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

Obesity Clinical Trial

— 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)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04307797
• Other study ID #: COCONUT
• Status: Recruiting
• Phase: Phase 4
• Start date: January 18, 2022
• Est. completion date: January 1, 2024

Study information

• Verified date: January 2022
• Source: Cambridge University Hospitals NHS Foundation Trust
• Contact: James Goodman, MD
• Phone: 01223 336806
• Email: jdhg3[@]medschl.cam.ac.uk
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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

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:

1. Cardiac positron emission tomography-magnetic resonance imaging (PET-MRI) with fluorine-18-fluorodeoxyglucose (18F-FDG) with placebo (0.9% saline) infusion

2. Cardiac PET-MRI with 18F-FDG with co-infusion of exenatide and glucagon

3. 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:

1. 7T Phosphorus (P) 31 magnetic resonance spectroscopy (MRS) (31P-MRS) with placebo (0.9% saline) infusion

2. 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

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 16
• Est. completion date: January 1, 2024
• Est. primary completion date: January 1, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 99 Years

Eligibility

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

Related Conditions & MeSH terms

• Diabetes Mellitus
• Diabetes Mellitus, Type 2
• Obesity
• Overweight
• Type 2 Diabetes

Intervention

Drug:
• 0.9% Sodium-chloride
Part A - 0.9% saline infusion during cardiac PET-MRI scan
• 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
• Glucagon 12.5ng/kg/min and 0.9% saline
Part A - Glucagon and 0.9% saline infusion during PET-MRI scan
• 0.9% Sodium-chloride
Part B - 0.9% saline infusion during 7T 31P MRS scan
• 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
• Glucagon 12.5ng/kg/min
Part B - Glucagon infusion during 7T 31P MRS scan

Locations

Country	Name	City	State
United Kingdom	Cambridge University Hospitals NHS Foundation Trust and The University of Cambridge	Cambridge	Cambridgeshire

Sponsors (2)

Lead Sponsor	Collaborator
Cambridge University Hospitals NHS Foundation Trust	Antaros Medical

Country where clinical trial is conducted

United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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