Haemodynamic Effects of GLP-1 and Glucagon in Healthy Male Volunteers

Study Overview
=================
Brief Summary
-----------------
The study seeks to explore the cardiovascular effects of co-agonism at two peptide receptors, GLP-1 and glucagon. Glucagon, exenatide and 0.9% saline will be intravenously infused, both in isolation, and combination into healthy male participants. Overall, the aim of the study is to further our understanding on the role these endogenous substances play (both in isolation and combination) in haemodynamic regulation.

Detailed Description
-----------------
Co-agonist peptides (such as at the GLP-1:glucagon receptor) are currently in clinical development for type 2 diabetes with the dual intention of reducing body weight and controlling blood glucose. However, there is a lack of data on the effects that co-agonism has on haemodynamic regulation. Part A - Healthy male participants, by acting as their own control, will attend for two intravenous infusion visits (combination of 0.9% saline and glucagon). These will occur in a predefined but random order so that participants will be blinded to the infusion they are receiving. Each infusion visit will comprise of 15 minute baseline followed by a 120 minute infusion. Detailed non-invasive cardiovascular measurements (including peripheral/central blood pressure, heart rate, stroke volume, heart rate variability) and bloods (including insulin, glucose, GLP-1, glucagon) will be collected as part of the study. It was previously planned that GLP-1 7-36 amide 0.6pmol/kg/min and 1.2pmol/kg/min would be infused for Part A resulting in 5 infusions (rather than current 2 infusions). However due to supply/technical issues this was not possible and therefore exenatide (GLP-1 receptor agonist) shall be used in Part B. Part B - Healthy male participants, by acting as their own control, will attend for four intravenous infusion visits (combination of 0.9% saline, glucagon, exenatide). These will occur in a predefined but random order so that participants will be blinded to the infusion they are receiving. Each infusion visit will comprise of 15 minute baseline followed by a 60 minute infusion. Detailed non-invasive cardiovascular measurements (including peripheral/central blood pressure, heart rate, stroke volume, heart rate variability) and bloods (including insulin, glucose, GLP-1, glucagon) will be collected as part of the study.

Official Title
-----------------
A Comparison of the Haemodynamic and Metabolic Effects of Intravenous Glucagon-like Peptide-1, Glucagon and Glucagon-like Peptide-1:Glucagon Co-agonism in Healthy Male Participants

Conditions
-----------------
Cardiovascular Diseases

Intervention / Treatment
-----------------
* Drug: Saline 0.9%
* Drug: Glucagon (25ng/kg/min)
* Drug: Glucagon (50ng/kg/min)
* Drug: Exenatide


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Written informed consent to participate Aged 18 to 40 Male Current non-smoker BMI >18.0 and <30kg/m2 Exclusion Criteria: Female Sustained Hypertension (sustained BP >160/100mmHg) or hypotension (systolic BP below 90 mmHg) Clinically significant heart disease Implanted heart pace-maker or implantable cardioverter defibrillator (ICD) Known active malignancy Known renal failure (creatinine >140μmol/L) Known diabetes mellitus (type 1 or 2) Use of vasoactive medications or NSAIDS/aspirin within 24 hours of study visits Use of formal anticoagulant therapy such as, but not limited to, heparin, warfarin or rivaroxaban Current involvement in the active treatment phase of other research studies, (excluding observations/noninterventional) Any other clinical reason which may preclude entry in the opinion of the investigator

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 40 Years

Sexes Eligible for Study
-----------------
Male

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Part A - 2 infusions Part B - 4 infusions
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Part A - Infusion A<br>60 minute intravenous infusion of 0.9% saline Followed by: 60 minute intravenous infusion of 0.9% saline | Drug: Saline 0.9%<br>* Intravenous infusion of 0.9% saline<br>* Other names: Placebo;|
| Active Comparator: Part A - Infusion B<br>60 minute intravenous infusion of glucagon 25ng/kg/min and 0.9% saline. Followed by: 60 minute infusion of glucagon 50ng/kg/min and 0.9% saline | Drug: Saline 0.9%<br>* Intravenous infusion of 0.9% saline<br>* Other names: Placebo;Drug: Glucagon (25ng/kg/min)<br>* Intravenous infusion of glucagon 25ng/kg/min<br>* Other names: Glucagon;Drug: Glucagon (50ng/kg/min)<br>* Intravenous infusion of glucagon 50ng/kg/min<br>* Other names: Glucagon;|
| Active Comparator: Part B - Infusion A<br>A 60 minute intravenous infusion of 0.9% saline | Drug: Saline 0.9%<br>* Intravenous infusion of 0.9% saline<br>* Other names: Placebo;|
| Active Comparator: Part B - Infusion B<br>A 60 minute intravenous infusion of exenatide (50ng/min for 30 minutes followed by 25ng/min) and 0.9% saline | Drug: Saline 0.9%<br>* Intravenous infusion of 0.9% saline<br>* Other names: Placebo;Drug: Exenatide<br>* Intravenous infusion of Exenatide (loading 50ng/min for 30 minutes followed by 25ng/min for 30 minutes<br>|
| Active Comparator: Part B - Infusion C<br>A 60 minute intravenous infusion of glucagon (25ng/kg/min) and 0.9% saline | Drug: Saline 0.9%<br>* Intravenous infusion of 0.9% saline<br>* Other names: Placebo;Drug: Glucagon (25ng/kg/min)<br>* Intravenous infusion of glucagon 25ng/kg/min<br>* Other names: Glucagon;|
| Active Comparator: Part B - Infusion D<br>A 60 minute intravenous infusion of exenatide (50ng/min for 30 minutes then 25ng/min) and glucagon (25ng/kg/min) | Drug: Glucagon (25ng/kg/min)<br>* Intravenous infusion of glucagon 25ng/kg/min<br>* Other names: Glucagon;Drug: Exenatide<br>* Intravenous infusion of Exenatide (loading 50ng/min for 30 minutes followed by 25ng/min for 30 minutes<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in haemodynamic parameters following intravenous infusion of 0.9% saline, glucagon, exenatide and their combination. | Heart rate (bpm) | Comparison between 2 hour infusion visit 1-2 (Part A) / 1 hour infusion visit 1-4 (Part B), over a maximum period of 15 weeks | 
| Changes in haemodynamic parameters following intravenous infusion of 0.9% saline, glucagon, exenatide and their combination. | Brachial systolic and diastolic blood pressure (mmHg) | Comparison between 2 hour infusion visit 1-2 (Part A) / 1 hour infusion visit 1-4 (Part B), over a maximum period of 15 weeks | 
| Changes in haemodynamic parameters following intravenous infusion of 0.9% saline, glucagon, exenatide and their combination. | Central systolic and diastolic blood pressure and mean arterial pressure (mmHg) measured with SphygmoCor XCEL | Comparison between 2 hour infusion visit 1-2 (Part A) / 1 hour infusion visit 1-4 (Part B), over a maximum period of 15 weeks | 
| Changes in haemodynamic parameters following intravenous infusion of 0.9% saline, glucagon, exenatide and their combination. | Stroke volume (ml) measured by bioimpedance | Comparison between 2 hour infusion visit 1-2 (Part A) / 1 hour infusion visit 1-4 (Part B), over a maximum period of 15 weeks | 
| Changes in haemodynamic parameters following intravenous infusion of 0.9% saline, glucagon, exenatide and their combination. | Cardiac output (L/min) measured by bioimpedance | Comparison between 2 hour infusion visit 1-2 (Part A) / 1 hour infusion visit 1-4 (Part B), over a maximum period of 15 weeks | 
| Changes in haemodynamic parameters following intravenous infusion of 0.9% saline, glucagon, exenatide and their combination. | peripheral vascular resistance (dynes/sec/cm) | Comparison between 2 hour infusion visit 1-2 (Part A) / 1 hour infusion visit 1-4 (Part B), over a maximum period of 15 weeks | 
| Changes in haemodynamic parameters following intravenous infusion of 0.9% saline, glucagon, exenatide and their combination. | Heart rate variability (normalised low frequency, LF, high frequency, HF and LF/HF ratio) | Comparison between 2 hour infusion visit 1-2 (Part A) / 1 hour infusion visit 1-4 (Part B), over a maximum period of 15 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in glucose homeostasis following intravenous infusion of 0.9% saline, glucagon, exenatide and their combination. | Glucose, in mmol/L | Comparison between 2 hour infusion visit 1-5 (Part A) / 1 hour infusion visit 1-4 (Part B), over a maximum period of 15 weeks | 
| Changes in glucose homeostasis following intravenous infusion of 0.9% saline, glucagon, exenatide and their combination. | C-peptide, in pmol/L | Comparison between 2 hour infusion visit 1-2 (Part A) / 1 hour infusion visit 1-4 (Part B), over a maximum period of 15 weeks | 
| Changes in glucose homeostasis following intravenous infusion of 0.9% saline, glucagon, exenatide and their combination. | Glucagon, in pg/ml | Comparison between 2 hour infusion visit 1-2 (Part A) / 1 hour infusion visit 1-4 (Part B), over a maximum period of 15 weeks | 
| Changes in glucose homeostasis following intravenous infusion of 0.9% saline, glucagon, exenatide and their combination. | Insulin, in pmol/L | Comparison between 2 hour infusion visit 1-2 (Part A) / 1 hour infusion visit 1-4 (Part B), over a maximum period of 15 weeks | 
| Changes in glucose homeostasis following intravenous infusion of 0.9% saline, glucagon, exenatide and their combination. | Free fatty acids, in μmol/L | Comparison between 2 hour infusion visit 1-2 (Part A) / 1 hour infusion visit 1-4 (Part B), over a maximum period of 15 weeks | 
| Changes in glucose homeostasis following intravenous infusion of 0.9% saline, glucagon, exenatide and their combination. | Total GLP-1 and total active GLP-1, in pg/ml | Comparison between 2 hour infusion visit 1-2 (Part A) / 1 hour infusion visit 1-4 (Part B), over a maximum period of 15 weeks | 
| Changes in glucose homeostasis following intravenous infusion of 0.9% saline, glucagon, exenatide and their combination. | Gastric inhibitory polypeptide, in pg/ml | Comparison between 2 hour infusion visit 1-2 (Part A) / 1 hour infusion visit 1-4 (Part B), over a maximum period of 15 weeks |