Modulation of Human Myocardial Metabolism by GLP-1 Dose Response

This study has been completed.
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Indiana University
ClinicalTrials.gov Identifier:
NCT01607450
First received: May 21, 2012
Last updated: April 17, 2013
Last verified: April 2013
  Purpose

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 Intervention Phase
Type 2 Diabetes Mellitus
Healthy
Drug: GLP-1 Low Dose
Drug: GLP-1 Mid-Range Dose
Drug: GLP-1 High Dose
Drug: Placebo
Phase 2
Phase 3

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Single Blind (Subject)
Primary Purpose: Treatment
Official Title: Modulation of Human Myocardial Metabolism by GLP-1 Dose Response

Resource links provided by NLM:


Further study details as provided by Indiana University:

Primary Outcome Measures:
  • Dose dependent myocardial glucose uptake. [ Time Frame: After 12 hours of GLP-1 exposure ] [ Designated as safety issue: No ]
    Myocardial glucose uptake will be quantified using a 3-compartment model, according to the methods of Morita and colleagues with a lumped constant of 1.0.


Secondary Outcome Measures:
  • Dose dependent Myocardial blood flow. [ Time Frame: After 12 hours of GLP-1 exposure ] [ Designated as safety issue: No ]
  • Myocardial total oxidation with a given dose of GLP-1 [ Time Frame: After 12 hours of GLP-1 exposure ] [ Designated as safety issue: No ]
  • Systemic hemodynamics measured by impedence cardiography [ Time Frame: After 12 hours of GLP-1 exposure ] [ Designated as safety issue: No ]
  • Circulating metabolic substrates and hormones [ Time Frame: After 12 hours of GLP-1 exposure ] [ Designated as safety issue: No ]

Enrollment: 29
Study Start Date: May 2010
Study Completion Date: December 2012
Primary Completion Date: December 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Placebo Comparator: Placebo
12 hour placebo (saline) infusion prior to PET study
Drug: Placebo
Saline placebo infusion for 12 hours prior to PET study
Experimental: GLP-1 Low dose Drug: GLP-1 Low Dose
0.5mmol/kg/hr GLP-1 for 12 hours prior to PET study
Experimental: GLP-1 Mid-Range Dose Drug: GLP-1 Mid-Range Dose
1.5mmol/kg/min for 12 hours prior to PET study
Experimental: GLP-1 High Dose Drug: GLP-1 High Dose
4.0mmol/kg/min GLP-1 for 12 hours prior to PET study

  Eligibility

Ages Eligible for Study:   18 Years to 60 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

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
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01607450

Locations
United States, Indiana
Indiana Clinical Research Center
Indianapolis, Indiana, United States, 46202
Sponsors and Collaborators
Indiana University
Investigators
Principal Investigator: Kieren J Mather, MD Indiana University
  More Information

No publications provided

Responsible Party: Indiana University
ClinicalTrials.gov Identifier: NCT01607450     History of Changes
Other Study ID Numbers: 1010002497, R21HL092799
Study First Received: May 21, 2012
Last Updated: April 17, 2013
Health Authority: United States: Food and Drug Administration
United States: Institutional Review Board

Keywords provided by Indiana University:
Type 2 diabetes mellitus
lean healthy control

Additional relevant MeSH terms:
Diabetes Mellitus
Diabetes Mellitus, Type 2
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Glucagon-Like Peptide 1
Incretins
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Pharmacologic Actions

ClinicalTrials.gov processed this record on August 25, 2014