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

Cardiovascular Diseases Clinical Trial

— COCOA  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03835013
• Other study ID #: COCOA
• Secondary ID: 18/EM/0417250402
• Status: Completed
• Phase: N/A
• Start date: February 11, 2019
• Est. completion date: November 1, 2021

Study information

• Verified date: April 2024
• Source: Cambridge University Hospitals NHS Foundation Trust
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 26
• Est. completion date: November 1, 2021
• Est. primary completion date: November 1, 2021
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Male
• Age group: 18 Years to 40 Years

Eligibility

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

Related Conditions & MeSH terms

• Cardiovascular Diseases

Intervention

Drug:
• Saline 0.9%
Intravenous infusion of 0.9% saline
• Glucagon (25ng/kg/min)
Intravenous infusion of glucagon 25ng/kg/min
• Glucagon (50ng/kg/min)
Intravenous infusion of glucagon 50ng/kg/min
• Exenatide
Intravenous infusion of Exenatide (loading 50ng/min for 30 minutes followed by 25ng/min for 30 minutes

Locations

Country	Name	City	State
United Kingdom	Addenbrooke's Hospital	Cambridge	Cambridgeshire

Sponsors (1)

Lead Sponsor	Collaborator
Cambridge University Hospitals NHS Foundation Trust

Country where clinical trial is conducted

United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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