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

Sponsor
Mette Zander (Other)
Overall Status
Completed
CT.gov ID
NCT02333591
Collaborator
Hvidovre University Hospital (Other)
25
Enrollment
1
Location
3
Arms
23
Duration (Months)
1.1
Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease Intervention/Treatment Phase
  • Drug: GlucagonLikePeptide-1 (7-36)
  • Drug: GlucagonLikePeptide-1 (9-36)
  • Drug: Saline
 Phase 4

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 Design

Study Type:
Interventional
Actual Enrollment :
25 participants
Allocation:
Randomized
Intervention Model:
Crossover Assignment
Masking:
Double (Participant, Outcomes Assessor)
Primary Purpose:
Basic Science
Official Title:
Effect of Intact GLP-1 (7-36) and GLP-1 Metabolite (9-36) on Coronary and Peripheral Vascular Function in Adults
Study Start Date :
Jul 1, 2016
Actual Primary Completion Date :
Jun 1, 2018
Actual Study Completion Date :
Jun 1, 2018

Arms and Interventions

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.

    Outcome Measures

    Primary Outcome Measures

    1. Coronary Flow Reserve [At baseline and after 2 hours of infusion]

      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).

    Secondary Outcome Measures

    1. Endothelial function (Assessed by Flow Mediated Dilation) [At baseline and after 1 hour of infusion]

      Assessed by Flow Mediated Dilation (FMD) The outcome is measured at every infusion/intervention (4 times).

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    35 Years to 70 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    Yes
    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.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Department of Research in Endocrinology, Bispebjerg University Hospital Copenhagen Denmark 2400

    Sponsors and Collaborators

    • Mette Zander
    • Hvidovre University Hospital

    Investigators

    • Principal Investigator: Mette Zander, PhD, MD, Department of Endocrinology, Bispebjerg University Hospital

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Mette Zander, MD, PhD, Bispebjerg Hospital
    ClinicalTrials.gov Identifier:
    NCT02333591
    Other Study ID Numbers:
    • MZ02
    • 2013-001240-64
    First Posted:
    Jan 7, 2015
    Last Update Posted:
    Mar 11, 2019
    Last Verified:
    Mar 1, 2019
    Individual Participant Data (IPD) Sharing Statement:
    Undecided
    Plan to Share IPD:
    Undecided

    Study Results

    No Results Posted as of Mar 11, 2019