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

NCT ID: NCT02333591

Last Updated: 2019-03-11

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 25 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2016-07-31
• Study Completion Date: 2018-06-30

Brief Summary

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.

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).

Conditions

Coronary Microvascular Dysfunction

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: BASIC_SCIENCE
• Blinding Strategy: DOUBLE

Study Groups

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.

Group Type: ACTIVE_COMPARATOR

Saline

Intervention Type: DRUG

Infused intravenously for 2,5 hours.

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

Group Type: ACTIVE_COMPARATOR

Saline

Intervention Type: DRUG

Infused intravenously for 2,5 hours.

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.

Group Type: PLACEBO_COMPARATOR

GlucagonLikePeptide-1 (7-36)

Intervention Type: DRUG

Diluted in saline and human serum albumin, then infused intravenously for 2,5 hours.

GlucagonLikePeptide-1 (9-36)

Intervention Type: DRUG

Diluted in saline and human serum albumin, then infused intravenously for 2,5 hours.

Interventions

GlucagonLikePeptide-1 (7-36)

Diluted in saline and human serum albumin, then infused intravenously for 2,5 hours.

Intervention Type: DRUG

GlucagonLikePeptide-1 (9-36)

Diluted in saline and human serum albumin, then infused intravenously for 2,5 hours.

Intervention Type: DRUG

Saline

Infused intravenously for 2,5 hours.

Intervention Type: DRUG

Other Intervention Names

NaCl, Placebo

Eligibility Criteria

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.

• Minimum Eligible Age: 35 Years
• Maximum Eligible Age: 70 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Hvidovre University Hospital

OTHER

Sponsor Role: collaborator

Mette Zander

OTHER

Sponsor Role: lead

Responsible Party

Mette Zander

MD, PhD

Responsibility Role: SPONSOR_INVESTIGATOR

Principal Investigators

Mette Zander, PhD, MD

Role: PRINCIPAL_INVESTIGATOR

Department of Endocrinology, Bispebjerg University Hospital

Locations

Department of Research in Endocrinology, Bispebjerg University Hospital

Copenhagen, , Denmark

Countries

Denmark

Other Identifiers

2013-001240-64

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

MZ02

Identifier Type: -

Identifier Source: org_study_id