Modulation of Human Myocardial Metabolism by GLP-1 Dose Response

January 19, 2016 updated by: Indiana University

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.

Study Overview

Study Type

Interventional

Enrollment (Actual)

33

Phase

  • Phase 2
  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

    • Indiana
      • Indianapolis, Indiana, United States, 46202
        • Indiana Clinical Research Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 60 years (Adult)

Accepts Healthy Volunteers

Yes

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Non-Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Single

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Other: Saline
12 hour saline (control) infusion prior to PET study
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
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
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
4.0mmol/kg/min GLP-1 for 12 hours prior to PET study

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Myocardial Glucose Uptake.
Time Frame: 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.
After 12 hours of glucagon-like peptide 1 (GLP-1) exposure

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Myocardial Blood Flow
Time Frame: After 12 hours of GLP-1 exposure
Myocardial perfusion derived from acetate kinetics
After 12 hours of GLP-1 exposure
Myocardial Total Oxidation Rate
Time Frame: After 12 hours of GLP-1 exposure
MVO2 derived from acetate kinetics
After 12 hours of GLP-1 exposure
Cardiac Index
Time Frame: 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.
After 12 hours of GLP-1 exposure
GLP-1 Concentrations
Time Frame: After 12 hours of GLP-1 exposure
Achieved GLP-1 concentrations at the end of the 12 hour treatment exposure
After 12 hours of GLP-1 exposure

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Investigators

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

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

May 1, 2010

Primary Completion (Actual)

December 1, 2012

Study Completion (Actual)

December 1, 2012

Study Registration Dates

First Submitted

May 21, 2012

First Submitted That Met QC Criteria

May 24, 2012

First Posted (Estimate)

May 30, 2012

Study Record Updates

Last Update Posted (Estimate)

February 17, 2016

Last Update Submitted That Met QC Criteria

January 19, 2016

Last Verified

January 1, 2016

More Information

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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