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

NCT04307797 | Completed Phase 4

• 1 other identifier: COCONUT
• Study Type: interventional
• Target: 10
• Locations: 1 country
• Sites: 1

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

Conditions

Type 2 Diabetes; Obesity

Outcome Measures

Primary Outcomes (7)

• 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 Outcomes (14)

• Part A - End systolic/diastolic ventricular/atrial volumes

  Comparison between scans over a maximum period of 16 weeks

• Part A - Radial strain

  Comparison between scans over a maximum period of 16 weeks

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

  Comparison between scans over a maximum period of 16 weeks

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

  Comparison between scans over a maximum period of 16 weeks

• Part A/B - Heart rate

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

Interventions

0.9% Sodium-chloride DRUG

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 DRUG

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

Also known as: Byetta

Glucagon 12.5ng/kg/min and 0.9% saline DRUG

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

Glucagon 12.5ng/kg/min DRUG

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

Eligibility Criteria

• Age: 18 Years - 99 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Cambridge University Hospitals NHS Foundation Trust: lead
• Antaros Medical: collaborator

Study Sites (1)

Cambridge University Hospitals NHS Foundation Trust and The University of Cambridge

Cambridge, Cambridgeshire, CB2 0QQ, United Kingdom

Location

MeSH Terms

Conditions

Diabetes Mellitus, Type 2; Obesity

Interventions

Sodium Chloride; Exenatide; Maintenance; Glucagon

Condition Hierarchy (Ancestors)

Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases; Overweight; Overnutrition; Nutrition Disorders; Body Weight; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Chlorides; Hydrochloric Acid; Chlorine Compounds; Inorganic Chemicals; Sodium Compounds; Peptides; Amino Acids, Peptides, and Proteins; Venoms; Complex Mixtures; Toxins, Biological; Biological Factors; Health Care Facilities Workforce and Services; Proglucagon; Pancreatic Hormones; Peptide Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists

Study Officials

• Ian Wilkinson, MD

  University of Cambridge

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Masking Details: Imaging analysis performed by Antaros Medical (blinded to infusion)
• Purpose: BASIC SCIENCE
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Therapeutics

Model Details: Single-centre, single-blinded, physiological pilot study

Study Record Dates

• First Submitted: February 19, 2020
• First Posted: March 13, 2020
• Study Start: January 18, 2022
• Primary Completion: October 7, 2022
• Study Completion: October 7, 2022
• Last Updated: September 19, 2024

Record last verified: 2024-09

Data Sharing

• IPD Sharing: Will not share

Locations

GB (1)