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

Study Overview
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Brief Summary
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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
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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

Official Title
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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)

Conditions
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Type 2 Diabetes, Obesity

Intervention / Treatment
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* Drug: 0.9% Sodium-chloride
* Drug: Exenatide (50ng/min for 30 minutes loading followed by 25ng/min maintenance) and glucagon 12.5ng/kg/min
* Drug: Glucagon 12.5ng/kg/min and 0.9% saline
* Drug: 0.9% Sodium-chloride
* Drug: Exenatide (50ng/min for 30 minutes loading followed by 25ng/min maintenance) and glucagon 12.5ng/kg/min
* Drug: Glucagon 12.5ng/kg/min


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 99 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Single Group Assignment
Interventional Model Description: Single-centre, single-blinded, physiological pilot study
Masking: Single


Arms and Interventions

| Intervention/Treatment |
| --- |
|Drug: 0.9% Sodium-chloride|Part A - 0.9% saline infusion during cardiac PET-MRI scan|
|Drug: Exenatide (50ng/min for 30 minutes loading followed by 25ng/min maintenance) and glucagon 12.5ng/kg/min|Part A - exenatide and glucagon infusion during cardiac PET-MRI scan|
|Drug: Glucagon 12.5ng/kg/min and 0.9% saline|Part A - Glucagon and 0.9% saline infusion during PET-MRI scan|
|Drug: 0.9% Sodium-chloride|Part B - 0.9% saline infusion during 7T 31P MRS scan|
|Drug: Exenatide (50ng/min for 30 minutes loading followed by 25ng/min maintenance) and glucagon 12.5ng/kg/min|Part B - exenatide and glucagon infusion during 7T 31P MRS scan|
|Drug: Glucagon 12.5ng/kg/min|Part B - Glucagon infusion during 7T 31P MRS scan|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part A - Myocardial glucose uptake | Difference in myocardial glucose uptake between 0.9% saline, glucagon:exenatide and glucagon scan as measured by 18F-FDG | Comparison between scans over a maximum period of 16 weeks | 
| 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 | Comparison between scans over a maximum period of 16 weeks | 
| Part A - Ejection fraction | Difference in ejection fraction between 0.9% saline, glucagon:exenatide and glucagon scan as measured by CMR | Comparison between scans over a maximum period of 16 weeks | 
| Part A - Stroke volume | Difference in stroke volume between 0.9% saline, glucagon:exenatide and glucagon scan as measured by CMR | Comparison between scans over a maximum period of 16 weeks | 
| Part A - Cardiac output | Difference in cardiac output between 0.9% saline, glucagon:exenatide and glucagon scan as measured by CMR | Comparison between scans over a maximum period of 16 weeks | 
| 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) | Comparison between scans over a maximum period of 16 weeks | 
| 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) | Comparison between scans over a maximum period of 16 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | Comparison between scans over a maximum period of 16 weeks | 
| Part A - Radial strain | Difference in radial strain between 0.9% saline, glucagon:exenatide and glucagon scan as measured by CMR | Comparison between scans over a maximum period of 16 weeks | 
| 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 | Comparison between scans over a maximum period of 16 weeks | 
| 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 | Comparison between scans over a maximum period of 16 weeks | 
| Part A/B - Heart rate | Difference in heart rate between 0.9% saline, glucagon:exenatide and glucagon | Comparison between infusions (placebo vs drug) over a maximum period of 16 weeks | 
| Part A/B - Blood pressure | Difference in blood pressure between 0.9% saline, glucagon:exenatide and glucagon | Comparison between infusions (placebo vs drug) over a maximum period of 16 weeks | 
| Part A/B - Glucose | Difference in glucose between 0.9% saline, glucagon:exenatide and glucagon | Comparison between infusions (placebo vs drug) over a maximum period of 16 weeks | 
| Part A/B - Glucagon | Difference in glucagon between 0.9% saline, glucagon:exenatide and glucagon | Comparison between infusions (placebo vs drug) over a maximum period of 16 weeks | 
| Part A/B - Insulin | Difference in insulin between 0.9% saline, glucagon:exenatide and glucagon | Comparison between infusions (placebo vs drug) over a maximum period of 16 weeks | 
| Part A/B - C-peptide | Difference in C-peptide between 0.9% saline, glucagon:exenatide and glucagon | Comparison between infusions (placebo vs drug) over a maximum period of 16 weeks | 
| Part A/B - fatty acids | Difference in fatty acids between 0.9% saline, glucagon:exenatide and glucagon | Comparison between infusions (placebo vs drug) over a maximum period of 16 weeks | 
| Part A/B - exenatide | Difference in exenatide between 0.9% saline, glucagon:exenatide and glucagon | Comparison between infusions (placebo vs drug) over a maximum period of 16 weeks | 
| Part A/B - Total GLP-1 and total active GLP-1 | Difference in GLP-1 between 0.9% saline, glucagon:exenatide and glucagon | Comparison between infusions (placebo vs drug) over a maximum period of 16 weeks | 
| Part A/B - gastric inhibitory polypeptide | Difference in gastric inhibitory polypeptide between 0.9% saline, glucagon:exenatide and glucagon | Comparison between infusions (placebo vs drug) over a maximum period of 16 weeks |