Effect of Intact GLP-1 (7-36) and GLP-1 Metabolite (9-36) on Coronary and Peripheral Vascular Function in Adults

GLP-1 is an agent for treatment of type 2 diabetes and may have protective effects on the cardiovascular system. The mechanism is complex and there seems to be a dual function with intact GLP-1 (7-36), acting through the GLP-1 receptor, and the GLP-1 (9-36) metabolite acting independently of the GLP-1 receptor.

Coronary flow reserve (CFR) is the ratio of flow through the coronary arteries during stress to during rest and it reflects coronary microcirculation. Impaired CFR is a strong predictor of poor prognosis of cardiovascular disease.

The aim of the study is to investigate the acute effects of GLP-1 on coronary microcirculation and endothelial function in adults with obesity.

Study Overview

• Status: Completed
• Conditions: Coronary Microvascular Dysfunction
• Intervention / Treatment: Drug: Saline; Drug: GlucagonLikePeptide-1 (7-36); Drug: GlucagonLikePeptide-1 (9-36)

Detailed Description

Several studies have shown beneficial effects of glucagon-like-peptide-1 (GLP-1) on the cardiovascular system. Native GLP-1 is secreted from L-cells in the intestine as GLP-1(7-36) 1 but is rapidly metabolised by the ubiquitous enzyme dipeptidyl-peptidase-4 (DPP4) to the metabolite GLP-1(9-36). However, the physiological effect of GLP-1 on the cardiovascular system is complex and there seems to be a dual function with intact GLP-1 (7-36), acting through the GLP-1 receptor, and the GLP-1 (9-36) metabolite acting independently of the GLP-1 receptor.

The aim of the study is to investigate the acute effects of intact GLP-1 and GLP-1 metabolite on coronary microcirculation and endothelial function in adults.

Method 20 adults with obesity are recruited to a double-blind randomized cross-over study.

The first 10 included adults will receive 2½ hours infusion of intact GLP-1 (7-36) together with a DPP-IV inhibitor and 2½ hours infusion of saline, on two separate occasions. The infusions will be given in randomized order with a minimum of 24 hours washout period.

The next 10 included adults will receive 2½ hours infusion of GLP-1 (9-36) metabolite and 2½ hours infusion of saline. These will also be given in randomized order with a minimum of 24 hours washout period. Endothelial function and CFR will be measured before and after one, respectively two, hours of infusion.

The effect of GLP-1 infusions on microvascular function is evaluated by coronary flow reserve (CFR), the ratio between echocardiographic measured coronary flow velocity in LAD during adenosine induced myocardial hyperaemia and rest. The effect on endothelial function is assessed by flow mediated dilation (FMD).

• Study Type: Interventional
• Enrollment (Actual): 25
• Phase: Phase 4

Contacts and Locations

Study Locations

• Denmark
  • Copenhagen, Denmark, 2400
    • Department of Research in Endocrinology, Bispebjerg University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 35 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age 35-70 years
• BMI > 25 kg/m2.
• Central obesity (measured by waist circumference, defined as ≥ 94cm for men and ≥ 80 cm for women)
• Non smokers (6 months abstinent is required)
• Normal creatinine
• For fertile women; negative pregnancy test and use of safe anticonception.
• Speak and understand Danish or English
• Mental ability to follow and understand the study

Exclusion Criteria:

• Known Diabetes
• Known hypertension (untreated hypertension ≤ 160/100 at inclusion is accepted)
• Haemoglobin < 6.5 mmol/l
• Allergy towards Januvia or Exenatide, Adenosin or Glycerylnitrate
• Documented significant stenosis of the left anterior descending artery (LAD) at coronary angiography or CT-angiography or regional dysfunction documented during dipyridamol stress-echocardiography. If stress test at baseline shows significant stenosis the patient will be excluded from the study.
• Pregnancy
• Severe asthma
• Active cancer, severe co-morbidity with limited life-expectancy, severe hepatic co-morbidity, chronic alcohol abuse, atrial fibrillation, chronic or previous acute pancreatitis, inflammatory bowel disease.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: GlucagonLikePeptide-1 (7-36); GLP-1 (7-36) is diluted in saline and human serum albumin. Plasma levels of GLP-1 (7-36) are rapidly raised and then maintained stable with 5,91 pmol/kg/min (0-2 min) reduced to 2,53 pmol/kg/min (2-4 min) reduced to 2,34 pmol/kg/min (4-6 min) reduced to 2,2 pmol/kg/min (6-8 min) reduced to 2,02 pmol/kg/min (8-10 min) and then maintained stable for 2½ hours with 1.5 pmol/kg/min. A DPP-IV inhibitor - Januvia 100 mg is given the evening before and ½ an hour before the infusion is started.	Drug: Saline; Infused intravenously for 2,5 hours.; Other Names: NaCl, Placebo
Active Comparator: GlucagonLikePeptide-1 (9-36); GLP-1 (9-36) is diluted in saline and human serum albumin. Plasma levels of GLP-1 (9-36) are rapidly raised and then maintained stable with 5,91 pmol/kg/min (0-2 min) reduced to 2,53 pmol/kg/min (2-4 min) reduced to 2,34 pmol/kg/min (4-6 min) reduced to 2,2 pmol/kg/min (6-8 min) reduced to 2,02 pmol/kg/min (8-10 min) and then maintained stable for 2½ hours with 1.5 pmol/kg/min	Drug: Saline; Infused intravenously for 2,5 hours.; Other Names: NaCl, Placebo
Placebo Comparator: NaCl; Saline is infused with a flow rate of 240 ml/h for 10 min and then reduced to 86 ml/h for 2½ hours.	Drug: GlucagonLikePeptide-1 (7-36); Diluted in saline and human serum albumin, then infused intravenously for 2,5 hours.; Drug: GlucagonLikePeptide-1 (9-36); Diluted in saline and human serum albumin, then infused intravenously for 2,5 hours.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Coronary Flow Reserve	Coronary flow reserve (CFR) reflects microvessel coronary function and is the ratio between echocardiographic measured coronary flow velocity in LAD during adenosine induced myocardial hyperaemia and rest. The outcome is measured at every infusion/intervention (4 times).	At baseline and after 2 hours of infusion

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Endothelial function (Assessed by Flow Mediated Dilation)	Assessed by Flow Mediated Dilation (FMD) The outcome is measured at every infusion/intervention (4 times).	At baseline and after 1 hour of infusion

Collaborators and Investigators

• Sponsor: Mette Zander
• Collaborators: Hvidovre University Hospital
• Investigators: Principal Investigator: Mette Zander, PhD, MD, Department of Endocrinology, Bispebjerg University Hospital

Study record dates

Study Major Dates

• Study Start: July 1, 2016
• Primary Completion (Actual): June 1, 2018
• Study Completion (Actual): June 1, 2018

Study Registration Dates

• First Submitted: January 6, 2015
• First Submitted That Met QC Criteria: January 6, 2015
• First Posted (Estimate): January 7, 2015

Study Record Updates

• Last Update Posted (Actual): March 11, 2019
• Last Update Submitted That Met QC Criteria: March 8, 2019
• Last Verified: March 1, 2019

More Information

Terms related to this study

• Other Study ID Numbers: MZ02; 2013-001240-64 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided