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

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

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.

Study Overview

• Status: Completed
• Conditions: Cardiovascular Diseases
• Intervention / Treatment: Drug: Saline 0.9%; Drug: Glucagon (25ng/kg/min); Drug: Glucagon (50ng/kg/min); Drug: Exenatide

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.

• Study Type: Interventional
• Enrollment (Actual): 26
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United Kingdom
  • Cambridgeshire
    • Cambridge, Cambridgeshire, United Kingdom, CB2 0QQ
      • Addenbrooke's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 40 years (Adult)
• Accepts Healthy Volunteers: Yes

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

6

Arms and Interventions

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

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

Collaborators and Investigators

• Sponsor: Cambridge University Hospitals NHS Foundation Trust
• Investigators: Principal Investigator: Ian Wilkinson, MA DM FRCP, University of Cambridge

Study record dates

Study Major Dates

• Study Start (Actual): February 11, 2019
• Primary Completion (Actual): November 1, 2021
• Study Completion (Actual): November 1, 2021

Study Registration Dates

• First Submitted: January 25, 2019
• First Submitted That Met QC Criteria: February 7, 2019
• First Posted (Actual): February 8, 2019

Study Record Updates

• Last Update Posted (Actual): April 3, 2024
• Last Update Submitted That Met QC Criteria: April 2, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Hypoglycemic Agents; Physiological Effects of Drugs; Gastrointestinal Agents; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Anti-Obesity Agents; Incretins; Glucagon-Like Peptide-1 Receptor Agonists; Glucagon; Exenatide; Glucagon-Like Peptide 1
• Other Study ID Numbers: COCOA; 18/EM/0417 (Other Identifier: REC-HRA); 250402 (Other Identifier: IRAS ID)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No