Modulation of Human Myocardial Metabolism by GLP-1 Dose Response

NCT ID: NCT01607450

Last Updated: 2016-02-17

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2/PHASE3
• Total Enrollment: 33 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2010-05-31
• Study Completion Date: 2012-12-31

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.

Conditions

Type 2 Diabetes Mellitus; Healthy

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: SINGLE

Study Groups

Saline

12 hour saline (control) infusion prior to PET study

Group Type: OTHER

Saline

Intervention Type: DRUG

Normal saline placebo infusion for 12 hours prior to PET study

GLP-1 Low dose

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

Group Type: EXPERIMENTAL

GLP-1 Low Dose

Intervention Type: DRUG

0.5mmol/kg/hr GLP-1 for 12 hours prior to PET study

GLP-1 Mid-Range Dose

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

Group Type: EXPERIMENTAL

GLP-1 Mid-Range Dose

Intervention Type: DRUG

1.5mmol/kg/min for 12 hours prior to PET study

GLP-1 High Dose

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

Group Type: EXPERIMENTAL

GLP-1 High Dose

Intervention Type: DRUG

4.0mmol/kg/min GLP-1 for 12 hours prior to PET study

Interventions

GLP-1 Low Dose

0.5mmol/kg/hr GLP-1 for 12 hours prior to PET study

Intervention Type: DRUG

GLP-1 Mid-Range Dose

1.5mmol/kg/min for 12 hours prior to PET study

Intervention Type: DRUG

GLP-1 High Dose

4.0mmol/kg/min GLP-1 for 12 hours prior to PET study

Intervention Type: DRUG

Saline

Normal saline placebo infusion for 12 hours prior to PET study

Intervention Type: DRUG

Other Intervention Names

Normal Saline

Eligibility 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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 60 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

National Heart, Lung, and Blood Institute (NHLBI)

NIH

Sponsor Role: collaborator

Indiana University

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Kieren J Mather, MD

Role: PRINCIPAL_INVESTIGATOR

Indiana University

Locations

Indiana Clinical Research Center

Indianapolis, Indiana, United States

Countries

United States

Other Identifiers

R21HL092799

Identifier Type: NIH

Identifier Source: secondary_id

View Link

1010002497

Identifier Type: -

Identifier Source: org_study_id