Modulation of Human Myocardial Metabolism by GLP-1 Dose Response

Healthy Clinical Trial

Official title:

Modulation of Human Myocardial Metabolism by GLP-1 Dose Response

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01607450
• Other study ID #: 1010002497
• Secondary ID: R21HL092799
• Status: Completed
• Phase: Phase 2/Phase 3
• First received: May 21, 2012
• Last updated: January 19, 2016
• Start date: May 2010
• Est. completion date: December 2012

Study information

• Verified date: January 2016
• Source: Indiana University
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug AdministrationUnited States: Institutional Review Board
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 33
• Est. completion date: December 2012
• Est. primary completion date: December 2012
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Both
• Age group: 18 Years to 60 Years

Eligibility

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 Design

Allocation: Non-Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Single Blind (Subject), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Diabetes Mellitus
• Diabetes Mellitus, Type 2
• Healthy
• Type 2 Diabetes Mellitus

Intervention

Drug:
• GLP-1 Low Dose
0.5mmol/kg/hr GLP-1 for 12 hours prior to PET study
• GLP-1 Mid-Range Dose
1.5mmol/kg/min for 12 hours prior to PET study
• GLP-1 High Dose
4.0mmol/kg/min GLP-1 for 12 hours prior to PET study
• Saline
Normal saline placebo infusion for 12 hours prior to PET study

Locations

Country	Name	City	State
United States	Indiana Clinical Research Center	Indianapolis	Indiana

Sponsors (2)

Lead Sponsor	Collaborator
Indiana University	National Heart, Lung, and Blood Institute (NHLBI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Myocardial Glucose Uptake.	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	No
Secondary	Myocardial Blood Flow	Myocardial perfusion derived from acetate kinetics	After 12 hours of GLP-1 exposure	No
Secondary	Myocardial Total Oxidation Rate	MVO2 derived from acetate kinetics	After 12 hours of GLP-1 exposure	No
Secondary	Cardiac Index	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	No
Secondary	GLP-1 Concentrations	Achieved GLP-1 concentrations at the end of the 12 hour treatment exposure	After 12 hours of GLP-1 exposure	No