5 pmol/kg/min for 12 hours prior to PET study GLP-1 Mid-Range Dose: 1.5 pmol/kg/min for 12 hours prior to PET study GLP-1 High Dose: 4.0 pmol/kg/min for 12 hours prior to PET study GLP-1 High Dose: 4.0 pmol/kg/min for 12 hours prior to PET study
    Measure Participants 6 11 1 8 7 0 0
    Mean (Standard Deviation) [ml/min/100g]
    34.66
    (4.60)
    44.44
    (9.17)
    47.61
    (0)
    35.30
    (7.35)
    51.19
    (19.39)
    3. Secondary Outcome
    Title Myocardial Total Oxidation Rate
    Description MVO2 derived from acetate kinetics
    Time Frame After 12 hours of GLP-1 exposure

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Lean Saline Lean GLP-1 Low Dose Type 2 DM GLP-1 Low Dose Lean GLP-1 1.5 Pmol/kg/Min Type 2DM GLP-1 1.5 Pmol/kg/Min Lean GLP-1 High Dose Type 2 DM GLP-1 High Dose
    Arm/Group Description 12 hour placebo (saline) infusion prior to PET study Placebo: Saline placebo infusion for 12 hours prior to PET study GLP-1 Low Dose: 0.5 pmol/kg/min for 12 hours prior to PET study GLP-1 Low Dose: 0.5 pmol/kg/min for 12 hours prior to PET study GLP-1 Mid-Range Dose: 1.5 pmol/kg/min for 12 hours prior to PET study GLP-1 Mid-Range Dose: 1.5 pmol/kg/min for 12 hours prior to PET study GLP-1 High Dose: 4.0 pmol/kg/min for 12 hours prior to PET study GLP-1 High Dose: 4.0 pmol/kg/min for 12 hours prior to PET study
    Measure Participants 6 11 1 8 7 0 0
    Mean (Standard Deviation) [ml/min/100g]
    15.25
    (2.39)
    30.21
    (14.32)
    65.30
    (0)
    18.57
    (3.78)
    59.85
    (30.47)
    4. Secondary Outcome
    Title Cardiac Index
    Description Impedance cardiography-derived measurement of cardiac index, assessed following 12 hour exposure to treatment condition concurrent with the PET measurements.
    Time Frame After 12 hours of GLP-1 exposure

    Outcome Measure Data

    Analysis Population Description
    Analyses performed only on the groups with relevant primary outcome data observed
    Arm/Group Title Lean Saline Lean GLP-1 0.5 Pmol/kg/Min Type 2 DM GLP-1 0.5 Pmol/kg/Min Lean GLP-1 1.5 Pmol/kg/Min Type 2 DM GLP-1 1.5 Pmol/kg/Min Lean GLP-1 4.0 Pmol/kg/Min Type 2 DM GLP-1 4.0 Pmol/kg/Min
    Arm/Group Description 12 hour placebo (saline) infusion prior to PET study Placebo: Saline placebo infusion for 12 hours prior to PET study GLP-1 Low Dose: 0.5 pmol/kg/min for 12 hours prior to PET study GLP-1 Low Dose: 0.5 pmol/kg/min for 12 hours prior to PET study GLP-1 Mid-Range Dose: 1.5 pmol/kg/min for 12 hours prior to PET study GLP-1 Mid-Range Dose: 1.5 pmol/kg/min for 12 hours prior to PET study GLP-1 High Dose:4.0 pmol/kg/min for 12 hours prior to PET study GLP-1 High Dose:4.0 pmol/kg/min for 12 hours prior to PET study
    Measure Participants 6 0 0 8 7 0 0
    Mean (Standard Deviation) [L/min/m^2]
    3.00
    (0.52)
    2.88
    (0.31)
    2.90
    (0.51)
    5. Secondary Outcome
    Title GLP-1 Concentrations
    Description Achieved GLP-1 concentrations at the end of the 12 hour treatment exposure
    Time Frame After 12 hours of GLP-1 exposure

    Outcome Measure Data

    Analysis Population Description
    Analyses performed only on the groups with relevant primary outcome data observed
    Arm/Group Title Lean Saline Lean GLP-1 0.5 Pmol/kg/Min Type 2 DM GLP-1 0.5 Pmol/kg/Min Lean GLP-1 1.5 Pmol/kg/Min Type 2 DM GLP-1 1.5 Pmol/kg/Min Lean GLP-1 4.0 Pmol/kg/Min Type 2 DM GLP-1 4.0 Pmol/kg/Min
    Arm/Group Description 12 hour placebo (saline) infusion prior to PET study Placebo: Saline placebo infusion for 12 hours prior to PET study GLP-1 Low Dose: 0.5 pmol/kg/min for 12 hours prior to PET study GLP-1 Low Dose: 0.5 pmol/kg/min for 12 hours prior to PET study GLP-1 Mid-Range Dose: 1.5 pmol/kg/min for 12 hours prior to PET study GLP-1 Mid-Range Dose: 1.5 pmol/kg/min for 12 hours prior to PET study GLP-1 High Dose:4.0 pmol/kg/min for 12 hours prior to PET study GLP-1 High Dose:4.0 pmol/kg/min for 12 hours prior to PET study
    Measure Participants 6 0 0 8 7 0 0
    Mean (Standard Deviation) [pmol/L]
    61.7
    (33.5)
    302.1
    (149.1)
    307.8
    (86.2)

    Adverse Events

    Time Frame
    Adverse Event Reporting Description
    Arm/Group Title Lean Saline Lean GLP-1 0.5 Pmol/kg/Min Type 2 DM GLP-1 0.5 Pmol/kg/Min Lean GLP-1 1.5 Pmol/kg/Min Type 2 DM GLP-1 1.5 Pmol/kg/Min Lean GLP-1 4.0 Pmol/kg/Min Type 2 DM GLP-1 4.0 Pmol/kg/Min
    Arm/Group Description 12 hour placebo (saline) infusion prior to PET study Placebo: Saline placebo infusion for 12 hours prior to PET study GLP-1 Low Dose: 0.5 pmol/kg/min for 12 hours prior to PET study GLP-1 Low Dose: 0.5 pmol/kg/min for 12 hours prior to PET study GLP-1 Mid-Range Dose: 1.5 pmol/kg/min for 12 hours prior to PET study GLP-1 Mid-Range Dose: 1.5 pmol/kg/min for 12 hours prior to PET study GLP-1 High Dose: 4.0 pmol/kg/min for 12 hours prior to PET study GLP-1 High Dose: 4.0 pmol/kg/min for 12 hours prior to PET study
    All Cause Mortality
    Lean Saline Lean GLP-1 0.5 Pmol/kg/Min Type 2 DM GLP-1 0.5 Pmol/kg/Min Lean GLP-1 1.5 Pmol/kg/Min Type 2 DM GLP-1 1.5 Pmol/kg/Min Lean GLP-1 4.0 Pmol/kg/Min Type 2 DM GLP-1 4.0 Pmol/kg/Min
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total / (NaN) / (NaN) / (NaN) / (NaN) / (NaN) / (NaN) / (NaN)
    Serious Adverse Events
    Lean Saline Lean GLP-1 0.5 Pmol/kg/Min Type 2 DM GLP-1 0.5 Pmol/kg/Min Lean GLP-1 1.5 Pmol/kg/Min Type 2 DM GLP-1 1.5 Pmol/kg/Min Lean GLP-1 4.0 Pmol/kg/Min Type 2 DM GLP-1 4.0 Pmol/kg/Min
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/6 (0%) 0/11 (0%) 0/1 (0%) 0/8 (0%) 0/7 (0%) 0/0 (NaN) 0/0 (NaN)
    Other (Not Including Serious) Adverse Events
    Lean Saline Lean GLP-1 0.5 Pmol/kg/Min Type 2 DM GLP-1 0.5 Pmol/kg/Min Lean GLP-1 1.5 Pmol/kg/Min Type 2 DM GLP-1 1.5 Pmol/kg/Min Lean GLP-1 4.0 Pmol/kg/Min Type 2 DM GLP-1 4.0 Pmol/kg/Min
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/6 (0%) 1/11 (9.1%) 0/1 (0%) 0/8 (0%) 0/7 (0%) 0/0 (NaN) 0/0 (NaN)
    General disorders
    Nausea 0/6 (0%) 0 1/11 (9.1%) 1 0/1 (0%) 0 0/8 (0%) 0 0/7 (0%) 0 0/0 (NaN) 0 0/0 (NaN) 0

    Limitations/Caveats

    This was a dose-finding study of myocardial responses to systemically infused GLP-1. After ascertaining no detectable response in controls with low dose, we completed mid dose studies. Finding an important difference there we did not do the high dose

    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.

    Results Point of Contact

    Name/Title Kieren J Mather MD FRCPC
    Organization Indiana University
    Phone 317-278-7826
    Email kmather@iu.edu
    Responsible Party:
    Indiana University
    ClinicalTrials.gov Identifier:
    NCT01607450
    Other Study ID Numbers:
    • 1010002497
    • R21HL092799
    First Posted:
    May 30, 2012
    Last Update Posted:
    Feb 17, 2016
    Last Verified:
    Jan 1, 2016