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)
试验速览
- 阶段
- 4 期
- 入组人数
- 16
- 试验地点
- 2
- 主要终点
- Part A - Ejection fraction
研究概览
简要总结
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
详细描述
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
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Single Group
- 主要目的
- Basic Science
- 盲法
- Single (Participant)
盲法说明
Imaging analysis performed by Antaros Medical (blinded to infusion)
入排标准
- 年龄范围
- 18 Years 至 99 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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
结局指标
主要结局
Part A - Ejection fraction
时间窗: Comparison between scans over a maximum period of 16 weeks
Difference in ejection fraction between 0.9% saline, glucagon:exenatide and glucagon scan as measured by CMR
Part A - Global longitudinal strain / global circumferential strain / global radial strain
时间窗: Comparison between scans over a maximum period of 16 weeks
Difference in global longitudinal strain / global circumferential strain / global radial strain between 0.9% saline, glucagon:exenatide and glucagon scan as measured by CMR
Part A - Myocardial glucose uptake
时间窗: Comparison between scans over a maximum period of 16 weeks
Difference in myocardial glucose uptake between 0.9% saline, glucagon:exenatide and glucagon scan as measured by 18F-FDG
Part A - Stroke volume
时间窗: Comparison between scans over a maximum period of 16 weeks
Difference in stroke volume between 0.9% saline, glucagon:exenatide and glucagon scan as measured by CMR
Part B - Changes in phosphocreatine/adenosine (PCr/ATP) radio
时间窗: Comparison between scans over a maximum period of 16 weeks
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)
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)
时间窗: Comparison between scans over a maximum period of 16 weeks
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)
Part A - Cardiac output
时间窗: Comparison between scans over a maximum period of 16 weeks
Difference in cardiac output between 0.9% saline, glucagon:exenatide and glucagon scan as measured by CMR
次要结局
- Part A - Radial strain(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 - End systolic/diastolic ventricular/atrial volumes(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/B - Heart rate(Comparison between infusions (placebo vs drug) over a maximum period of 16 weeks)
- Part A/B - Blood pressure(Comparison between infusions (placebo vs drug) over a maximum period of 16 weeks)
- Part A/B - Glucose(Comparison between infusions (placebo vs drug) over a maximum period of 16 weeks)
- Part A/B - Glucagon(Comparison between infusions (placebo vs drug) over a maximum period of 16 weeks)
- Part A/B - Insulin(Comparison between infusions (placebo vs drug) over a maximum period of 16 weeks)
- Part A/B - C-peptide(Comparison between infusions (placebo vs drug) over a maximum period of 16 weeks)
- Part A/B - fatty acids(Comparison between infusions (placebo vs drug) over a maximum period of 16 weeks)
- Part A/B - exenatide(Comparison between infusions (placebo vs drug) over a maximum period of 16 weeks)
- Part A/B - Total GLP-1 and total active GLP-1(Comparison between infusions (placebo vs drug) over a maximum period of 16 weeks)
- Part A/B - gastric inhibitory polypeptide(Comparison between infusions (placebo vs drug) over a maximum period of 16 weeks)
研究者
Dr Ian B Wilkinson
Professor of Therapeutics
Cambridge University Hospitals NHS Foundation Trust