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Effect of Glucagon and Glucagon-like Peptide-1 Co-agonism on Cardiac Function and Metabolism in Overweight Participants With Type 2 Diabetes (COCONUT)

Primary Purpose

Type 2 Diabetes, Obesity

Status

Recruiting

Phase

Phase 4

Locations

United Kingdom

Study Type

Interventional

Intervention

0.9% Sodium-chloride

Exenatide (50ng/min for 30 minutes loading followed by 25ng/min maintenance) and glucagon 12.5ng/kg/min

Glucagon 12.5ng/kg/min and 0.9% saline

0.9% Sodium-chloride

Exenatide (50ng/min for 30 minutes loading followed by 25ng/min maintenance) and glucagon 12.5ng/kg/min

Glucagon 12.5ng/kg/min

About this trial

This is an interventional basic science trial for Type 2 Diabetes

Eligibility Criteria

18 Years - 99 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Written informed consent to participate
Aged >18 years
Clinical diagnosis of T2DM, either diet controlled or treated with metformin (to be withheld on the morning of the imaging visit)
BMI ≥25kg/m2
Current non-smoker

Exclusion Criteria:

Females of childbearing potential (Part A only) / current pregnancy (all parts)
Sustained Hypertension (sustained BP >160/100mmHg) or hypotension (systolic BP below 90 mmHg)
Clinically significant heart disease
Implanted heart pacemaker or implantable cardioverter defibrillator (ICD)
Known active malignancy other than skin cancer
Known renal failure (creatinine >150µmol/L)
Known type one diabetes mellitus / known or clinically suspected diagnosis of a monogenic form of diabetes
Poorly controlled blood glucose
Current daily use of anti-diabetic medication including Insulin, GLP-1 based agonists, DPP4i or any other medication known to interact with either of the study drugs (exenatide or glucagon)
Current involvement in the active treatment phase of other research studies, (excluding observational/non-interventional).
Contraindication for MRI/PET scan, i.e. any reason which precludes MRI imaging according to local policy (ie internal pacemaker/defibrillator, metal fragments, claustrophobia)
Participation in research studies in the last 3 years involving radiation (if the effective dose exceeded 10mSv). This does not include any diagnostic or therapeutic exposures which were clinically justified.
Any other clinical reason which may preclude entry in the opinion of the investigator

Sites / Locations

Cambridge University Hospitals NHS Foundation Trust and The University of CambridgeRecruiting

Outcomes

Primary Outcome Measures

Part A - Myocardial glucose uptake

Difference in myocardial glucose uptake between 0.9% saline, glucagon:exenatide and glucagon scan as measured by 18F-FDG

Part A - Global longitudinal strain / global circumferential strain / global radial strain

Difference in global longitudinal strain / global circumferential strain / global radial strain between 0.9% saline, glucagon:exenatide and glucagon scan as measured by CMR

Part A - Ejection fraction

Difference in ejection fraction between 0.9% saline, glucagon:exenatide and glucagon scan as measured by CMR

Part A - Stroke volume

Difference in stroke volume between 0.9% saline, glucagon:exenatide and glucagon scan as measured by CMR

Part A - Cardiac output

Difference in cardiac output between 0.9% saline, glucagon:exenatide and glucagon scan as measured by CMR

Part B - Changes in phosphocreatine/adenosine (PCr/ATP) radio

Changes in PCr/ATP radio between 0.9% saline, glucagon:exenatide and glucagon (optional) in the mid-interventricular septum as a measure of cardiac energy status as measured by 7T phosphorus (P) 31 magnetic resonance spectroscopy (MRS)

Part B - Changes in absolute concentrations of PCr and ATP defined by AHA 17- segment territory as a measure of cardiac energy status (determined by 31P-MRS)

Changes in absolute concentrations of PCr and ATP between 0.9% saline, glucagon:exenatide and glucagon (optional) as defined by AHA 17-segment territory as a measure of cardiac energy status (determined by 7T 31P-MRS)

Secondary Outcome Measures

Part A - End systolic/diastolic ventricular/atrial volumes

Difference in end systolic/diastolic ventricular/atrial volumes between 0.9% saline, glucagon:exenatide and glucagon scan as measured by CMR

Part A - Radial strain

Difference in radial strain between 0.9% saline, glucagon:exenatide and glucagon scan as measured by CMR

Part A - Global systolic/diastolic longitudinal/circumferential/radial strain rate

Difference in global systolic/diastolic longitudinal/circumferential/radial strain rate between 0.9% saline, glucagon:exenatide and glucagon scan as measured by CMR

Part A - Relationship between early and late filling (from mitral flow)

Difference in early and late filling (from mitral flow) between 0.9% saline, glucagon:exenatide and glucagon scan as measured by CMR

Part A/B - Heart rate

Difference in heart rate between 0.9% saline, glucagon:exenatide and glucagon

Part A/B - Blood pressure

Difference in blood pressure between 0.9% saline, glucagon:exenatide and glucagon

Part A/B - Glucose

Difference in glucose between 0.9% saline, glucagon:exenatide and glucagon

Part A/B - Glucagon

Difference in glucagon between 0.9% saline, glucagon:exenatide and glucagon

Part A/B - Insulin

Difference in insulin between 0.9% saline, glucagon:exenatide and glucagon

Part A/B - C-peptide

Difference in C-peptide between 0.9% saline, glucagon:exenatide and glucagon

Part A/B - fatty acids

Difference in fatty acids between 0.9% saline, glucagon:exenatide and glucagon

Part A/B - exenatide

Difference in exenatide between 0.9% saline, glucagon:exenatide and glucagon

Part A/B - Total GLP-1 and total active GLP-1

Difference in GLP-1 between 0.9% saline, glucagon:exenatide and glucagon

Part A/B - gastric inhibitory polypeptide

Difference in gastric inhibitory polypeptide between 0.9% saline, glucagon:exenatide and glucagon

Full Information

NCT ID

NCT04307797

First Posted

February 19, 2020

Last Updated

January 18, 2022

Sponsor

Cambridge University Hospitals NHS Foundation Trust

Collaborators

Antaros Medical

1. Study Identification

Unique Protocol Identification Number

NCT04307797

Brief Title

Effect of Glucagon and Glucagon-like Peptide-1 Co-agonism on Cardiac Function and Metabolism in Overweight Participants With Type 2 Diabetes

Acronym

COCONUT

Official Title

A Pilot Study on the Effect of Glucagon and Glucagon-like Peptide-1 Co-agonism on Cardiac Function and Metabolism in Overweight Participants With Type 2 Diabetes (COCONUT)

Study Type

Interventional

2. Study Status

Record Verification Date

January 2022

Overall Recruitment Status

Recruiting

Study Start Date

January 18, 2022 (Actual)

Primary Completion Date

January 1, 2023 (Anticipated)

Study Completion Date

January 1, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Cambridge University Hospitals NHS Foundation Trust

Collaborators

Antaros Medical

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

Data Monitoring Committee

5. Study Description

Brief Summary

The study seeks to explore the cardiovascular effects of co-agonism at the glucagon and (glucagon-like peptide-1) GLP-1 receptor. Glucagon and exenatide will be intravenously infused into participants with type 2 diabetes (T2DM). Overall, the aim of the study is to further the investigator's understanding on the role these endogenous substances have on normal cardiac physiology, myocardial energetics and myocardial glucose uptake through a series of PET and MRI imaging studies

Detailed Description

This is a single-centre, single-blinded pilot study designed to understand the role the GLP-1 receptor agonist, exenatide, and glucagon receptor co-agonism has on normal cardiac physiology, myocardial energetics and myocardial glucose utilisation. Part A - Overweight participants with type 2 diabetes will act as their own control and will undergo a series of three imaging studies (in a randomised order) as detailed below: Cardiac positron emission tomography-magnetic resonance imaging (PET-MRI) with fluorine-18-fluorodeoxyglucose (18F-FDG) with placebo (0.9% saline) infusion Cardiac PET-MRI with 18F-FDG with co-infusion of exenatide and glucagon Cardiac PET-MRI with 18F-FDG with infusion of glucagon Part B - Overweight participants with type 2 diabetes will act as their own control and will undergo a series of two imaging studies (in a randomised order), followed by one optional visit as detailed below: 7T Phosphorus (P) 31 magnetic resonance spectroscopy (MRS) (31P-MRS) with placebo (0.9% saline) infusion 7T 31P-MRS with co-infusion of glucagon and exenatide 3 (optional) 7T 31P-MRS with infusion of glucagon Study outcome measures are detailed below

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Type 2 Diabetes, Obesity

7. Study Design

Primary Purpose

Basic Science

Study Phase

Phase 4

Interventional Study Model

Single Group Assignment

Model Description

Single-centre, single-blinded, physiological pilot study

Masking

Participant

Masking Description

Imaging analysis performed by Antaros Medical (blinded to infusion)

Allocation

Randomized

Enrollment

16 (Anticipated)

8. Arms, Groups, and Interventions

Intervention Type

Drug

Intervention Name(s)

0.9% Sodium-chloride

Intervention Description

Part A - 0.9% saline infusion during cardiac PET-MRI scan

Intervention Type

Drug

Intervention Name(s)

Exenatide (50ng/min for 30 minutes loading followed by 25ng/min maintenance) and glucagon 12.5ng/kg/min

Other Intervention Name(s)

Byetta

Intervention Description

Part A - exenatide and glucagon infusion during cardiac PET-MRI scan

Intervention Type

Drug

Intervention Name(s)

Glucagon 12.5ng/kg/min and 0.9% saline

Intervention Description

Part A - Glucagon and 0.9% saline infusion during PET-MRI scan

Intervention Type

Drug

Intervention Name(s)

0.9% Sodium-chloride

Intervention Description

Part B - 0.9% saline infusion during 7T 31P MRS scan

Intervention Type

Drug

Intervention Name(s)

Exenatide (50ng/min for 30 minutes loading followed by 25ng/min maintenance) and glucagon 12.5ng/kg/min

Intervention Description

Part B - exenatide and glucagon infusion during 7T 31P MRS scan

Intervention Type

Drug

Intervention Name(s)

Glucagon 12.5ng/kg/min

Intervention Description

Part B - Glucagon infusion during 7T 31P MRS scan

Primary Outcome Measure Information:

Title

Part A - Myocardial glucose uptake

Description

Difference in myocardial glucose uptake between 0.9% saline, glucagon:exenatide and glucagon scan as measured by 18F-FDG

Time Frame

Comparison between scans over a maximum period of 16 weeks

Title

Part A - Global longitudinal strain / global circumferential strain / global radial strain

Description

Difference in global longitudinal strain / global circumferential strain / global radial strain between 0.9% saline, glucagon:exenatide and glucagon scan as measured by CMR

Time Frame

Comparison between scans over a maximum period of 16 weeks

Title

Part A - Ejection fraction

Description

Difference in ejection fraction between 0.9% saline, glucagon:exenatide and glucagon scan as measured by CMR

Time Frame

Comparison between scans over a maximum period of 16 weeks

Title

Part A - Stroke volume

Description

Difference in stroke volume between 0.9% saline, glucagon:exenatide and glucagon scan as measured by CMR

Time Frame

Comparison between scans over a maximum period of 16 weeks

Title

Part A - Cardiac output

Description

Difference in cardiac output between 0.9% saline, glucagon:exenatide and glucagon scan as measured by CMR

Time Frame

Comparison between scans over a maximum period of 16 weeks

Title

Part B - Changes in phosphocreatine/adenosine (PCr/ATP) radio

Description

Time Frame

Comparison between scans over a maximum period of 16 weeks

Title

Part B - Changes in absolute concentrations of PCr and ATP defined by AHA 17- segment territory as a measure of cardiac energy status (determined by 31P-MRS)

Description

Time Frame

Comparison between scans over a maximum period of 16 weeks

Secondary Outcome Measure Information:

Title

Part A - End systolic/diastolic ventricular/atrial volumes

Description

Difference in end systolic/diastolic ventricular/atrial volumes between 0.9% saline, glucagon:exenatide and glucagon scan as measured by CMR

Time Frame

Comparison between scans over a maximum period of 16 weeks

Title

Part A - Radial strain

Description

Difference in radial strain between 0.9% saline, glucagon:exenatide and glucagon scan as measured by CMR

Time Frame

Comparison between scans over a maximum period of 16 weeks

Title

Part A - Global systolic/diastolic longitudinal/circumferential/radial strain rate

Description

Difference in global systolic/diastolic longitudinal/circumferential/radial strain rate between 0.9% saline, glucagon:exenatide and glucagon scan as measured by CMR

Time Frame

Comparison between scans over a maximum period of 16 weeks

Title

Part A - Relationship between early and late filling (from mitral flow)

Description

Difference in early and late filling (from mitral flow) between 0.9% saline, glucagon:exenatide and glucagon scan as measured by CMR

Time Frame

Comparison between scans over a maximum period of 16 weeks

Title

Part A/B - Heart rate

Description

Difference in heart rate between 0.9% saline, glucagon:exenatide and glucagon

Time Frame

Comparison between infusions (placebo vs drug) over a maximum period of 16 weeks

Title

Part A/B - Blood pressure

Description

Difference in blood pressure between 0.9% saline, glucagon:exenatide and glucagon

Time Frame

Comparison between infusions (placebo vs drug) over a maximum period of 16 weeks

Title

Part A/B - Glucose

Description

Difference in glucose between 0.9% saline, glucagon:exenatide and glucagon

Time Frame

Comparison between infusions (placebo vs drug) over a maximum period of 16 weeks

Title

Part A/B - Glucagon

Description

Difference in glucagon between 0.9% saline, glucagon:exenatide and glucagon

Time Frame

Comparison between infusions (placebo vs drug) over a maximum period of 16 weeks

Title

Part A/B - Insulin

Description

Difference in insulin between 0.9% saline, glucagon:exenatide and glucagon

Time Frame

Comparison between infusions (placebo vs drug) over a maximum period of 16 weeks

Title

Part A/B - C-peptide

Description

Difference in C-peptide between 0.9% saline, glucagon:exenatide and glucagon

Time Frame

Comparison between infusions (placebo vs drug) over a maximum period of 16 weeks

Title

Part A/B - fatty acids

Description

Difference in fatty acids between 0.9% saline, glucagon:exenatide and glucagon

Time Frame

Comparison between infusions (placebo vs drug) over a maximum period of 16 weeks

Title

Part A/B - exenatide

Description

Difference in exenatide between 0.9% saline, glucagon:exenatide and glucagon

Time Frame

Comparison between infusions (placebo vs drug) over a maximum period of 16 weeks

Title

Part A/B - Total GLP-1 and total active GLP-1

Description

Difference in GLP-1 between 0.9% saline, glucagon:exenatide and glucagon

Time Frame

Comparison between infusions (placebo vs drug) over a maximum period of 16 weeks

Title

Part A/B - gastric inhibitory polypeptide

Description

Difference in gastric inhibitory polypeptide between 0.9% saline, glucagon:exenatide and glucagon

Time Frame

Comparison between infusions (placebo vs drug) over a maximum period of 16 weeks

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

99 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Written informed consent to participate Aged >18 years Clinical diagnosis of T2DM, either diet controlled or treated with metformin (to be withheld on the morning of the imaging visit) BMI ≥25kg/m2 Current non-smoker Exclusion Criteria: Females of childbearing potential (Part A only) / current pregnancy (all parts) Sustained Hypertension (sustained BP >160/100mmHg) or hypotension (systolic BP below 90 mmHg) Clinically significant heart disease Implanted heart pacemaker or implantable cardioverter defibrillator (ICD) Known active malignancy other than skin cancer Known renal failure (creatinine >150µmol/L) Known type one diabetes mellitus / known or clinically suspected diagnosis of a monogenic form of diabetes Poorly controlled blood glucose Current daily use of anti-diabetic medication including Insulin, GLP-1 based agonists, DPP4i or any other medication known to interact with either of the study drugs (exenatide or glucagon) Current involvement in the active treatment phase of other research studies, (excluding observational/non-interventional). Contraindication for MRI/PET scan, i.e. any reason which precludes MRI imaging according to local policy (ie internal pacemaker/defibrillator, metal fragments, claustrophobia) Participation in research studies in the last 3 years involving radiation (if the effective dose exceeded 10mSv). This does not include any diagnostic or therapeutic exposures which were clinically justified. Any other clinical reason which may preclude entry in the opinion of the investigator

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

James Goodman, MD

Phone

01223 336806

Ext

+44

jdhg3@medschl.cam.ac.uk

First Name & Middle Initial & Last Name or Official Title & Degree

Ian Wilkinson, MD

Phone

01223 336806

Ext

+44

ibw20@medschl.cam.ac.uk

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Ian Wilkinson, MD

Organizational Affiliation

University of Cambridge

Official's Role

Principal Investigator

Facility Information:

Facility Name

Cambridge University Hospitals NHS Foundation Trust and The University of Cambridge

City

Cambridge

State/Province

Cambridgeshire

ZIP/Postal Code

CB2 0QQ

Country

United Kingdom

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

James Goodman, MBChB. MRCP

Phone

01223 336806

Ext

+44

jdhg3@medschl.cam.ac.uk

12. IPD Sharing Statement

Plan to Share IPD

Learn more about this trial

Effect of Glucagon and Glucagon-like Peptide-1 Co-agonism on Cardiac Function and Metabolism in Overweight Participants With Type 2 Diabetes

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