Study Looking at Cardiovascular Effects of Exenatide, Its Blood Pressure Lowering Effect and Its Mechanisms

March 4, 2018 updated by: Elizabeth Simpson, University of Nottingham

Investigation of the Cardiovascular Effects of Exenatide in Healthy Male Subjects

Exenatide is a new drug which lowers blood sugar (glucose) levels for people with type 2 diabetes. It has significant advantages over other treatments such as insulin as it causes weight loss in a group of people that is generally overweight. Data from studies involving exenatide have shown that it also has an effect on blood pressure. The mechanism for the blood pressure lowering effect is not known and has not been investigated previously. Exenatide may have an effect on blood vessels throughout the body and gut to reduce blood pressure. 12 healthy men (18-45yr) will be studied on 2 occasions. Limb blood flow, skin blood flow, gut blood flow, blood pressure, and heart rate will be measured half hourly for 4 hours. Blood samples (3ml) for insulin and glucose determination will be taken via a cannula and 3-way tap at the same time points. A dose of either 5μg exenatide or saline will be injected under the skin of the abdomen and a breakfast will be provided during the study. A urine collection will be made over the duration of the study.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

Background:

Glucagon-like peptide-1 (GLP-1) is an incretin hormone secreted from the L-cells of the gut following a meal (1). GLP-1 has multiple modes of action, including to augment the usual rise in insulin release and decrease in glucagon that follows carbohydrate ingestion (2). GLP-1 therefore plays a part in glucose homeostasis. GLP-1 secretion is reduced in patients with type 2 diabetes (T2DM) and extended-action GLP-1 agonists or mimetics are currently being introduced for use as glucose lowering medications. The peptide exendin-4 has considerable homology with GLP-1 but is resistant to degradation by the enzyme Dipeptidyl peptidase-4 (DPP-IV) and so has a much longer duration of action. The synthetic exendin, 'Exenatide', is a novel GLP-1 mimetic which has recently been licensed for the treatment for T2DM and has shown to be an effective glucoregulatory agent when administered as a twice- daily subcutaneous injection (11).

GLP-1 agonists give a low risk of significant hypoglycaemia as effects on insulin and glucagon are largely glucose-dependent. In addition, considerable weight loss is often observed with GLP-1 agonists in clinical practice, and these drugs are currently being considered in treating obesity, even outside the context of diabetes.

A moderate blood-pressure (BP) lowering effect of GLP-1 agonists has also been noted as a secondary outcome measure in large clinical trials in patients with T2DM. In one such study, Exenatide was associated with a reduction in systolic/diastolic BP of 5/2 mmHg The mechanism for this apparent hypotensive effect is not known. An infusion of GLP-1 agonists induces a natriuresis, which may contribute to a reduction in BP.

Aims:

The aim of this study is to assess the cardiovascular effects of Exenatide in young, healthy, non-obese male subjects. We propose to compare the effect of Exenatide vs. placebo and study the cardiovascular effects by a number of non invasive techniques.

Experimental protocol and methods:

12 healthy male subjects aged 18-45 years with BMI 20-27 kg/m2 will be recruited. Subjects will attend for an initial screening visit and initial assessments. This will enable familiarization with the room and equipment to be used. On arrival at the laboratory, subjects will be asked to void their bladder and a urine collection will be commenced. Subjects will be asked to wear shorts during the study and rest semi-supine on a hospital bed. They will place their hand in a heated hand warming unit and an intravenous cannula will be inserted, for arterialized venous blood sampling,. Subjects will rest for 1hour before receiving either Exenatide or placebo injection. Measurements of Limb blood flow (by venous occlusion plethysmography); skin blood flow (by laser Doppler); blood pressure, heart rate (HR) and cardiac output (by Finometry™);and regional blood flow (by ultrasound imaging and flow velocity measurement of the superior mesenteric arteries (SMA) will take place every 30minutes. Blood sampling for insulin and glucose will be carried out every 15minutes throughout the study. Subjects will rest for 120 minutes after injection with measurements every 30 minutes as before with blood sampling every 15 minutes until 120 minutes post injection. Subjects will receive a high carbohydrate breakfast 60 minutes post injection. Urine will be collected during the study to assess urinary sodium excretion.

Measurable end points/statistical power of the study:

Our primary end point will be to measure meal induced changes in superior mesenteric (SMA) blood flow in the 2 groups (Exenatide vs. placebo.)Secondary endpoints will be measures including: BP, HR, Limb Blood Flow, Skin Blood Flow, and peripheral resistance responses when fasted and after eating- (both Exenatide and placebo groups).

From previous studies we calculated that SMA blood flow at rest = 346 (27) ml/min and peak SMA blood flow after high carbohydrate meal = 611(80) ml/min. With 12 subjects, a reduction in blood flow of 71ml/min, following Exenatide injection, would be required if powered at 80%.

Study Type

Interventional

Enrollment (Actual)

8

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United Kingdom
    • Notts
      • Nottingham, Notts, United Kingdom, NG72UH
        • David Greenfield Human Physiology Laboratories

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 45 years (Adult)

Accepts Healthy Volunteers

Yes

Genders Eligible for Study

Male

Description

Inclusion Criteria:

  • male,
  • non-obese (BMI 20-27: those with a BMI > 25 will be excluded if they have a waist circumference > 90cm),
  • aged 18-45yrs,
  • non-smoker.

Exclusion Criteria:

  • any metabolic or endocrine abnormalities,
  • clinically significant abnormalities on screening,
  • taking regular medication.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Basic Science
  • Allocation: Randomized
  • Interventional Model: Crossover Assignment
  • Masking: Triple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: Exenatide
subcutaneous administration of Exenatide (0.02ml)
Drug: Exenatide
single dose of 5 microg Exenatide. Subcutaneous administration
Other Names:
  • Byetta
Placebo Comparator: 0.9% Saline
subcutaneous administration of 0.9% saline solution (0.02 ml)
Drug: Saline
subcutaneous administration of 0.9% saline solution (0.02 ml)
Other Names:
  • 0.9% Saline solution

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
superior mesenteric (SMA) blood flow
Time Frame: 0, 30, 60, 90, 120, 150, & 180 min after meal
Meal induced changes in superior mesenteric (SMA) blood flow - exenatide versus placebo.
0, 30, 60, 90, 120, 150, & 180 min after meal

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Blood Pressure (BP)
Time Frame: 0, 30, 60, 90, 120, 150, & 180 min after meal
BP responses when fasted and after eating- Exenatide vs. placebo.
0, 30, 60, 90, 120, 150, & 180 min after meal
Heart Rate (HR)
Time Frame: 0, 30, 60, 90, 120, 150, & 180 min after meal
HR responses when fasted and after eating- Exenatide vs. placebo.
0, 30, 60, 90, 120, 150, & 180 min after meal
Limb Blood Flow (LBF)
Time Frame: 0, 30, 60, 90, 120, 150, & 180 min after meal
Limb Blood Flow responses when fasted and after eating- Exenatide vs. placebo.
0, 30, 60, 90, 120, 150, & 180 min after meal
Skin Blood Flow
Time Frame: 0, 30, 60, 90, 120, 150, & 180 min after meal
Skin Blood Flow responses when fasted and after eating- Exenatide vs. placebo.
0, 30, 60, 90, 120, 150, & 180 min after meal
Peripheral resistance
Time Frame: 0, 30, 60, 90, 120, 150, & 180 min after meal
peripheral resistance responses when fasted and after eating- Exenatide vs. placebo.
0, 30, 60, 90, 120, 150, & 180 min after meal

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Nottingham

Investigators

  • Principal Investigator: Peter I Mansell, FRCP, University of Nottingham

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

September 1, 2009

Primary Completion (Actual)

December 1, 2012

Study Completion (Actual)

December 1, 2012

Study Registration Dates

First Submitted

January 11, 2010

First Submitted That Met QC Criteria

January 11, 2010

First Posted (Estimate)

January 12, 2010

Study Record Updates

Last Update Posted (Actual)

March 6, 2018

Last Update Submitted That Met QC Criteria

March 4, 2018

Last Verified

March 1, 2018

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • A/6/2009-exenatide-CVS

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

Clinical Trials on Type 2 Diabetes

Clinical Trials on Exenatide

Search Similar Trials

Sponsors and Collaborators

Medical Conditions

Drug Interventions

CROs by country

CROs in Oman

Conditions

Rare Diseases

Drug Interventions

Dietary Supplements

Sponsor/Collaborators

Locations

3
Subscribe