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

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)

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

Study Overview

• Status: Completed
• Conditions: Obesity; Type 2 Diabetes
• Intervention / Treatment: 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

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:

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

• Study Type: Interventional
• Enrollment (Actual): 10
• Phase: Phase 4

Contacts and Locations

Study Locations

• United Kingdom
  • Cambridgeshire
    • Cambridge, Cambridgeshire, United Kingdom, CB2 0QQ
      • Cambridge University Hospitals NHS Foundation Trust and The University of Cambridge

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 99 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Single Group Assignment
• Masking: Single

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Cambridge University Hospitals NHS Foundation Trust
• Collaborators: Antaros Medical
• Investigators: Principal Investigator: Ian Wilkinson, MD, University of Cambridge

Study record dates

Study Major Dates

• Study Start (Actual): January 18, 2022
• Primary Completion (Actual): October 7, 2022
• Study Completion (Actual): October 7, 2022

Study Registration Dates

• First Submitted: February 19, 2020
• First Submitted That Met QC Criteria: March 12, 2020
• First Posted (Actual): March 13, 2020

Study Record Updates

• Last Update Posted (Actual): September 19, 2024
• Last Update Submitted That Met QC Criteria: September 12, 2024
• Last Verified: September 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Overnutrition; Nutrition Disorders; Body Weight; Diabetes Mellitus; Diabetes Mellitus, Type 2; Overweight; Hypoglycemic Agents; Physiological Effects of Drugs; Gastrointestinal Agents; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Anti-Obesity Agents; Incretins; Glucagon-Like Peptide-1 Receptor Agonists; Glucagon; Exenatide; Glucagon-Like Peptide 1
• Other Study ID Numbers: COCONUT

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No