Modulation of Human Myocardial Metabolism by GLP-1 Dose Response

NCT01607450 | Completed Phase 2 Results DMC

• 2 other identifiers: 1010002497R21HL092799
• Study Type: interventional
• Target: 33
• Locations: 1 country
• Sites: 1

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

Keywords

Type 2 diabetes mellitus; lean healthy control

Outcome Measures

Primary Outcomes (1)

• 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

Secondary Outcomes (4)

• Myocardial Blood Flow

  After 12 hours of GLP-1 exposure

• Myocardial Total Oxidation Rate

  After 12 hours of GLP-1 exposure

• Cardiac Index

  After 12 hours of GLP-1 exposure

• GLP-1 Concentrations

  After 12 hours of GLP-1 exposure

Study Arms (4)

Saline

OTHER

12 hour saline (control) infusion prior to PET study

Drug: Saline

GLP-1 Low dose

EXPERIMENTAL

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

Drug: GLP-1 Low Dose

GLP-1 Mid-Range Dose

EXPERIMENTAL

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

Drug: GLP-1 Mid-Range Dose

GLP-1 High Dose

EXPERIMENTAL

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

Drug: GLP-1 High Dose

Interventions

GLP-1 Low Dose DRUG

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

GLP-1 Low dose

GLP-1 Mid-Range Dose DRUG

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

GLP-1 Mid-Range Dose

GLP-1 High Dose DRUG

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

GLP-1 High Dose

Saline DRUG

Normal saline placebo infusion for 12 hours prior to PET study

Also known as: Normal Saline

Saline

Eligibility Criteria

• Age: 18 Years - 60 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

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

Study Sites (1)

Indiana Clinical Research Center

Indianapolis, Indiana, 46202, United States

Location

MeSH Terms

Conditions

Diabetes Mellitus, Type 2

Interventions

Glucagon-Like Peptide 1; Sodium Chloride; Saline Solution

Condition Hierarchy (Ancestors)

Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases

Intervention Hierarchy (Ancestors)

Glucagon-Like Peptides; Proglucagon; Gastrointestinal Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Chlorides; Hydrochloric Acid; Chlorine Compounds; Inorganic Chemicals; Sodium Compounds; Crystalloid Solutions; Isotonic Solutions; Solutions; Pharmaceutical Preparations

Limitations and 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

Results Point of Contact

• Title: Kieren J Mather MD FRCPC
• Organization: Indiana University

kmather@iu.edu

317-278-7826

Study Officials

• Kieren J Mather, MD

  Indiana University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 21, 2012
• First Posted: May 30, 2012
• Study Start: May 1, 2010
• Primary Completion: December 1, 2012
• Study Completion: December 1, 2012
• Last Updated: February 17, 2016
• Results First Posted: February 17, 2016

Record last verified: 2016-01

Locations

US (1)