Clinical trial NCT04307797: Effect of Glucagon and Glucagon-like Peptide-1 Co-agonism on Cardiac Function and Metabolism in Overweight Participants with Type 2 Diabetes
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
Overall status: COMPLETED
Phase: PHASE4
Conditions: Type 2 Diabetes
Obesity
Lead sponsor: Cambridge University Hospitals NHS Foundation Trust
Sponsor class: OTHER
Collaborators: name: Antaros Medical
First posted: 2020-03-13
Enrollment: 10
Sex: ALL
Minimum age (years): 18
Maximum age (years): 99
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SINGLE_GROUP
Intervention model description: Single-centre, single-blinded, physiological pilot study
Primary purpose: BASIC_SCIENCE

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:

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

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

Primary outcomes:
measure: Part A - Myocardial glucose uptake
timeFrame: Comparison between scans over a maximum period of 16 weeks
measure: Part A - Global longitudinal strain / global circumferential strain / global radial strain
timeFrame: Comparison between scans over a maximum period of 16 weeks
measure: Part A - Ejection fraction
timeFrame: Comparison between scans over a maximum period of 16 weeks
measure: Part A - Stroke volume
timeFrame: Comparison between scans over a maximum period of 16 weeks
measure: Part A - Cardiac output
timeFrame: Comparison between scans over a maximum period of 16 weeks
measure: Part B - Changes in phosphocreatine/adenosine (PCr/ATP) radio
timeFrame: Comparison between scans over a maximum period of 16 weeks
measure: 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)
timeFrame: Comparison between scans over a maximum period of 16 weeks
Secondary outcomes:
measure: Part A - End systolic/diastolic ventricular/atrial volumes
timeFrame: Comparison between scans over a maximum period of 16 weeks
measure: Part A - Radial strain
timeFrame: Comparison between scans over a maximum period of 16 weeks
measure: Part A - Global systolic/diastolic longitudinal/circumferential/radial strain rate
timeFrame: Comparison between scans over a maximum period of 16 weeks
measure: Part A - Relationship between early and late filling (from mitral flow)
timeFrame: Comparison between scans over a maximum period of 16 weeks
measure: Part A/B - Heart rate
timeFrame: Comparison between infusions (placebo vs drug) over a maximum period of 16 weeks
measure: Part A/B - Blood pressure
timeFrame: Comparison between infusions (placebo vs drug) over a maximum period of 16 weeks
measure: Part A/B - Glucose
timeFrame: Comparison between infusions (placebo vs drug) over a maximum period of 16 weeks
measure: Part A/B - Glucagon
timeFrame: Comparison between infusions (placebo vs drug) over a maximum period of 16 weeks
measure: Part A/B - Insulin
timeFrame: Comparison between infusions (placebo vs drug) over a maximum period of 16 weeks
measure: Part A/B - C-peptide
timeFrame: Comparison between infusions (placebo vs drug) over a maximum period of 16 weeks
measure: Part A/B - fatty acids
timeFrame: Comparison between infusions (placebo vs drug) over a maximum period of 16 weeks
measure: Part A/B - exenatide
timeFrame: Comparison between infusions (placebo vs drug) over a maximum period of 16 weeks
measure: Part A/B - Total GLP-1 and total active GLP-1
timeFrame: Comparison between infusions (placebo vs drug) over a maximum period of 16 weeks
measure: Part A/B - gastric inhibitory polypeptide
timeFrame: Comparison between infusions (placebo vs drug) over a maximum period of 16 weeks
Other outcomes:
Locations:
city: Cambridge
country: United Kingdom
facility: Cambridge University Hospitals NHS Foundation Trust and The University of Cambridge
state: Cambridgeshire
Study officials:
affiliation: University of Cambridge
name: Ian Wilkinson, MD
role: PRINCIPAL_INVESTIGATOR
References: